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Olefin Metathesis in Carbohydrate and Norbornene Applications

Permanent Link: http://ufdc.ufl.edu/UFE0021741/00001

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Title: Olefin Metathesis in Carbohydrate and Norbornene Applications
Physical Description: 1 online resource (165 p.)
Language: english
Creator: Mondal, Kalyan
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: acyclic, carbohydrates, norbornene, olefin, rcmp, ring, romp
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Olefin metathesis is a convenient route for the synthesis of functionalized higher alkenes from simple alkene precursors. Our research goals comprised of developing olefin metathesis in ring opening metathesis (ROMP) of norbornene scaffold, cross-metathesis of carbohydrates used as a precursors of dynamic combinatorial libraries (DCLs), and employing for the first time to study the acyclic diene metathesis (ADMET) polymerization of carbohydrates. Functionalized norbornene monomers have been the subject of interest due to facile preparation and high reactivity in the ROMP. We choose norbornene aldehyde as the starting material for synthesizing the norbornene polymer scaffold using Grubbs? catalyst, which can later be crosslinked the polymers using a diyl and nitrogen aerosol. Olefin metathesis in dynamic combinatorial chemistry is of interest as a method in generating libraries. We have synthesized a series of carbohydrate based homodimers by cross metathesis reaction using Grubbs? second generation catalyst. Sophisticated products were observed bearing a variety of functions and protecting groups on the carbohydrates. The carbohydrate-linking alkene was trans with several versions examined. Products yields were dependent on the carbohydrate R groups, and whether the ester group possessed an allyl or pentenyl moiety at the carboxylate side. In addition, several carbohydrate derivatives were made containing diene functionality. When subjected to the cross-metathesis condition such diene carbohydrate system generated cyclic dimer. The utility of ADMET chemistry for the polymerization of dienes containing silyl, aromatic, and ester functional groups have been investigate. We had synthesized the diesters of carbohydrates (D)-mannitol, (D)-ribose, (D)-isomannide, and (D)-isosorbide. Thus we are the first to report ADMET chemistry of carbohydrates.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Kalyan Mondal.
Thesis: Thesis (Ph.D.)--University of Florida, 2007.
Local: Adviser: Enholm, Eric J.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0021741:00001

Permanent Link: http://ufdc.ufl.edu/UFE0021741/00001

Material Information

Title: Olefin Metathesis in Carbohydrate and Norbornene Applications
Physical Description: 1 online resource (165 p.)
Language: english
Creator: Mondal, Kalyan
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: acyclic, carbohydrates, norbornene, olefin, rcmp, ring, romp
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Olefin metathesis is a convenient route for the synthesis of functionalized higher alkenes from simple alkene precursors. Our research goals comprised of developing olefin metathesis in ring opening metathesis (ROMP) of norbornene scaffold, cross-metathesis of carbohydrates used as a precursors of dynamic combinatorial libraries (DCLs), and employing for the first time to study the acyclic diene metathesis (ADMET) polymerization of carbohydrates. Functionalized norbornene monomers have been the subject of interest due to facile preparation and high reactivity in the ROMP. We choose norbornene aldehyde as the starting material for synthesizing the norbornene polymer scaffold using Grubbs? catalyst, which can later be crosslinked the polymers using a diyl and nitrogen aerosol. Olefin metathesis in dynamic combinatorial chemistry is of interest as a method in generating libraries. We have synthesized a series of carbohydrate based homodimers by cross metathesis reaction using Grubbs? second generation catalyst. Sophisticated products were observed bearing a variety of functions and protecting groups on the carbohydrates. The carbohydrate-linking alkene was trans with several versions examined. Products yields were dependent on the carbohydrate R groups, and whether the ester group possessed an allyl or pentenyl moiety at the carboxylate side. In addition, several carbohydrate derivatives were made containing diene functionality. When subjected to the cross-metathesis condition such diene carbohydrate system generated cyclic dimer. The utility of ADMET chemistry for the polymerization of dienes containing silyl, aromatic, and ester functional groups have been investigate. We had synthesized the diesters of carbohydrates (D)-mannitol, (D)-ribose, (D)-isomannide, and (D)-isosorbide. Thus we are the first to report ADMET chemistry of carbohydrates.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Kalyan Mondal.
Thesis: Thesis (Ph.D.)--University of Florida, 2007.
Local: Adviser: Enholm, Eric J.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0021741:00001


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OLEFIN METATHESIS IN CARBOHYDRATE AND NORBORNENE APPLICATIONS


By

KALYAN MONDAL

















DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

2007









ACKNOWLEDGMENTS

The rewards associated with completing this dissertation and earning my Ph.D. would not

be a nearly as great if it hadn't been for the very special people who gave me their support along

the way. I would like to extend my sincere appreciation to my research advisor, Dr. Eric Enholm,

for his support, patience, understanding and invaluable help throughout my graduate career at the

University of Florida. I am forever grateful for his patience during my ever-developing skill in

the lab. His enthusiasm and knowledge have been motivating, and his instruction has not only

given me the technical abilities, but also the confidence needed for a successful career. Looking

back I have come a long way with regards to chemical knowledge and problem solving. It has

been a real pleasure for me to conduct and discuss research with Dr. Enholm. He provided me all

the necessary guidance to complete my dissertation and allowed me the research freedom to

develop my own ideas. He has been a great advisor and I will never forget his encouragement

and kindness.

I would like to thank my committee members for their constructive feedback and advice.

Special thanks go to Dr. William Dolbier. He is one of the most sincere and helpful professors I

have ever met, who shows true concern and interest toward his students. I would also like to

thank Dr. Ronald Castellano. His excellent teaching style and well organized lectures gave me a

great start to the PhD program. I sincerely thank Dr. Ion Ghiviriga for helping with the

elucidation of the structure of my organic compounds and for sharing his vast NMR expertise,

more than I thought I could ever learn about NMR. I also appreciate Dr. Kenneth Sloan for being

on my committee and providing valuable feedback during my oral qualifier and the preparation

of this dissertation. I truly have been fortunate to have these individuals on my committee.









Graduate school would not have been enjoyable without my fellow Enholm group

members-Jed Hastings, Sophie Klein, Tammy Low, and Ryan Martin. It has been a blessing to

work in a cooperative environment, where laboratory discussions are open and free, and

everyone is so helpful and genuinely friendly. I especially like to thank Jed for his patience in

helping with my lab experiments early on, for exchanging knowledge and for providing feedback

as I prepared for my oral qualifier. Not only has it been a joy working with these individuals, I

also appreciate their friendship outside of lab.

Special thanks go to Dr. Tammy Davidson, my M.S. adviser from my previous school East

Tennessee State University and currently working at University of Florida for her consistent

mental support throughout my PhD career. Finally, my most heartfelt acknowledgement must go

to my parents, sisters and my wife Debalina for their continuous support, encouragement and

kindness. I specially thank my parents for their inspiration, infinite love and faith. They have

made me a better person by being my role models and instilling me with strong values. I would

not have been in the position to write this dissertation without my parents. Last and not the least,

I would like to thank my wife Debalina for her consistent support for the last one year. Words

alone cannot express my gratitude, especially for their tremendous love and belief in me during

the PhD period.

Special acknowledgement foes to the faculty and staff of the Department of Chemistry at

the University of Florida for providing an excellent environment for graduate study that has

helped me to make my stay here quite enjoyable and rewarding.











TABLE OF CONTENTS



A C K N O W L E D G M E N T S ..............................................................................................................2

LIST OF TABLE S ................ .................................... ........ ........................

LIST O F FIG U RE S ................................................................. 8

LIST OF SCHEMES................................ ......................... ........ 10

ABSTRAC T ................................................... ............... 13

CHAPTER

1 H ISTO R ICA L B A CK G R O U N D ........................................................... ..........................15

1.1 O lefin M etathesis ................................. .. .............................................. .... 15
1.1.1 Development of Olefin Metathesis and Catalyst........................................ 15
1.1.2 M echanism of Olefin M etathesis...................................................... ................ 19
1.1.3 Important Types of Metathesis Reactions and Applications................................21
1.2 Ring Opening Metathesis Polymerization (ROMP).................. ...............25
1.3 Dynamic Combinatorial Chemistry ........... .. ......... ................... 27
1.4 C carbohydrate chem istry ...................................................................... .......................33
1.5 Tissue Engineering ...................................... .. ......... ...... ....... 36
1 .6 H y d ro g els.............................. ......................................3 8
Physically Cross-linked H ydrogels ........................................ ........................... 40
Chem ically Cross-linked H ydrogels.......................................... ........... ............... 41
1.7 Acyclic Diene M etathesis (ADM ET) ........................................ .......................... 41
1.8 Scope of the Thesis............. ... .. ................ ...................43

2 RING OPENING METATHESIS POLYMERIZATION OF NORBORNENE
DERIVATIVES ....... ....... ...... ........ ................................45

2 .1 In tro d u ctio n .....................................................................................................4 5
2.2 Results and Discussion ....................................... .. .......... ....... ..... 48
2 .3 C o n clu sio n ........................................................................................... 5 4

3 M ETATHESIS OF CARBOHYDRATES ........................................ ........................ 56

3 .1 In tro d u ctio n ................................................................................................................. 5 6
3.2 R results and D iscu ssion ........... .... ........................................................ .. ...... .. 63
3.2.1 M etathesis of the monoester of carbohydrates .....................................................63
3.2.2 M etathesis of Tri-esters of Phloroglucinol ............. .............................................77
3 .4 C o n c lu sio n ................................ ......................................................7 9



4









4 ACYCLIC DIENE METATHESIS REACTIONS OF CARBOHYDRATES ......................81

4 .1 In tro d u ctio n ......... .. ....... ...................................................................................... 8 1
4.2 Results and Discussion .................................... ..... .......... ......... .... 86
4.3 C conclusion ......... ......... ......... ..................................... ............................93

5 EXPERIM ENTALS M ETHODS ...................................................................... ............... 94

5.1 General M methods and Instrum entation......................................... ......................... 94
5.2 Experim ental Procedure and Data .............................................................................95
N orbom enem ethanol 2-13 ...................... .. .. ......... .. ......................... .......................95
Ester carbamate of norbomene 2-14................................ 95
A m ino acetate of norbornene 2-15 ........................................... ........................... 96
Fmoc protected ester carbamate of norbornene 2-16 ....................................................97
D protection of the Fm oc group ........................................................ ............. 98
N orbornene ketoester 2-17 ......... ...................................................... ......................... 98
p-Toluene sulfonyl azide (2-18) .............. .............................. .............................99
D iazo-ester of norbo ene 2-19.................. ......... ............................... ..... ............ 100
Norbom ene oxohexanoate 2-22 ..................................... ...................................101
R OM P of the Com pound 2-17 ............................................... ............ ............... 102
R OM P of the Com pound 2-22 ............................................. ............................. 103
D iacetone D -m annose (3-25) ....................................................... ................... 104
Carbonate of diacetone (D)-mannose 3-26.............................. 104
Metathesis of the carbonate of D-mannose 3-27 ................ ...................105
Hydrogenation of the metathesis product of carbonate of diacetone (D)-mannose 3-
2 8 ......................................... ................ ............................... . 1 0 6
Esterification of diacetone D-mannose 3-29 ..........................................107
Metathesis of the ester of D-mannose 3-30 .............. ............................................108
Ester of diacetone D-glucose 3-32 ................................ 109
M etathesis of the glucose ester 3-33 ..................................... ........................ .......... 110
Synthesis of diacetone D-galactose 3-35.................................................... ............... 111
Ester of protected D -galactose 3-36 ..................................... ........................ ........... 112
Metathesis of the ester of (D)-galactose 3-37............... .......................................113
Protected m onoacetone -D -ribose 3-39.............................................. ..................114
TBDM S protected monoacetone-D-ribose 3-40 ...................................... .................114
Esterification of m onoacetone (D)-ribose 3-41 ............................................................115
Esterification of TBDMS protected monoacetone-D-ribose 3-45............................. 116
Monobenzylation of monoacetone (D)-ribose 3-44 .................. ...................... 117
Esterification of benzylated monoacetone-D-ribose 3-46 ............................................ 118
Metathesis of the monoacetone (D)-ribose 3-47 ............................... ............... 119
Metathesis of benzylated monoacetone (D)-ribose 3-49 ......................................120
Metathesis of the diester of monoacetone (D)-ribose 4-14(HH/HT) ..........................121
Benzylation of D-isomannide 3-51 ......................................... 122
Esterification of monobenzylated (D)-Isomannide 3-52............................ 123
Metathesis of the ester of benzylated (D)-Isomannide 3-53 ......................................124
Benzylation of D-isosorbide (exo) 3-55 ...................................125
Esterification ofbenzylated (D)-isosorbide (exo) 3-56.............................................. 125









Metathesis of the ester of benzylated (D)-isosorbide (exo) 3-57 ............................... 127
E ster of phloroglucinol 3-62 .................. ...... ................. ................................. 128
CM of the ester of phloroglucinol and glucose 3-63 ........... ................ 129
Formation of diacetone D-mannitol (4-5) .............. .... ........................................ 130
Esterifiction of diacetone D-mannitol 4-9 ............................ ............ ............... 131
Diester of the monoacetone (D)-ribose 3-43 or 4-10 ............................... ...............132
Esterification of D -isom annide 4-11 ........................................................ ............... 133
Diesterification of (D)-Isosorbide 4-12 ....................... ........................... 134
ADM ET of the diacetone (D)-mannitol 4-13 ............. ........................... .................135
ADMET of the diester of (D)-ribose 4-15.................. ... .... ................136
ADM ET of the diester of (D)-isomannide 4-16 ........................................ .................137
ADMET of the diester of (D)-isosorbide 4-17................................. ....................138

APPENDIX

A SELECTED NMR SPECTRAL DATA................................................... ...............140

LIST OF REFERENCES ......... ......... ........................... ......... ...... ................... 154

B IO G R A PH IC A L SK E T C H ............................................................. ......... ........................... 165









LIST OF TABLES


Table page

1-1 Potential application of different dynamic process in DCC systems ..............................32

2-1 t-Boc Cleavage of the com pound 2-14. ................................................................... ... 50

2-2 Deprotection of Fmoc group to get the compound 2-15 .............................. ............... 51

3-1 Olefin self-metathesis of alkenyl 0- and C-glycopyranosides. .......................................61

3-2 Yields, and optical properties of carbohydrate derivatives..............................................64

3-3 Yields, and optical properties of the metathesis products...............................................65

3-4 Comparison of the optical property of the esters of (D)-mannose and (D)-glucose.........69

4-1 Yield of diene from the protected carbohydrates.................................... ...............86

4-2 A D M E T of the carbohydrates......................................... .............................................87

4-3 M n of the A D M E T polym er ............................................................................... ....... 93









LIST OF FIGURES


Figure pe

1-1 Alkoxy imidomolybdenum-based Schrock's catalyst. .............................. ... ................. 18

1-2 R uthenium cataly sts. ................................................................................ ................ .. 19

1-3 Schematic representation of the concept involved in DCC. .................. ............... 29

1-4 Molding and casting processes in dynamic combinatorial libraries. ................................30

1-5 Templating of hydrazone-based library (a) in (b) the absence and (c) the presence of
acetylch olin e. ........................................................... ................. 33

1-6 Structures of natural glycopolymers: (1) Starch; (2) Chitin; (3) Cellulose. ....................34

1-7 Physical cross-linking by noncovalent interactions. ................... .......................... 40

1-8 Acyclic diene metathesis (ADMET) polymerization ....................................................... 42

3-1 Tungsten aryloxo complex used by Descotes. ........................................ ............... 59

4-1 Head-to-Tail, Head-to-Head, Tail-to-Tail arrangement ...............................................84

4-2 Hydrogels with carbohydrates lengthwise, crosswise or rings. .......................................85

4-3 Schematic representation of the HH or HT cyclic dimer of diacetone (D)-ribose. ...........91

A-i Proton NM R of diacetone (D)-mannitol .......... .......................................................... 140

A-2 Proton NMR of the ADMET of diacetone (D)-mannitol............................141

A-3 Proton NMR of the t-Boc amino acetate of norbornene...................... ................142

A-4 Proton NMR of ketoester of norbornene. ...............................................................143

A-5 Proton NMR of diazo-ketoester of norbornene. ....................................................... 144

A-6 Proton NMR of the homodimer of diacetone (D)-mannose. ........................ ..........145

A-7 Proton NMR of the homodimer of diacetoned (D)-glucose. ...........................................146

A-8 Proton NMR of the homodimer of the diacetoned (D)-galactose..................................147

A-9 Proton NMR of the homodimer of the benzylated monoacetoned (D)-ribose...............48

A-10 Proton NMR of the homodimer of monoacetoned (D)-ribose.....................................149









A-11 Proton NMR of the diester of monoacetoned (D)-ribose.......................................50

A-12 Proton NMR of the homodimer of benzylated (D)-isomannide .............................. 151

A-13 Proton NMR of the diester of (D)-isomannide. ... ......................... ............... 152

A-14 Proton NM R of the diester of (D)-isosorbide. ......... ........... ....................... .. ........ 153









LIST OF SCHEMES


Scheme age

1-1 Olefin m etathesis. ................................... ... .. ......... ........ ..... 16

1-2 Proposed intermediates for olefin metathesis. ...................................... ............... 17

1-3 Chauvin proposed metallacyclobutane intermediate. .............................. ................17

1-4 Dissociative substitution of ruthenium catalyst. ..................................... ...............20

1-5 Proposed m echanism of olefin m etathesis ........................................ ...... ............... 20

1-6 Quenching of ruthenium catalyst with ethyl vinyl ether (EVE) ..................................21

1-7 Different types of olefin m etathesis ...................................................... ............... 22

1-8 Utilizing RCM for the synthesis of Epothilones using different alcohol protection
and different solvents .................. .................. ................. .......... .. ............ 23

1-9 Application of ROMP to synthesize new materials ........................................................23

1-10 Cross-metathesis of asymmetric internal olefins. ................................... ............... 24

1-11 Prim ary and secondary CM reactions. ......................................................................... 25

1-12 Cross-metathesis of 0- and C- allyl galactopyranoside derivatives ................................25

1-13 Ring opening metathesis polymerization of norbornene. .............. ...............25

1-14 Mechanism of the ROMP of norbornene using Grubbs' catalyst..............................27

1-15 Representative ADMET polymerization cycle....................................... ............... 43

2-1 N itrogen aerosol through elim nation. ......................................................................... 46

2-2 ROM P to synthesize polymer scaffold. ........................................ ........................ 47

2-3 Other nitrogen-releasing products......... .................................................. ............... 47

2-4 Synthesis of norbornene diazoester. .................................................................. ..........48

2-5 Synthesis of norbornenem ethanol ......... ......... ................ ..................... ............... 48

2-6 Deprotection of t-Boc protected ester carbamate of norbornene.............. .....................49

2-7 D protection of Fm oc group ........................................................................ 50









2-8 Synthesis of norbornene amino acetate using Fmoc protecting group .............................51

2-9 Synthesis of norbornene ketoester 2-17 .................................. ............ ...52

2-10 Synthesis of diazoester 2-19. ............. .............. ................. ................. 52

2-11 Attempt to make polymer by ROM P. ..........................................................................52

2-12 ROM P of the ketoester of norbornene. ................................................ ...........53

2-13 Unsuccessful attempt to make co-polymer using ROMP.............................................53

2-14 R O M P of the m onom er 2-22. ................................................................. ................. .... 54

2-15 Synthesis of co-polym er 2-27. ............ ................ ...... ................................ 55

2-16 Diazotization of the co-polymer 2-27. ....................................................... ............. 55

3-1 Illustration of the structural diversity in pyranose scaffolds............................................57

3-2 Homodimerization of O-acetyl-a-D-galactopyranoside 3-2............................................60

3-3 General scheme for the self-metathesis of O-pentenoate of a furanose...........................62

3-4 Protecting group and hydroxyl reactivity strategy ....................................................63

3-5 Synthesis of the carbonate of diacetone (D)-mannose................... ..................................65

3-6 Metathesis followed by hydrogenation to obtain saturated homodimer..........................67

3-7 M etathesis of the ester of (D)-m annose ............................................................................68

3-8 Metathesis of the ester of diacetone (D)-glucose............................................................69

3-9 M etathesis of the protected (D)-galactose. .................................... ........... .................. 71

3-10 Monoesterification of the monoacetone (D)-ribose.......... ......................................72

3-11 M etathesis of com pound 3-41........................................ .............................................72

3-12 Synthesis of TBDMS and benzyl protected monoacetone (D)-ribose ............................73

3-13 Synthesis of esters of TBDMS and benzyl protected monoacetone (D)-ribose. ...............74

3-14 Metathesis of the ester of TBDMS protected monoacetone (D)-ribose. ...........................75

3-15 Metathesis of the ester of benzyl protected monoacetone (D)-ribose............................75

3-16 Synthesis of metathesis product of benzylated (D)-isomannide................................76









3-17 Metathesis of the benzylated (D)-isosorbide in the exo position................................77

3-18 Schematic representation of the cross-metathesis between carbohydrate and
phloroglucinol esters..................... ....................................78

3-19 Tri-ester of phloroglucinol 3-62......... ......... ................ ........................ ............... 78

3-20 Cross-metathesis of phloroglucinol ester and glucose ester. ............................................79

4-1 General scheme for the ADMET polymerization of functionalized carbohydrate
derivatives with terminal double bond............................ ............................ 83

4-2 Diacetone D-mannitol as a hydrogel precursor. ..................................... ............... 85

4-3 Synthesis of the diester of diacetone (D)-mannitol...... ............................ ......... .... ...88

4-4 Synthesis of the diester of the monoacetone (D)-ribose. ............................................88

4-5 Synthesis of the diester of monoacetone (D)-isomannide. ...............................................89

4-6 Synthesis of the diester of monoacetone (D)-isosorbide. ............. .................................. 89

4-7 ADM ET of the diester of (D)-mannitol .................... ........................................ ... ............ 90

4-8 ADM ET of the diester of (D)-ribose. ............. ........................................ ....................92

4-9 ADMET of the diester of (D)-isomannide................................ ...............92

4-10 ADM ET of the diester of (D)-isosorbide................................................. .. ... .......... 92









Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

OLEFIN METATHESIS IN CARBOHYDRATE AND NORBORNENE APPLICATIONS

By

Kalyan Mondal

December 2007

Chair: Eric J. Enholm
Major: Chemistry

Olefin metathesis is a convenient route for the synthesis of functionalized higher alkenes

from simple alkene precursors. Our research goals are comprised of developing olefin metathesis

in ring opening metathesis polymerization (ROMP) of norbornene scaffold, in self-metathesis

reactions of carbohydrates, which can be used as precursors for the generation of dynamic

combinatorial libraries (DCLs), and in employing for the first time to study the acyclic diene

metathesis (ADMET) polymerization of carbohydrates.

Functionalized norbornene monomers have been the subject of interest due to facile

preparation and high reactivity in ROMP. We choose norbornene aldehyde as the starting

material for synthesizing the norbornene polymer scaffold, which can later be crosslinked using a

diyl and by the release of nitrogen gas.

Olefin metathesis is an important methodology for the generation of library members in

dynamic combinatorial chemistry. We have synthesized a series of carbohydrate based

homodimers by self metathesis reaction using Grubbs' second generation catalyst. Sophisticated

products were observed bearing a variety of functional and protecting groups on the

carbohydrates. The carbohydrate-linked alkenes were trans with several versions examined.

Products yields were dependent on the type of carbohydrate groups, and whether the ester group









possessed an allyl or pentenyl moiety at the carboxylate side. In addition, several carbohydrate

derivatives were made containing diene functionality. When subjected to the self-metathesis

condition, such diene carbohydrate system generated cyclic dimer.

The utility of ADMET chemistry for the polymerization of dienes containing silyl,

aromatic, and ester functional groups have been investigate. We have synthesized the diesters of

carbohydrates (D)-mannitol, (D)-ribose, (D)-isomannide, and (D)-isosorbide. We performed the

ADMET chemistry for those carbohydrates. To our best knowledge, we are the first to report the

ADMET chemistry of carbohydrates.









CHAPTER 1
HISTORICAL BACKGROUND

1.1 Olefin Metathesis

Throughout the history of chemistry, any reaction that has the ability to form

carbon-carbon bonds receives a significant amount of attention; and olefin metathesis is not an

exception to it. Olefin metathesis is a powerful synthetic tool that has found its way into the vast

array of scientific disciplines, starting from the development of small molecular drug candidates

to the industrial sized synthesis of petrochemicals. 1-7 The word, metathesiss", derived from the

Greek words meta (change) and tithemi (place), means an exchange; thus the term olefinn

metathesis", originally introduced by Calderon in 1967,9 refers to the interchange of carbon

atoms (with their substituents) between a pair of alkene bonds.10 This catalytic organic reaction

is unlike other carbon-carbon bond forming strategies due to the versatility of synthetic

transformations it promotes, such as the synthesis of various sized cycloalkenes from dienes and

specialized polymers by the ring opening metathesis polymerization of the cyclic molecules.

Olefin metathesis has opened efficient synthetic routes for the synthesis of complex natural

products, medicinal drugs, and new materials as demonstrated by the explosion of the metathesis

related applications found in literature during the past decade. In 2005, the importance of this

organic reaction was prestigiously recognized by the Nobel Prize Award in Chemistry to the

major contributors of olefin metathesis-Yves Chauvin, Robert H. Grubbs, and Richard R.

Schrock.

1.1.1 Development of Olefin Metathesis and Catalyst

Olefin metathesis was first discovered accidentally by researchers in petrochemical

companies in the 1950s when they were searching for heterogeneous catalyst to produce high-

octane gasoline products from olefins.7' Instead of their expected products, the chemists









observed newly developed olefins. It was not until the 1960s, when researchers at Goodyear Tire

& Rubber determined that these new products were the result of exchange of substituents on

different olefins, which they officially referred to as olefinn metathesis" (Scheme 1-1).1

R'

R Catalyst R R2

+ \ + \ 4
R3 R3 R4

R4

Scheme 1-1. Olefin metathesis.

For several years, chemist tried to explain the mechanism involved in this novel reaction

that involves a skeletal transformation of olefins. Calderon,12 Pettit,13 and Grubbs and Brunck14

initially suggested cyclobutane, tetramethylene complex, and a rearranging metallacyclopentane

intermediate as part of the mechanism, respectively, but all of the proposals were later found to

be incorrect (Scheme 1-2).8 It was in the year 1971 when French chemist Yves Chauvin

proposed a metal-carbene mechanism, which involved the formation of a metallacyclobutane

intermediate (Scheme 1-3).8, 15 However, the mechanism for the olefin metathesis was not to be

established for years yet. The independent works of Katz, Schrock, and Tebbe supported the

mechanism proposed by Chauvin and is now accepted widely.1' 8

Several groups had tried to develop transition metal carbene complexes. These include

Fischer carbenes (involving low oxidation state metals and electron deficiency at the carbon

center) and Schrock carbenes (involving high oxidation state metals and electron deficiency at

the metal center).1 8 The Fischer carbenes involved little activity for the olefin metathesis, while

Schrock's tantalum and niobium metal complexes were also proved unsuccessful.' 8 The

propagating species could not be obtained, isolated, or structurally characterized and the metal

catalysts involved in the olefin metathesis are often referred as "classical" or "ill-defined"









catalysts. However, all these initial studies helped to improve the synthesis of alkylidene

complexes that eventually demonstrated improved reactivity for olefin metathesis.

A B A- /B- A B
+ I _
I II
C D ",
C D ;;'------; ~
C D
M
Cyclobutane
intermediate


A B
+

C D


+M .


A B -
-M A


C D
Tetramethylene
complex


A B
I +M A B C A
+ d I-

C D C D M
D B
M = metal Rearrangement of
metallacycl opentane

Scheme 1-2. Proposed intermediates for olefin metathesis.8





LnMR LnM

Rl^= R1


A + (
C D


Scheme 1-3. Chauvin proposed metallacyclobutane intermediate.

Despite of all these early developments, Olefin metathesis did not find any practical

application due to the following reasons:

1. Low reactivity of the metal catalyst.


R2









2. Lack of stability and tolerance toward the functional group of the alkene involved.

In the 1990s, Schrock introduced first a well-defined alkoxy imidomolybdenum-based

catalytic system 1-1, which allowed successful application of olefin metathesis

(Figure 1-1).16 17 In contrast to the earlier developed catalysts, the molybdenum alkylidene

complex is highly reactive and leads to the desired product with higher percentage of yield

including starting materials with sterically hindered alkenes. '18 However, the catalyst was

found to be ineffective for the starting materials containing polar functional groups like alcohols

and carboxylic acids. Also, this catalyst is highly air and moisture sensitive and needs absolute

dry conditions to carry out the olefin reaction.5



iPr iPr
N Ph
I I ---
(F3C)2MeO 1*Mo. CH3
(F3C)2MeO CH3
1-1

Shrock's catalyst

Figure 1-1. Alkoxy imidomolybdenum-based Schrock's catalyst.

To improve the moisture-air and the functional group sensitivity, Grubbs and coworkers

examined ruthenium based catalysts having an oxidation state higher than the Fischer carbenes

but lower than Schrock's catalyst.1' 19 The first Grubbs' catalyst [(PPh3)2Cl2Ru=CHCH=C(Ph)2]

(1-2) was developed in 1992 and was stable in protic and aqueous solvents. However, the

catalyst exhibited limited reactivity in comparison with Schrock's carbene complex (Figure

1-2). 1, 2021 In 1996 Grubbs and coworkers introduced a modified form of their earlier ruthenium

based catalyst (Figure 1-2, Grubbs' catalyst 1-3), and is commonly known as Grubbs' first

generation catalyst. It not only displayed better functional group tolerance but also was observed









to be 20-10,000 times more reactive than the earlier version of the ruthenium catalyst 1-2

(Figure 1-2).22 Based on Herrmann's studies on N-heterocyclic carbenes23 Grubbs replaced one

of the tricyclohexyl phosphine (PCy3) ligands with a mesityl N-heterocyclic ligand to afford a

more stable ruthenium catalyst 1-4, which is commonly referred as "Grubbs' second generation

catalyst". This second generation catalyst shows far more superiority in terms of its tolerance

towards moisture, air, and a wide variety of functional groups (Figure 1-2).1' 18, 24, 25 As a result

of this enhanced reactivity our research efforts were focused on olefin metathesis using Grubbs'

second generation catalyst 1-4 along with the use of Grubbs' first generation catalyst 1-3.


PCy3 PCy3 Mes-N N-Mes
Cl,. 1 Cl1,, I
ClRu Ph Ru C1 ,,,
Ce Cl= Ru .,
PCy3 Ph PCy3 Ph Cl 1 P
PCy3
1-2 1-3
1-4
Grubbs' First Grubbs' Second
Generation Catalyst Generation Catalyst

Figure 1-2. Ruthenium catalysts.

1.1.2 Mechanism of Olefin Metathesis

The commercial availability of ruthenium catalysts 1-3 and 1-4 has made them a practical and

standard organic tool. The synthesis of this metal alkylidene complexes will not be discussed

here. However, to better apply olefin metathesis towards the synthesis of target compounds and

polymers, it is helpful to examine the mechanism that was first introduced by Chauvin. When

utilizing Grubbs' catalysts 1-3 and 1-4, the first step of the mechanism involves the dissociation

of the PCy3 ligand, followed by the binding of the alkene to the carbene (Scheme 1-4).26, 27 The

next step is a [2+2] cycloaddition with the metal catalyst to form the metallacyclobutane

intermediate, which can then undergo a cycloreversion process to produce a new metal









alkylidene complex (Scheme 1-5).4, 27 The mechanism proceeds as a catalytic cycle where the

metal alkylidene undergoes another [2+2] cycloaddition with a second alkene, followed by the

cycloreversion leaving the newly formed olefin with R1 and R2 groups and the metal alkylidene

for further catalytic use.

L R L
CU I R i ( R
IRu -PCy3 Ci,, R + olefin,,
Cl Ru olefin C
PCy3 +PCy3 Cl

R

Scheme 1-4. Dissociative substitution of ruthenium catalyst.

R2

LnM=
R1 + x

cycloreversion

R2


n R1 LnM R1
X 1-1



/0 RI cycloreversion

+ H2C=CH2
LnM=\
R2

Scheme 1-5. Proposed mechanism of olefin metathesis.

Because ethylene gas is released as a byproduct,6 it is possible to shift the equilibrium

towards the desired products by deliberately evacuating or flushing the headspace with argon to

remove ethylene.28 The cycle continues until the reaction is quenched. Ethyl vinyl ether (EVE)

reacts with the ruthenium catalyst and forms the Fischer carbene L(PCy3)(Cl)2 Ru=CHOEt









(Scheme 1-6).26 This new, electron rich carbene complex formed by the reaction between

ruthenium catalyst and EVE is virtually irreversible in nature and significantly less reactive than

the ruthenium alkylidenes.26 29


Mes-N N-Mes Mes-N N-Mes
Cl,,. Cl,,,
Rum> Rum>-
Cl Ph CH2CI2 Cl OEt
PCy3 PCy3

Scheme 1-6. Quenching of ruthenium catalyst with ethyl vinyl ether (EVE).29

1.1.3 Important Types of Metathesis Reactions and Applications

As highlighted many times, olefin metathesis is a versatile technique which includes

ring-closing metathesis (RCM), ring-opening metathesis (ROM), cross-metathesis (CM), ring-

opening metathesis polymerization (ROMP), and acyclic diene metathesis (ADMET) (Scheme

1-7).6 The three main metathesis reactions, used in our studies, RCM, ROMP, and ADMET will

be discussed in greater detail.

RCM is olefin metathesis involving the cyclization of a diene to generate various sized

cycloalkenes, from small 5-membered rings to macrocycles.18 The stereochemistry of the

cycloalkene products are dependent on the substrates; for example, small and medium sized rings

formed from RCM are in a less strained cis conformation while in contrast, the stereochemistry

of the non-rigid RCM derived macrocyclic compounds is difficult to predict and can encompass

a mixture of cis and trans stereoisomers.30

RCM reactions are conducted under highly dilute conditions to prevent ADMET

polymerization. In addition, heat is often employed to improve ring closures due to the entropy

of activation required to bring the two ends of the chain together.31 However, higher

temperatures can cause the catalyst to decompose, thus a greater catalyst loading is required.5









Despite this requirement, RCM has provided a shorter, more efficient synthetic route to natural

products,184 medicinal drugs,32 and new materials185 compared to conventional methods, as

attested by the numerous studies found in literature.59 83, 89, 123 An example is shown in

Scheme 1-8 in which Danishefsky and coworkers utilized RCM to synthesize Epothilones using

different alcohol protection groups.32


RCM
-- C2H4 -



ROM
ADME
-n C2H4 ROMP






n


RI RI R2
cross-metathesis + + +
+ *
R-- H2C =CH2 R2 R R
R22


Scheme 1-7. Different types of olefin metathesis.

The reverse reaction of the RCM is called ROM, where the cycloalkene breaks open to

form terminal diene, which can be followed by a CM reaction with other acyclic alkenes to form

new products.5 Similar to RCM, ROM requires dilute conditions due to the resulting dienes

undergoing polymerization, referred to as ROMP. The polymerization is quite practical and is

more widely used than the ROM itself. Cycloalkenes, which possess ring strain, such as

norbornene, cyclopentene and cyclooctene, favor ROMP.16 Removing ring strain leads to a

reversible reaction that is driven forward, and is not reversible anymore.









O O
S \ S R / R-
0 O Grubbs' II Catalyst S\ / 0 OR,1 )N :
S R1 R^-N
'N /p 3 (10%) 10
77 O CH2C2 / toluene O OR2
7 O 0.002 M 11 OR2
OR2
Epo490 (R1, R2 = H)


1-5a R1 = TES, R2 = Troc 35% / 58%b 15% / 6%b
1-5b R1 = H, R2 = Troc 41% / 57% 0% / 0%
1-5c R = TES, R2 = H 57% / n.d. 0% /n.d.
1-5d R1 = H, R2 = H 64% / 55% 0% / 0%
a Reaction in CH2C12 were run for 5.5 h at 350C; reactions in toluene for 25 min at 1100C. b Done
with 20 mol% catalyst at 0.0005 M dilution. CNot determined.

Scheme 1-8. Utilizing RCM for the synthesis of Epothilones using different alcohol protection
and different solvents a 32

Grubb's second generation catalyst 1-4 has high functional group tolerance and has been

demonstrated in ROMP to generate functionalized, telechelic and trisubstituted polymers.33

ROMP is responsible for the synthesis of a variety of new materials, starting from the

development of nonlinear optics to biologically relevant polymers.32 A recent application of this

polymerization is shown in Scheme 1-9, where a polymer was synthesized to create biomaterials

that can undergo a [2+2] cycloaddition when irradiated with UV light.35

o

Ph ROMP O)L Ph
#- ph 1-3, CH2CI n Ph
0 79% O
1-7 Mn = 24,937
1-8

Scheme 1-9. Application of ROMP to synthesize new materials.

RCM and ROMP started as the most popular types of metathesis reactions, but due to

recent studies and a better understanding of the selectivity and stereoselectivity of CM, the later









has become a more useful and versatile synthetic technique over the years. The concerns over

selectivity arise from the mixture of heterodimers, homodimers, cis and trans stereoisomers that

can be generated from CM reactions. In addition, employing internal olefins in CM can also lead

to a greater number of product mixtures (Scheme 1-10). Factors such as steric and electronic

effects may also affect CM reactivity and selectivity, and must be considered when planning

reactions. For example, olefins possessing electron withdrawing or bulky substituents often lead

to little or no CM products because of the poor reactivity with the catalyst, but steric effects

nearly always favor trans selectivity.34

R1 RI R2 R2
RI + + + Heterodimers
R3 R4 R3 R4
R2 cross-metathesis
+ +
R3R

R 1 R21 R32+ R + Homodimers
RI R2 R3 R4

Scheme 1-10. Cross-metathesis of asymmetric internal olefins.

Fortunately, new models and methodology were developed to improve selective CM. For

instance, Grubbs categorized olefin metathesis as Type I, II, III and IV based on their reactivity

to form homodimers by CM with catalyst 1-3 and 1-4. Primary allylic alcohols, protected

amines and esters are the examples of Type I alkenes (sterically unhindered, and electron-rich)

because they readily form homodimers by CM and also undergo secondary metathesis

reactions.28 36 37 The more sterically hindered Type II alkenes (i.e., secondary alcohols and vinyl

ketones) are less reactive and Type III alkenes are nonreactive (i.e., tertiary allylic carbons).

Type IV alkenes (i.e., protected trisubstituted allyl alcohols) are spectators and do not participate

in the CM reaction. The examples given above are based on the utilization of catalyst 1-4. One

strategy towards selective CM involves a two steps procedure in which homodimers of Type I









alkenes are generated, followed by a secondary metathesis reaction with Type II / III alkenes to

preferentially form the heterodimer product with trans favored in the presence of selected

functional groups (Scheme 1-11).36 CM is more widely used now and an example of a recent

application of CM is shown in Scheme 1-12, where Roy and coworkers were able to carry out

cross-metathesis of 0- and C- galactopyranosides in good to excellent yields with predominantly

trans selectivity.38

R1

R1 catalyst R2
+ =- catalyst ca
R1 R R1 +

R1

Scheme 1-11. Primary and secondary CM reactions.

AcO OAc --R AcO OAc

AcO 20 mol% 1-3 AcO
AcO O0 CH2C12, reflux, 6h Ac O R


Scheme 1-12. Cross-metathesis of 0- and C- allyl galactopyranoside derivatives.38

1.2 Ring Opening Metathesis Polymerization (ROMP)

Ring opening metathesis polymerization (ROMP) (Scheme 1-13) involves a chain growth

process resulting in the formation of linear high molecular weight polymers. Norbornene is often

used in these studies, due to a small strain release.


catalyst Y n


Scheme 1-13. Ring opening metathesis polymerization of norbomene.

Like all olefin metathesis reactions, ROMP is governed by competing equilibrium. The

thermodynamics of the ring-chain equilibrium dictate the polymerizability of cyclic olefins:49









AG = -RT InKeq= AH- TAS (1)

Polymerization is governed by the enthalpy (AH) since with the polymerization the ring

strain of the monomer unit gets released. The bond-angle strain in 3, 4, and 8-membered rings as

well as in bicyclic monomers like norbornene provides the necessary energy for the

polymerization process. The inherent ring strain in these monomer units allow the equilibrium to

be shifted from the cyclic monomer towards the liner polymer. The polymerization of the strain

free (i.e., AH = 0) macrocyclic olefin is an entropically (AS) driven process as a result of the

formation of linear polymer. The ROMP of 5, 6, and 7-membered rings, however, presents a

thermodynamic uncertainty. Due to comparable entropy and enthalpy (AH TAS z 0) values,

such stable cyclic olefin monomers can undergo polymerization at Tc, the polymerization ceiling

temperature (the temperature above which no polymerization can take place for any cyclic

monomer).50, 51 Patton and McCarthy demonstrated that at a temperature of -23C cyclohexene

could polymerize.51 In general, monomers with greater ring strain (i.e., larger negative value of

AH of the reaction) are more prone to undergo ring-opening polymerization reactions.

The mechanism of ROMP chemistry is outlined in Scheme 1-14 using norbornene as the

monomer and Grubbs' catalyst. The catalyst, M, is a transition metal carbene complex. The first

step of polymerization involves coordination of the monomer unit to the metal to form an initial

7t-complex [A]. The monomer then undergoes an insertion process through a [2+2]-like

cycloaddition to form the metallacyclobutane intermediate [B]. The double bond of the cyclic

intermediate is highly strained and is energetically unfavorable. The successive cleavage of the

metallacyclobutane by a retro [2+2] addition generates a chain extended t-complex [C]. The

final step involves the dissociation of the 7t-complex. This whole process repeats itself and









thereby creating potentially high molecular weight polymers, until the reaction is halted by the

addition of a capping reagent like EVE.




+ Ru
Ru=\ _
R Ru R[B]
R
Ru = Grubbs' Catalyst [A]

H
R Ru

Ru
[E] [D] [C] R

Scheme 1-14. Mechanism of the ROMP ofnorbornene using Grubbs' catalyst.

Ring opening polymerization is controlled by a chain growth mechanism, as shown in the

above mentioned mechanism (Scheme 1-14). Polymerization or chain propagation continues at

the reactive, growing chain end until secondary metathesis reactions, called chain transfer or

cyclization, become significant. When this secondary reaction predominates over the primary

chain propagation reaction, the thermodynamics of the polymerization is controlled by the ring-

chain equilibria.52

1.3 Dynamic Combinatorial Chemistry

For the discovery of biologically active substances, especially drugs, it is necessary to find

molecules that react selectively with the given biological targets. Within less than one decade,

combinatorial chemistry has established itself as a versatile and attractive approach for the

synthesis of libraries of compounds that are able to be tested for their biological activities and

desirable properties.54'55 It was first developed for the synthesis of peptide libraries for screening

against antibodies or receptors. However, the technology has evolved rapidly to become a









powerful technique primarily in the drug discovery processes.56 The goal of combinatorial

chemistry is to synthesize a large number of products via condensation of a small numbers of

starting materials in all possible combinations. For example, let us consider a chemical reaction

in which there are three different reactants: A, B, C. If we start with only one type of each

reagent, and then the reaction will result in 1 x 1 x 1 = 1 product as the result of a total of three

reactions. On the other hand, if we use 10 types of each reagent, then there will be a total 30

reactions which would result in the formation of 10 x 10 x 10 = 1000 products, while 100 types

of each reagent would result in the formation of 1,000,000 products as a result of 300 total

reactions only.

Traditional combinatorial chemistry involves sequential and irreversible syntheses

irrespective of whether they are performed individually in parallel, or concertedly in the same

compartment. Another characteristic feature is that all constituents of the library are more or less

robust molecules. The major disadvantage of this process is the lack of flexibility or limited

flexibility in the generation of the library, since almost all structures have to be designed

distinctly and synthesized separately.57 In contrast to the static approaches involved in traditional

combinatorial chemistry, the library may be produced from a set of reversibly interchanging

reactants. This technique introduces a dynamic equilibrium into the system. The interesting

feature of dynamic combinatorial chemistry (DCC) is that each library member affects all other

surrounding constituents and components.58 Also, DCC combines the generation of the library

and the screening processes in a single step. There is a continuous interchange of building blocks

between different members, and hence the composition of a dynamic combinatorial library

(DCL) is governed by thermodynamics rather than kinetics. The major advantage of DCC over

the traditional or static combinatorial chemistry is that the desired compound is amplified at the









expense of the undesired compounds. This is due to the fact that the molecular recognition events

are specific for a particular member, and thus will stabilize that particular substance only. This

induces a shift in equilibrium towards the formation of recognized species at the expense of

59
unrecognized species.5





Library Receptor
generation selection

br brar of
inter hanging
4^P species
9 Y Initial
building Receptor



^ 6 ^ ^ Selection of
Receptor best binder



Figure 1-3. Schematic representation of the concept involved in DCC.73

In the simplest fashion, we can describe the principle involved in dynamic combinatorial

chemistry by means of Emil Fischer's lock-and-key metaphor.74 The whole process can be

divided into three steps. The first step involves selection of initial building blocks, which are

capable of interacting with each other in a reversible fashion. The second step involves the

development of the conditions for the generation of the library, where the building blocks can

form interchanging, individual molecular "keys" (for example, ligands). In the last step, the

library is subjected to a selection process, which results from binding strength to a molecular

"lock" (for example, a receptor).73 With this concept, two situations can arise. In the first case,

the receptor can itself act as the trap for the given ligand. Under this condition the ensemble of

candidates will be forced to rearrange in order to produce that species. In the second case, a









specific synthetic receptor is selected from a series of interconverting receptors by addition of a

certain ligand. These two cases have been termed as "substrate casting" and "receptor molding"

respectively. Figure 1-4 shows the schematic representation of the casting and the molding

process.


















Figure 1-4. Molding and casting processes in dynamic combinatorial libraries.7

Thus, in DCC, there are two concepts, depending on whether a receptor or a substance acts

as a target-template for the assembly of the other partners. Casting involves the receptor-induced

assembly of a substrate that fits the receptor; whereas, the molding involves substrate-induced

assembly of a receptor that fits the substrate.76

There are three steps involved in a dynamic combinatorial approach. These are:

(1) synthesis of a mixture of inter-converting molecules; (2) amplification of the best binder(s)

through non-covalent interactions with a template; and (3) isolation (or re-synthesis) of the best

binder(s). The success of each step depends upon the type of reversible reaction used to connect

the building blocks. Under ideal conditions, we look for a rapid reversible reaction which is

tolerant towards a wide-range of functional groups, proceeds under mild conditions, and does not

interfere with the recognition events.59 A series of different types of reversible reactions have









been studied for their use in DCC. Table 1-1 shows a series of such reactions. These include

disulfide exchange,77 metal-ligand coordination,78 exchange of oximes,79 and hydrazones,80 and

olefin metathesis.81' 82 There are two basic procedures involved in the implementation of the

DCC approach, depending on whether library generation and screening are performed in a single

step or in two steps. This result in two types of dynamic libraries: adoptive combinatorial

libraries and pre-equilibrated dynamic combinatorial libraries.7

Earlier using the reversible chemistry, diverse libraries were generated. However, recent

emphasis in combinatorial chemistry is to shift the equilibrium towards templating by exposing

those libraries to targets.59 These targets can either be a receptor or ligand molecules. The most

significant examples of templating have been observed when a molecule selects its best receptor

from small dynamic libraries of macrocycles of different sizes.80' 86, 87 Figure 1-5 shows an

example of hydrogen-bond based dynamic system prepared from a building block derived from

L-proline. Acid catalyzed cyclization results in the formation of 15 macrocycles initially, which

changes mainly into cyclic dimers. At equilibrium, the library comprises 88% of the dimers and

11% of trimers. Addition of template acetylcholine to the reaction mixture significantly changes

the equilibrium to produce a 50-fold amplification of the cyclic trimer.59










Table 1-1. Potential application of different dynamic process in DCC systems.59


0
(a) Ri'oR'1


0 Base
R2 0R2 RIOAR2


0 0 Pd(0) O 0
(b) RI O- R R2I O Roo. R -' R,,,R R2. o-' R1


0
O

H

H
R1pC.N-R'


0 Protease
R2N" NR2 -
H


0
R'1A R2
R R
H


0
R2A N R
H


H Acid H H
RI2,CtNR2 RC ,-NR2 R2- N 1


H H H H H H H H
(e) R'oCNN'R CR' R2 N R2 A R CeN'R2 R2'C NN'R1


H H H H
(f) RIC",N '0 R R2N "0'R2 R1 R2 R2,C*N0'-R1


R1^S- R1


H
RC R'
H


R2,'Ss-R2 R FiSR2 R2S-,S^
RR1 S' R2"~


H
R2C C, R2
H


Grubbs H H
catalyst R1C R2 R2C R1

cy3P H H
I R
Ru=P
Cy1P


O
0
R2AQ#0, R'










(a) H (b) 100 2mer


o CHCWTFA \ HNO 60


OMe H H NH 20
MeO 0 o 3mer

N, ,+/Me
I t'Me
Acetylcholine o Me
Acetylcholine
H (C) 1:: 3mer


H N 1N0 -20
S Me H 40
H 2merN
0 ;V 20
-V

Figure 1-5. Templating of hydrazone-based library (a) in (b) the absence and (c) the presence of
acetylcholine.59

1.4 Carbohydrate chemistry

The study of carbohydrates began in the late nineteenth century with the work of Emil

Fischer. Carbohydrate ring structure was elucidated in the 1930s by Haworth and colleagues.

Polysaccharides were discovered soon after and appeared to be present in every living organism,

such as vegetables and animals. In addition to determining the structure of this new category of

molecules, chemists and biologists focused on the functions of these ubiquitous polymers.

Polysaccharides display a very wide range of biological functions from acting as nature's source

of energy (such as starch and glycogen), to providing structural materials (cellulose, chitin,

collagen, and proteoglycans) 1-3 (Figure 1-6).62 Carbohydrates are now known to assume wider

variety of biological roles. For example, the sulfated polysaccharide, heparin plays an essential

role in blood coagulation,70 while hyaluronan acting as a lubricant in joints has been used in the

implantation of plastic intra-ocular lenses in the 1980s.71









OH

0 HO




OH| \
1 OHj

OH n
HO
OH
SO O HO
O O O
OH O OO 1 0O O0
NHAc n HO OH HO O
2 3 OH

Figure 1-6. Structures of natural glycopolymers: (1) Starch; (2) Chitin; (3) Cellulose.62

Moreover, hyaluronan, as well as another sulfated polysaccharide, chondroitin sulfate,

exhibit anti-inflammatory activity and were investigated for the treatment of osteoarthritis and

rheumatoid arthritis.72 A large number of syntheses involving carbohydrate chemistry are

directed increasingly toward the preparation of artificial glycoconjugates. Such glycoconjugates

contain sugars and/or naturally occurring compounds.58 88 However, it has been recognized that

it is not necessary to have actual glycoconjugates in order to study and understand various

biological processes. Several artificial carbohydrate compounds exhibiting parallel or even

improved biological interactions can be synthesized.58 Carbohydrate recognition plays an

important role in many biological processes like, cell-cell interaction, cell communication, and

others. They are also used as ligands for endogenous lectins, used to mediate various regulatory

processes.587 Therefore, carbohydrate groups are highly attractive tools for the generation of

mimics and analogues. Eventually, by identifying and tailoring potent new ligands, medicinal

application in drug designing and glycohistochemistry can be accomplished.58









Unlike other compound groups, synthesis of carbohydrate libraries using classical methods

have never witnessed identical rapid progress. In spite of suffering identical problems, DCC still

offers a complementary route for the synthesis of carbohydrate libraries, especially, the synthesis

of dynamically interchanging carbohydrates "clusters".58 Only a few examples of DCLs

containing carbohydrates are reported and none of them involve metathesis.58' 77, 88-91

Multicovalent neoglycoconjugates have been extensively utilized to probe and enhance

carbohydrate-protein interactions at the molecular level.92-94 Moreover, glycoclusters92 and

dendrimers93 are also emerging as potential carbohydrates therapeutic agents.94 Several examples

exist in which ligand-induced receptor and protein dimerization occurred as a general mechanism

for signal transduction.95 It is conceivable that signal transduction and receptor shedding could

be triggered by carbohydrate oligomers.96

Cross-metathesis of a hydrocarbon chain having terminal double bond involves elimination

of ethylene gas. If elimination of the ethylene gas can shift the equilibrium towards the product

side, then the addition of the gas can shift the equilibrium towards the reactant side. This is the

basic concept involved in developing carbohydrate based dynamic combinatorial library using

the cross-metathesis method. We examined the reactivity of various types of sugars in the self-

metathesis reactions. Roy and coworkers employed Grubbs' catalyst based cross-metathesis for

0- and C- allyl and O-pentenyl galactopyranosides.150 Considering the growing importance of

carbohydrates in the study of carbohydrate-protein interactions, our research goal is to generate a

series of O-esters of furanose and pyranose with pendant terminal double bonds and examine

their applications in the olefin metathesis reaction.











1.5 Tissue Engineering

Peppas and Langer defined biomedical engineering as an extension of chemical

engineering towards biomaterials.39 Tissue engineering is one of its main branches. Various

disciplines, such as materials science, cell biology, chemistry, reactor engineering, as well as

clinical research contribute to tissue engineering. It requires a balanced combination of cell

culture growth with biomaterials to support it and with bioactive molecules to enhance and direct

it.40 A quite successful approach in tissue engineering involves replacement or repair of damaged

or failed tissues with viable ones by creation of an environment, which promotes the native

capacity of cell to integrate, differentiate, and proliferate.41-43

Every year, millions of patients suffer the loss, or failure of an organ or tissue as a result of

accidents or disease. Similarly, traumatic injuries, cancer treatment, and congenital abnormalities

are often associated with abnormal bone shape or segmental bone loss. Restoration of normal

structure and function in these cases requires replacement of the missing bone that may be

accomplished by surgical transfer of natural tissue from an uninjured location elsewhere in the

body. However, these approaches are extremely limited and have several drawbacks including

shortage of donor, infection or pain of patients due to second surgery for the removal of

implanted metal plate, inadequate blood supply, and secondary deformities at the donor site.44

Recently, tissue engineering has found enormous applications in generating artificial

constructs to direct tissue regeneration.45 Scaffolds made from synthetic and natural polymers

and ceramics have been investigated extensively for orthopedic treatment. This approach has

several advantages including ability to generate desired pore structures with matching size, shape

and mechanical properties. The major disadvantages it has include shaping them to fit in cavities

or defects, bonding to the bone tissues, and requirement of an open surgery to get rid of it.46









A material that can be employed as a scaffold in tissue engineering must satisfy a number

of requirements. These include biocompatibility, biodegradation to non toxic products within the

time frame required for the application, processability to complicated shapes with appropriate

porosity, ability to support cell growth and proliferation, and appropriate mechanical strength

during the major part of the tissue regeneration process. Biodegradable synthetic polymers offer

a number of advantages over other materials for developing scaffolds in tissue engineering. The

ideal biomaterial must be biocompatible, promote cellular interaction and tissue development,

and possess proper physical and mechanical properties. The key advantages include the ability to

tailor mechanical properties and degradation kinetics to suite various applications. However, in

addition to the main requirements mentioned earlier, an injectable polymer composition must be

in liquid or paste form, sterilizable without causing any chemical change, and must have the

capacity to incorporate biological matrix components. Upon injection the prepolymer

composition should bond to the biological surface and cure to the solid and porous structural

form with appropriate mechanical properties. The curing process should take place with

minimum heat generation and chemical reactions involved in curing should not damage the cells

and adjacent tissues. The cured polymer while facilitating the cell-in-growth proliferation and

migration should ideally be degraded into biocompatible materials that are either absorbed within

the body or released from the body without any side reaction or damage to the body.46

Among the families of synthetic polymers, polyesters have been found attractive due to the

ease of degradation by hydrolysis of ester linkage (degradation products being reabsorbed

through the metabolic pathways in some cases) and the potential to tailor the structure to alter

degradation rates. Biodegradable synthetic polymers such as polyglycolides, polylactides,

polycaprolactone (PCL) and their copolymers, poly(p-dioxanone), and copolymers of









trimethylene carbonate and glycolide have been used in a number of clinical applications for the

preparation of the scaffolds.40' 47-48 However, the hydrophobicity of such polyester based

biodegradable polymers, acidity of the decomposed material; and self acceleration of degradation

are the major drawbacks they have.40

Attempts to find tissue-engineered materials to cure orthopedic injuries/diseases have made

necessary the development of new polymers that meet a number of demanding requirements.

Such requirements include ability of scaffold to provide mechanical support during tissue growth

and gradually degrade to biocompatible products, to withstand several requirements including

ability to incorporate cells, growth factors etc. and to provide osteoconductive and osteoinductive

environments. Recent studies in tissue engineering involve development of in-situ

polymerization of the biocompatible compositions. This can function as cell delivery systems in

the form of an injectable liquid/paste. Many of the currently available degradable polymers do

not comply with all of these necessary requirements and significant chemical changes are

required to their structure to achieve their role for the desired applications.46 One strategy to

overcome these problems is to develop living tissue substitutes based on synthetic biodegradable

polymers. We hope our research efforts to synthesize the biomaterials for tissue engineering

from norbornenemethanol will satisfy the criteria mentioned above.

1.6 Hydrogels

A hydrogel is a network of polymer chains that are water-insoluble, sometimes found as a

colloidal gel in which water is the dispersion medium. Hydrogels are superabsorbent (they can

contain over 99% water) natural or synthetic polymers. Hydrogels possess also a degree of

flexibility very similar to natural tissue, due to their significant water content. Common uses of

hydrogels are--









Currently used as scaffolds in tissue engineering. When used as scaffolds, hydrogels may
contain human cells in order to repair tissue.

Environmentally sensitive hydrogels. These hydrogels have the ability to sense changes
of pH, temperature, or the concentration of metabolite and release their contents as result
of such a change.

As sustained-release delivery system.

Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be
used as biosensors as well as in DDS.

In disposable diapers where they "capture" urine, or in sanitary towels.

Contact lenses (silicone hydrogels, polyacrylamides).

Medical electrodes using hydrogels composed of cross linked polymers (polyethylene
oxide, polyAMPS and polyvinylpyrrolidone).

Water gel explosives.

Other, less common applications include---

Breast implants.

Granules for holding soil moisture in arid areas.

Dressings for healing of bum or other hard-to-heal wounds. Wound GEL are excellent for
helping to create or maintain environment.

Common ingredients are e.g., polyvinyl alcohol, sodium polyacrylate, acrylate polymers

and copolymers with an abundance of hydrophilic groups. Natural hydrogel materials are being

investigated for tissue engineering. These materials include agarose, methylcellulose,

hyaluronan, and other naturally derived polymers.

Hydrogels swell strongly in aqueous media, and are composed of hydrophilic organic

polymer components that are cross-linked into a three-dimensional network either by covalent or

non-covalent interactions. The cross-linking nature of hydrogels provides it with dimensional

stability, whereas the high solvent content gives rise to fluid-like transportation properties.

Physical properties of hydrogels make it suitable for various applications. Initially it was used as









superabsorbent where it can act as an absorber entrapping water and are used where a large

volume of aqueous media needs to be removed from a localized source. With an eye to applying

those in several areas like in vivo diagnostics, drug/gene delivery, chemical separations, and

chemical and biological sensors scientists have now started to synthesize more complex polymer

architectures. Such materials must satisfy conditions like biocompatibility, biodegradation,

encapsulation, and biorecognition etc.

Based on the type of cross-links hydrogels are classified into two different categories-

(a) Physically cross-linked hydrogels, and (b) Chemically cross-linked hydrogels.10s

Physically Cross-linked Hydrogels

This class of hydrogels is classified by its reversibility or by its degradation properties.

These hydrogels are mostly used to encapsulate proteins,109 cells,110 or drugs,11 followed by

dissolution of the structure to release them. The noncovalent attractive forces like hydrophobic

interactions, hydrogen bonding, or ionic interactions between the polymer chains are responsible

for the cross-linking here (Figure 1-7).

--/ ~ Coordination Bond
S' Hydrogen Bond
SHydrophobic Interaction
S' Ionic Interaction
Cross-lk Protein-Ligand Association
Cross-link




Hydrogel Network


Figure 1-7. Physical cross-linking by noncovalent interactions.108

Hydrogel formation is based on the pH value of the medium as the hydrogen bonds, the

main source of such noncovalent bonding, are formed only when the acid groups are

protonated.112, 113









Chemically Cross-linked Hydrogels

These kinds of hydrogels are more stable because the cross-links are covalent bonds.114

They have permanent structures unlike the physically cross-linked hydrogels. Such hydrogels are

made by polymerizing monomers containing the cross-linking agent. One example is the

chemically cross-linked hydrogel poly(2-hydroxyethyl methacrylate). It is typically synthesized

by polymerizing 2-hydroxy methacrylate (H2C=C-(CH3)COOCH2CH2OH) with ethylene glycol

dimethacrylate (CH2=C(CH3)COOCH2CH2OCO(CH3)C=CH2) as the cross-linking agent.

Hydrogels can also be formed by cross-linking of the various functional groups present on the

polymer backbone.

1.7 Acyclic Diene Metathesis (ADMET)

The introduction of the well-defined alkylidene metal catalysts by Schrock and Grubbs

continues to have profound impact on the viability of ring opening metathesis polymerization

(ROMP) reactions. However, it was the early contributions made specifically by Schrock that

introduced a new metathesis polymerization reaction. Acyclic diene metathesis (ADMET)

polymerization has been an area of intermittent study for the last 30 years. However, the

discovery of Schrock's alkylidines was the first practical reality.

Acyclic diene metathesis (ADMET) polymerization (Figure 1-8) has proven to be a viable

synthetic route for the synthesis of high molecular weight unsaturated polymers and copolymers,

including polymers possessing various functionalities.98 ADMET represents a unique equilibrium

step condensation route for the synthesis of polyalkenylenes. The ADMET condensation, like the

cross metathesis, is a reversible reaction which is driven by the continuous production and

removal of ethylene gas.100










R Ca Cat. R R + n H2C=CH2
n

Figure 1-8. Acyclic diene metathesis (ADMET) polymerization.

In order to understand the ADMET chemistry, structure-reactivity studies have been done.

The mechanism of ADMET chemistry is shown in Scheme 1-15.98, 100 By examining the

mechanism of both the ADMET and ROMP chemistry, it is found that the reaction intermediate,

the metallacyclobutane ring, is common to both and this is the only common feature between

them as one is a chain growth polymerization and the other is step growth polymerization. In

ADMET chemistry, two metallacyclobutane rings must be proposed in a propagation step

(whereas only one is needed in ROMP chemistry). The first metallacyclobutane ring is the result

of joining two monomers together followed by cleavage of methylidine carbene, which becomes

the active catalyst entity during the polymerization itself. The methylidine carbene continues to

react with either monomer or polymer, leading to a new metallacyclobutane ring acting as the

precursor of ethylene evolution. Once the ethylene is evolved and removed from the reaction

system, the cycle repeats itself, and further connection with monomers results in the formation of

high molecular weight polymer.

The utility of ADMET chemistry for the polymerization of dienes containing silyl,

aromatic, and ester functional groups has been investigated.98' 100-101 ADMET has been shown to

be an efficient technique for the preparation of unsaturated polyethers,103 unsaturated

polyesters,104 as well as variety of functionalized polyethylenes105 and polyalkenylenes

containing heteroatoms (N106, Si98) in the polymer main chain.









CH2+

+
R
LnM=
R


.(


LnM= Hn


Monomer, dimer,
trimer etc.


Monomer, dimer,
trimer etc.


H
LnM=<
H


H-Hn


Scheme 1-15. Representative ADMET polymerization cycle.

To our best knowledge no ADMET chemistry has been reported for the polymerization of

dienes containing carbohydrates. Shown later in this dissertation, we have for the first time,

synthesized a number of carbohydrate based dienes, which can be subjected to the ADMET

chemistry.

1.8 Scope of the Thesis

Olefin metathesis is a powerful organic synthetic tool, as attested by the large volume of

research found in literature. Grubbs' second generation catalyst 1-4 and its tolerance for

functional groups have made this methodology even more useful. However, there are still areas









of olefin metathesis that require more studies: peptidomimetics and carbohydrates. The work

presented here will examine the use of olefin metathesis in several applications.

1. Development of ROMP reactions on a norbornene scaffold as a means to later crosslink
the polymers using a diyl and release of nitrogen gas.

2. Self-metathesis of carbohydrates to make homodimers could be prepared and used as
precursors of DCLs bearing a variety of functions and protecting groups on the
carbohydrates. The carbohydrate- linking alkene was trans with several versions
examined.

3. ADMET reactions of carbohydrates. The preliminary work is seen in this dissertation for
the first time. Very complex products with new protecting group, strategies, and
numerous asymmetric centers are produced.









CHAPTER 2
RING OPENING METATHESIS POLYMERIZATION OF NORBORNENE DERIVATIVES

2.1 Introduction

Synthetic biopolymers are designed with unique properties and biodegradability. A vast

majority of biodegradable polymers belongs to the polyester family, including polyglycolides,

and polylactides. Biodegradable synthetic polymers offer a number of advantages over the other

materials in respect to developing scaffolds in tissue engineering. Key advantages include ability

to modify the mechanical properties, and the degradation kinetics facilitating their application in

different fields.46 Another major advantage of synthetic polymers include fabrication to the

different shapes with desired pore morphology. Major disadvantages of such polymers include

poor biocompatibility, poor processability, release of acidic degradation product, and loss of

mechanical properties during the early stages of degradation.46

Major research efforts have been directed to the development of medically applicable

biomaterials.169 Photopolymerization of multifunctional monomers allows the synthesis of

highly cross-linked polymer networks, which is useful for applications like contact lenses, dental

restorative materials, and coatings for optical fibers.170-172 Numerous groups are involved in

developing advanced experimental techniques and models in order to understand the

polymerization of such multifunctional monomers to develop biomaterials. 173-177 Of particular

interest discussed here is an exploration into the use of multifunctional monomers for orthopedic

biomaterial applications. One of the traditional treatments of many fractures is the application of

metal plates for fixing the joints. However, it has several drawbacks like surgery for removing

the plates, stress shielding during healing, fatigue, loosening of implants etc. Synthesis of

degradable polymers as biologically useful materials is an area of great interest. The major

advantage of using a degradable polymer is its ability to provide temporary mechanical support









as well as the elimination of the requirement of second surgery. Our research group was

interested in synthesizing new biomaterials with increased mechanical strength.77

Our goal is to apply ring opening metathesis polymerization (ROMP) as a tool to

photocrosslink a polymer. Since this cross-linking is covalent, better mechanical strength is

possible. Earlier work done by previous group member Aarti Joshi had developed new

biomaterials using cinnamate esters and coumarin esters as functional groups and ROMP,

combined with [2+2] cross-linking as the methodology. The advantages include flexibility

caused by the mild polymerization and ability to accommodate different functional groups giving

better mechanical strength obtained by the linear ladder-like cross-linking throughout the

polymer chain length.

Our approach is to incorporate the elimination of nitrogen into the photo-crosslinking

reaction to prepare a porous architecture within the hard polymers that should permit the flow of

water, nutrients, and other biomolecules throughout the new artificial tissue. We aim to use a free

radical nitrogen release reaction to introduce the holes and open architecture. Our research group

had developed the following novel approach (Scheme 2-1, 2-2) to developing a cross-link while

simultaneously releasing nitrogen gas to synthesize the desired cross-linked polymer.





+ N N2 0

hv O


Scheme 2-1. Nitrogen aerosol through elimination.
Scheme 2-1. Nitrogen aerosol through elimination.









0

ROMP
2-1
+ Grubbs' II
H 0 Trace amount

B of BHT
N2 N
S2-4


Scheme 2-2. ROMP to synthesize polymer scaffold.

We extend our research in order to increase the size of pores within the cross-linked

polymers in order to allow passage of tissue fluid and achieving the goal with fewer numbers of

steps, thus minimizing the time and cost factor for the synthesis of such biomaterials. Scheme

2-3 shows several other nitrogen releasing methods that could be investigated. Each example

lead to slightly different intermediate with 2-7, 2-8, 2-9 leading to a carbine, nitrene, and

diradical species, respectively.


(a ) O2/ lig h t (h v ) ) 0O C
(a II -N2 0 )CH
2-6 N2 2-7

Forms carbene

(b) O light (hv) 0
b0 AN3 -N2 0 AN
2-8 2-9
Forms nitrene


(c) _, light (hv) N
N- -N2
N
N 2-11
2-10 Forms diradical

Scheme 2-3. Other nitrogen-releasing products.








We used the method (a) for the synthesis of nitrogen-releasing system. Scheme 2-4 shows

the basic concept of the development of diazoester, which when exposed to light can undergo

nitrogen elimination. Thus a polymer of norbornene diazoesters can undergo photocross-linking

to generate the hard polymer with pores for the flow of the fluid.


OH --------------- O N z ----------* O N 2
OH---- ------ /-----
./--.. 0_

2-13 2-15
2-19

Grubbs' II catalyst
n ------------------

O0

N2
2-20

Scheme 2-4. Synthesis of norbornene diazoester.

2.2 Results and Discussion

We started with commercially available norbornene aldehyde 2-12, which was a mixture

and exo and endo isomers. First step involves the synthesis of norbornenemethanol by treating

the aldehyde in methanol with sodium borohydride and sodium hydroxide at 0C with an overall

yield of 80% (Scheme 2-5). This gives a mixture of exo and endo isomers of

norbomrenemethanol.

0

T OH NaBH4, NaOH / "OH

2-12 0C, 80% 2-13

Scheme 2-5. Synthesis of norbornenemethanol.









The norbornene alcohol was then treated with N- t-Boc glycine in dichloromethane

(CH2C12) in presence of diisopropylcarbodiimide (DIC) and 4-N, N-dimethylaminopyridine

(DMAP) to generate the corresponding ester carbamate of norbornene 2-14 with a yield of 71%.

The next step was the deprotection of the amine group to generate the amino acetate of

norbornene 2-15 (25% yield one time only) (Scheme 2-6). t-BOC Deprotection was carried out

in the presence of acid trifluoroacetic acid (TFA) using different concentration and different

solvents. Table 3-1 shows the t-BOC cleavage using different reaction conditions.

H 0

OH 0 OH ONHO
H
2-13 DIC, DMAP, CH2C12
00 C R.T., 71% 2-14

TFA, CH2C12




2-15

Scheme 2-6. Deprotection of t-Boc protected ester carbamate of norbornene.

However, the deprotection work of 2-14 to generate the corresponding amino acetate of

norbornene did not proceed as expected. The TLC of the reaction showed several spots and

purification of the crude product resulted in a very poor yield (less than 10%). Presence of acid

like TFA might be responsible for the poor recovery of the deprotected product 2-15. Also the

deprotected amino acetate is highly reactive and can undergo a possible reaction with each other

to generate the dimer. This factor might also be responsible for having undesired results during

the acid catalyzed deprotection of 2-14.









Table 2-1. t-Boc Cleavage of the compound 2-14.
S1. No. Starting Material (SM) SM: TFA Solvent % Yield
1 1:8 -Several spots
2 1:4 -Several spots
3 2-14 1:3 CH2C12 (0.5 equiv) 25%
4 1:2.5 CH2C12 (0.5 equiv) 10%
5 1:2.0 CHC13 (1 equiv) 10%
6 1:1.4 CH3CN (0.5 equiv) 15%

Our aim was to synthesize the amino acetate of norbornene, which could be converted to

the corresponding diazoester. Considering the fact that acid deprotection of a t-Boc group lead to

either several products or a poor yield, we changed the path to generate 2-16 (yield 75%) by

treating the norbornenemethanol with Fmoc glycine in anhydrous tetrahydrofuran (THF) using

DIC, and DMAP as the catalyst. Fmoc functional group is stable under acidic condition, but

undergoes deprotection under basic condition. The Fmoc protected ester carbamate can be

subjected to the base catalyzed deprotection to generate the desired amino acetate 2-15 (Scheme

2-8). Table 2-2 shows a series of reactions involved in the deprotection of the Fmoc group to get

2-15. In one method, 2-16 was added to the solution of piperidine in DMF (20%).179, 180 In

another method 2-16 was treated with 0.10 M TBAF in DMF (10 equiv). Scheme 2-7 shows the

possible product of the deprotection of Fmoc protecting group in presence of TBAF in DMF

along with the side product dibenzofulvene.181



0 H 0.1M TBAF 0
/ OK.N NH_
0 DMF +
2-16 R.T. 2-15

Scheme 2-7. Deprotection of Fmoc group.

However, the deprotection of Fmoc did not provide the necessary results. The possible

reason for the failure of piperidine catalyzed Fmoc deprotection is that the piperidine prefers to









attack at the ester carbonyl compared to the attack to the amide carbonyl as the former (ester

carbonyl) is more reactive than the later. The 1H NMR of the deprotected product showed mostly

the norbornenemethanol and not the desired compound 2-15.


H O

OH

DIC, DMAP, CH2CI2
00C R.T., 75%


O H


2-16

S Piperidine


O

O2-1 NH2

2-15


Scheme 2-8. Synthesis of norbornene amino acetate using Fmoc protecting group.

Table 2-2. Deprotection of Fmoc group to get the compound 2-15.
S1. No. Starting Material Reagent Quenching Product
1 0.1 TBAF in DMF CH2C12 Major yield was
2 2.16 0.1 TBAF in DMF H20 Norobomenemethanol
3 50% piperidine in DMF H20
4 _20% piperidine in DMF H20

The base catalyzed deprotection of Fmoc ester carbamate of norbornene did not work

either. So we changed the route of making the diazoester from the amino acetate of norbornene.

We use a new intermediate ketoester for this purpose. In this method, we synthesized the

ketoester 2-17 from norbornenemethanol (Scheme 2-9) with an overall yield of 75%.


1_ OH

2-13









0 0
H3C 0AJcOH 0 0
OH O CH3 O CH 3
DMAP, Benzene CH3
2-13 Reflux, 75% 2-17

Scheme 2-9. Synthesis of norbornene ketoester 2-17.

Ketoester 2-17 was then subjected to diazotization by treating it with p-TsN3 to make the

corresponding diazoester 2-18 with an overall yield of 70% (Scheme 2-10).182, 183 This

diazoacetate product is potentially explosive material and proper care was taken in making the

product as well as preserving it for future use.


HN=NN-S- -CH3
000
0 CH3O 2-18 O GN

2-17 anhyd. CH3CN, 70%
2-19

Scheme 2-10. Synthesis of diazoester 2-19.

The next step was the synthesis of the polymer containing the diazo functional group using

ROMP methodology (Scheme 2-11). However, the reaction was unsuccessful employed under

several reaction conditions due to the formation of insoluble polymer of the diazoester of

norbornene.


Grubbs' II Catalyst, CH2C12
0 n
1 N? N / n

0

2-19
N2
2-20

Scheme 2-11. Attempt to make polymer by ROMP.









The reason behind the formation of the insoluble polymer is the possible cross-linking

reaction was the diazoketone likely reacted faster than the ROMP with the catalyst. Also there

could be a possibility that the release of nitrogen can cause the formation of new metal-

alkyledene with the ruthenium catalyst causing a complicated ring opening metathesis reaction.

Similar kind of cyclization reaction was observed by Padwa for a series of a-diazo ketones in

presence of rhodium catalyst. We checked whether the norbornene with ketoester pendent

functional group (compound 2-17) is capable of undergoing polymerization or not (Scheme

2-12). The reaction took place successfully giving the corresponding ROMP product. In our next

step we tried to make copolymer using different ratio of norbornene and norbornene diazoester

without any success (Scheme 2-13). We have also successfully polymerized the keto hexanoate

of norbornene using Grubbs' first generation catalyst (Scheme 2-14).



n
0 0 Grubbs' I, CH2C12



2-17 O
2-26

Scheme 2-12. ROMP of the ketoester of norbomene.


nO .N=N Grubbs' II Catalyst, CH2C12 m

+ )
2-19 O

N2
2-25 2-23

Scheme 2-13. Unsuccessful attempt to make co-polymer using ROMP.











/b OH


2-13


O O
H3C -21,-OH
2-21

DIC, DMAP, CH2C12
0C R.T., 73%


0 0
2O 2 CH3

I 2-22


Grubbs' II Catalyst, CH2C12


2-24


Scheme 2-14. ROMP of the monomer 2-22.

2.3 Conclusion

We successfully synthesized the monomer 2-19 for the synthesis of the polymer 2-20.

However, polymerization of 2-19 was not successful as the resultant polymerization using

ROMP generated an insoluble cross-linked polymer. We have synthesized the polymer of the

norbornene ketoesters, both the compound 2-17 and the compound 2-24. We have now observed

the diazoketone group is not compatible with the Grubbs' catalyst and metathesis. Compound

2-19 will need to be modified. So we proposed the polymerization of the compound 2-17

followed by the incorporation if the diazo functional group into the polymer (Scheme 2-15 and

2-16). This approach will be studied later.










00

2- CH3
2-17


Grubbs' catalyst


ROMP


2-25


Scheme 2-15. Synthesis of co-polymer 2-27.


00 O
NNN-S-- -CH3

2-18


anhyd CH3CN


O




2-27


Scheme 2-16. Diazotization of the co-polymer 2-27.


0"
O



H3C

2-27


O


N2

2-28









CHAPTER 3
METATHESIS OF CARBOHYDRATES

3.1 Introduction

In the current era of proteomics, genomics, and glycomics, there is an exponential increase

in potential therapeutic targets, which in turn increases the demand to access novel and diverse

chemical libraries.130 Molecular diversity131'132 is based on the "similar property principle"133

which suggests that structurally similar molecules should have similar physiological and

biological properties. One way to interpret the molecular diversity is to split it into the functional

and structural parts, and then reduce the structural part into the rigid portion of the scaffold. For

example, some libraries can be described in terms of (a) functional diversity, (b) structural

diversity, (c) type of side chains and/or substituents, or (d) relative orientation of the side

chains.134, 135 Such orientations are defined by the carbon-carbon (Ca-Cp) bonds linking the side

chain to the backbone. A variety of scaffolds have been examined. These scaffolds are basically

controlled by the orientation of the functional group and have lower impact on the biological

properties of the compound.130

Monosaccharide-based scaffolds that contain several chiral centers were targeted in this

work. In principle we can incorporate various alkoxy substituents at each position and not alter

the chirality at that center. Sugar scaffolds provide an unparalleled opportunity to generate

libraries of high functional and structural diversity. For example, three different pharmacophore

groups in glucose generates up to 60 unique products of similar molecular properties but with

different orientations of the pharmacophore groups (Scheme 3-1).130









Substitution patterns


-,< Some ofthe 60 unique presentations
^ ,B for one scaffold (5x4x3)
1,2,4 32,4 2,1,


Scaffold
c Some of the 8 unique presentations
for one substituent pattern (2x2x2)
0 0 0

B BAltrose
Glucose Galactose Altrose


Scheme 3-1. Illustration of the structural diversity in pyranose scaffolds.130

A great deal of synthesis in carbohydrate chemistry is increasingly directed towards the

synthesis of artificial glycoconjugates containing the sugars and/or naturally occurring

compounds instead of the natural compounds itself117' 118 The artificial carbohydrate compounds

can be synthesized to exhibit parallel or even improved biological interactions. Many biological

interactions require two or more carbohydrate moieties.118 Many combinatorial approaches

involving carbohydrates have been investigated. For example the structural diversity of

carbohydrates has been coupled with the Ugi four component condensation reactions in both

solid and solution phase.130' 160 There are no DCL libraries that use solid phase synthesis. In spite

of this drawback solid phase organic synthesis is still an attractive and powerful tool for the

development of compound libraries. Little is known about static libraries using sugars. Sofia et

al.136 demonstrated this by generating a large library of disaccharide-based moenomycin

mimetics and identified several compounds which displayed high activity against Gram-positive

bacteria. Orthogonally protected scaffolds of D-glucose137 and D-galactose138 have been used by

Kunz's group to exploit the concept of regioselective introduction of a variety of substituents









using solid support chemistry. However, none are used to make dynamic combinatorial libraries

and none use metathesis.

It is therefore clear that sugars possess a great deal of potential as medical compounds.

However, the application of combinatorial chemistry to the carbohydrate class of biomolecules

has arrived "late to the party" with only recent consideration of these compounds as potential

therapeutic agents.121-123 Carbohydrates are biological information molecules with the possibility

of dense functionalization and stereochemistry, thereby potentially could lead to excellent

libraries.124 Only a few example of DCLs containing carbohydrates are available and none of

them involves a metathesis method.57' 117-118, 125-126, 162 A few classes of biomolecules have been

used with DCLs, including lectins, enzymes, polynucleotides, etc., and libraries have been

constructed using a variety of elements. Most of these are associated with non-natural cores and

connectors. Efforts are now being made to develop strategies that can join the carbohydrates

through this synthetic linkages.118, 127 Several chemical reactions including the aldol

condensation,128 and free-radical couplings129, 162 are used to synthesize these connectors. Such

linkages are more resistant towards acids and enzymes.

The concept of employing homodimeric compounds139 to increase the ligand-binding

affinity140 and ultimately shed light on enzymatic and cellular processes has generated

considerable interest in the drug discovery arena.141, 142 Such homodimeric compounds prepared

by metathesis are discussed below. The use of naturally occurring compounds like peptides,143

steroids,144 and carbohydrates145 as scaffolds in combinatorial synthesis has received

considerable attention. In spite of their good qualities, carbohydrate molecules have an

unfortunate drawback of being water soluble.









Olefin metathesis has emerged as a versatile technology for the synthesis of combinatorial

libraries in respect to scaffold creation and embellishment.146 The advantages of olefin

metathesis over the other transition-metal-catalyzed reactions can be seen in catalyst efficiency,

accessibility and functional group compatibility.116 Cross-metathesis also opens the door to

DCLs. In spite of having advantages like unique properties, high reactivity, stability to air and

remarkable functional group tolerance, ruthenium carbene catalysts (Grubbs' first and second

generation catalyst) have scarcely been used in carbohydrate chemistry.148 The example of

carbohydrate homodimerization was reported by Descotes et.al. 149 in his sugar syntheses using a

tungsten aryloxo complex such as 3-1 (Figure 3-1).




Of~
Cl OAoEt2


3-1

Figure 3-1. Tungsten aryloxo complex used by Descotes.150

However, such tungsten-catalyzed alkenyl glycoside homodimerizations were unsuccessful

with O-allyl glycosides as well as benzyl-protected sugar derivatives. Roy and coworkers first

prepared a range of "homodimers" starting from peracetylated or perbenzylated 0- and C-allyl as

well as O-pentenyl galactopyranosides using ruthenium benzylidene complex 1-3 (Scheme 3-

2).150 Table 3-1 shows a series of 0- and C-allyl and O-pentenyl (entry 3-6) galactopyranosides

using ruthenium catalyst 1-3.150 Such carbohydrate dimers represent appealing tools to quickly

titrate distances between carbohydrate binding sites in polyvalent recognition. Moreover, they

can represent potent noncovalent cross-linking reagents.163










OA OAc

AcO
AcO O-"",

3-2


10 mol% 1-3

SH2C=CH2 CH2C2, reflux

OAc
OAc OAc AcO
AcO O AcO OAc
AcO AcO
2'
3-3

Scheme 3-2. Homodimerization of O-acetyl-a-D-galactopyranoside 3-2.150

The examples above demonstrate the importance of ruthenium catalyzed cross-metathesis

reaction in carbohydrate chemistry. As part of the continuing interest in the application of cross-

metathesis in carbohydrates we envisioned ring closing metathesis (RCM) as a means to generate

the homodimer 3-19 (Scheme 3-3). We envisioned the self-metathesis products possessing

several anchoring groups where pharmacophoric groups can be attached. Also some

carbohydrates can have two hydroxyl groups (primary, and secondary hydroxyl groups), which

can be protected in different ways. Such carbohydrates can also be subjected to different olefin

metathesis reactions.










Table 3-1. Olefin self-metathesis of alkenyl 0- and C-glycopyranosides.150
10 mol%, 1-3

CH2C12, reflux, 6h R
3-2, 3-4, 3-3, 3-5,
3-6 3-9, 3-12 3-7 3-11, 3-13
Entry Substrate R Product (E/Z) Yield (%)
1 3-2 OAcOAc 3-3(5/1) 92

AcO
cO 0
2 3-4 OAc OA 3-5 (4/1) 95

AcOOlz
OAc
3 3-6 OAc OAc 3-10 (5/1) 85

AcO AO\

4 3-7 OAc 3-11(4/1) 89
OAc
4 3-7 Ac 3-11 (4/1) 89

O c OAc
OAc OAc
5 3-8 OAcOc 3-12 (2/1) 82

AcO
AcO
6 3-9 OAc OAc 3-13(1/1) 75

AcO -f'
OAc
7 3-12 OBnOBn 3-15 (3/1) 76

BnO- V .
OBn











H3c O
H33-O O O

HO 0
3-16


0
HO
3-18


DIC, DMAP, CH2C12
0C -R.T., 71%


Grubbs' I, CH2C12
Reflux, 18h, 83%


H3C,


3-19


CH3


Scheme 3-3. General scheme for the self-metathesis of O-pentenoate of a furanose.









0
OH o O OH 0
OH HOOH 0
3-18 1 +
0OxO (1-equiv.)0 0 0

3-20 3-21 3-22


0
HOC', (2 equiv)
3-18
0
0 0
T 0



3-23

Scheme 3-4. Protecting group and hydroxyl reactivity strategy.
3.2 Results and Discussion
3.2.1 Metathesis of the monoester of carbohydrates
In order to study the viability of olefin metathesis for DCC, we first required synthesis of

the various monomers and ester derivatives. It was then necessary to react the monomers with

Grubbs' second generation catalyst 1-4 to study the selectivity and reactivity of olefin

metathesis. A series of 5- and 6- member carbohydrate derivatives (furanosides and pyranosides)

were synthesized by coupling acetone, benzyl, and TBDMS protected carbohydrates with allyl

chloroformate and 4-pentenoic acid using DIC, DMAP, or/and HOBT. The starting material was

typically consumed within the next 3 h as indicated by TLC. Purification by column









chromatography gave the 4-pentenoic esters of the 5- and 6- member carbohydrates in moderate

to high yield (Table 3-2) with the exception of 3-41 (26% only).

Table 3-2. Yields, and optical properties of carbohydrate derivatives.
Entry Carbohydrates Protecting group Product Yield (%) [a]2 D
1 3-26 71 +59.820
(C=1.57, MeOH)
D-Mannose Acetone protected 3-29 76 + 49.55
(C = 1.19, MeOH)
2 D-Glucose Acetone protected 3-32 71 -27.50 o
(C= 1.19, MeOH)
3 D-Galactose Acetone protected 3-36 87 -48.22 o
(C = 2.71, MeOH)
Acetone protected 3-41 26 -60.34 0 (C = 1.46,
MeOH)
4 D-Ribose TMS protected 3-45 89 -51.16
(C = 2.05, MeOH)
Benzyl protected 3-46 81 -71.55 0
(C = 1.57, CH2C12)
5 D-Isomannide Benzyl protected 3-52 84 +168.51
___(C = 1.66, CH2Cl2)
6 D-Isosorbide Benzyl protected 3-56 71 +74.19
(C = 1.87, CH2C12)

The resultant 4-pentenoate monomers of the protected carbohydrates were then subjected

to olefin metathesis in presence of Grubbs' second generation catalyst in anhydrous CH2C12 or

CHC13 under reflux condition. Table 3-3 shows the olefin metathesis of the monomers of

different carbohydrates.

We started with commercially available D-mannose (3-24). The first step was the

protection of four out of five hydroxyl groups available in the furanose form of the sugar. The

protection of the D-mannofuranose (3-24) (mannose) was performed in presence of acetone and

2, 2-dimethoxy propane (2, 2 DMP). Catalytic amount ofp-toluenesulfonic acid (p-TsOH) was

added to facilitate the reaction, resulting in the formation of 71% of the diacetone D-mannose (3-

25). This protected mannose was then treated with allylchloroformate in presence of DMAP to

obtain the corresponding carbonate 3-26 with an overall yield of 67%. Scheme 3-5 shows the









synthesis of 3-26, the carbonate of the protected D-mannose. The carbonate, thus formed, was

subjected to metathesis reaction using Grubbs' first and second generation catalyst.

Table 3-3. Yields, and optical properties of the metathesis products.
Entry Carbohydrates Protecting Product Yield (%) mp (C) [a]2 D
group
3-27 61 Oil + 15.6
1 Acetone ____(C = 1.04, CH2C2)
D-Mannose protected 3-30 72 88.5- + 28.88
90.0 (C = 1.04, CH212)
2 D-Glucose Acetone 3-33 83 Oil 0
protected___ (C = 1.28, CH2C2)
3 D-Galactose Acetone 3-37 74 86.0-
protected 87.0
Acetone 3-44 81 Oil -1.35
protected___ (C = 1.11, CH2C2)
4 D-Ribose TBDMS 3-48 0
protected_
Benzyl 3-49 81 Oil -6.60
protected ____(C = 1.51, CH2C2)
5 D-Isomannide Benzyl 3-53 82 Oil +0.13
protected___ (C = 1.68, CH212)
6 D-Isosorbide Benzyl 3-57 80 Oil +0.23 o
protected ____ (C = 1.87, CH212)


H3c0
HO. O)HHO H3C OO0.-OH
HO OHHO 2,2 DMP, Acetone (1:2)H3C XOH
O- p-TsOH R.T. 0 O
HO OH 71%H 1
3-24 H3C CH3
3-25

Cl 0
DMAP, CH2C12
0C R.T., 76%

H3C> 0- .OO


3-26


Scheme 3-5. Synthesis of the carbonate of diacetone (D)-mannose.









The metathesis of the carbonate of (D)-mannose was carried out in presence of Grubbs'

first and second generation catalysts. Prior to the addition of Grubbs' catalyst (both first and

second generation), butylated hydroxytoluene (BHT) was added to prevent any possible atom

transfer radical polymerization (ATRP). All reactions were refluxed either in anhydrous

chloroform or in anhydrous methylene chloride overnight. The reaction was quenched with EVE.

EVE reacts with the catalyst (both first and second generation) in an irreversible manner, making

it inactive to other kind of olefins.152 Metathesis of compound 3-26 resulted in the formation of

metathesis product 3-27 with an overall yield of 61%. Use of methylene chloride as the solvent

helps to maintain the reactivity of Grubbs' catalyst during the reflux. The reaction was expected

to result in the formation of both E and Z isomer, with the E isomer having a well-known

preference over the Z due to steric hindrance. Once the metathesis product was formed, it was

subjected to hydrogenation via Pd on activated carbon (10% Pd) under H2 atmosphere to give

compound 3-28 in good yield (90%). Scheme 3-6 shows the formation of the saturated

metathesis product 3-28.

To increase the yield of the metathesis product, we had increased the chain by one

methylene and removed the carbonate. Instead of allyl chloroformate, the diacetone (D)-mannose

3-25 was treated with 4-pentenoic acid in the presence of DIC and DMAP to give the ester 3-29

with a yield of 76%. The ester of mannose was then subjected to metathesis with Grubbs' first

generation catalyst (10 mol%) in anhydrous dichloromethane (0.50 M) resulting in the formation

of the self-metathesis product 3-30 with a yield of 72%. A series of self metathesis of (D)

mannose carbonate were done and everytime the yield was around 74% (varying from 72% -

76%).










H3C 0
H3cUO0
HgCoOYO
0 0
H3C CH3
3-26

Grubbs' II, CHC13
Reflux,18h, 61%


H3C O0
H3C 0-


3-27


H2 (g), Pd Catalyst, 90%


-O
-JCH3
CH3


3-28


Scheme 3-6. Metathesis followed by hydrogenation to obtain saturated homodimer.

Thus, with the use of new terminal alkene with longer chain length, there is an

improvement in the overall metathesis yield. Scheme 3-7 shows the metathesis reaction

involving the longer terminal alkene chain. Only a single trans isomer was produced.









H13C O H3C O
H3 XO 0 ,,OH C O

O O DIC, DMAP, CH2C2 O O
H3C CH3 0C R.T., 76% H3C CH3
3-25 3-29
Grubbs' I, CH2Cl2
Reflux, 18h, 74%



C3 0 CCH3



O;O

H3C CH3

Scheme 3-7. Metathesis of the ester of (D)-mannose.

The next sugar used for the metathesis was glucose. The diacetone D-glucofuranose (3-31)

is commercially available. It was subjected to esterification with 4-pentenoic acid in presence of

DIC and catalytic amount of DMAP. The yield was 70%. The metathesis of ester 3-32 under

identical conditions to those used for the mannose derivative 3-29 resulted in the formation of

compound 3-33, with a yield of 83%. Scheme 3-8 shows the overall reactions involved in the

metathesis of glucose.

Both the sugars, (D)-mannose and (D)-glucose are chiral in nature and the esterification

may lead to possible isomerization of the product. In order to find out whether actual

racemization took place during the esterification or not, we did the esterification of both

(D)-mannose and (D)-glucose in presence and absence of hydroxybenzotriazole (HOBT). The C1

of the ester compound is particularly labile, especially in the presence of acids or HOBT. Since

no change in the NMR as well as the optical rotational properties was observed, we were









convinced that C1 epimerization had not occurred. Table 3-4 shows the optical properties of the

ester of sugars in presence and absence of HOBT.

Table 3-4. Comparison of the optical property of the esters of (D)-mannose and
(D)-glucose.
Type of ester [a]25D of the ester without [a]25D of the ester with
HOBT HOBT
H3C
H +49.55 +49.25

0 V 0
0 0
H3C CH3

H3C O 0 -27.500 -27.030

0\' 0CH3
O C 3


0
HO
DIC, DMAP, CH2C12
0C -R.T., 71%


H3C
H3C


H3C,
H3C'


3-32

Grubbs' I, CH2C12
Reflux, 18h, 83%


3-33


CH3


Scheme 3-8. Metathesis of the ester of diacetone (D)-glucose.


HO'"


3-31









The NMR of the metathesis of D-mannose indicates that the product is mostly trans

isomer. However, in the case of D-glucose, the metathesis product contains both cis and trans

isomers. Considering the steric factor, the trans isomer is expected to predominate over the cis

isomer. However, a combination of 1H NMR and 2-D NMR of the product give the ratio of cis

and trans isomers.

The third sugar we used was D-galactose. Like mannose, the commercially available

D-galactose was first protected by treating it with acetone in the presence of a catalytic amount

of anhydrous copper sulfate to give compound 3-34 with an overall yield of 43%.153 However,

the protected D-galactopyaranose is also available commercially. This protected galactose was

then subjected to esterification with 4-pentenoic acid (3-18) to give the ester with a yield of 87%.

It was subjected to metathesis with 10 mol% of Grubbs' first generation catalyst, using

anhydrous methylene chloride (0.50 M), resulting in the formation of 74% of the metathesis

product 3-37. In fact, we noticed some double bond isomerization with the galactose system

when the ester of the D-galactopyranose was subjected to the metathesis with Grubbs' second

generation catalyst using chloroform during reflux. We used Grubbs' second generation catalyst

and the chloroform system for the metathesis of the ester of D-mannose and the D-glucose also

without any evidence of double bond isomerization. Again, a single geometric isomer of 3-37,

was observed and it was trans. As a result we have shifted to the Grubbs' first generation catalyst

and dichloromethane system for all metathesis reaction conditions applied in later part of the

project. Scheme 3-9 shows the formation of the metathesis product of (D)-galactose 3-37.










OH

HO O
OH .'OH

OH
3-34


Acetone

CuSO4. R.T. 43%.


HO
S ."0 CH3


H3C-O
CH3 3-35

4-Pentenoic acid
DIC, DMAP, CH2C12
0C R.T., 87%

//


Grubbs' I, CH2C12 )

Reflux, 18h, 74% 0 O "0C
-0 "O CH3
H3C -O
CH3
3-36


Scheme 3-9. Metathesis of the protected (D)-galactose.

The fourth sugar we used was D-ribose. Unlike the first three sugars, D-mannose, D-

glucose, and D-galactose, protection of the D-ribose resulted in the formation of compound

3-39, which has two hydroxyl groups. One of the hydroxyl groups is 1 (primary), while the

other hydroxyl group is 2 (secondary). From the steric hindrance point of view, a primary

alcohol is expected to be more reactive than a secondary one. However, when the monoacetone

D-ribose was subjected to monoesterification with 4-pentenoic acid, using the same conditions,

the esterification took place not only at the desired 1 alcohol to give 3-41, but also at the other

available position 3-42, 3-43, resulting into an overall poor yield (26%) of the desired sugar

derivative 3-41. We changed the concentration of the reaction medium using 0.50 M, 1.0 M, and

0.10 M of dichloromethane without any significant improvement in the percentage yield of the

desired product 3-41.









Acetone, HO j OH HO
O/y. OH Conc. H2SO4 H(
OH/ R.T., 67% o
HO OH H3C CH3 DIC, DMAP, CH2C12,
3-38 3-39 0C R.T.






OO O HOF roO
o 0o )o

H3C CH3
H3 CH3 H3C CH 3-41
3-43 3-42 26%
Major product (40%)


Scheme 3-10. Monoesterification of the monoacetone (D)-ribose.

Metathesis of compound 3-41 using standard reaction conditions resulted in the

formation of compound 3-47 with an overall yield of 81% (Scheme 3-11).

H3C CH3
SO O
O O Grubbs' catalyst I, 10 mol% HO 0 0 OH
X Gx0 CH2Cl2, Reflux, 81%
H3C CH3 H3C CH3
3-41 3-47

Scheme 3-11. Metathesis of compound 3-41.

Even the less reactive alcohol site (20 hydroxyl site) of the monoacetone D-ribose took

part in esterification (compound 3-42), yet the overall yield was low (no significant amount was

recovered after column chromatography each time). So, our next attempt was to protect the most

reactive alcohol site, so that the esterification of the corresponding ribose would lead to the

incorporation of the ester group exclusively in the less reactive site. We used both tert-butyl









dimethylsilyl chloride, (TBDMSC1)154 and benzyl chloride for the protection of the primary

hydroxyl site of monoacetone (D)-ribose. Scheme 3-12 shows the synthesis of TBDMS protected

monoacetone (D)-ribose 3-40 (52%), and benzyl protected monoacetone (D)-ribose 3-44 (47%).

0 OH
NaH, CH2C12, TBAI O T ,
TBSC1, DMF
BnC1, R.T., 47% O Imidazole, R.T.
H3C CH3 52%
3-39


H3C CH3
PhOO i OH H C-- H30 OH
= HaCH3c

oo odo
H3C CH3 H3C CH3
3-44 3-40

Scheme 3-12. Synthesis of TBDMS and benzyl protected monoacetone (D)-ribose.

Compounds 3-40 and 3-44 were then subjected to the esterification reaction with

4-pentenoic acid, using DIC and catalytic amount of DMAP. Esterification of TBDMS protected

monoacetone (D)-ribose resulted in the formation of compound 3-45 with an 89% yield.

Esterification of the benzyl protected monoacetone (D)-ribose resulted in the formation of

compound 3-46 with an overall yield of 81%. Scheme 3-13 shows the esters of the two di-

protected (D)-ribose 3-45 benzyll protected) and 3-46 (TBDMS protected).












H3C 1CH 3 H3C i ,H
H C C ,i.OH HOH HCC O OO
H3C H3C 3

0 0 DIC, DMAP, CH2CI2
SH3C CH3
H3C CH3 0C R.T., 89%
3-40


Ph Ph

O OH 4-Pentenoic Acid 'o \ OO

0XO DIC, DMAP, CH2C 2 X0

H3C CH3 0C R.T., 81% H3C CH3

3-44 3-46

Scheme 3-13. Synthesis of esters of TBDMS and benzyl protected monoacetone (D)-ribose.

When the ester of TBDMS protected monoacetone (D)-ribose 3-45, was subjected to the

metathesis reaction, no significant result was obtained. Our attempt of the metathesis of

compound 3-45 did not yield the desired self-metathesis product. The ester of benzyl

monoacetone (D)-ribose, 3-46, was then subjected to the metathesis reaction with Grubbs' first

generation catalyst using methylene chloride as the reflux solvent with a concentration of

0.50 M. Scheme 3-15 shows the metathesis of the compound 3-46, which resulted in the

formation of the self-metathesis compound 3-49 with an overall yield of 81%.

The last two sugars we used are commercially available (D)-isomannide and

(D)-isosorbide, which are diastereoisomers. In the case of (D)-isomannide (3-50), both the

hydroxyl groups are cis, whereas for (D)-isosorbide (3-54), they are trans with respect to each

other.









H3C CH3

H3CHCd 0 /

O Grubbs' I,
H3C CH3
3-45 CH2Cl2, Reflux, 18h

H3C CH3 )O
H3CH3d C 0 o i o -uCH3
0.6 O 0 O CH3CH3

H3C CH3 3-48

Self-metathesis product

Scheme 3-14. Metathesis of the ester of TBDMS protected monoacetone (D)-ribose.

frPh



PhO _J OO Grubbs'Cat I I0 0 CH3
O6- CH2C12, Reflux, 81% H
H33C CH3
H3C CH3
3-46 3-49

Scheme 3-15. Metathesis of the ester of benzyl protected monoacetone (D)-ribose.

Scheme 3-16 shows the metathesis of the ester of benzyl protected (D)-isomannide, where

the first step involved the synthesis mono benzylated (D)-isomannide 3-51 by following the

literature procedure.124 This was then subjected to esterification to get 3-52 (84%) followed by

metathesis reaction using Grubbs' first generation catalyst to get the self-metathesis product 3-53

(82%).









HOH HO H
HO H KOH, H20, Reflux, 30 min. O

O_ PhCH2C1, Reflux, 3 hr. 0O
H OH 40Ph
3-50 3-51
4-Pentenoic Acid
DIC, DMAP, CH2CI2
00C R.T., 84%

O O H O

H 0 H
SH- O O Grubbs' I, CH2C12, 0
S/H -o Ph
O0-^n Reflux, 18h, 82%
I O~ HO gph
Ph
-Ph 3-52
3-53

Scheme 3-16. Synthesis of metathesis product of benzylated (D)-isomannide.

However, in case of (D)-isosorbide the two hydroxyl groups are trans to each other. Due

to the cis-fused bicyclic system, one hydroxyl group is in the exo position while the other one is

in the endo position. From a steric point of view, the hydroxyl group in the exo position is

expected to be more reactive than the hydroxyl group in the endo position. Benzylation of the

(D)-isosorbide with KOH, water, and benzyl bromide resulted in the formation of mostly exo

protected (D)-isosorbide 3-55, following the literature procedure.155 It was then subjected to the

esterification reaction to give the product 3-56, followed by the self-metathesis reaction in

presence of Grubbs' first generation catalyst to give the metathesis product 3-57 with an yield of

80%. Scheme 3-17 shows the metathesis of the exo-benzylated (D)-isosorbide.









HOH
HO H 0
0 KOH, H20, Reflux, 30 min.

1O HO
H OH PhCH2C1, Reflux, 3 hr. H Ph
3-54 40% 3-55
4-Pentenoic Acid
DIC, DMAP, CH2C12,
00C RT., 71%

O
0 0 H
OoOH

SGrubbs' I, CH22,
H O Ph O-
0-- Reflux, 18h, 80% 0H 0 ph
H 6 3-57
H 3-56

Ph

Scheme 3-17. Metathesis of the benzylated (D)-isosorbide in the exo position.

Table 3-3 shows the all the homodimers made from esters of different o-oligosaccharides

3.2.2 Metathesis of Tri-esters of Phloroglucinol

We diversify the concept of making library of metathesis products of carbohydrates. In

this approach we tried the cross metathesis reaction between the ester of phloroglucinol with the

ester of different carbohydrates to generate a second library (Scheme 3-18).

The first step involves the synthesis of the tri-ester of phloroglucinol 3-62 using the usual

esterification reaction conditions between phloroglucinol 3-61 and 4-pentenoic acid 3-18

(Scheme 3-19). The second step involves the cross-metathesis reaction between the ester of

diacetone (D)-glucose and the ester of phloroglucinol using Grubbs' first-generation catalyst

(Scheme 3-20). The reaction gives a whole bunch of possible cross-metathesis as well as self-

metathesis products as observed from the TLC of the crude product. However, the major product









isolated from the crude mixture was the compound 3-63 with a yield of 58%. Using a preparative

column chromatography, it is possible to separate each fraction as well as identify them by NMR









| 0

3-58


Grubbs' I Catalyst
CH2C12, Reflux
0 0
o o
0 0 0 0




CM with three different sugars CM with one sugar
3-59 3-60
and several other possible cross-metathesis products

Scheme 3-18. Schematic representation of the cross-metathesis between carbohydrate and
phloroglucinol esters.

O
0
OH
HOJ )^- 3-18 0

HO OH DIC, DMAP, CH2C12 O O0
3-61 0C-R.T., 70% 3
Scheme 3-19. Tri-ester ofphloroglucinol 3-62.
Scheme 3-19. Tri-ester of phloroglucinol 3-62.









0

3C-32
OO H3C00O CH3
0 =0 X 3



3-623-32
Grubbs' I Catalyst
SO" 0







0 0
O O



O0 0
O^^^s^^


o0 0
3-63 O



along with the CM products of glucose itself

Scheme 3-20. Cross-metathesis of phloroglucinol ester and glucose ester.



3.4 Conclusion

Our main objective in this project was to examine the olefin self-metathesis reactivity and

selectivity of the esters of pentose and fructose. The extension of carbon skeletons by the

construction of carbon-carbon bonds represents one of the most important areas in synthetic

organic chemistry. We applied this self-metathesis technique on different carbohydrates in their

5-membered as well as 6-membered ring formations. We synthesized the olefin metathesis

products of functionalized carbohydrate derivatives in good yields with the Grubbs' first









generation catalyst used mostly. It is considered that having the olefin moiety further from the

ester functional groups increased the yields of the homodimer products. The stereochemistry of

the homodimers was found to be predominantly trans. The flexibility of our route is illustrated

by the different types of O-glycoside that have been prepared from the commercially available

monosaccharides (Table 3-2). Our metathesis-based approach to O-saccharide formation allows

for structural diversity in the olefin.









CHAPTER 4
ACYCLIC DIENE METATHESIS REACTIONS OF CARBOHYDRATES

4.1 Introduction

Hydrogels have increased popularity as scaffolds for tissue engineering due to their high

water content, good biocompatibility, and consistency similar to soft tissue. Natural and

synthetic hydrogels retain water in a three-dimensional network of polymer chains.83 Examples

of such degradable polymers include series of polyesters such as poly(lactic acid) (PLA),

poly(glycolic acid) (PGA), and their copolymers. But these have their own problems like early

loss of mechanical properties, generation of acidic products during degradation creating harsh

environments that are not compatible with cells and tissues.

Carbohydrates are mostly present in nature in the form of glycoconjugates glycoproteinss

and glycolipids).60 Their role is unambiguously important but remains often vague. If the

understanding of the biological role of carbohydrates is to approach that of nucleic acids and

proteins, access to well-defined pure oligosaccharide structures will have to be improved. While

the sequencing of samples of oligonucleotides and proteins is routine and has been automated,

carbohydrate sequencing has been particularly challenging.61 Glycopolymers, synthetic sugar-

containing macromolecules, are attracting ever-increasing interest from the chemistry

community due to their role as biomimetic analogues and their potential for commercial

applications. Recent developments in polymerization techniques have enabled the synthesis of

glycopolymers featuring a wide range of controlled architectures and functionalities.62

Condensation polymers and the corresponding monomers and macrocycles can generally

be interconverted by a series of closely related reactions, where the nature of the major reaction

products) depends greatly on the concentration of reactants.63-65 Acyclic Diene Metathesis

chemistry is used to produce polymers of unique and fixed architecture utilizing diene









monomers. ADMET is a condensation polymerization reaction that connects molecules through

terminal alkenes with the release of small molecules ethylene. The release of this gaseous

molecule is the driving force for this reaction and allows high molecular weight to be reached

with a variety of monomers. Essentially this is an example of self-metathesis with a diene.

The use of monosaccharides in hydrogels for soft tissues has not been investigated. This is

somewhat unusual because sugars are nontoxic food to most animal forms and highly

hydroxylated. Absorption with time as new tissue grows into the biomaterial will not be

problematic in this case. Traditionally, carbohydrate substituted polymers have been synthesized

by polymerization of acrylamide derivatives. The naturally occurring carbohydrates are chiral

molecules. The racemizations of chiral centers are of great concern when polymerization method

requires the use of basic or highly thermal conditions. ADMET is a thermally and chemically

neutral polymerization method. These conditions make ADMET an ideal candidate for studying

polymers that are sensitive to harsher polymerization methods. These polymers (4-14, 4-15, 4-

16, and 4-17) made by ADMET chemistry therefore represent an opportunity to develop

hydrogel from them.

In connection with our interest in the potential applications of such reactions,64 66-69 in

particular the preparation of combinatorial libraries of either macrocycles and/or polymers, we

decided to polymerize a series of carbohydrate based pentenoic ester with pendent terminal

double bond by ADMET polymerization method using Grubbs' first generation catalyst. Scheme

4-1 shows the basic idea behind the ADMET of functionalized carbohydrate derivatives.









O
Ho 0 OH HO
HO-" HO-n- 0"iV 0^
0 0 DIC, DMAP O n
HsC CH3
H3C CH3
4-1
4-2
Grubbs' first generation catalyst



On
O O m
H3C CH3
4-3


Scheme 4-1. General scheme for the ADMET polymerization of functionalized carbohydrate
derivatives with terminal double bond.

Another interesting feature of ADMET chemistry is the regiochemistry of the polymer,

i.e., the structural arrangements of the monomer units. When ethylene is polymerized into linear

chains, only one arrangement of atoms is possible. However, the incorporation of substituents

into the olefin monomer introduces the opportunity for some structural variability. For example,

when propylene is polymerized, the monomers can arrange themselves along the chain in three

different ways. If we call the CH2 end of the propylene the "head" and the CH(CH3) end the

"tail", then a head-to-tail (HT) polymerization would lead to a polymer chain with a methyl

group (CH3) located on every other carbon (Figure 4-1). On the other hand, if the polymerization

occurred in a head-to-head (HH), tail-to-tail (TT) fashion, methyl groups would be located on

adjacent carbons in pairs.









H CH3 H CH3 H CH3 H CH3



H H H H H H H H

Head-to-Tail Arrangement



H CH3 CH3 H H CH3 CH3 H


HHHHHHHH
H H H H H H H H

Head-to-Head, Tail-to-Tail Arrangement


Figure 4-1. Head-to-Tail, Head-to-Head, Tail-to-Tail arrangement.

A third possibility involves random orientation of monomer units along the polymer chain.

These three different structural forms of polypropylene would be expected to have different

physical properties. Generally, the head-to-tail polymer is produced using heterogeneous Ziegler-

Natta or homogeneous cyclopentadienyl-zirconium catalysts. Ring closing metathesis

polymerization of the diester of (D)-ribose results in the formation of a cyclic structure with a

possibility of the formation of the HH/TT or HT structure pattern (Figure 4-3). If the H and T

monomer units are equally reactive the repeat units would be linked statistically. In that case the

expected proportions of HT: HH: TT linkages are 50:25:25. On the other if the head groups are

much more reactive than the tail group, then HH link would be formed first, followed later by TT

linkages and polymer would contain only HH and TT linkages.178

Scheme 4-2 shows an example how the carbohydrate D-mannitol 4-4 might be

incorporated into the backbone of a metathesis polymer. Instead of placing the sugar into the

polymer lengthwise where it is a major structural unit, this time the polymer is placed across the

carbohydrate (Figure 4-2).











Acetone

ZnC12, 230C


H3C O0
H3C O
H--OH
HO--H

O CH

4-5


4-Pentenoic acid


H
H


OH
H--H
HO--H
H--OH
HO--H
H--OH
H--H
OH


H20


4-18


Scheme 4-2. Diacetone D-mannitol as a hydrogel precursor.

O OH OH 0 OH OH


OH OH O OH OH O
Lengthwise

HO HO HO

HO 0 HO 0 HO


S OH 0 OHOH
OH OH OH
Crosswise 0
(^ Crosswise O


Rings


Figure 4-2. Hydrogels with carbohydrates lengthwise, crosswise or rings.


H3 O0
H3C 0
S H--O
0-- H
0 CH3
/^ 0 XCH3
4-9




H3C O
H3C O
H--n n









Adding two alkenes as ester linkages for the construction of 4-9 serves two purposes.

First, it allows for the ADMET reaction to occur by providing two alkenes to build on. Secondly,

the esters provide a point for natural degradation in time by esterases in the cells.

4.2 Results and Discussion

In order to study the viability of olefin metathesis for ADMET, we first required to

synthesize a number of monomers-ester derivatives with pendent diene. It was then necessary to

allow the monomers to undergo metathesis reaction in presence of Grubbs' first generation

catalyst 1-3. A series of carbohydrate derivatives were synthesized by coupling acetone protected

carbohydrates with 4-pentenoic acid using DIC, DMAP. The starting material was typically

consumed within 3 h as indicated by TLC. Purification by column chromatography gave the

4-pentenoic esters of the protected carbohydrates in moderate to high yield (Table 4-1).

Table 4-1. Yield of diene from the protected carbohydrates.
Enter Carbohydrate Product Yield (%) [a]25D
1 D-Mannitol 4-9 71 +13.88
(C = 2.33, MeOH)
2 D-Ribose 4-10 72 -44.25
(C = 2.13, MeOH)
3 D-Isomannide 4-11 65 +142.68
(C = 2.20, CH2C12)
4 D-Isosorbide 4-12 70 +87.39
(C = 2.06, CH2C12)

The resultant monomers with two pendent alkene groups were then subjected to ADMET

in presence of Grubbs' first generation catalyst in anhydrous CHC13 under vacuum condition

resulting in the formation of the polymers in high yield. Table 4-2 shows the acyclic diene

metathesis polymerization of different carbohydrates monomers.









Table 4-2. ADMET of the carbohydrates.
Enter Carbohydrate Product Yield (%)
1 D-Mannitol 4-13 90
2 D-Ribose 4-15 92
3 D-Isosorbide 4-16 90
4 D-Isomannide 4-17 94

Monoacetone protected sugars, used for the preparation of dynamic combinatorial libraries,

like (D)-ribose (4-6) (similar to the compound earlier named as (3-38)), (D)-isomannide (4-7)

(similar to the compound earlier named as (3-50)), (D)-isosorbide (4-8) (similar to the

compound earlier named as (3-54)) have two hydroxyl groups and therefore, can be subjected to

diesterification reaction, resulting in the synthesis of dienes. Also we have synthesized the

diester of diacetone (D)-mannitol (4-9). All these dienes can be subjected to ADMET chemistry.

Depending on the reaction condition available, it is possible to obtain either a ring closing

metathesis product or an ADMET product as observed with the diene of monoacetone D-ribose

4-10 (similar to the compound earlier named as 3-39). A high concentration of catalyst

(monomer: catalyst, 10:1) can lead to RCM product 4-14, whereas a much lower concentration

of catalyst (monomer: catalyst, 100:1) gives rise to the formation of the ADMET polymer 4-15.

The first diene subjected to ADMET was based on the sugar (D)-mannitol (4-4). Scheme

4-3 shows the synthesis of the diester of diacetone D-mannitol 4-9. The first step involves the

protection of the (D)-mannitol using the literature procedure126 4-5 with an overall yield of 51%.

Compound 4-5 was then been subjected to esterification using the normal esterification reaction

conditions to make the compound 4-9 with an overall yield of 70%.









OH
H--H
HO--H Acetone
H--OH
HO--H ZnC12, 230C
H- OH 51%
H- H
OH

4-4


H3CO
H3C 0
H --OH
HO -H

O' CH3
4-5

H3C O
4-Pentenoic acid H3 0
0--H
DIC, DMAP, CH2C12 LO CH3
00C R.T., 70% O/ CH3
4-9


Scheme 4-3. Synthesis of the diester of diacetone (D)-mannitol.

The monoacetone (D)-ribose (4-6) has two hydroxyl groups. Therefore, esterification of

the monoacetone D-ribose (4-6) with 4-pentenoic acid (using 2.10 equivalents with respect to the

moles of the carbohydrate 4-6) results in the formation of the diester of the monoacetone (D)-

ribose 4-10 with an overall yield of 72%. Scheme 4-4 shows the synthesis of the diester of

monoacetone (D)-ribose.


HO~ OH

O o
H3C CH3

4-6


4-Pentenoic Acid

DIC, DMAP, CH2C12
0C R.T., 72%


0

S 0


H3C CH3
4-10


Scheme 4-4. Synthesis of the diester of the monoacetone (D)-ribose.

The other two carbohydrates used for ADMET polymerization are (D)-isomannide (4-7)

and (D)-isosorbide (4-8). Scheme 4-5 shows the synthetic route for the synthesis of compound









4-11 (65%). Scheme 4-6 shows the synthesis of diester of (D)-isosorbide 4-12 with a yield of

70%.

0
HO H0 H
-O O 4-Pentenoic Acid -

O H DIC, DMAP, CH2C12 H 0
H OH HO
0C R.T., 65%
4-7 4-11 O

Scheme 4-5. Synthesis of the diester of monoacetone (D)-isomannide.

0
HO H
0 4-Pentenoic Acid H

O DIC, DMAP, CH2C12 O 0
H H 0C-R.T., 70% H

4-8 4-12 0

Scheme 4-6. Synthesis of the diester of monoacetone (D)-isosorbide.

First ADMET chemistry was performed with diester of (D)-mannitol following the usual

ADMET reaction condition (Scheme 4-7). First attempt resulted in the formation of expected

polymer product, which was insoluble in almost all common organic solvents. No further

characterization of the highly viscous, gluey material could be done. In our second attempt, we

carried out the ADMET polymerization in presence of BHT. The product so obtained was

soluble in dichloromethane. It appeared to be highly viscous liquid and could not be precipitated,

unlike usual ADMET products.









H3C O, / H3CO 0o
H {3C 0O CHCl3, Grubbs' II H3C 0

0--H 0--H
0 'O CH3 R.T.-550C, 90% -0 CH3

4-9 4-13

Scheme 4-7. ADMET of the diester of (D)-mannitol.

Carbohydrates with two terminal double bonds can undergo either self-metathesis (like the

one mentioned earlier in chapter 3) to make a homodimer with linear structure or ADMET

polymerization reaction to give a polymer depending upon the reaction conditions employed.

However, when the diene of monoacetone (D) ribose 4-10 was subjected to the metathesis

reaction condition using 10 mol% of Grubbs' first generation catalyst in anhydrous

dichloromethane (0.50 M), a new compound 4-14 was synthesized. In case of the diester of D-

ribose 4-10, the 1H NMR shows specific peak at 6 = 5.0 ppm for the hydrogen at the terminal

double bond and a peak at 6 = 5.8 ppm due to hydrogen at the internal double bond, whereas for

the ADMET product of the diester of monoacetone D-ribose 4-15 there is no peak either at

6 = 5.8 ppm or at 6 = 5.0 ppm, instead a new broad multiplate has appeared at 6 = 6.0-5.0 ppm.

The 1H NMR of the compound 4-14 shows two multiplates at 6 = 5.52-5.42 ppm (2H) and at

6 = 5.38-5.26 ppm (2H). If the compound 4-14 is a regular self-metathesis product then we

would see the peak for the hydrogens at the terminal carbon of the double bond. The HRMS

analysis shows that it is a dimer [calcd 653.2809 against found 653.2783). The absence of any

peak corresponding to the terminal double bond hydrogen suggests that it is a cyclic dimer

product (Figure 4-3) and not a polymer or linear dimer.









0 Tail end
O O


Head End H3C CH3
4-10
Grubbs' I catalyst
CH2C12, Reflux, 74%


4-14(HT) H3C
Head-to-Tail combination 4-14(HH)
Head-to-Head and Tail-to-Tail combination

Figure 4-3. Schematic representation of the HH or HT cyclic dimer of diacetone (D)-ribose.

Such a variation in the possible structure of the cyclic dimer 4-14(HH)/4-14(HT) is due

to the presence of two different hydroxyl groups as the two ester functional groups are not

equivalent. In the Figure 4-3 the pentenoate end attached to the 1 hydroxyl end is assumed to be

the head whereas the pentenoate end attached to the 20 hydroxyl end is assumed to be the tail.

Further analysis of the product 4-14(HH)/4-14(HT) by 2-D NMR, and crystallography will help

to determine the actual structure of the compound.

The next carbohydrate used for ADMET is (D)-ribose. It is the concentration of the

catalyst used for the reaction which determines whether the reaction would be ADMET type or









RCM. ADMET polymerization requires much less amount of ruthenium catalyst compared to

that for the RCM reaction. The usual ratio of monomer to catalyst ratio for ADMET is 100:1 or

even less than that, whereas the ratio for the RCM reaction is 10:1. Scheme 4-8 shows the

synthesis of the ADMET polymer for the carbohydrate (D)-ribose. Scheme 4-9, and 4-10 show

the synthesis of the ADMET of carbohydrates (D)-isomannide and (D)-isosorbide respectively.


0



x 1
H3C CH3
4-10


O
CHC13, Grubbs' II O O

R.T.-550C, 85% O- -
H3C CH3
4-15


Scheme 4-8. ADMET of the diester of (D)-ribose.


CHC13, Grubbs' II

R.T.-550C, 80%


4-11


O

O HO
n

HO
S4-16
4-16 0


Scheme 4-9. ADMET of the diester of (D)-isomannide.


0

OH



4-H 12
4-12 0


CHC13, Grubbs' II

R.T 550C, 85%


4-17


Scheme 4-10. ADMET of the diester of (D)-isosorbide.









Also for the carbohydrate (D)-isosorbide, the two hydroxyl groups are trans to each other.

Even though the hydroxyl groups for (D)-isosorbide are not of 1l/2 type, but their reactivity are

different. One of the hydroxyl groups occupies the exo orientation while the other occupies the

endo orientation. From the steric point of view hydroxyl group at exo orientation is more reactive

than the hydroxyl group at the endo orientation. Hence the polymer 4-17 formed by ADMET

polymerization method will be of different type compared to the polymer of (D)-mannitol or (D)-

isomannide. Thus we have a possibility of having a mixture of HH/TT as well as HT polymer

linkages in both polymers 4-15 and 4-17.

The molecular weight of the polymers (Mn) was determined by GPC with respect to

polystyrene as the standard. Table 4-3 shows the Mn of the polymers 4-13, 4-15, 4-16, and 4-17.

Table 4-3. Mn of the ADMET polymer.
S1. No. ADMET Mn DPI

1 4-13 5000 1.11

2 4-15 4500 1.10

3 4-16 7000 1.14

4 4-17 6250 1.13


4.3 Conclusion

We have successfully developed ADMET chemistry for carbohydrates for the first time.

This opens up a new field of chemistry. Of the four carbohydrates we used, monoacetone (D)-

ribose has two different reactive sites, primary and secondary hydroxyl groups. Similarly the

hydroxyl groups of (D) isosorbide are different in reactivity based on the steric factor. So we

expect to get polymers with a mixture of head-to-head or tail-to-tail and head-to-tail linkages.









CHAPTER 5
EXPERIMENTAL METHODS

5.1 General Methods and Instrumentation

All moisture and air-sensitive reactions were performed under argon atmosphere in flame-

dried glassware. Solvents were distilled under N2 from appropriate drying agents according to

the established procedures. Rf values were obtained by using thin-layer chromatography.

Analytical thin-layer chromatography (TLC) was performed using Kiesel gel 20 F-254 pre-

coated 0.25 mm silica gel plates. UV light, phosphomolybdic acid in ethanol, anisaldehyde in

ethanol, permanganate, and vanillin were used as indicators for spot identification in TLC.

Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Gemini, VXR, and

Mercury 300MHz spectrometer. Carbon nuclear magnetic resonance (13C) spectra were recorded

at 75 MHz on the same spectrometers. Some of the chemical shifts were reported in ppm

downfield with respect to trimethylsilane (TMS) as an internal standard, while in other cases the

chemical shift of the solvent (for example, the chemical shift of solvent CDC13 is 7.27 ppm) was

used for standardization. Infrared spectra were obtained from KBr-pellets using a Bruker Vector

22 IR and are reported in wavelength (cm-1). Unless reported all yields refer to the isolated

materials, determined by TLC and NMR. High-resolution mass spectroscopy (HRMS) was

performed by the Mass Spectroscopy Laboratory at the University of Florida. Optical rotations

were recorded on a Perkin-Elmer 241 digital polarimeter (10-ldegcm2 g-1). Melting points were

obtained on a Thomas-Hoover capillary melting point apparatus.









5.2 Experimental Procedure and Data


Norbornenemethanol 2-13


/ b OH

A solution of norbornene-1-carboxaldehyde (11.67 gm, 96 mmol) in MeOH (58 mL) was

added dropwise over 1 h to a suspension of NaBH4 (1.74 gm, 46 mmol) in 2N NaOH (20 mL) at

0C under Ar. The reaction mixture was stirred at room temperature for further 3 h, monitored by

TLC. The pH of the reaction medium was brought back to 6 at 0C with 30% H2SO4 (30 mL).

The methanol was evaporated, and the resulting residue was extracted with diethyl ether (3 x 70

mL). The combined organic layers were washed with saturated NaHCO3 and brine (3 x 100 mL

with each), dried over anhydrous MgSO4, and concentrated under reduce pressure, affording 2-

13 as a white liquid (9.50 g, 80%).35

2-13: Rf= 0.71 (CH2Cl2/MeOH, 9:1); IR (film) Vmax 3333, 2967, 1682, 1570, 1337, 1252,

1146 cm-1; H NMR (300MHz, CDC13) 6 6.20-5.90 (m, 2H, CH=CH), 3.70-3.20 (m, 2H,

CH2OH), 2.90-2.70 (m, 2H, C=CCH, C=CCH), 2.40-2.20 (m, 1H), 2.10-1.90 (s, 1H, OH), 1.85-

1.70 (m, 1H), 1.50-1.40 (m, 1H), 1.40-1.10 (m, 2H); 13C NMR 6 137.3, 136.8, 136.6, 132.3,

64.2, 66.2, 49.5, 44.9, 43.6, 43.3, 42.2, 41.74, 41.6, 41.6, 29.6, 28.9. This compound is

commercially available from Aldrich.

Ester carbamate of norbornene 2-14

0 0
0 NO

A solution of N-tertiary-butoxycarbonyl-glycine (N-tBoc) (1.34 g, 0.01 mol) in anhydrous

CH2C12 (3 mL) was added to a solution of the norbornenemethanol 2-13 (1 g, 8 mmol), catalytic

amount of DMAP, and DIC (1.10 g, 9 mmol) in anhydrous CH2C12 (13 mL) over a period of 20

min at 0C under Ar. The reaction mixture was then stirred for an additional 3 h at room









temperature monitored by TLC. The precipitate was filtered and the organic phase was washed

with saturated NaHCO3 and brine (3 x 30 mL each), dried over anhydrous MgSO4 and

concentrated under reduce pressure. The crude product was then purified by silica gel column

chromatography using hexane and ethyl acetate (90:10) as eluent to afford the pure product 2-14

as colorless oil (1.60 g, 71%).

2-14: Rf= 0.52 (CH2Cl2/MeOH, 9:1); IR (film) Vmax, 3067, 2978, 1692, 1575, 1347, 1258,

1146 cm-1; 1H NMR (300MHz, CDC13) 6 6.20-5.85 (m, 2H, CH=CH), 5.22-5.00 (s, 1H,-NH),

4.25-3.72 (m, 4H, CH2OH, OCOCH2NH), 2.90-2.70 (m, 2H, C=CCH, C=CCH), 2.45-2.30 (m,

1H), 1.90-1.80 (m, 1H), 1.50-1.40 (s, 9H, C(CH3)3), 1.30-1.10 (m, 3H); 13C NMR 6 170.6,

170.5, 155.9, 137.9, 137.1, 136.3, 132.2, 80.0, 69.5, 68.8, 49.5, 45.0, 43.9, 43.7, 42.6, 42.3, 41.7,

38.0, 37.9, 31.7, 29.6, 29.1, 28.5, 22.8, 14.3.

Amino acetate of norbornene 2-15

O

/O NH2
In a 5 mL round bottom flask under argon, 0.26 g (0.93 mmol) of 2-14 in 1 mL of

anhydrous CH2C12 was taken. 0.10 mL of TFA was added into it at 0C under Ar over 15 min.

The reaction mixture was stirred for an additional 2 h at 0C and was followed by overnight

stirring under Ar at room temperature. The volatilities were removed under reduced pressure and

the residue was treated with saturated NaHCO3, and extracted with ethyl acetate (3 x 10 mL).

The pooled organic extracts were then dried over anhydrous MgSO4 and concentrated under

reduced pressure. The residue was purified by silica gel column chromatography using hexane

and ethyl acetate (40:60) as eluent to afford the pure product 2-15 (45 mg, 25% yields) as

colorless oil. Possible reason for the low yield could be the use of high concentrated acid TFA.

Also a possible dimerization of the amino acetate of norbornene 2-15 may also be responsible for









the low yield. Reaction conditions had been changed with the change in concentration of acid

TFA and the solvent (Table 2-1) without any significant change in yield.

2-15: Rf = 0.52 (CH2Cl2/MeOH, 9:1); IR (film) vmax3054, 2975, 1698, 1625, 1578, 1378,

1244, 1048 cm1; 1H NMR (300MHz, CDC13) 6 6.80-6.20 (m, 2H, CH=CH), 4.60-3.90 (m, 2H),

3.40-3.20 (m, 2H), 3.00-2.80 (m, 1H), 2.60-2.40 (s, 2H), 2.40-2.30 (m, 1H), 2.10-1.90 (m, 1H),

1.90-1.60 (m, 2H); 13C NMR 6170.8, 170.4, 170.3, 137.9, 137.1, 136.3, 132.2, 69.5, 68.9, 49.5,

45.1, 43.9, 43.7, 42.3, 41.7, 41.5, 38.0, 37.8, 29.6, 29.1, 22.94.

Fmoc protected ester carbamate of norbornene 2-16



OH


A solution of N-Fmoc-glycine (3.95 g, 13 mmol) in anhydrous THF (13 mL) was added at

0C under Ar over a period of 20 min into a solution of norbornenemethanol (1.50 g, 12 mmol)

in anhydrous THF (9 mL) along with DIC (1.59 g, 13 mmol) and DMAP (0.14 g, 1.10 mmol).

After completion of addition, the reaction mixture was warmed to room temperature and stirred

for an additional 3 h. The reaction was monitored by TLC (hexane/EtOAc, 6:4). The product was

then filtered to remove the precipitate. The organic phase was then washed with aqueous

saturated NaHCO3 and brine solution (3 x 50 mL each), dried over anhydrous MgSO4, and

concentrated over reduced pressure. The crude product was then purified by silica gel column

chromatography using hexane and ethyl acetate (90:10) as eluent to afford the pure product as

highly viscous oil (3.82, 79%).

2-16: Rf= 0.72 (hexane/EtOAc, 6:4); IR (film) vmax3033, 2967, 1685, 1572, 1347, 1250,

1151 cm1; 1H NMR (300MHZ, CDC13) 6 7.8-7.2 (m, 8H, CH=CH of benzene ring part), 6.2-5.8

(m, 2H, CH=CH of norbornene part), 4.42-4.34 (d, J= 8.1 Hz, 2H), 4.26-4.16 (t, J= 7.2 Hz,









2H); 4.06-3.86 (m, 3H), 3.78-3.66 (t, J= 7.2 Hz, 1H), 2.88-2.74 (m, 2H), 2.44-2.28 (m, 1H),

1.88-1.76 (m, 1H), 1.48-1.18 (m, 2H); 13C NMR 6170.2, 156.5, 147.3, 143.9, 141.4, 137.9, 1372,

136.2, 132.2, 127.8, 127.1, 125.2, 120.1, 69.7, 69.0, 67.3, 49.5, 47.2, 45.0, 43.9, 43.7, 42.9, 42.3,

41.7, 38.0, 37.8, 29.6, 29.0.

Deprotection of the Fmoc group


0
/0 ANH2
2-16 (1.61 g, 2.75 mmol) was added to a solution of piperidine in DMF (20%). The

mixture was heated for 30 min or until disappearance of starting material by TLC

(CHCl3/MeOH, 9:1). The solution was cooled back to room temperature and poured into cold

water (50 mL). The white solid of dibenzofulvene was removed by vacuum filtration. The filtrate

was then extracted with diethyl ether (3 x 50 mL), washed with water, dried under anhydrous

MgSO4, and concentrated under reduced pressure to get the deprotected compound, which is

mostly the norbomenemethanol (0.12 g, 25%).

2-13: Rf= 0.71 (CH2Cl2/MeOH, 9:1); IR (film) Vmax 3333, 2967, 1682, 1570, 1337, 1252,

1146 cm-1; 1H NMR (300MHZ, CDC13) 6 6.20-5.90 (m, 2H, CH=CH), 3.70-3.20 (m, 2H,

CH2OH), 2.90-2.70 (m, 2H, C=CCH, C=CCH), 2.40-2.20 (m, 1H), 2.10-1.90 (s, 1H, OH), 1.85-

1.70 (m, 1H), 1.50-1.40 (m, 1H), 1.40-1.10 (m, 2H); 13C NMR 6 137.3, 136.8, 136.6, 132.3,

64.2, 66.2, 49.5, 44.9, 43.6, 43.3, 42.2, 41.74, 41.6, 41.6, 29.6, 28.9.

Norbornene ketoester 2-17


00
y 0o CH3
5.30 g of the norbornenemethanol 2-13 (43 mmol) was taken in a round bottom flask under

Ar and was dissolved in 86 mL of anhydrous benzene. 7.82 g of DMAP (64 mmol, 1.50 equiv)









was added into it. 14.87 g of methyl acetoacetate (13 mmol, 3 equiv) was added and the reaction

mixture was refluxed overnight under Ar. The crude product was then washed with water and

brine (3 x 50 mL each) and dried over anhydrous MgSO4. The pooled organic layers were then

concentrated under reduced pressure and purified by silica gel column chromatography using

hexane and ethyl acetate (70:30) as eluent affording the pure compound 2-17 (6.67g, 75%) as a

colorless oil.

2-17: Rf = 0.54 (hexane:EtOAc, 4:6); IR (film) Vmax 3053, 2965, 1715, 1655, 1568, 1357,

1256, 1149 cm1; 1H NMR (300MHZ, CDC13) 6 6.18-5.86 (m, 2H, CH=CH), 4.22-3.64 (m, 2H,

CH20), 3.46-3.40 (s, 2H, COCH2CO), 2.87-2.64 (d, 2H, C=CCH, C=CCH), 2.26-2.22 (s, 3H,

COCH3), 1.90-1.60 (m, 1H), 1.50-1.10 (m, 3H); 13C NMR 6 200.9, 167.2, 137.8, 137.0, 136.2,

132.1, 69.5, 68.8, 50.2, 49.4, 44.9, 43.9, 43.6, 42.3, 41.6, 37.9, 37.7, 30.2, 29.6, 28.9.

p-Toluene sulfonyl azide (2-18)



H3Ca /"-NN:N
0
Sodium azide (3.34 g, 51 mmol) was added into a 20 mL of ethanol. To this solution was

added 8.89 gm (50 mmol) ofp-toluene sulfonyl chloride in 40 mL acetone. A precipitate of NaCl

was formed. The reaction mixture was then stirred for an additional 15 h and then filtered.

Acetone was removed by rotary evaporation and the organic phase was separated and diluted

with CH2C12. The solution was then washed with distilled water (3 x 50 mL) and dried over

anhydrous MgSO4. Removal of the solvent was left 8.24 gm ofp-toluene sulfonyl azide (2-18)

(90% yields) as colorless oil. Spectral data are in agreement with literature.182 Necessary

precautions were taken to preserve this highly explosive compound in a sealed vial.









2-18: Rf= 0.21 (hexane/CH2Cl2, 6:4); IR (film) vmax 3238, 3067, 2927, 2100, 1595, 1494,

1451.5 cm-1; 1HNMR (300MHZ, CDC13) 6 7.90-7.20 (d, J= 8.4 Hz, 4H), 2.60-2.40 (s, 3H, tosyl

CH3); 13C NMR 6 141.2, 139.5, 128.3, 125.6, 14.4.

Diazo-ester of norbornene 2-19

0


To a stirred solution of the norbornene keto ester 2-17 (1.33 g, 6 mmol) in 7 mL of

anhydrous acetonitrile andp-TsN3 (1.52 g, 8 mmol), triethyl amine (3.60 mL, 4 equiv) was

added at 0C under Ar over 10 min. The reaction mixture was stirred for additional 2 h at 0C. It

was then warmed to room temperature and was stirred for another additional 5 h. Then 1M

NaOH (60 mL) was added to the stirred solution. The reaction mixture was stirred for additional

12 h. It was extracted with dichloromethane (3 x 50 mL). The combined extracts were washed

with 1M NaOH (3 x 75 mL), dried over anhydrous MgSO4 and concentrated under reduced

pressure to obtain a yellow crude oil. The product was purified by silica gel column

chromatography using hexane and ethyl acetate (60:40) as eluent to afford a pure product 2-19

(0.93 g, 81%).183

2-19: Rf= 0.56 (hexane/EtOAc, 6:4); IR (film) max 3123, 2968, 2111, 1696, 1549, 1363,

1241, 1185 cm-; 1H NMR (300MHZ, CDC13) 6 6.18-5.88 (m, 2H, CH=CH), 8 4.82-4.66 (s, 1H,

COCHN2), 4.24-3.66 (m, 2H, CH20), 2.92-2.72 (m, 2H, C=CCH, C=CCH), 2.44-2.28 (1H),

1.86-1.74 (m, 1H), 1.48-1.10 (m, 3H); 13C NMR 6 177.1, 166.4, 137.3, 136.6, 135.8, 131.8, 68.9,

68.5, 37.9, 49.0, 45.7, 44.6, 43.6, 43.5, 43.2, 41.9, 41.2, 38.0, 37.8, 37.6, 37.4, 36.5, 29.1, 28.5;











Norbornene oxohexanoate 2-22


O O
yO CH3
To an ice-cooled solution of norbornenemethanol 2-13 (6.13 g, 50 mmol), DIC (9.64 g, 74

mmol) and catalytic amount of DMAP (0.86 g, 7 mmol) in 99 mL anhydrous CH2C12, 4-acetyl

butyric acid (9.64 g, 70 mmol) was added over 20 min. After completion of addition, the reaction

mixture was stirred at room temperature for an additional 4 h until there was no more starting

material monitored by TLC (hexane/EtOAc, 6:4). It was then filtered and washed with water (2 x

75 mL) and brine (1 x 50 mL). The organic layer was dried over anhydrous MgSO4 and

concentrated under reduced pressure. The crude was then purified by silica gel column

chromatography using hexane and ethyl acetate (90:10) as eluent affording the pure product 2-22

(8.50 g, 73%) as colorless oil.

2-22: Rf= 0.65 (hexane/EtOAc, 6:4); IR (film) Vmax 3053, 2967, 2667, 1714, 1669, 1573,

1424, 1343, 1266, 1158 cm-; H NMR (300MHZ, CDC13) 6 6.20-5.60 (m, 2H, CH=CH), 6 4.20-

3.50 (m, 2H, CH20), 8 2.80-2.68 (m, 2H, C=CCH, C=CCH), 8 2.45-2.38 (m, 2H), 2.35-2.20 (m,

3H), 6 2.10-2.05 (s, 3H, CH3), 6 1.85-1.70 (m, 3H), 6 1.40-1.00 (m, 3H); 13C NMR 6 207.8,

172.9, 137.6, 136.9, 136.1, 132.1, 68.4, 67.7, 49., 44.9, 43.8, 43.6, 42.4, 42.2, 41.5, 37.9, 37.8,

33.2, 29.8, 29.54, 28.96, 18.9, 18.9.









ROMP of the Compound 2-17


A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with Ar and charged with 0.61 g (2.90

mmol) of the keto-ester of the norbomenemethanol and 4-acetyl butyric acid 2-17, catalytic

amount of BHT and 20 mg of the Grubbs' first-generation catalyst (0.01 equiv.) in 15 mL of

anhydrous CH2C2 (0.20 equiv). The mixture was stirred rapidly for an additional 15 min at the

room temperature and then quenched with ethyl vinyl ether to afford the ROMP product 2-23

(0.51g).

2-26: Rf= 0.21 (CHC13/MeOH, 9:1); IR vmax 3015, 2985, 2678, 1725, 1661, 1575, 1428,

1353, 1265, 1163 cm-1; 1H NMR (300MHz, CDC13) 6 5.80-5.40 (m, 2H), 4.60-4.20 (m, 2H),

3.80-3.60 (m, 2H), 3.50-2.50 (m, 6H), 2.40-2.20 (m, 2H), 2.20-1.60 (m, 12H); 13C NMR 6 205.6,

205.3, 172.7, 172.3, 137.5, 136.3, 135.9, 133.1, 69.5, 68.6, 67.3, 50.2, 49.5, 45.3, 44.8, 43.7,

43.5, 42.8, 42.6, 41.8, 38.2, 37.9, 33.7, 30.2, 29.7, 29.2.









ROMP of the Compound 2-22


n

O
0



0

A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with Ar and charged with 0.51 g (2.10

mmol) of the keto-ester of the norbomenemethanol and 4-acetyl butyric acid 2-22, catalytic

amount of BHT and 18 mg of the Grubbs' first-generation catalyst (0.01 equiv.) in 10 mL of

anhydrous CH2C2 (0.20 equiv). The mixture was stirred rapidly for the next 15 min at the room

temperature and then quenched with ethyl vinyl ether to afford the ROMP product 2-24 (0.44g)

as a highly viscous oil.

2-24: Rf= 0.23 (CHC13/MeOH, 9:1); IRVmax 3013, 2965, 2678, 1725, 1669, 1573, 1423,

1344, 1264, 1157 cm-1; 1H NMR (300MHz, CDC13) 6 5.30-5.20 (m, 2H), 4.05-3.70 (m 2H),

2.55-2.40 (m, 4H), 2.30-2.15 (m, 4H), 2.10-2.05 (m, 5H), 1.95-1.70 (m, 6H); 13C NMR 6 207.6,

172.7, 137.5, 136.3, 135.9, 133.1, 68.4, 67.3, 49.5, 44.8, 43.7, 43.5, 42.8, 42.6, 41.8, 38.2, 37.9,

33.7, 30.2, 29.7, 29.2, 19.5, 19.2.










Diacetone D-mannose (3-25)


H3C 0
H3C O ,\OH

0 O
H3C CH3
A solution of D-mannose (3-24) (10 g, 0.06 mol) and 2,2 DMP (31 mL) in acetone (74

mL) was placed in a round bottom flask under Ar. Catalytic amount ofp-toluenesulfonic acid (p-

TsOH) (80 mg, 0.46 mmol) was added. The reaction mixture was stirred at r.t. overnight. The

reaction was monitored by TLC (hexane/EtOAc, 6:4). After 10 h of reaction, the solvent was

removed under reduced pressure to afford a pure white solid product (m.p. 119.0 121.0 C) of

diacetone D-mannose (3-25) (10.1 Ig, 71% yield).

3-25: Rf= 0.25 (hexane/EtOAc, 6:4); m.p. 119.0-121.0 C (lit 123-124 C); a25D +17.16 o

(C = 1.35, MeOH); IR (KBr) vmax 3435, 2988, 2948, 2901, 1459,1439, 1319 cm-1; 1HNMR

(300MHz, CDC13) 6 5.39-5.36 (d, J= 5.84 Hz, 1H), 4.83-4.78 (dd, J= 5.88 Hz, 3.69 Hz, 1H),

4.63-4.58 (d, J= 5.88 Hz, 1H), 4.44-4.37 (m, 1H), 4.21-4.16 (dd, J = 6.99 Hz, 3.72 Hz, 1H),

4.20-4.02 (m, 2H), 3.14-3.18 (d, 1H, hydroxyl OH), 1.48-1.44 (s, 6H), 1.4.-1.30 (s, 3H, 3H);

13C NMR 6 112.8, 109.3, 101.4, 85.7, 80.4, 79.8, 73.5, 66.1, 26.9, 26.0, 25.3, 24.6. Spectral data

and m.p. are in agreement with literature.159

Carbonate of diacetone (D)-mannose 3-26


H3C O
H3C 1 -1 0 .1









To a solution of the diacetone-D-mannose (3-25) (4 g, 15 mmol) together with DMAP

(5.63 g, 46 mmol) in CHC13 (31 mL, 0.5 M), allyl chloroformate (5.57 g, 46 mmol) was added.

The reaction mixture was then refluxed for an additional 3 h under Ar until the complete

consumption of the starting material. Reaction was monitored by TLC (hexane/EtOAc, 6:4). The

crude product was filtered, washed with water (3 x 100 mL) and brine (3 x 100 mL). The organic

layer was then dried over anhydrous MgSO4, concentrated under reduced pressure, and purified

by silica gel column chromatography using hexane and ethyl acetate (90:10) to afford the

product 3-26 (3.55 g, 67%) as a colorless oil.

3-26: Rf = 0.51 (hexane/EtOAc, 6:4); [a]25D +59.82 0 (C = 1.57, MeOH); IR (neat) Vmax

3643, 3087, 2987, 2338, 1754, 1640, 1456, 1381, 1296 cm-1; 1HNMR (300MHz, CDC13) 6 6.02-

5.99 (s, 1H), 5.98-5.84 (ddt, J= 17.33 Hz, 10.28 Hz, 7.34 Hz, 1H), 5.40-5.24 (m, 2H), 4.86-4.80

(dd, J= 5.88 Hz, 3.69 Hz, 1H), 4.76-4.72 (d, J= 5.88 Hz, 1H), 4.65-4.60 (m, 2H), 4.42-4.34 (m,

1H), 4.10-3.98 (m, 3H), 1.48-1.44 (s, 3H), 1.44-1.40 (s, 3H), 1.36-1.34 (s, 3H), 1.34-1.30 (s,

3H); 13C NMR (CDC13) 6 153.3, 131.3, 119.6, 113.5, 109.6, 103.9, 84.9, 82.5, 79.4, 72.9, 68.9,

66.9, 27.1, 26.1, 25.3, 24.8; HRMS (CI pos) for C16H2508 [M+H]+, calcd 345.1549, found

345.1539.

Metathesis of the carbonate of D-mannose 3-27


H3C H3

H3C 0 O0 O


O .
Y0

H3C CH3
A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with Ar and charged with 0.50 g (2









mmol) of the carbonate of protected (D)-mannose 3-26, 167 mg of the Grubbs' first-generation

catalyst (10 mol %) in 4.0 mL of CH2C2 (0.50 M). The reaction mixture was stirred and refluxed

for 18 h. Ethyl vinyl ether (1 mL) was added to quench the metathesis reaction. The crude

product was then concentrated under reduced pressure, and purified by silica gel column

chromatography using hexane and ethyl acetate (70/30) as eluent to afford the metathesis product

3-27 (0.41 g, 61%) as a highly viscous oil.

3-27: Rf = 0.35 (hexane/EtOAc, 6:4); IR (neat) Vmax 3643, 3087, 2987, 2338, 1754, 1640,

1456, 1381, 1296 cm-1; 1HNMR (300MHz, CDC13) 6 6.04-6.00 (s, 2H), 6 5.96-5.90 (m, 2H),

6 4.88-4.82 (dd, J= 5.85 Hz, 3.67 Hz, 2H), 4.78-4.74 (dd, J= 5.98 Hz, 2.19 Hz, 2H), 6 4.70-4.64

(m, 4H), 4.44-4.36 (m, 2H), 6 4.14-4.02 (m, 6H), 1.50-1.42 (two s, 6H, 6H), 1.38-1.32 (two s,

6H, 6H); 13C NMR (CDC13) 187.8, 183.7, 173.2, 154.3, 154.5, 131.3, 131.5, 113.7, 109.8, 103.9,

103.4, 84.9, 82.5, 79.4, 72.9, 68.9, 66.9, 27.1, 26.1, 25.3, 24.8, 24.6.

Hydrogenation of the metathesis product of carbonate of diacetone (D)-mannose 3-28


H3C CH3
O 0
H3C0 0

H30 0^0 0 .'0 0
O- O CH3
0 0 CH3

H3C CH3

Metathesis product of carbonic acid allyl ester 3-26 (102 mg, 0.15 mmol) was

hydrogenated in presence of Pd catalyst. The product 3-28 was used directly for the NMR

analysis in CDCl3.

3-28: Rf = 0.56 (hexane/EtOAc, 6:4); IR (neat) Vmax 3087, 2987, 2338, 1754, 1640, 1456,

1381, 1296 cm1; H NMR (300MHz, CDC13) 6 6.06-6.02 (s, 2H), 4.90-4.84 (dd, J= 5.81 Hz,









2.13 Hz, 2H), 4.80-4.74 (dd, J= 6.32 Hz, 1.9 Hz, 2H), 4.46-4.36 (m, 4H), 4.26-4.18 (m, 2H),

4.12-4.02 (m, 6H), 1.60-1.54 (m, 4H), 1.50-1.42 (two s, 6H, 6H), 1.38-1.32 (two s, 6H, 6H); 13C

NMR (CDCl3) 154.3, 154.5, 131.3, 131.5, 113.7, 109.8, 103.9, 103.4, 84.9, 82.5, 79.4, 72.9,

68.9, 66.9, 27.1, 26.1, 25.3, 24.8, 24.6, 23.6, 23.8.

Esterification of diacetone D-mannose 3-29


H3C 0

H3C 0 O~
10 0
0 0
H3C CH3
To a solution of the diacetone D-mannose (3-25) (5.17 g, 0.02 mol) was added DIC (3.01

g, 24 mmol) and a catalytic amount of DMAP (0.49 g, 4 mmol) in anhydrous CH2C2 (40 mL,

0.50 M) in a round bottom flask under Ar. 4-Pentenoic acid (2.39 g, 24 mmol) at 0C over the

10 min. After completion of the addition, the reaction mixture was warmed to the room

temperature and stirred for an additional 3.5 h. Reaction was monitored by TLC (hexane/EtOAc,

6:4). After the completion of the reaction, the product was filtered, and washed with water (2 x

100 mL) and brine (1 x 75 mL). The crude product was then dried over anhydrous MgSO4,

concentrated under reduced pressure, and purified by silica gel column chromatography using

hexane and ethyl acetate (90:10) as eluent to afford the desired product 3-29 (5.12 g, 76 %) as a

colorless oil.

3-29: Rf = 0.47 (hexane/EtOAc, 6:4); [a]25D + 49.55 o (C = 1.19, MeOH); IR (neat) Vmax

3080.17, 2987.39, 1747.39, 1642.32, 1455.96, 1373.83, 1071.79 cm1; 1HNMR (300MHz,

CDC13) 6 6.14-6.08 (s, 1H), 5.86-5.72 (ddt, J= 17.33, Hz, 10.28, 7.34, 1H), 5.08-4.97 (m, 2H),

4.85-4.80 (dd, J= 5.88 Hz, 2.69 Hz, 1H), 4.69-4.64 (d, J= 5.88 Hz, 1H), 4.42-4.32 (m, 1H),

4.10-3.96 (m, 3H), 2.44-2.30 (m, 4H), 1.46-1.44 (s, 3H), 1.44-1.41 (s, 3H), 1.36-1.32 (s, 3H),









1.32-1.28 (s, 3H); 13C NMR (CDC13) 6 171.5, 136.4, 115.9, 113.4, 109.5, 100.9, 85.2, 82.4, 79.5,

73.0, 66.9, 33.6, 28.7, 27.1, 26.1, 25.3, 24.8; HRMS (CI pos) for C17H2707 [M+H] calcd

343.1757, found 343.1762.

Metathesis of the ester of D-mannose 3-30


H3CXO 0 CH3

H3CO O ,o C3
0

H3C CH3 O O
H3C CH3
A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with argon and charged with 0.63 g (1.80

mmol) of the ester of diacetoned (D)-mannose 3-29, 150 mg of the Grubbs' first-generation

catalyst (10 mol %) in 4.0 mL of CH2C12 (0.50 M). The reaction mixture was stirred and refluxed

for 18 h. Ethyl vinyl ether (1 mL) was added to quench the metathesis reaction. The crude

product was then concentrated under reduced pressure, and purified by silica gel column

chromatography using hexane and ethyl acetate (70:30) as eluent to afford the solid metathesis

product 3-30 (0.43 g, 72%) (m.p. 88.5 90.0 C).

3-30: Rf = 0.26 (hexane/EtOAc, 6:4); m.p. 88.5 C 90.0 C ; [a]25D + 28.88 o

(C = 1.04, CH2C2); IR (KBr) Vmax 2987, 2671, 1742, 1459, 1382, 1250 cm1; 1H NMR (300MHz,

CDC13) 6 6.02-6.00 (s, 2H), 5.48-5.34 (m, 2H), 4.88-4.80 (dd, J= 7.55 Hz, 4.63 Hz, 2H), 4.70-

4.64 (dd, J= 5.49 Hz, 3.69 Hz, 2H), 4.42-4.34 (m, 2H), 4.12-4.06 (m, 6H), 2.40-2.24 (m, 8H),

1.50-1.46 (s, 6H), 1.46-1.42(s, 6H), 1.38-1.34 (s, 6H), 1.34-1.30 (s, 6H); 13C NMR (CDC13)

6 171.5, 171.5, 129.5, 129.0, 113.4, 109.4, 100.9, 100.9, 85.2, 82.4, 79.5, 73.0, 66.9, 34.2, 27.6,









27.1, 26.1, 25.3, 24.8, 22.6; HRMS (CI pos) C32H49014 [M+H] calcd 657.3122, found

657.3118.

Ester of diacetone D-glucose 3-32


H3C3? O
H3C 0 ~\CH3
0" OCH3
0=o

To a solution of the diacetone-D-glucose (3-31) (6 g, 0.02 mol) at 0C was added DCC

(2.30 g, 0.02 mol) and a catalytic amount of DMAP (0.47 g, 4 mmol) in anhydrous CH2C12 (40

mL, 0.50 M) taken in a round bottom flask under Ar. 4-Pentenoic acid (2.31 g, 0.02 mol) was

then added at 0 C over the 10 min. After completion of the addition, the reaction mixture was

warmed to the room temperature and stirred for 3.5 h. Reaction was monitored by TLC

(hexane/EtOAc, 6:4). At the end of the reaction, the product was filtered, and washed with water

(2 x 50 mL) and brine (1 x 50 mL). The crude product was then dried over anhydrous MgSO4,

concentrated under reduced pressure, and purified by silica gel column chromatography using

hexane and ethyl acetate (95:5) as eluent to afford the desired product 3-32 (5.60 g, 71 %) as a

colorless oil.

3-32: Rf= 0.51 (hexane/EtOAc, 6:4); [a]25D -27.50 o (C = 1.19, MeOH); IR (neat) vmax

3080, 2988, 1748, 1642, 1455, 1374, 1163, 1076 cm-1; 1HNMR (300MHz, CDC13) 6 5.85-5.70

(m, 2H), 5.30-5.20 (m, 1H), 5.10-4.90 (m, 2H), 4.45-4.35 (d, J= 7.1 Hz, 1H), 4.20-4.10 (m, 2H),

4.10-4.00 (m, 1H), 4.00-3.90 (m, 1H), 2.50-2.30 (m, 4H), 1.50-1.40 (s, 3H), 1.40-1.30 (s, 3H),

1.20-1.30 (s, 6H); 13C NMR (CDC13) 6 171.4, 136.3, 115.7, 112.2, 109.3, 105.1, 83.4, 79.9, 76.0,

72.4, 67.2, 33.4, 28.7, 26.8, 26.7, 16.2, 25.3; HRMS (CI pos) for C16H2307 [M-CH3]+, calcd

327.1444, found 327.1448.









Metathesis of the glucose ester 3-33


A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with argon and charged with 0.56 g (2

mmol) of the monoester of diacetone (D)-glucose 3-32, 0.25 g of the Grubbs' first-generation

catalyst (10 mol %) in 6 mL of anhydrous CH2C12 (0.5 M). The reaction mixture was stirred and

refluxed for 18 h. The metathesis reaction was then brought back to room temperature and

quenched with ethyl vinyl ether (1 mL). The crude product was concentrated under reduced

pressure, and purified by silica gel column chromatography using hexane and ethyl acetate

(70:30) as eluent to afford the desired metathesis product 3-33 (0.45 g, 83%) as a highly viscous

oil.

3-33: Rf = 0.34 (hexane/EtOAc, 6:4); [a]25D 0 o (C = 1.28, CH2C12); IR (neat) Vmax 3627,

2988, 2254, 1952, 1747, 1455, 1374, 1075 cm-1; H NMR (300MHz, CDC13) 6 5.85-5.78 (m,

2H), 5.48-5.34 (m, 2H), 5.24-5.18 (m, 2H), 4.60-4.40 (m, 2H), 4.22-4.12 (m, 4H), 4.06-3.92 (m,

4H), 2.42-2.22 (m, 8H), 1.50-1.46 (s, 6H), 1.38-1.34 (s, 6H), 1.29-1.24 (s, 12H); 13C NMR

(CDC13) 6 171.5, 129.5, 129.0, 112.3, 109.4, 105.1, 83.5, 79.9, 79.9, 76.1, 72.5, 67.3, 37.1, 34.0,

27.7, 26.9, 26.9, 26.8, 26.3, 25.4, 25.4, 22.7; HRMS (CI pos) for C31H45014 [M-CH3]+, calcd

641.2809, found 641.2824.









Synthesis of diacetone D-galactose 3-35


HO

03 O CH3
H3C ~O
CH3
Anhydrous CuSO4 (3.0 g, 19 mmol) (dried at 110 C for 24 h) and (D)-galactose (3-34)

(1.35 g, 7 mmol) were suspended in dry acetone (30 mL) in a 50 mL round bottom flask under

Ar, and were treated with catalytic amount of conc. H2SO4 (0.50 mL). The resulting mixture was

stirred at room temperature for 24 h. The cupric sulfate was then removed by filtration and

washed with acetone. The combined organic phases were then neutralized by addition of K2CO3.

The resulting mixture was then filtered, washed with brine (3 x 50 mL) and dried over anhydrous

MgSO4. The organic layer was then evaporated under reduced pressure, and purified by silica gel

column chromatography using hexane and ethyl acetate (40:60) affording the desired diacetone

D-galactose (3-35) (0.83 g, 43 % yield). Spectral data are in agreement with literature.153

3-35: Rf= 0.18 (hexane/EtOAc, 6:4); [a]25D -48.22 o (C = 2.71, MeOH); IR (neat) Vmax,

3489, 2996, 1713, 1645, 1458, 1388, 1309, 1260 cm-1; 1HNMR (300MHz, CDC13) 6 5.50-5.44

(d, J= 5.1 Hz, 1H), 4.60-4.52 (dd, J= 7.8 Hz, 2.4 Hz, 1H), 4.28-4.24 (dd, J= 5.1 Hz, 2.4 Hz,

1H), 4.24-4.18 (dd, J= 8.1 Hz, 1.8 Hz, 1H), 3.80-3.65 (m, 3H), 2.45-2.25 (br s, 1H, hydroxyl

OH), 1.48-1.42 (s, 3H), 1.38-134 (s, 3H), 1.28-1.24 (s, 6H); 13C NMR (CDC13) 6 109.6, 108.9,

96.5, 71.7, 70.9, 70.8, 68.3, 62.4, 26.2, 26.1, 25.1, 24.5.









Ester of protected D-galactose 3-36


H"30 CH3

0Y'A 0 CH3

CH3
To a solution of the diacetone D-galactose (3-35) at 0C (1.85 g, 7 mmol) was added DIC

(1.35 g, 11 mmol) and a catalytic amount of DMAP (0.12 g, 1 mmol) in anhydrous CH2C12 (15

mL, 0.50 M) taken in a round bottom flask under Ar. 4-Pentenoic acid (1.10 g, 11 mmol) was

added at 0C over the next 10 min. After completion of the addition, the reaction mixture was

brought back to the room temperature and stirred for an additional 3 h. Reaction was monitored

by TLC (hexane/EtOAc, 6:4). At the end of the 3 h, the product was filtered, and washed with

water (2 x 50 mL) and brine (1 x 50 mL). The crude product was then dried over anhydrous

MgSO4, concentrated under reduce pressure, and purified by silica gel column chromatography

using hexane and ethyl acetate (90:10) as eluent to give the desired product 3-36 (2.1 Ig, 87 %)

as a colorless oil.

3-36: Rf = 0.51 (hexane/EtOAc, 6:4); [a]25D -38.03 0 (C = 2.08, MeOH); IR (neat) Vmax

3080, 2988, 2937, 1738, 1642, 1455, 1383, 1071 cm-1; H NMR (300MHz, CDC13) 6 5.86-5.70

(m, 1H), 5.52-5.46 (d, J= 5.1 Hz, 1H), 5.06-4.90 (m, 2H), 4.62-4.54 (d, J= 7.2 Hz, 1H), 4.32-

4.02 (m, 4H), 4.02-3.92 (m, 1H), 2.46-2.27 (m, 4H), 1.48-1.44 (s, 3H), 1.42-1.38 (s, 3H), 1.32-

1.25 (s, 6H); 13C NMR (CDC13) 6 172.86, 136.7, 115.5, 109.6, 108.7, 96.4, 71.1, 70.8, 70.5, 66.1,

63.4, 33.5, 28.9, 26.1, 26.0, 25.0, 24.5; HRMS [CI pos] for C17H2707 [M+H] calcd 343.1757,

found 373.1748.









Metathesis of the ester of (D)-galactose 3-37


0
CH3 O
HIC O--CH3 O CH3
H3CO, 0 CH,
H3C O O
ooyo
H3C CH3
A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with argon and charged with 0.48 g

(0.001 mol) of the ester of protected diacetone-D-galactose 3-36, 115 mg of the first-generation

Grubbs' catalyst (10 mol %) in 3.mL of anhydrous CH2C12 (0.50 M). The reaction mixture was

stirred and refluxed for next 18 h. Ethyl vinyl ether (1 mL) was added to quench the metathesis.

The crude product was concentrated under reduced pressure, and purified by silica gel column

chromatography using hexane and ethyl acetate (70:30) as eluent to afford the desired solid

metathesis product 3-37 (0.34 g, 74%) (m.p. 86-87 C).

3-37: Rf= 0.34 (hexane/EtOAc, 6:4); m.p. 86-87 C ; [a]25D 43.81 0 (C = 1.00, CH2C12);

IR (KBr) Vmax 2994, 2943, 1736, 1451, 1381, 1250 cm1; 1H NMR (300MHz, CDC13) 6 5.56-

5.51 (d, J= 8.1 Hz, 2H), 5.50-5.36 (m, 2H), 4.65-4.58 (dd, J= 9.2 Hz, 2.5 Hz, 2H), 4.36-3.99

(m, 10H), 2.44-2.26 (m, 8 H), 1.52-1.48 (s, 6H), 1.46-1.42 (s, 6H), 1.36-1.31 (dd, 12H); 13C

NMR (CDC13) 6 172.7, 129.2, 128.8, 109.4, 108.5, 96.1, 70.9, 70.5, 70.3, 65.8, 63.2, 63.1, 33.8,

27.5, 25.8, 25.7, 24.8, 24.3, 22.5; HRMS (CI pos) for C32H49014 [M+H]+, calcd 657.3122, found

657.3099.









Protected monoacetone -D-ribose 3-39


HO~0OH


H3C CH3
Catalytic amount of cone. H2SO4 was added to a stirring mixture of D-ribose (3-38) (5 g,

33 mmol) in dry acetone (33 mL, 1M) at room temperature under Ar. A clear solution was

obtained within 10 minutes. Stirring was continued for the next 5 minutes. The reaction medium

was then neutralized by adding NaHCO3, filtered, and extracted with ether. The combined

organic medium was then washed by water (3 x 50 mL) and brine (3 x 50 mL), dried over

anhydrous MgSO4, and concentrated under reduced pressure. The crude product was then

purified by silica gel column chromatography using hexane and ethyl acetate (60:40) as eluent

affording a pure product of 3-39 (4.20 g, 67%) as a colorless oil.

3-39: Rf= 0.38 (CH2C12/MeOH, 9:1); [a]25D -35.57 0 (C = 1.69, MeOH); IR (neat) vmax

3385, 2942, 1736, 1643, 1459, 1377, 1325 cm-1; H NMR (300MHz, CDC13) 6 5.68-5.5.62 (d, J

= 6 Hz, 1H), 5.38-5.32 (d, J= 6 Hz, 1H), 4.79-4.73 (d, J= 6.0 Hz, 1H), 4.56-4.50 (d, J= 6.0 Hz,

1H), 4.38-4.26 (br m, 2H, two hydroxyl OH), 3.3.72-3.62 (m, 2H), 1.56-1.42 (s, 3H), 1.30-1.24

(s, 3H); 13C NMR (CDC13) 6 112.3, 102.8, 87.7, 86.8, 81.7, 63.5, 26.4, 24.8.


TBDMS protected monoacetone-D-ribose 3-40


H3C CH3
H CC i ,O OH
13CH3e U


H3C CH3
To a solution of 2,3-o-isopropylidine-D-ribofuranose (3-39) (2.25 g, 12 mmol) and

imidazole (2.25 g, 33 mmol) in anhydrous DMF (6 mL, 2M) was added TBDMS chloride (2.05









g, 14 mmol) in one portion. The resulting solution was then stirred at room temperature for 3.5 h

and was subsequently diluted in water (30 mL). The product was then extracted with ethyl

acetate (3 x 30 mL). The combined extract was washed with water (2 x 50 mL) and brine (1 x 50

mL), dried over anhydrous MgSO4, and purified by silica gel column chromatography with

hexane and ethyl acetate (90:10) as eluent affording the pure white solid 3-40 (1.86g, 52% yield)

(m.p. 54-57C). Spectral data and melting point are in agreement with literature.154

3-40: Rf= 0.51 (hexane/EtOAc, 6:4); m.p. 54.0-55.0 C (lit 55.0-57.0 C)24 [a]25 D-14.02 o

(C = 1.64, MeOH), lit C = -13.4 0 (C = 1.0, CHC13); 24 IR (neat) Vmax 3422, 2935, 2859, 1472,

1374 cm-1; 1H NMR (300MHz, CDC13) 6 5.20-5.12 (d, J= 12 Hz, 1H), 4.70-4.62 (d, J= 6.2 Hz,

1H), 4.62-4.56 (d, J= 6 Hz, 1H), 4.42-4.36 (d, J= 8.1 Hz, 1H), 4.24-4.18 (m, 1H, hydroxyl

OH), 3.65-3.62 (d, 2H), 1.80-1.34 (s, 3H), 1.24-1.20 (s, 3H), 0.85-0.80 (s, 9H), 0.01-0.05 (s, 6H);

13C NMR (CDC13) 6 111.9, 103.4, 87.5, 86.9, 81.9, 64.8, 26.5, 26.1, 25.9, 25.8, 25.6, 24.9, 24.7,

18.3, -5.6, -5.7.

Esterification of monoacetone (D)-ribose 3-41


O



H3C CH3
To a solution of the monoacetone-D-ribose (3-39) (3.00 g, 16 mmol) at 0C was added

DIC (2.39 g, 19 mmol) and a catalytic amount of DMAP (0.48 g, 4 mmol) in anhydrous CH2C12

(32 mL, 0.50 mol) taken in a round bottom flask under Ar. 4-Pentenoic acid (1.58 g, 16 mmol)

was added at 0C over the next 20 min. After completion of the addition, the reaction mixture

was warmed to the room temperature and stirred for 4 h. Reaction was monitored by TLC

(hexane/EtOAc, 6:4). The crude product was filtered, and washed with water (2 x 50 mL) and









brine (1 x 50 mL). It was then dried over anhydrous MgSO4, concentrated under reduced

pressure, and purified by silica gel column chromatography using hexane and ethyl acetate

(60:40) as eluent to give the desired product 3-41 (1.15 g, 26 %). Majority of the product is the

diester of the monoacetone (D)-ribose. All products were colorless oil.

3-41: Rf = 0.28 (hexane/EtOAc, 6:4); [a]25D -60.34 o (C = 1.46, MeOH); IR (neat) Vmax

3494, 3080, 2986, 1744, 1642, 1417, 1382 cm-1; 1HNMR (300MHz, CDC13) 6 6.20-6.15 (s,

1H), 5.82-5.68 (m, 1H), 5.06-4.94 (m, 2H), 4.73-4.68 (d, J= 8.1 Hz, 1H), 4.65-4.60 (d, J= 8.1

Hz, 1H), 4.36-4.28 (t, J= 7.1 Hz, 1H), 3.62-3.52 ( m, 2H), 2.64-2.54 (br s, 1H, hydroxyl OH),

2.40-2.26 (m, 4H), 1.46-1.42 (s, 3H), 1.28-1.24 (s, 3H); 13C NMR (CDC13) 6171.3, 136.2, 115.9,

112.9, 102.6, 88.8, 85.5, 81.2, 63.4, 33.6, 28.5, 26.5, 24.9; HRMS [CI pos] for C13H2106

[M+H]+, calcd 273.1338, found 273.1336.

Esterification of TBDMS protected monoacetone-D-ribose 3-45



H3C CH3
H C--Si ^ O',0 0
H3CHdc u 0 C O
i. 0
O

H3C CH3
To a solution of the TBDMS protected monoacetone-D-ribose 3-40, (1.20 g, 4 mmol) was

added DIC (0.60 g, 5 mmol) and DMAP (0.14 g, 12 mmol) in anhydrous CH2C12 (8 mL, 0.50 M)

taken in a round bottom flask under Ar. 4-Pentenoic acid (0.47 g, 5 mmol) was added at 0C over

the next 10 minutes. After completion of the addition, the reaction mixture was warmed to the

room temperature, and stirred for an additional 3 h. Reaction was monitored by TLC

(hexane/EtOAc, 6:4). At the end of 3 h, the product was filtered, washed with water (2 x 50 mL)

and brine (1 x 50 mL). The crude product was then dried over anhydrous MgSO4, concentrated









under reduce pressure, and purified by silica gel column chromatography using hexane and ethyl

acetate (95:5) as eluent to give the desired product 3-45 (1.36 g, 89 %) as a colorless oil.

3-45: Rf= 0.65 (hexane/EtOAc, 6:4); [a]25D -51.16 0 (C = 2.05, MeOH); IR (neat) vmax

3081, 2956, 1752, 1472, 1417, 1374, 1105 cm1; 1H NMR (300MHz, CDC13) 6 6.18-6.14 (s, 1H),

5.84-5.70 (m, 1H), 5.08-4.94 (m, 2H), 4.78-4.72 (d, J= 5.1 Hz, 1H), 4.66-4.62 (d, J= 5.1 Hz,

1H), 4.30-4.22 (dd, J= 8.1 Hz, 2.3 Hz, 1H), 3.68-3.60 (dd, J= 8.1 Hz, 2.3 Hz, 1H), 3.56-3.46

(dd, J= 8.1 Hz, 2.3 Hz, 1H), 2.38-2.32 (m, 4H), 1.48-1.44 (s, 3H), 1.32-1.28 (s, 3H), 0.90-0.86

(s, 9H), 0.06--1.02 (s, 6H); 13C NMR (CDC13) 6 171.4, 136.4, 115.8, 112.9, 102.7, 88.2, 85.3,

81.8, 63.7, 33.8, 28.6, 26.6, 25.9, 25.2, 18.4, -5.3, -5.3; HRMS [CI pos] for C18H3106Si [M-

CH3]+, calcd 371.1890, found 371.1882.

Monobenzylation of monoacetone (D)-ribose 3-44


Ph O


H3C CH3
In a 100 mL oven-dried round bottom flask, 4.06 g of acetone D-ribose (3-39) (21 mmol)

was taken in 11 mL of anhydrous CH2C12 (2M) and was stirred for the next 10 min. 0.90 g of

NaH (60% in oil dispersion) was added to it and the reaction mixture was stirred for the next 15

min under Ar, till no more hydrogen gas was evaporated, as noticed by the absence of an

bubbling. This was followed by the addition of TBAI (0.80 g, 2 mmol). Then 2.70 g of benzyl

chloride (21 mmol) was added over the next 15 min under Ar. The reaction mixture was stirred

for overnight. At the end of 12 h stirring it was quenched with water and the organic layer was

extracted with CH2C12. The combined organic medium were then washed with water (3 x 20 mL)

and brine (3 x 20 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure.









The crude product was then purified by silica gel column chromatography using hexane and

ethyl acetate (80:20) as eluent affording the pure product 3-44 (2.80 g, 47 %) as a white solid

(m.p. 98.5 100.0 C).

3-44: Rf = 0.35 (hexane/EtOAc, 6:4); [a]25D -82.08 0 (C = 1.08, CH2C12); m.p. 98.5 100.0

oC; IR (neat) Vmax 3476, 3032, 2930, 1947, 1892, 1498 cm-1; 1H NMR (300MHz, CDC13) 6 7.38-

7.28 (m, 5H), 5.22-5.16 (s, 1H), 4.88-4.84 (d, J= 6 Hz, 1H), 4.80-4.73 (d, J= 6 Hz, 1H), 4.70-

4.64 (d, J= 6 Hz, 1H), 4.60-4.53 (d, J= 7.1 Hz, 1H), 4.47-4.42 (t, J= 7.1 Hz, 1H), 3.75-3.56 (m,

2H), 3.20-3.12 (dd, J= 10.1 Hz, 5.1 Hz, 1H), 1.50-1.46 (s, 3H), 1.34-1.28 (s, 3H); 13C NMR

(CDC13) 6136.5, 128.8, 128.4, 128.4, 112.3, 108.2, 88.6, 86.1, 81.7, 70.3, 64.2, 26.5, 24.8;

HRMS (ESI FT-ICR) for C15H20OsNa [M+Na] calcd 303.1203, found 303.1210.

Esterification of benzylated monoacetone-D-ribose 3-46






o 0)
:- 0
-0
H3C CH3
To a solution of the benzylated monoacetone-D-ribose 3-44 (2.20 g, 8 mmol) was added

DIC (1.19 g, 9 mmol) and a catalytic amount of DMAP (0.29 g, 2 mmol) in anhydrous CH2C12

(79 mL, 0.10 M) taken in a round bottom flask under argon atmosphere, 4-pentenoic acid (0.94

g, 9 mmol) was added at 0C over the next 15 min. After completion of the addition, the reaction

mixture was warmed to the room temperature and stirred for 3 h. Reaction was monitored by

TLC (hexane/EtOAc, 6:4). At the end of 3 h, the product was filtered, and washed with water (2

x 50 mL) and brine (1 x 50 mL). The crude product was then dried over anhydrous MgSO4,

concentrated under reduce pressure, and purified by silica gel column chromatography using









hexane and ethyl acetate (70:30) as eluent to give the desired product 3-46 (2.30 g, 81 %) as a

colorless oil.

3-46: Rf = 0.61 (hexane/EtOAc, 1:2); [a]25D -71.55 0 (C = 1.57, CH2C12); IR (neat) Vmax

3067, 3033, 2941, 1740, 1642, 1498, 1455, 1374, 1078 cm-1; 1HNMR (300MHz, CDC13)

6 7.37-7.24 (m, 5H), 5.87-5.72 (m, 1H), 5.18-5.16 (m, 1H), 5.09-4.96 (m, 2H), 4.72-4.66 (t, J=

7.1 Hz, 3H), 4.46-4.37 (m, 2H), 4.24-4.12 (m, 2H), 2.46-2.30 (m, 4H), 1.49-1.46 (s, 3H), 1.33-

1.29 (s, 3H); 13C NMR (CDC13) 6 172.7, 137.2, 136.8, 128.7, 128.4, 128.2, 115.9, 112.8, 107.6,

85.6, 84.7, 82.2, 69.5, 64.9, 33.6, 28.9, 26.7, 25.2; HRMS (ESI FT-ICR) for C20H2606Na

[M+Na]+, calcd 385.1622, found 385.1623.

Metathesis of the monoacetone (D)-ribose 3-47




OO


H3C CH3 0AO3
3 CH3

A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with argon and charged with 0.51 g (1

mmol) of the ester of monoacetone (D)-ribose 3-41, 0.15 g of the Grubbs' first-generation

catalyst (10 mol %) in 4 mL of anhydrous CH2C12 (0.50 M). The reaction mixture was stirred

and refluxed for 18 h. The metathesis reaction was then brought back to room temperature and

quenched with ethyl vinyl ether (1 mL). The crude product was concentrated under reduced

pressure, and purified by silica gel column chromatography using hexane and ethyl acetate

(40:60) as eluent to afford the desired metathesis product 3-47 (0.39 g, 81%).









3-47: Rf = 0.23 (hexane/EtOAc, 1:2); [a]25D -1.35 0 (C = 1.11, CH2C12); IR (neat) Vmax

3492, 2941, 1743, 1377, 1111 cm-1; 1HNMR (300MHz, CDC13) 6 6.22-6.18 (s, 2H), 5.46-5.14

(m, 2H), 4.77-4.4.72 (dd, J= 8.1 Hz, 2.1 Hz, 2H), 4.70-4.62 (m, 2H), 4.40-4.32 (t, J= 7.1 Hz,

2H), 3.68-3.54 (m, 4H), 2.72-2.52 (br s, 2H), 2.40-2.22 (m, 8H), 1.48-1.44 (s, 6H), 1.32-1.26 (s,

6H); 13C NMR (CDC13) 6 171.5, 171.4, 129.4, 129.1, 113.0, 102.7, 88.8, 85.5, 85.5, 81.3, 63.5,

34.3, 34.2, 27.4, 26.5, 24.9, 22.5; HRMS (ESI FT-ICR) for C24H36012Na [M+Na] calcd

539.2099, found 539.2102.

Metathesis of benzylated monoacetone (D)-ribose 3-49


[-Ph



phO/ 0 01 0 : CH3
0 CH3
-o
H3C CH3
A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with argon and charged with 0.66 g (2

mmol) of the ester of benzylated monoacetone (D)-ribose 3-46, 0.15 g of the Grubbs' first-

generation catalyst (10 mol %) in 4 mL of anhydrous CH2C12 (0.50 M). The reaction mixture was

stirred and refluxed for 18 h. The metathesis reaction was then brought back to room temperature

and quenched with ethyl vinyl ether (1 mL). The crude product was concentrated under reduced

pressure, and purified by silica gel column chromatography using hexane and ethyl acetate

(70:30) as eluent to afford the desired metathesis product 3-49 (0.51 g, 74%).

3-49: Rf = 0.64 (hexane/EtOAc, 1:2); [a]25D -6.60 o (C = 1.51, CH2C12); IR (neat) Vmax

3065, 3032, 2940, 1952, 1739, 1607, 1498, 1455 cm1; 1H NMR (300MHz, CDC13) 6 7.38-7.28

(m, 10H), 5.46-5.32 (m, 2H), 5.18-5.16 (s, 2H), 4.72-4.66 (t, J= 7.3 Hz, 6H), 4.47-4.41 (d, J=









8.1 Hz, 2H), 4.40-4.36 (m, 2H), 4.20-4.15 (dd, J= 7.1 Hz, 2.1 Hz, 4H), 2.42-2.22 (m, 8H), 1.49-

1.46 (s, 6H), 1.34-1.30 (s, 6H); 13C NMR (CDC13) 6 172.3, 136.7, 129.0, 128.2, 127.9, 127.7,

112.3, 107.1, 85.1, 84.2, 81.7, 69.1, 64.4, 64.3, 33.6, 27.4, 26.2, 24.7; HRMS (ESI FT-ICR) for

C38H48012Na [M+Na] calcd 719.3055, found 719.3038.

Metathesis of the diester of monoacetone (D)-ribose 4-14(HH/HT)


0
0
'0O CH3
O /"/O CH3

o 0
So



H3C 0
O
A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with argon and charged with 0.51 g (2

mmol) of the diester of monoacetone (D)-ribose 3-43, 0.12 g of the Grubbs' first-generation

catalyst (10 mol %) in 15 mL of anhydrous CH2C12 (0.10 M). The reaction mixture was stirred

and refluxed for 18 h. The metathesis reaction was then brought back to room temperature and

quenched with ethyl vinyl ether (1 mL). The crude product was concentrated under reduced

pressure, and purified by silica gel column chromatography using hexane and ethyl acetate

(70:30) as eluent to afford the desired metathesis product 4-14 (HH/HT) (0.47 g, 74%).

4-14: Rf = 0.34 (hexane/EtOAc, 6:4); [a]25D -59.47 0 (C = 1.48, CH2C12); IR (neat) Vmax

2989, 2863, 1736, 1427, 1357 cm-; H NMR (300MHz, CDC13) 6 6.18-6.12 (s, 2H), 5.52-5.42

(m, 2H), 5.38-5.26 (m, 2H), 4.76-4.70 (d, J= 5.1 Hz, 2H), 4.60-4.44 (m, 4H), 4.00-3.80 (m, 4H),

2.44-2.34 (m, 8H), 2.32-2.22 (m, 4H), 2.18-2.02 (m, 4H), 1.50-1.40 (s, 6H), 1.32-1.24 (s, 6H);









13C NMR (CDCl3) 6 173.6, 172.1, 129.8, 129.5, 113.5, 102.6, 85.1, 84.3, 81.4, 64.9, 34.4, 33.5,

28.1, 28.0, 26.5, 25.3; HRMS (CI pos) for C32H45014 [M+H] calcd 653.2809, found 653.2783.

Benzylation of D-isomannide 3-51


HO H

O-o

H _Ph
D-Isomannide (3-50) (5.20 g, 36 mmol), potassium hydroxide (5.20 g, 36 mmol) were

dissolved in water (18 mL) and the resulting solution was heated to reflux for 20 min. the

mixture was cooled to room temperature, benzyl chloride (4.51 g, 36 mmol) was added. The

solution was refluxed for additional 3h. The reaction was quenched with acid (HC1, 2N, 15 mL),

followed by extraction with ethyl acetate (3 x 15 mL). The combined organic layers were dried

over anhydrous MgSO4 and concentrated under vacuum. The crude product was then purified by

silica gel column chromatography using hexane and ethyl acetate (30:70) as eluent to afford the

pure product 3-51 with a yield of 3.36 g (40% yield) as a white solid (m.p. 90-92.C). Spectral

data and m. p. are in agreement with literature.155

3-51: Rf = 0.22 (hexane/EtOAc, 6:4); m.p. 90-92 C (lit. reported m.p. 93 C), [a]25D

+122.25 o (C = 1.03, CH2C12) (lit reported [a]20D +138 o (C = 1.00, CHC13)); IR (neat) Vmax 3423,

3063, 3031, 2875, 1496, 1455, 1405 cm-1; H NMR (300MHz, CDC13) 6 7.34-7.16 (m, 5H),

4.70-4.62 (d, J= 11.8 Hz, 1H), 4.50-4.40 (dd, J= 8.5 Hz, 5.5 Hz, 2H), 4.38-4.32 (t, J= 7.1 Hz,

1H), 4.20-4.10 (dq, J= 8.5 Hz, 5.5 Hz, 1H), 4.14-3.94 (m, 3H), 3.77-3.66 (m, 2H), 3.00-2.84

(dd, J= 8.5 Hz, 2.1 Hz, 1H); 13C NMR (CDC13) 6 137.6, 128.4, 127.9, 81.7, 80.5, 79.0, 74.5,

72.5, 72.3, 71.3.









Esterification of monobenzylated (D)-Isomannide 3-52


O

O H


H 0-Ph
To a solution of benzylated-D-isomannide (3-51) (0.53 g, 2 mmol) was added DIC (0.34 g,

2.70 mmol) and catalytic amount of DMAP (70 mg, 6 mmol) in anhydrous CH2C12 (6 mL, 0.5

mol) taken in a round bottom flask under Ar. 4-Pentenoic acid (0.28 g, 3 mmol) was added at

0C over the next 5 min. After completion of the addition, the reaction mixture was warmed to

the room temperature, and stirred for an additional 2.5 h. Reaction was monitored by TLC

(hexane/EtOAc, 6:4). After the completion of the reaction, the product was filtered, washed with

water (2 x 20 mL) and brine (1 x 20 mL). The crude product was then dried over anhydrous

MgSO4, concentrated under reduce pressure and purified by silica gel column chromatography

using hexane and ethyl acetate (90:10) as eluent to afford the pure product 3-52 with a yield of

3.24 g (84%).

3-52: Rf= 0.31 (hexane/EtOAc, 6:4); [a]25D +168.51 o (C = 1.66, CH2C12); IR (neat) Vmax

3067, 3031, 2879, 1740, 1642, 1500, 1455, 1367 cm-1; 1HNMR (300MHz, CDC13) 6 7.40-7.20

(m, 5H), 5.90-5.74 (m, 1H), 5.12-5.07 (m, 2H), 5.06-4.96 (m, 2H), 4.78-4.71 (d, J= 8.1 Hz, 1H),

4.70-4.65 (t, J= 7.1 Hz, 1H), 4.50-4.45 (t, J= 7.1 Hz, 1H), 4.08-3.98 (m, 2H), 3.96-3.88 (dd, J=

8.5 Hz, 5.5 Hz, 2H), 3.68-3.60 (t, J= 7.1 Hz, 1H), 2.52-2.44 (m, 1H), 2.42-2.34 (m, 2H); 13C

NMR (CDCl3)6 172.4, 137.6, 136.5, 128.4, 127.9, 115.5, 80.7, 80.2, 78.8, 70.5, 38.1, 28.7;

HRMS (ESI FT-ICR) for Cs1H220sNa [M+Na] calcd 343.1359, found 343.1359.









Metathesis of the ester of benzylated (D)-Isomannide 3-53


o 0o
0 H 0 0
S O O
-O-
0- H O Ph
H Ph
A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with Ar and charged with 0.52 g (16

mmol) of the ester of benzylated (D)-isomannide 3-52, 0.13 g of the Grubbs' first-generation

catalyst (10 mol %) in 5 mL of anhydrous CH2C12 (0.50 M). The reaction mixture was stirred

and refluxed for 18 h. The metathesis reaction was then brought back to room temperature and

quenched with ethyl vinyl ether (1 mL). The crude product was then concentrated under reduced

pressure, and purified by silica gel column chromatography using hexane and ethyl acetate

(70:30) as eluent to afford the desired metathesis product 3-53 (0.41 g, 82%) as a highly viscous

oil.

3-53: Rf = 0.35 (hexane/EtOAc, 1:2); [a]25D +0.13 o (C = 1.68, CH2C12); IR (neat) Vmax

3031, 2878, 1739, 1657, 1497, 1455, 1367 cm1; 1HNMR (300MHz, CDC13) 6 7.40-7.26 (m,

12H), 5.50-5.36 (m, 2H), 5.16-5.06 (dd, J= 5.1 Hz, 2.1 Hz, 2H), 4.78-4.72 (d, J= 7.1 Hz, 2H),

4.70-4.64 (t, J= 7.1 Hz, 2 H), 4.60-4.54 (d, J= 7.2 Hz, 2H), 4.51-4.46 (t, J= 7.1 Hz, 2H), 4.10-

3.98 (m, 4H), 3.96-3.88 (m, 4H), 3.68-3.59 (t, J= 7.1 Hz, 2H), 2.46-2.26 (m, 8H); 13C NMR

(CDC13) 6 172.7, 137.7, 129.4, 129.0, 128.6, 128.1, 80.8, 80.3, 78.9, 74.3, 74.2, 72.7, 71.2, 70.6,

33.8, 27.8, 22.7; HRMS (ESI FT-ICR) for C34H40010Na [M+Na] calcd 631.2514, found

631.2518.










Benzylation of D-isosorbide (exo) 3-55


OH H


H~-
OH Ph
D-Isosorbide (3-54) (5.20 g, 36 mmol), potassium hydroxide (2 g, 36 mmol) were

dissolved in water (18 mL) and the resulting solution was heated to reflux for 20 min. the

mixture was cooled to r.t., benzyl chloride (4.51 g, 36 mmol) was added. The solution was

refluxed for an additional 3h followed by an acid quench (HC1, 2N, 15 mL), and extraction with

ethyl acetate (3 x 25 mL). The combined organic layers were dried over anhydrous MgSO4 and

concentrated under vacuum. The crude product was then precipitated in cold diethyl ether (30

mL) to obtain the final product 3-55 with a yield of 40%. Spectral data are in agreement with

literature.155

3-55: Rf= 0.18 (hexane/EtOAc, 6:4); [a]25D+29.76 0 (C = 1.32, CH2C2), (lit, [a]27D+27.60

o (C = 0.51, CHC13)26; IR (neat) vmax 3489, 2996, 1713, 1645, 1458, 1388, 1309, 1260 cm-1; 1H

NMR (300MHZ, CDC13) 67.38-7.26 (m, 5H), 4.65-4.60 (t, J= 7.1 Hz, 1H), 4.60-4.55 (d, J= 8.1

Hz, 2H), 4.54-4.48 (d, J= 8.1 Hz, 1H), 4.32-4.21 (m, 1H), 4.14-4.04 (m, 2H), 3.92-3.80 (m, 2H),

3.58-3.50 (m, 1H), 2.84-2.76 (d, J= 8.1 Hz, 1H); 13C NMR (CDC13) 6 137.6, 128.6, 128.0,

127.8, 86.1, 83.6, 81.9, 73.5, 73.5, 72.4, 71.6.

Esterification of benzylated (D)-isosorbide (exo) 3-56


0

OH
0 H

H Ph









To a solution of benzylated (D)-isosorbide (exo) 3-55 (1.2 g, 0.005 mol) at 0C was added

DIC (0.69 g, 5 mmol) and a catalytic amount of DMAP (0.21 g, 2 mmol) in anhydrous CH2C12

(50 mL, 0.10 M) taken in a round bottom flask under Ar. 4-Pentenoic acid (0.55 g, 6 mmol) was

added at 0C over the next 10 min. After completion of the addition, the reaction mixture was

warmed to the room temperature, and stirred for an additional 3 h. Reaction was monitored by

TLC (hexane/EtOAc, 6:4). At the end of 3h, the product was filtered, washed with water (2 x 35

mL) and brine (2 x 35 mL). The crude product was then dried over anhydrous MgSO4,

concentrated under reduce pressure and purified by silica gel column chromatography using

hexane and ethyl acetate (90:10) as eluent to afford the pure product 3-56 with a 71 % yield

(1.15 g) as a colorless oil.

3-56: Rf = 0.47 (hexane/EtOAc, 6:4); [a]25D+74.19 0 (C = 1.87, CH2C12); IR (neat) vmax

3489, 2996, 1713, 1645, 1458, 1388, 1309, 1260 cm-1; 1HNMR (300MHz, CDC13) 6 7.36-7.22

(m, 5H), 5.88-5.72 (m, 1H), 5.14-5.04 (m, 2H), 5.02-4.94 (m, 2H), 4.83-4.74 (t, J= 7.1 Hz, 1H),

4.58-4.54 (s, 2H), 4.54-4.49 (d, J= 5.1 Hz, 1H), 4.10-4.06 (m, 1H), 4.06-3.98 (m, 1H), 3.95-3.82

(m, 2H), 3.77-3.69 (dd, J= 5.1 Hz, 1.9 Hz, 1H), 2.49-2.42 (m, 2H), 2.41-2.34 (m, 2H); 13C NMR

(CDC13) 6 172.6, 137.6, 136.5, 128.4, 127.8, 127.6, 115.5, 86.1, 83.2, 80.5, 73.9, 73.0, 71.3,

69.9, 33.1, 28.7; HRMS (ESI FT-ICR) for Cs1H220sNa [M+Na]+, calcd 343.1359, found

343.1369.









Metathesis of the ester of benzylated (D)-isosorbide (exo) 3-57


O"( 0 0O
Ph o O0

0" 0 O

Ph
A 25 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with argon and charged with 0.47 g (15

mmol) of the ester ofbenzylated (D)-isosorbide (exo) 3-56, 0.12 g of the Grubbs' first-generation

catalyst (10 mol %) in 5 mL of anhydrous CH2C12 (0.30 M). The reaction mixture was stirred

and refluxed for 18 h. The metathesis reaction was then brought back to room temperature and

quenched with ethyl vinyl ether (1 mL). The crude product was concentrated under reduced

pressure, and purified by silica gel column chromatography using hexane and ethyl acetate

(70:30) as eluent to afford the desired metathesis product 3-57 (0.37 g, 82%) as a colorless oil.

3-57: Rf= 0.35 (hexane/EtOAc, 1:2); IR (neat) vmax 3031, 2878, 1739, 1657, 1497, 1455,

1367 cm-1; H NMR (300MHz, CDC13) 6 7.38-7.26 (m, 10H), 5.52-5.38 (m, 2H), 5.16-5.09 (m,

2H), 4.84-4.78 (t, J= 7.1 Hz, 2H), 4.58-4.55 (m, 2H), 4.54-4.51 (d, J= 7.1 Hz, 2H), 4.12-4.06

(m, 2H), 4.05-3.99 (m, 2H), 3.96-3.85 (m, 4H), 3.77-3.70 (m, 2H), 2.47-2.28 (m, 8H); 13C NMR

(CDC13) 6 172.9, 138.1, 129.9, 129.4, 128.9, 128.4, 128.2, 86.7, 86.7, 81.1, 74.5, 74.4, 73.6,

71.89, 70.5, 34.3, 28.2, 23.2.









Ester of phloroglucinol 3-62


0
-0

0 ^ O 0




To a solution of the phloroglucinol 3-61 (2.30 g, 0.018 mol) taken in a round bottom flask

was added DIC (7.10 g, 56 mmol) and DMAP (2.97 g, 24 mmol) in anhydrous THF (37 mL,

0.50 M) under Ar. 4-Pentenoic acid (5.65 g, 56 mmol) was added at 0 C over the next 15

minutes. After completion of the addition, the reaction mixture was warmed to the room

temperature and stirred for an additional 3 h. Reaction was monitored by TLC (hexane/EtOAc,

6:4). After the completion of the reaction, the product was filtered, and washed with water (2 x

50 mL) and brine (1 x 50 mL). As observed from the TLC plate, a significant portion of the

crude product was the di-ester of phloroglucinol. The crude product was then dried over

anhydrous MgSO4, concentrated under reduce pressure, and purified by silica gel column

chromatography using hexane and ethyl acetate (95:5) as eluent to afford the desired product 3-

62 (5.03 g, 75 %) as a colorless oil.

3-62: Rf= 0.62 (hexane/EtOAc, 6:4); IR (neat) vmax 3081, 2981, 2922, 1767, 1642, 1608,

1457, 1363, 1126, 1004 cm-1; 1HNMR (300MHz, CDC13) 6 6.84-6.81 (m, 3H), 5.96-5.81 (m,

3H), 5.18-5.04 (m, 6H), 2.68-2.62 (t, J= 7.1 Hz, 6H), 2.53-2.44 (q, J= 12.1 Hz, 6H); 13C NMR

(CDC13) 6 170.8, 151.3, 136.2, 116.2, 112.7, 33.6, 28.8; HRMS [ESI-FTICR-MS] for

C21H2406Na [M+Na] calcd 395.1465, found 395.1459.









CM of the ester of phloroglucinol and glucose 3-63


CH3 O


A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame

dried and cooled under vacuum. The flask was flushed with argon and charged with 0.16 g (0.43

mmol) of the ester of phloroglucinol 3-62 and 0.51 g (1.49 mmol) of the ester of diacetone-D-

glucose 3-32), 37 mg of the first-generation Grubbs' catalyst (10 mol %) in 17 mL of anhydrous

CH2C2 (0.50 M). The reaction mixture was stirred and refluxed for 18 h. The cross metathesis

reaction was then brought back to room temperature and quenched with ethyl vinyl ether (1 mL).

The crude product was concentrated under reduced pressure, and purified by silica gel column

chromatography using hexane and ethyl acetate (70:30) as eluent to afford the desired metathesis

product 3-63 (0.11 g, 58%) as a highly viscous oil.

3-63: Rf = 0.35 (hexane/EtOAc, 1:2); [a]25D +0.15 o (C = 1.68, CH2C2); IR (neat) Vmax

3081, 2981, 2922, 1767, 1748, 1642, 1608, 1457, 1363, 1126, 1004 cm1; 1H NMR (300MHz,

CDC13) 6 7.40-7.26 (m, 3H), 5.90-5.80 (m, 4H), 5.7-5.0 (m, 12H), 4.5-4.4 (m, 4H), 4.3-4.1 (m,









8H), 4.1-3.9 (m, 8H), 2.5-2.2 (m, 18H), 1.6-1.4 (s, 12 H), 1.4-1.3 (s, 12H), 1.30-1.25 (m, 12 H);

1C NMR (CDC13) 6 172.7, 137.7, 129.4, 129.0, 128.6, 128.1, 80.8, 80.3, 78.9, 74.3, 74.2, 72.7,

71.2, 70.6, 33.8, 27.8, 22.7.

Formation of diacetone D-mannitol (4-5)


H3C
H3C 0-
H--OH
HO--H
,0 CH3
O >CH3
Anhydrous zinc chloride (28.0 g) was placed in an oven-dried 500 mL round bottom flask

and 141 mL of acetone was added. The mixture was stirred under argon atmosphere until the salt

had dissolved completely. The suspension was filtered into another round-bottom flask

containing 16.0 g of D-mannitol (4-4) and stirred in a bath of cool water until it had just

dissolved (several hours). The solution was poured with stirring into a beaker containing a

solution of 35 g of potassium carbonate in 35 mL of water. The suspension was filtered with

suction and the precipitate was stirred several times with dichloromethane. The aqueous layer

was also extracted with dichloromethane two times. The combined organic extracts were dried

over anhydrous MgSO4, evaporated to dryness under reduced pressure. The crude product was

then recrystallized with dichloromethane/n-hexane (1:10) resulting in the formation of 11.75 g

(51%) of the pure product 4-5. Spectral data are in agreement with literature.126

4-5: Rf= 0.09 (hexane/EtOAc, 6:4); m.p. 117.0-119.0 C (lit 118.0 120.0 C); 126 25D

+2.09 (C = 1.46, MeOH); IR (KBr)vmax 3319, 2986, 2893, 1457, 1418, 1372, 1214, 1159, 1065

cm ; H NMR (300MHz, CDC13) 6 4.20-4.10 (m, 4H), 4.00-3.94 (dd, J= 8.4 Hz, 5.4 Hz, 2H),

3.78-3.70 (d, J = 6.7 Hz, 2H), 3.00-2.62 (br s, 2H, OH), 1.44-1.40 (s, 6H), 1.38-1.34 (s, 6H); 13C

NMR 6 109.6, 76.4, 71.3, 66.9, 26.9, 25.4.









Esterifiction of diacetone D-mannitol 4-9


H3,C

H O
H--0-
O--H
,0O CH3
S O CH3

To a solution of the diacetone D-mannitol (4-5) (4 g, 15 mmol) taken in a 100 mL round

bottom flask was added at 0C DIC (5.77 g, 45 mmol) and DMAP (0.53 g, 0.28 mol) in

anhydrous CH2C12 (30 mL, 0.50 equiv.) under Ar. 4-Pentenoic acid (4.60 g, 0.05 mol) was added

at 0C over the next 10 minutes. After completion of addition the reaction mixture was warmed

to room temperature and stirred for the next 3.5 h. The reaction was monitored by TLC

(hexane/EtOAc, 6:4). At the end of 3.5h, the product was filtered, and washed with water (2 x 50

mL) and brine (1 x 50 mL). The crude product was then dried over anhydrous MgSO4,

concentrated under reduced pressure; and purified by silica gel column chromatography using

hexane and ethyl acetate (100:0 to 90:10) as eluent to give the desired product 4-9 (4.60 g, 71%).

4-9 : Rf = 0.53 (hexane/EtOAc, 6:4); a25D +13.88 o (C = 2.33, MeOH); IR (KBr) Vmax 3081,

2987, 1747, 1642, 1455, 1418, 1372, 1156 cm-1; 1HNMR (300MHz, CDC13) 6 5.95-5.85 (m,

2H), 5.40-5.30 (m, 2H), 5.10-4.90 (m, 4H), 4.20-4.10 (dd, J = 8.2 Hz, 5.4 Hz, 2H), 3.94-3.84 (dd,

J= 9.5 Hz, 5.4 Hz, 2H), 3.82-3.76 (dd, J = 12.5 Hz, 4.5 Hz, 2H), 2.50-2.30 (m, 8H), 1.38-1.30 (s,

6H), 1.28-1.20 (s, 6H); 13C NMR 6 171.8, 136.4, 115.9, 109.5, 74.4, 71.5, 68.1, 33.5, 28.8, 26.6,

25.3.









Diester of the monoacetone (D)-ribose 3-43 or 4-10


0
o O0


So oxo
H3C CH3
To a solution of monoacetone (D)-ribose 3-39 (or 4-6) (2.10 g, 0.011 mol) at 0C was

added DIC (2.30 g, 25 mmol) and a catalytic amount of DMAP (0.34 g, 3 mmol) in anhydrous

CH2C12 (22 mL) taken in a round bottom flask under Ar. 4-Pentenoic acid (2.54 g, 25 mmol) was

added dropwise at 0 oC over the next 15 minutes. After completion of the addition, the reaction

mixture was warmed to the room temperature and stirred for the next 3.5 h. Reaction was

monitored by TLC (hexane/EtOAc, 6:4). At the end of 3.5 h, the product was filtered, and

washed with water (2 x 50 mL) and brine (1 x 50 mL). The crude product was then dried over

anhydrous MgSO4, concentrated under reduce pressure, and purified by silica gel column

chromatography using hexane and ethyl acetate (90:10) as eluent to give the desired product 3-43

(or 4-10) (2.83 g, 72 %).

4-10: Rf= 0.52 (hexane/EtOAc, 6:4); [a]25D -44.25 0 (C = 2.13, MeOH); IR (neat) vmax

3079, 2979, 2881, 1743, 1703, 1642, 1520, 1419, 1366, 1066 cm1; H NMR (300MHz, CDC13) 6

6.20-6.18 (s, 1H), 5.84-5.70 (m, 2H), 5.06-4.94 (m, 4H), 4.68-4.64 (s, 2H), 4.44-4.38 (t, J = 7.1

Hz, 1H), 4.14-4.02 (m, 2H), 2.46-2.26 (m, 8H), 1.48-1.44 (s, 3H), 1.32-1.28 (s, 3H); 13C NMR

(CDC13) 6 172.9, 171.7, 136.9, 136.8, 116.3, 116.2, 113.7, 102.6, 85.8, 85.6, 82.1, 64.5, 34.1,

33.8, 29.2, 28.9, 26.9, 25.5; HRMS [CI pos] for C18H2607 [M] calcd 354.1679, found 354.1691.









Esterification of D-isomannide 4-11


0




H0


To a solution of D-isomannide (4-7) (or compound 3-50) (6 g, 0.04 mol) in anhydrous

THF (82 mL, 0.50 equiv) was added DIC (11.41 g, 0.09 mol) and DMAP (3.80 g, 31 mmol) at

0C under Ar. 4-Pentenoic acid (8.65 g, 90 mmol) was added at 0C under Ar over the next 20

min. The reaction mixture was warmed to room temperature and stirred for the next 4h. The

crude product was then filtered, washed with water (2 x 50 mL) and brine (1 x 50 mL). The

combined organic layer were then dried over anhydrous MgSO4, concentrated under reduced

pressure, and purified by silica gel column chromatography using hexane and ethyl acetate

(90:10) as eluent to afford the pure product 4-11 (8.28 g, 65%) as a colorless oil.

4-11: Rf= 0.39 (hexane/EtOAc, 6:4); [a]25D +142.68 0 (C = 2.20, CH2C2); IR (neat) Vmax

3079, 2979, 2881, 1743, 1703, 1642, 1520, 1419, 1366, 1066 cm1; 1H NMR (300MHz, CDC13)6

5.80-5.64 (m, 2H), 5.02-4.94 (m, 3H), 4.94-4.88 (m, 2H), 4.88-4.84 (dd, J= 10.1 Hz, 5.1 Hz,

1H), 4.60-4.54 (m, 2H), 3.94-3.86 (dd, J= 8.1 Hz, 2.1 Hz, 2H), 3.71-3.64 (dd, J= 5.1 Hz, 2.1

Hz, 2H), 2.42-2.34 (m, 4H), 2.32-2.22 (m, 4H); 13C NMR (CDC13) 6 172.4, 136.5, 115.6, 80.4,

73.7, 70.4, 22.1, 28.8; HRMS (ESI FT-ICR) for C16H2206Na [M+Na] calcd 333.1309, found

333.1310.









Diesterification of (D)-Isosorbide 4-12


0

OH





To a solution of (D)-isosorbide (4-8) (or compound 3-54) (2.06 g, 0.01 mol) at OCwas

added DIC (3.73 g, 0.03 mol), and DMAP (1.03 g, 8 mmol) in anhydrous THF (30 mL, 0.50 M)

taken in a round-bottom flask under Ar. 4-Pentenoic acid (3.03 g, 0.03 mol) was added over the

next 10 min at 0C. After completion of addition the reaction medium was warmed to room

temperature and was stirred for the next 6h. The reaction was monitored by TLC (hexane/EtOAc,

6:4). At the end of 6h, the reaction medium was diluted with EtOAc (30 mL), and washed with

water (2 x 30 mL), and brine (2 x 30 mL). The combined organic layer were then dried over

anhydrous MgSO4, and concentrated under reduced pressure followed by purification by column

chromatography, using ethyl acetate and hexane as eluent (90:10) to afford the pure product 4-12

(3.06 g, 70%) as a colorless oil.

4-12: Rf= 0.42 (hexane/EtOAc, 6:4); [a]25D +153.71.39 0 (C = 2.10, CH2C2); IR (neat)

Vmax 3060, 2980, 2877, 1741, 1703, 1642, 1520, 1419, 1365 cm1; 1H NMR (300MHz, CDC13)

6 5.86-5.68 (m, 2H), 5.17-5.14 (m, 1H), 5.14-5.08 (m, 1H), 5.07-5.03 (m, 1H), 5.01-4.97 (m,

2H), 4.97-4.94 (m, 1H), 4.81-4.76 (t, J= 7.2 Hz, 1H), 4.44-4.40 (d, J= 5.1 Hz, 1H), 3.94-3.91

(m, 1H), 3.91-3.86 (m, 1H), 3.79-3.72 (dd, J= 8.1 Hz, 5.1 Hz, 1H), 2.48-2.28 (m, 8H); 13C NMR

(CDC13) 6172.3, 172.0, 136.5, 136.3, 115.8, 115.6, 85.9, 80.8, 78.0, 73.9, 73.4, 70.4, 33.4, 33.2,

31.6, 28.8, 22.7, 14.1.









ADMET of the diacetone (D)-mannitol 4-13


H3Cb O- n
H--0
0--H

o CH3

4-13
A 25 mL round bottom flask equipped with stir-bar was placed under argon atmosphere.

Ester of diacetone protected (D)-mannitol 4-9 (2.86 g, 7 mmol) in anhydrous chloroform (7 mL)

was added to it. Grubb's second-generation catalyst (56.93 mg) was added to the monomer and

stirred (monomer: catalyst ratio 100:1). The reaction system was placed under argon atmosphere

and vacuum alternatively. With the first addition of the catalyst, there was little evolution of

ethylene gas as observed from the bubbles formed. As the reaction progressed the medium

became more and more viscous and it had been changed from alternate argon vacuum state to

total vacuum condition. It was kept under this condition for next 48 hours with two more

addition of 1 equivalent CHC13 and subsequent vacuuming. After 48 hours of reaction, half of

the amount of Grubbs' second generation catalyst used initially was added. With the second

addition of catalyst, there were formation huge bubbles and the system was kept under total

vacuum for the next 24 hours. The reaction was monitored by taking NMR of the crude time to

time, as there was no significant information available from the TLC monitoring. The NMR of

the crude taken after first 24, 48 and 72 hours showed disappearance of the hydrogen of the

terminal double bond. The polymerization was terminated by adding ethyl vinyl ether. Any

further purification of the polymer could not be performed due its inability to be precipitated in

an appropriate cold solvent.









4-13: Rf = 0.22 (CHC13/MeOH, 9:1); [a]25D +15.65 0 (C = 2.02, MeOH); IR (neat) Vmax

3071, 2977, 1767, 1647, 1465, 1438, 1382, 1186 cm-1; 1HNMR (300MHz, CDC13) 6 6.0-5.2 (m,

11H), 6 4.2-4.0 (m, 7H), 6 4.0-3.7 (m, 14 H), 6 3.2-3.0 (m, 14H), 6 2.6-2.2 (m, 16H), 6 1.4-1.2

(m, 45H); 13C NMR: 6 172.3, 130.1, 110.0, 109.5, 74.5, 74.2, 71.7, 71.5, 65.9, 65.6, 34.9, 34.0,

33.7, 30.42, 29.0, 27.7, 26.6, 26.2, 25.7, 25.3.

ADMET of the diester of (D)-ribose 4-15


n
0




H3C CH3
A 25 mL round bottom flask equipped with stir-bar was placed under Ar. Diester of

diacetone protected (D)-ribose 4-10 (2.86 g, 7 mmol) in anhydrous chloroform (8 mL) was added

to it. Grubb's second-generation catalyst (57 mg) was added to the monomer and stirred

(monomer: catalyst ratio 100:1). The reaction system was placed under argon atmosphere and

vacuum alternatively. With the first addition of the catalyst, there was little evolution of ethylene

gas as observed from the bubbles formed. As the reaction progressed the medium became more

and more viscous and it had been changed from alternate argon vacuum state to total vacuum

condition. It was kept under this condition for next 48 hours with two more addition of 1

equivalent CHC13 and subsequent vacuuming. After 48 hours of reaction, half of the amount of

Grubbs' second generation catalyst used initially was added. With the second addition of

catalyst, there were formation huge bubbles and the system was kept under total vacuum for the

next 24 h. The reaction was monitored by taking NMR of the crude time to time, as there was no

significant information available from the TLC monitoring. The NMR of the crude taken after

first 24, 48 and 72 hours showed disappearance of the hydrogen of the terminal double bond. The









polymerization was terminated by adding ethyl vinyl ether. Any further purification of the

polymer could not be performed due its inability to be precipitated in an appropriate cold solvent.

4-15: Rf= 0.21 (CHC13/MeOH, 9:1); [a]25D +141.65 (C = 1.76, MeOH); IR (neat) vmax

3058, 2983, 1745, 1646, 1523, 1420, 1375, 1123 cm-1; 1H NMR (300MHz, CDC13) 6 6.20-6.18

(m, 6H), 5.0-4.0 (m, 22H), 2.46-2.26 (m, 30H), 1.5-1.1 (m, 10H); 13C NMR: 6 172.9, 172.7,

172.3, 171.5, 136.9, 136.7, 136.2, 136.1, 135.9, 134.7, 102.1, 101.9, 101.5, 85.8, 85.7, 85.5, 85.3,

85.1, 84.9, 82.7, 82.5, 82.1, 64.5, 64.3, 64.2, 63.9, 34.5, 33.7, 27.4, 26.3, 25.3, 24.9.

ADMET of the diester of (D)-isomannide 4-16


0

O H

O"
0



A 25 mL round bottom flask equipped with stir-bar was flamed dried and placed under Ar.

Ester of diacetone protected (D)-isomannide 4-10 (2.56 g, 8 mmol) in anhydrous chloroform (10

mL) was added to it. Grubb's second-generation catalyst (58 mg) was added to the monomer and

stirred (monomer: catalyst ratio 100:1). The reaction system was placed under argon atmosphere

and vacuum alternatively. With the first addition of the catalyst, there was little evolution of

ethylene gas as observed from the bubbles formed. As the reaction progressed the medium

became more and more viscous and it had been changed from alternate argon vacuum state to

total vacuum condition. It was kept under this condition for next 48 hours with two more

addition of 1 equivalent CHC13 and subsequent vacuuming. After 48 hours of reaction, half of

the amount of Grubbs' second generation catalyst used initially was added. With the second

addition of catalyst, there were formation huge bubbles and the system was kept under total









vacuum for the next 24 hours. The reaction was monitored by taking NMR of the crude time to

time, as there was no significant information available from the TLC monitoring. The NMR of

the crude taken after first 24, 48 and 72 hours showed disappearance of the hydrogen of the

terminal double bond. The polymerization was terminated by adding ethyl vinyl ether. Any

further purification of the polymer could not be performed due its inability to be precipitated in

an appropriate cold solvent.

4-16: Rf = 0.23 (CHC13/MeOH, 9:1); [a]25D+148.39 o (C = 2.01, MeOH); IR (neat) Vmax

3078, 2971, 2885, 1763, 1698, 1632, 1523, 1423, 1316 cm1; 1H NMR (300MHz, CDC13) 6 5.3-

5.0 (m, 6H), 6 4.4-4.0 (m, 6H), 6 4.0-3.5 (m, 16H), 6 3.4-3.0 (m, 16H), 6 2.50-2.20 (m, 32H), 6

1.6-1.1 (m, 32H); 13C NMR: 6 109.1, 74.0, 71.2, 65.6, 34.5, 33.7, 27.4, 26.3, 25.3, 24.9.

ADMET of the diester of (D)-isosorbide 4-17


0
O

n




A 25 mL round bottom flask equipped with stir-bar was flame dried and placed under Ar.

Ester of diacetone protected (D)-isosorbide 4-11 (2.76 g, 9 mmol) in anhydrous chloroform (8

mL) was added to it. Grubb's second-generation catalyst (57 mg) was added to the monomer and

stirred (monomer: catalyst ratio 100:1). The reaction system was placed under argon atmosphere

and vacuum alternatively. With the first addition of the catalyst, there was little evolution of

ethylene gas as observed from the bubbles formed. As the reaction progressed the medium

became more and more viscous and it had been changed from alternate argon vacuum state to

total vacuum condition. It was kept under this condition for next 48 hours with two more









addition of 1 equivalent CHC13 and subsequent vacuuming. After 48 hours of reaction, half of

the amount of Grubbs' second generation catalyst used initially was added. With the second

addition of catalyst, there were formation huge bubbles and the system was kept under total

vacuum for the next 24 hours. The reaction was monitored by taking NMR of the crude time to

time, as there was no significant information available from the TLC monitoring. The NMR of

the crude taken after first 24, 48 and 72 hours showed disappearance of the hydrogen of the

terminal double bond. The polymerization was terminated by adding ethyl vinyl ether. Any

further purification of the polymer could not be performed due its inability to be precipitated in

an appropriate cold solvent.

4-17: Rf= 0.25 (CHC13/MeOH, 9:1); [a]25D +154.39 0 (C = 2.26, MeOH); IR (film) vmax

3061, 2988, 2857, 1743, 1709, 1644, 1412, 1375 cm-1; 1H NMR (300MHz, CDC13) 6 5.3-5.0 (m,

6H), 6 4.4-4.0 (m, 6H), 6 4.0-3.5 (m, 18H), 6 3.4-3.0 (m, 18H), 6 2.50-2.20 (m, 28H), 6 1.6-1.1

(m, 34H); 13C NMR: 6 172.3, 172.0, 171. 6, 170.9, 136.4, 135.8, 135.4, 135.2, 86.9, 86.5, 81.2,

80.8, 78.5, 78.3, 77.8, 77.4, 73.9, 73.6, 73.1, 70.6, 70.3, 69.8, 69.5, 69.1, 68.8, 33.7, 33.3, 33.1,

32.9, 31.9, 31.7, 31.5, 31.3, 28.9, 28.7, 28.3, 27.9, 22.9, 22.5, 22.2, 21.7.












APPENDIX A
SELECTED NMR SPECTRAL DATA


The 1H NMR spectra of selected compounds from Chapter 2-4 are illustrated in this
appendix. The spectra along with the proposed structure are shown.


H3C 0,

H3C O

0--H
O CH3

O CH3































:


- .n













-rt



M


Figure A-1. H NMR of diacetone (D)-mannitol.































N
0H OO n

ao -












U














Figure A-2. 1H NMR of the ADMET of diacetone (D)-mannitol.









141












O O
0 0


H


""


-iigt W t ^*- */*n-
i~ e rh N

a a ..- -
.o t u
^ Sb- **u *t n.L r4 -. a
4a Z* *f-f4q-T 1 1JXc4'
; a ft: = ss


Id I. -
5~~8~~~11 C *1i' s s ?L


Figure A-3. 1H NMR of the t-Boc amino acetate of norbomene.
































O OCH3
00
~b-tJVNCI3


- I m |1


-t


Figure A-4. 1H NMR of ketoester of norbornene.









143


-.4








4.-
a























































Figure A-5. 1H NMR of diazo-ketoester of norbomene.







144












H3CO 0 CH3

x o..o 0H3 /OH3
H3C 0 (9y\{ 0 00CH3
ox0 0
H3CCH3 H3C3


Figure A-6. 1H NMR of the homodimer of diacetone (D)-mannose.


145


_ __


I















-_ ____ -3


Figure A-7. H NMR of the homodimer of diacetoned (D)-glucose.




146


U5
i* V-


- gq


~'q


S]
,-16
[IC


`I


















O -




CH 0
H3CcO i3 H 3
H3C O O 0 0 0
0 H3C CH3













.U)










Figure A-8. 1H NMR of the homodimer of the diacetoned (D)-galactose.







147














I .









SPh-
i













Ph O CH3
OO' 0 0 u F

H3C CH3


__________.________ ______J K




I

t "






















Figure A-9. 1H NMR of the homodimer of the benzylated monoacetoned (D)-ribose.







148
I









I [
















148










9.







OOH
HO __o_ H-
Ox O 'O CH3
H3C CH3 0 'CH3
0 CHI









I




i IC


i.






I P










Figure A-10. 1H NMR of the homodimer of monoacetoned (D)-ribose.








149











0


6 6O
H3C CH3


F-.
[,, ..-



i.

H--


7
r;


N
,Hi


4


Figure A-11. 1H NMR of the diester of monoacetoned (D)-ribose.






150


















0 /O H


H Ph
0 Ph H O~Ph
O


K:


K-


es





K,





K,


Figure A-12. 1H NMR of the homodimer of benzylated (D)-isomannide.





151


_ L_

_
~ ~1_1








~C~L











0


0 H



0





I,
I


















*.


























Figure A-13. H NMR of the diester of (D)-isomannide.
152
----------""---, -s




.---



1
















FiueA1.b M ftedetro D-smnie











-L
O a-1
0,


0 H



OH

0 j



-~ --S :C

.






I
---- -I -














131









Figure A-14. H NMR of the diester of (D)-isosorbide.

















153









LIST OF REFERENCES

(1) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140.

(2) Furstner, A. Adv. Synth. Catal. 2002, 344, 567-567.

(3) Ivin, K. J. J. Mol. Cat. A: Chemical 1998, 133,1-16.

(4) Randall, M. L.; Snapper, M. L. J. Mol. Cat. A: Chemical 1998, 133, 29-40.

(5) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.

(6) Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3013-3043.

(7) Mol, J. C. J. Mol. Cat. A: Chemical 2004, 213, 39-45.

(8) Rouhi, A. M. Chem. Eng. News 2002, 80, 34-38.

(9) Calderon, N. et al. Chem. Eng. News 1967, 45, 51.

(10) Ivin, K. J.; Mol, J. C. Olefin Metathesis and Polymerization; Academic Press: San Diego,
CA, 1997.

(11) Calderon, N.; Chen, H. Y.; Scott, K. W. Tetrahedron Lett. 1967, 3327-3329.

(12) Calderon, N.; Ofstead, E. A.; Ward, J. P.; Judy, W. A.; Scott, K. W. J. Am. Chem. Soc.
1968, 90, 4133-4140.

(13) Lewandos, G.S.; Pettit, R. J. Am. Chem. Soc. 1971, 93, 7087-7088.

(14) Grubbs, R. H.; Brunck, T. K. J. Am. Chem. Soc. 1972, 94, 2538-2540.

(15) Herisson, J. L.; Chauvin, Y. Makromol. Chem. 1971, 141, 161-176.

(16) Bazan, G. C.; Oskam, J. H.; Cho, H. N.; Park, L. Y.; Schrock, R. R. J. Am. Chem. Soc.
1991, 113, 6899-6907.

(17) Schrock, R. R.; Murdzek, J. S.; Basan, G. C.; Robbins, J.; Dimare, M.; Oregan, M. J. Am.
Chem. Soc. 1990, 112, 3875-3886

(18) Furstner, A. Topics in Organometallic Chemistry: Alkene A A'ti/, he%/i' in Organic
Syinhe/i', Springer; New York, 1998; Vol. 1.

(19) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem. Int. Ed. 1995, 34,
2039-2041.

(20) Nguyen, S. T.; Johnson, L. K.; Grubbs, R.H.; Ziller, J. W. J. Am. Chem. Soc. 1992, 114,
3974-3975.









(21) Rouhi, A. M. Chem. Eng. News 2002, 80, 29-33.

(22) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110.

(23) Herrmann, W. A.; Elison, M.; Fischer, J.; Kocher, C.; Artus, G. R. J. Angew. Chem. Int.
Ed. 1995, 34, 2371-2374.

(24) Scholl, M.; Tmka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247-
2250.

(25) Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem. 2002, 74, 7-10.

(26) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem. Soc. 2001,123, 749-750.

(27) Dias, E.L.; Nguyen, S.T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887-3897.

(28) Blackwell, H. E.; O'Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D.
A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58-71.

(29) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153-2164.

(30) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 2, 371-388.

(31) Smith, M. B.; March, J. March's Advanced Organic Chemistry; John Wiley & Sons, Inc.:
New York, 2001.

(32) Rivkin, A.; Cho, Y. S.; Cho, Gabarda, A. E.; Yoshimura, F.; Danishefsky, S. J. J. Nat.
Prod. 2004, 67, 139-143.

(33) Bielawski, C.W.; Grubbs, R. H. Angew. Chem. Int. Ed. 2000, 39, 2903-2906.

(34) Frenzel, U.; Nuyken, O. J. Polym. Sci. Part A: Polym. Chem 2002, 40,
2895- 2916.

(35) Enholm, E.; Joshi, A.; Wright, D. Tetrahedron Lett. 2004, 45, 8635-8637.

(36) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360-11370.

(37) Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187-190.

(38) Roy, R.; Dominique, R.; Das, S. K. J. Org. Chem. 1999, 64, 5408-5412.

(39) Peppas, N. A.; Langer, R. Origins and development of biomedical engineering within
chemical engineering. AICHEJ. 2004, 50, 536-545.

(40) Jagur-Grodzinski, J. Polyme. Adv. Technol. 2006, 17, 395-418.









(41) Lavik, E.; Langer, R. Tissue engineering: current state and perspectives. Appl. Micrbiol.
Biotechnol. 2004, 65, 1-8.

(42) Cao, Y.; Carol, T. I., et.al. Scaffolds, stem cells, and tissue engineering: a potent
combination. Aust. J. Chem.i 2005, 58, 691-703.

(43) Wang, Y. K.; Yong, T.; Ramakrishna, S. Nanofibers and their influence on cells for the
tissue engineering. Aust. J Chem. 2005, 58, 704-712.

(44) Langer, R.; Vacanti, J. P. Science, 1993, 260, 920.

(45) Vacanti, J. P.; Langer, R. Lancet, 1999, 354, 32-34.

(46) Gunatillake, P. A.; Adhikari, R. Euro. Cells andMaterials, 2003, 5, 1-6.

(47) Harris, L. D.; Kim, B. S.; Mooney, D. Biomed. Master. Res 1998, 42, 396.

(48) Thomson, R. C.; Mikos, A. G.; Beahm, E.; Lemon, J. C.; Satterfield, W. C.; Aufdemorte,
T. B.; Miller, M. J. Biomaterials, 1999, 20, 2007.

(49) Ivin, K. J.; Olefin3 i/,l, lw i/ Academic Press: London, 1983.

(50) Patton, P. P.; McCarthy, T. J. Macromolecules 1987, 20, 778.

(51) Patton, P. P.; Lillya, C. P.; McCarthy, T. J. Macromolecules 1986, 19, 1266.

(52) Jacobson, H.; Stockmayer, W. H. J. Chem. Phys. 1950, 18, 1600.

(53) Wagener, K. B.; Nel, J. G.; Konzelman, J.; Boncella, J. M. Macromolecules 1990, 23,
5155-5157.

(54) Ballkenhol, F.; Bussche-Hunnefeld, C.V.; Lansky, C.; Zachel, C. Angew. Chem. Int. Ed
1996, 35, 2288.

(55) Czamik, A. W. Acc. Chem. Res. 1996, 79, 112.

(56) Terrett, N. K. Combinatorial Chemistry, Oxford Univ. Press, Oxford, 1998.

(57) Ramstrom, O.; Lehn, J. M. Chembiochem 2000, 1, 41-48.

(58) Ramstrom, O.; Bunyapaiboonsri, T.; Lohmann, S.; Lehn, J. M. Biochimica et Biophysica
Acta 2002, 1572, 178-186.

(59) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Combinatorial Chemistry 2002, 7, 117-125.

(60) Varki, A.; Cummins, R.; Freeze, H.; Hart, G.; Marth, J. Essentials ofGlycobiology, 1999,
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.









(61) Rudd, P. M.; Guile, G. R.; Kuster, B.; Harvey, D. G.; Oppendaker, G.; Dwek, R. A.
Nature, 1997, 388, 205.

(62) Ladmiral, V.; Melia, E.; Haddleton, D. M. Eu. Polymer J. 2004, 40, 431.

(63) Wang, Y. F.; Chan, K. P.; Hay, A. S. React. Funct. Polym.1996, 30, 205.

(64) Hodge, P.; Colquhoun, H. M. Polym. Adv. Technol. 2005, 16, 84.

(65) Hodge, P. React. Funct. Polym. 2001, 48, 15.

(66) Hodge, P.; Kamau, S. D. Angew. Chem. Int. Ed. 2003, 42, 2412.

(67) Ivin, K. J.; Mol, J. C. (Eds) Olefin metathesis and Metathesis Polymerization, Academic
Press, London, 1997.

(68) Grubbs, R. H. (Ed) Handbook of Metahthesis, vols 1-3, Wiley-VCH, 2003.

(69) Ben-Haida, A.; Colqhoun, H. M.; Hodge, P.; Stanford, J. L. Macromol. Rapid Commun.
2005, 26, 1377.

(70) Linhardt, R. J.; Toida, T. Carbohydrates in drug design. New York: Marcel Dekker,
1997.

(71) Goa, K. L.; Benfield P. Drugs, 1994, 47, 536-566.

(72) McAlindon, T. E.; LaValley, M. P.; Gulin, J. P.; Felson, D. T. Jama-J. Am. Med. Assoc.
2000, 283, 1469-1475.

(73) Ramstrom, O.; Lehn, J. M. Nature 2001, 1, 26-36.

(74) Fischer, E. Enzyme. Chem. Ber. 1894, 27, 2985-2993.

(75) Lehn, J. M.; Eliseev, A. V. Science. 2001, 5512, 2331-2332.

(76) Lehn, J. M. Chem. Eur. J. 1999, 9, 2455-2463.

(77) Ramstrom, O.; Lehn, J. M. Chembiochem 2000, 1, 41-48.

(78) Kubota, Y.; Sakamato, S.; Yamaguchi, K.; Fujita, M. Proc. Natl. Acad. Sci. USA. 2002,
99, 4854-4856.

(79) Nazarpack-Kandlousy, N.; Zweigenbaum, J.; Henion, J.; Eliseev, A. V J. Comb. Chem.
1999, 1, 4854-4856.

(80) Furlan, R. L. E.; Ng, Y. F.; Otto, S.; Sanders, J. K. M. J. Am. Chem. Soc. 2001, 123,
8876-8877.

(81) Giger, T.; Wigger, M.; Audetat, S.; Benner, S. A. Synlett 1998, 688-691.









(82) McNaughton, B. R.; Bucholtz, K. M.; Camaano-Moure, A.; Miller, B. L. Org. Lett. 2005,
7, 733-736.

(83) Ramstrom, O.; Lehn, J.M. Nature Rev. Drug Discov.; 2002, 1, 26-36.

(84) Reprinted from Publication: Nature Rev. Drug Discov.; Vol 1, R., O.; Lehn, J. M.; Drug
Discovery by Dynamic Combinatorial Libraries; 26-36; Copyright 2002, with permission
from nature publishing Group.

(85) Nazarpack-Kandlously, N.; Zweigenbaum, J.; Henion, J.; Eliseev, A. V. J. Comb. Chem.
1999, 1, 199-206.

(86) Cousins, G. R. L.; Furlan, R. L. E.; Ng, Y. F.; Redman, J. E.; Sanders, J. K. M. Angew.
Chem. Int. Ed. 2001, 40, 423-428.

(87) Furlan, R.L.E. et al. Chem. Commun. 2000, 1761-1762.

(88) Ramstrom, O.; Lohmann, S.; Bunyapaiboonsri, T.; Lehn, J. M. Chemistry-A European
Journal 2004, 10, 1711-1715.

(89) Otto, S. Current Opinion in Drug Discovery & Development 2003, 6,
509-520.

(90) Almogren, A.; Koury, S.; Rittenhouse-Diakun, K. FASEB JOURNAL 1999, 13, A646-
A646.

(91) Fukuda, M.; Ohyama, C.; Lowitz, K.; Matsuo, O.; Pasqualini, R.; Ruoslahti, E. CANCER
RESEARCH 2000, 60, 450-456

(92) Roy, R. Carbohydrate Chemistry, ed. G. J. Boons, Chapman & Hall, UK, 1998, 243;
Roy, R. Curr. Opin. Struct. Biol., 1996, 6, 692; Kiessling, L. L.; Pohl, N. L. Chem. Biol.
1996, 3, 71; Bovin, N. V.; Gabius, H.-J. Chem. Biol.1995, 24, 413.

(93) Lee, Y. C.; Lee, R. T. Ace. Chem. Res. 1995, 28, 322; Lubineau, A.; Escher, S.; Alais, J.;
Bonnaffe, D. Tetrahedron Lett. 1997, 38, 4087; Patch, R. J.; Chen, H.; Pandit, C. R. J
Org. Chem. 1997, 62, 1543; Page, D.; Roy, R. Bioorg. Med. Chem. Lett. 1996, 6, 1765;
DeFrees, S. A.; Kosch, W.; Way, W.; Paulson, J. C.; Sabesan, S.; Halcomb, R. L.;
Huang, D. -H.; Ichikawa, Y.; Wong, C. -H. J Am. Chem. Soc. 1995, 117, 66.

(94) Roy, R. Top. Curr. Chem. 1997, 187, 241; Zanini, D.; Roy, R. Carbohydrate Mimics:
Concepts and Methods. ed.; Chapleur, Y.; Chemie, Verlag; Weinheim, Germany, 1998,
p. 385; Jayaraman, N.; Nepogodiev, S. A.; Stoddart, J. F. Chem. Eur. J. 1997, 3, 1193.

(95) Yarema, K. J.; Bertozzi, C. R. Curr. Opin. Chem. Biol. 1998, 2, 49; Roy, R.
Carbohydrates in Drug Design, ed.; Witczak, Z. J.; Nieforth, K. A.; Dekker, Marcel, NY,
1997, p. 83.









(96) Wells, J. A. Curr. Opin. CellBiol., 1994, 6, 163; Heldin, C. -H. Cell., 1995, 80, 213;
Boger, D. L.; Chai, W. Tetrahedron, 1998, 54, 3955; Diver, S. T.; Schreiber, S. L. J.
Am. Chem. Soc., 1997, 119, 5106.

(97) Velupillai, P.; Harn, D. A. Proc. Natl. Acad. Sci. U.S.A., 1994, 91, 18; Takata, I.; Chida,
K.; Gordon, M. R.; Myrvik, Q. N.; Ricardo, M. J.; Jr.; Kucera, L. S. J. Leukocyte., 1987,
41, 248; Gordon, E. J.; Sanders, W. J.; Kiessling, L. L. Nature, 1998, 392, 30.

(98) Wagener, K. B.; Smith, Jr.., D. W. Macromolecules 1991, 24, 6073-6078.

(99) Odian, G. G.; Principles in Polymerization, 3rd Ed., John Wiley & Sons, Inc.: New York,
1991

(100) Wagener, K. B.; Wolf, A. Polymer Preprints (American Chemical Society, Division of
Polymer Chemistry) 1991, 32, 535-536.

(101) Bauch, C. G. Wagener, K. B.; Boncella, J. M. Polymer Preprints (American Chemical
Society, Division of Polymer Chemistry) 1991, 32, 377-378.

(102) Wagener, K. B; Boncella, J. M. Macromolecules, 1991, 24, 2649.

(103) Wagener, K. B.; Brzezinska, K. Macromolecules, 1991, 25, 5273.

(104) Patton, J. T.; Boncella, J. M.; Wagener, K. B. Macromolecules, 1992, 25, 3862.

(105) Watson, M. D; Wagener, K. B. Macromolecules, 2000, 33, 8963.

(106) Portmess, J. D.; Wagener, K. B. J. Polymer Sci., Polymer Chem. 1996, 24, 6073.

(107) Corkhill, P. H.; Trevett, A. S.; Tighe, B. J. Proc Inst Mech Eng, 1990, 204, 147-155.

(108) Nayak, S.; Lyon, L. A. Angew. Chem. Int. Ed. 2005, 44, 7686 7708.

(109) Gombotz, W. R.; Wee, S. Adv. Drug Delivery Rev. 1998, 31, 267.

(110) Goosen, M. F. A.; OEShea, G. M. H.; Gharapetian, M.; Chou, S.; Sun, A. M. Biotechnol.
Bioeng. 1985, 27, 146.

(111) Lutolf, M. P.; Raeber, G. P.; Zisch, A. H.; Tirelli, N.; Hubbell, J. A. Adv. Mater. 2003,
15, 888.

(112) Eagland, D.; Crowther, N. J.; Butler, C. J. Eur. Polym. J. 1994, 30, 767.

(113) Mathur, M.; Hammonds, K. F.; Klier, J.; Scranton, A. B. J. ControlledRelease 1998, 54,
177.

(114) Hennink, W. E.; van Nostrum, C. F. Adv. Drug Delivery Rev. 2002, 54, 13.

(115) Dusek, K.; Patterson, K. J. Poly. Sci. Poly. Phys. Ed. 1968, 6, 1209.









(116) Staudinger, H.; Husemann, E. Ber. Dtsch. Chem. Ges. A 1935, 68, 1618.

(117) Ramstrom, O.; Lohmann, S.; Bunyapaiboonsri, T.; Lehn, J. M., Dynamic Combinatorial
Carbohydrate Libraries: Probing the Binding Site of the Concanavalin a Lectin.
Chemistry-A European Journal 2004, 10, (7), 1711-1715.

(118) Ramstrom, O.; Bunyapaiboonsri, T.; Lohmann, S.; Lehn, J. M., Chemical Biology of
Dynamic Combinatorial Libraries. Biochimica Et Biophysica Acta-General Subjects
2002, 1572, (2-3), 178-186.

(119) Bloodworth, A. J.; Davies, A. G., The Addition of Tin Alkoxides to Isocyanates. J
Chem. Soc. 1965, 5238-5244.

(120) Amaya, T.; Tanaka, H.; Takahashi, T., Combinatorial Synthesis of Carbohydrate Cluster
on Tree-Type Linker with Orthogonally Cleavable Parts. SYNLETT 2004, (3), 497-502.

(121) Hummel, G.; Jobron, L.; Hindsgaul, O., Solid-Phase Synthesis of a 1-Thio-Beta-D-
Glcnac Carbohydrate Mimetic Library. J. OF CARBOHYDRATE CHEM. 2003, 22, (7-8),
781-800.

(122) Lohse, A.; Schweizer, F.; Hindsgaul, O., Synthesis of a 56 Component Library of Sugar
Beta-Peptides. COMB. CHEM. & HIGH THROUGHPUT SCREENING 2002, 5, (5),
389-394.

(123) Nilsson, U.; Fournier, E.; Fryz, E.; Hindsgaul, O., Parallel Solution Synthesis of a
"Carbohybrid" Library Designed to Inhibit Galactose-Binding Proteins. COMB. CHEM.
& HIGH THROUGHPUT SCREENING 1999, 2, (6), 335-352.

(124) Marcaurelle, L.; Seeberger, P., Combinatorial Carbohydrate Chemistry. CURRENT
OPINIONIN CHEM. BIO. 2002, 6, (3), 289-296.

(125) Kerckhoffs, J.; Ishi-i, T.; Paraschiv, V.; Timmerman, P.; Crego-Calama, M.; Shinkai, S.;
Reinhoudt, D. N., Complexation of Phenolic Guests by Endo- and Exo-Hydrogen-
Bonded Receptors. Organic & Biomolecular Chemistry 2003, 1, (14), 2596-2603.

(126) Lins, R. J.; Flitsch, S. L.; Turner, N. J.; Irving, E.; Brown, S. A., Generation of a
Dynamic Combinatorial Library Using Sialic Acid Aldolase and in Situ Screening
against Wheat Germ Agglutinin. Tetrahedron 2004, 60, (3), 771-780.

(127) Bunyapaiboonsri, T.; Ramstrom, O.; Lohmann, S.; Lehn, J. M.; Peng, L.; Goeldner, M.,
Dynamic Deconvolution of a Pre-Equilibrated Dynamic Combinatorial Library of
Acetylcholinesterase Inhibitors. Chembiochem 2001, 2, (6), 438-444.

(128) Misske, A.; Hoffmann, H., High Stereochemical Diversity and Applications for the
Synthesis of Marine Natural Products: A Library of Carbohydrate Mimics and Polyketide
Segments. CHEMISTRY-A EUROPEAN JOURNAL 2000, 6, (18), 3313-3320.









(129) Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser, R., Serial Radical Cyclization of
Branched Carbohydrates. Part 1. Simple. J. Org. Chem. 1989, 54, 5350-5356.

(130) Le, G. T.; Abbenante, G.; Becker, B.; Grathwohl, M.; Halliday, J.; Tometzki, G.; Zuegg,
J.; Meutermans, W. Drug discovery today, 2003, 8, 701-709.

(131) Martin, E. J. et al. Measuring diversity: experimental design of combinatorial libraries for
drug discovery. J. Med. Chem. 1995, 38, 1431-1436.

(132) Dean, P. M. Molecular Similarity in Drug Design, Champman & Hall.

(133) Johnson, M. A.; Maggiora, G. M. Concepts and Application of Molecular Similarity,
1990, Wiley-Interscience.

(134) Bourne, G. T. et al.b-tum nomenclature: a topographical classification system. In
Peptides: Chemistry. Structure andBiology (kaumaya, P. T. P. and Hodges, R. S., eds)
354-355.

(135) Tran, T. T. et al. The side-chain classification of loops from high-resolution protein
crystal structures. In Peptidesfor the New Millenium (Fields, G. B. et al., eds), 320-321.

(136) Sofia, M. et al. Discovery of novel disaccharide antibacterial agents using a
combinatorial library approach. J. Med. Chem. 1999, 42, 3193-3198

(137) Opatz, T. et al. D-Glucose as a pentavalent chiral scaffold. Eur. J Org. Chem. 2003, 8,
1527-1536.

(138) Kallus, C. et al. Combinatorial solid-phase synthesis using D-Galactose as a chiral five-
dimension-diversity scaffold, Tetrahedron Lett. 1999, 40, 7783-7786.

(139) Clemons, P. A. Curr. Opin. Chem. Biol. 1999, 1, 112-115.

(140) Nicolaou, K. C.; Hughes, R.; Cho, S. Y.; Winssinger, N.; Smethurst, C.; Labischinski, H.;
Endermann, R. Angew. Chem. Int. Ed. Engl. 2000, 39, 3823-3828.

(141) Nicolaou, K. C.; Pfefferkorn, J. A.; Schuler, F.; Roecker, A. J.; Cao, G. Q.; Casida, J. E.
Chem. Biol. 2000, 12, 979-992.

(142) Burgess, L. E.; Newhouse, B. J.; Ibrahim, P.; Kashem, M. A.; Hartman, A.; Brandhuber,
B. J.; Wright, C. D.; Thomson, D. S.; Vigers, G. P. A.; Koch, K. Proc. Natl. Acad. Sci.
USA. 1999, 96, 8348-8352.

(143) Dolle, R. E.; J. Comb. Chem. 2002, 4, 369-418.

(144) Hirschmann, R.; sprengeler, P. A.; Kawasaki, T.; Leahy, J. W.; Shakespeare, W. C.;
Smith, A. B. III. Tetrahedron, 1993, 49, 3665-3676.









(145) Hirschmann, R.; Nicolau, K. C.; Pietranico, S.; Leahy, E. M.; Salvino, J.; Arison, B.;
Cichy, M. A.; Spoors, P. G.; Shakespeare, W. C. J. Am. Chem. Soc. 1993, 115, 12550-
12568.

(146) Piscopio, A.; Robinson, J. E.; Curr. Opion. In Chem. Bio. 2004, 8, 245-254.

(147) Reetz, M. T. Comp. Coord. Chem I. 2004, 9, 509-548.

(148) Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett., 1996, 37, 547; Furstner, A.; Muller, T.
J. Org. Chem. 1998, 63, 424; Van Hooft, P. A.; Leeuwenburgh, M. A.; Overkleeft, H. S.;
Van der Marel, G. A.; Boeckel, C. A. A. van; Boom, J. H. van. Tetrahedron Lett. 1998,
39, 6061; Feng, J.; Schuster, M.; Blechert, S. Synlett, 1997, 129; Schuster, M.; Lucas, N.;
Blechert, S. Chem. Commun. 1997, 823; Mortell, K. H.; Gingras, M.; Kiessling, L. L. J.
Am. Chem. Soc. 1994, 116, 12053; Fraser, C.; Grubbs, R. H. Macromolecules, 1995, 28,
7248; Nomura, K.; Schrock, R. R. Macromolecules, 1996, 29, 540.

(149) Descotes, G.; Ramza, J.; Basset, J.- M.; Pagano, S. Tetrahedron Lett., 1994, 35, 7379;
Ramza, J.; Descotes, G.; Basset, J. M.; Mutch, A. J. Carbohydr. Chem., 1996, 15, 125.

(150) Dominique, R.; Das, S. K.; Roy, R. Chem. Commun. 1998, 8, 2437-2438.

(151) Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115, 9858; Dias, E.
L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887; Schwab, P.;
Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100; Schuster, M.; Blechert, S.
Angew. Chem., Int. Eng 1997, 36, 2036; Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413; Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446

(152) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 749-750.

(153) Burkart, M. D. V.; Stephane. P.; Diiffels, A.; Murry, B. W.; Ley, S. V.; Wong, C.
Bioorganic & Medicinal Chemistry 2000, 8, 1937-1946.

(154) Kaskar, B.; Heise, G. L.; Michalak, R. S.; Vishnuvajjala, B. R. Synthesis 1990, 1031-
1032.

(155) Loupy, A.; Monteux, D. A. Tetrahedron 2001, 58, 1541-1549.

(156) Bauch, C. G. Wagener, K. B.; Boncella, J. M. Polymer Preprints (American Chemical
Society, Division of Polymer Chemistry) 1991, 32, 377-378.

(157) Danielmeier, K.; Steckhan, E. Tetrahedron Asymmetry 1995, 6, 1181-1190.

(158) Loupy, A.; Monteux, D. A. Tetrahedron 2001, 58, 1541-1549.

(159) Vonlanthen, D.; Leumann, C. J. Syi)hlii, 2003, 1087-1090.

(160) D6mling, A.; Ugi, I. Angew. Chem. Int. Edu. Engl. 2000, 39, 3168-3210.









(161) Sando, S.; Narita, A.; Aoyama, Y. Bioorganic & Medicinal Chemistry Letters 2004, 14,
(11), 2835-2838.

(162) Enholm, E. J.; Jiang, S., Highly Stereoselective Couplings of Carbohydrate Lactones with
Terpene. Tetrahedron Lett. 1992, 33, 6069-72.

(163) (a) Roy, R. In carbohydrate Chemistry; Boons, G. J., Ed.: Chapman & Hall: London,
UK, 1998; p 243. (b) Roy, R. In Toipcs in Current Chemistry Thiem, J., Driguez, H.,
Eds.: Springer: Heidelberg, 1997; Vol. 187, p 241.

(164) Dai, W. S.; Barbari, T. A. J. Membr. Sci.2000, 171, 79

(165) Peppas, N. A.; Benner, Jr. R. E. Biomaterials, 1980, 1, 158.

(166) Gehrke, S. H. Adv. Polym. Sci. 1993, 110, 82.

(167) Hoffman, A. S. Adv. Drug. Delivery Rev. 2002, 54, 3.

(168) Yeomans, K. Chem. Rev. 2000, 100, 2.

(169) Pit, C. G.; Schindler, A. In Biodegradation of Polymers. Controlled Drug Delivery;
Bruck, S. D. Ed.; CRC Press: Bocaraton, FL, 1983, Vol 53.

(170) Anseth, K. S.; Newman, S. M.; Bowman, C. N. iAdv. Polym. Sci. 1995, 122, 177.

(171) Kloosterboer, J. G. Adv. Polym. Sci. 1998, 84, 1.

(172) Mathias, L. J.; Kusefoglu, S. H.; kress, A. O.; Lee, S.; Wright, J. R.; Culberson, D. A.;
Warren, S. C.; Warren, R. M.; Huang, S.; Lopez, D. R.; Ingram, J. E.; Dickerson, C. W.;
Jeno, M.; Halley, R.J.; Colletti, R. F.; Cei, G.; Geiger, C. C. Makromol. Chem.
Macromol. Symp. 1991, 51, 153.

(173) Zhu, S.; Tian, Y.; Hamielec, A. E.; Eaton, D. R. Macromolecules, 1990, 23, 1144.

(174) Decker, C. Polym Int. 1998, 45, 133.

(175) Matsumoto, A. Adv. Polym. Sci. 1995, 123, 41.

(176) Anseth, K. S.; Decker, C.; Bowman, C. N. Macromolecules, 1995, 28, 403.

(177) Nelson, E. W.; Scranton, A. B. J. Polym. Sci., Polym. Chem. 1996, 34, 403.

(178) Hall, A. J.; Hodge, P.; Kamau, S. D.; Ben-Haida, A. J. Organometallic Chem. 2006, 691,
5431-5437.

(179) Chang, C. D.; Waki, M.; Ahmed, M.; Meienhofer, J.; Lundell, E. O.; Hang, J. D. Pept.
Prot. Res. 1980, 15, 59.

(180) Atherton, E.; Logan, C. J.; Sheppard, R. C. J. Chem.Soc. Perkin Trans 1981, 538.









(181) Ueki, M.; Amemiya, M. Tetrahedron Letter. 1987, 28, 6617-6620.

(182) McElwee-White, L.; Dougherty, D. A. J. Am. Chem. Soc.1984, 106, 3466-3474.

(183) Jung, M. E; Min, S.J.; Houk, K. N.; Ess, D. J. Org. Chem.2004, 69, 9085-9089.

(184) Firstner, A.; Kindler, N. Tetrahedron Letters, 1996, 117, 5855.

(185) Houri, A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem.Soc. 1996, 118, 10926.









BIOGRAPHICAL SKETCH

Kalyan Mondal was born in 1974, in Calcutta, India. He completed his schooling from

Taki High School, Calcutta with Science as major. He received his bachelor's degree from the

University of Calcutta. Dr. S. P. Basak inspired him in organic chemistry throughout his

teaching. Kalyan gladly recognizes his contribution for his basic chemistry knowledge. He then

joined B.Tech course under University of Calcutta and studied about Reverse Engineering on

Rubber based products. This Graduation course introduced him with new prospects of study in

Polymer Science. Dr. S. N. Gupta, Advisor had helped him to enrich his knowledge in Polymer

Science. After graduation, he decided to do further research work in synthesizing of Prostate

specific Antigen field and thus did his M.Tech from the same University under the guidance of

Dr. P. Sarkar. He always wanted to carry on his research work to develop his knowledge. This

passion of knowledge brought him to USA and opened new scopes and opportunities before him.

He received his second M.S. degree in chemistry from East Tennessee State University under the

guidance of Dr. Tammy Davidson, working on the synthesis of Chiral Surfactants for

Enantioselective Organic Synthesis. He always wanted to be innovative and versatile and get

every possible knowledge from various fields of synthesis. He joined Dr. Eric Enholm's group to

enrich his knowledge on synthetic chemistry for PhD program at University of Florida. Kalyan

has learned much about the field of synthetic organic chemistry, especially chemistry related to

developing new methodology and multi-step synthesis. His graduate career is reached to a

pinnacle from where he is eager to step forward to apply his knowledge in practical field of

various industries engaged in different research & development works.





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1 OLEFIN METATHESIS IN CARBOHYDR ATE AND NORBORNENE APPLICATIONS By KALYAN MONDAL DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2007

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2 ACKNOWLEDGMENTS The rewards associated with completing this dissertation and earni ng my Ph.D. would not be a nearly as great if it hadn’t been for the very special people who gave me their support along the way. I would like to extend my sincere apprecia tion to my research advisor, Dr. Eric Enholm, for his support, patience, understanding and invalu able help throughout my graduate career at the University of Florida. I am forever grateful for his patience during my ever-developing skill in the lab. His enthusiasm and knowledge have been motivating, and his instruction has not only given me the technical abilities, but also the confid ence needed for a succ essful career. Looking back I have come a long way with regards to chemical knowledge and problem solving. It has been a real pleasure for me to conduct and discu ss research with Dr. Enholm. He provided me all the necessary guidance to complete my dissertat ion and allowed me the research freedom to develop my own ideas. He has been a great advi sor and I will never forget his encouragement and kindness. I would like to thank my committee members fo r their constructive feedback and advice. Special thanks go to Dr. William Dolbier. He is on e of the most sincere and helpful professors I have ever met, who shows true concern and inte rest toward his students. I would also like to thank Dr. Ronald Castellano. His excellent teachi ng style and well organized lectures gave me a great start to the PhD program. I sincerely th ank Dr. Ion Ghiviriga for helping with the elucidation of the structure of my organic compounds and for sharing his vast NMR expertise, more than I thought I could ever learn about NMR. I also appreci ate Dr. Kenneth Sloan for being on my committee and providing valuable feedback during my oral qualifier and the preparation of this dissertation. I truly have been fortunate to have these individuals on my committee.

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3 Graduate school would not have been enjoyable without my fellow Enholm group members–Jed Hastings, Sophie Klein, Tammy Low, and Ryan Martin. It has been a blessing to work in a cooperative environment, where la boratory discussions ar e open and free, and everyone is so helpful and genuine ly friendly. I especially like to thank Jed for his patience in helping with my lab experiments early on, for ex changing knowledge and for providing feedback as I prepared for my oral qualifier. Not only ha s it been a joy working with these individuals, I also appreciate their fri endship outside of lab. Special thanks go to Dr. Tammy Davidson, my M.S. adviser from my previous school East Tennessee State University and currently working at University of Florida for her consistent mental support throughout my Ph D career. Finally, my most h eartfelt acknowledgement must go to my parents, sisters and my wife Debalina for their continuous s upport, encouragement and kindness. I specially thank my parents for their in spiration, infinite love and faith. They have made me a better person by being my role models and instilling me with strong values. I would not have been in the position to write this dissert ation without my parents. Last and not the least, I would like to thank my wife Debalina for her consistent support for the last one year. Words alone cannot express my gratitude, especially fo r their tremendous love and belief in me during the PhD period. Special acknowledgement foes to the faculty a nd staff of the Department of Chemistry at the University of Florida for providing an ex cellent environment for graduate study that has helped me to make my stay he re quite enjoyable and rewarding.

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4 TABLE OF CONTENTS page ACKNOWLEDGMENTS ............................................................................................................... 2LIST OF TABLES ................................................................................................................ ...........7LIST OF FIGURES ............................................................................................................... ..........8LIST OF SCHEMES................................................................................................................ ......10ABSTRACT ...................................................................................................................... .............13CHAPTER 1 HISTORICAL BACKGROUND ...........................................................................................151.1 Olefin Metathesis ......................................................................................................... .....151.1.1 Development of Olefin Metathesis and Catalyst ....................................................151.1.2 Mechanism of Ol efin Metathesis ...........................................................................191.1.3 Important Types of Metathesis Reactions and Applications ..................................211.2 Ring Opening Metathesis Polymerization (ROMP) .........................................................251.3 Dynamic Combinatorial Chemistry ..................................................................................271.4 Carbohydrate chemistry .................................................................................................... 331.5 Tissue Engineering ........................................................................................................ ...361.6 Hydrogels ................................................................................................................. .........38Physically Cross-linked Hydrogels .................................................................................40Chemically Cross-linked Hydrogels ................................................................................411.7 Acyclic Diene Metathesis (ADMET) ...............................................................................411.8 Scope of the Thesis ....................................................................................................... ....432 RING OPENING METATHESIS PO LYMERIZATION OF NORBORNENE DERIVATIVES ................................................................................................................... ...452.1 Introduction .............................................................................................................. .........452.2 Results and Discussion .................................................................................................... .482.3 Conclusion ................................................................................................................ ........543 METATHESIS OF CARBOHYDRATES .............................................................................563.1 Introduction .............................................................................................................. .........563.2 Results and Discussion .................................................................................................... .633.2.1 Metathesis of the m onoester of carbohydrates .......................................................633.2.2 Metathesis of Tri-este rs of Phloroglucinol .............................................................773.4 Conclusion ................................................................................................................ ........79

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5 4 ACYCLIC DIENE METATHESIS RE ACTIONS OF CA RBOHYDRATES ......................814.1 Introduction .............................................................................................................. .........814.2 Results and Discussion .................................................................................................... .864.3 Conclusion ................................................................................................................ ........935 EXPERIMENTALS METHODS ...........................................................................................945.1 General Methods and Instrumentation ..............................................................................945.2 Experimental Procedure and Data ....................................................................................95Norbornenemethanol 2-13 ...............................................................................................95Ester carbamate of norbornene 2-14 ................................................................................95Amino acetate of norbornene 2-15 ..................................................................................96Fmoc protected ester carbamate of norbornene 2-16 ......................................................97Deprotection of the Fmoc group ......................................................................................98Norbornene ketoester 2-17 ..............................................................................................98p -Toluene sulfonyl azide (2-18) ......................................................................................99Diazo-ester of norbornene 2-19 .....................................................................................100Norbornene oxohexanoate 2-22 ....................................................................................101ROMP of the Compound 2-17 ......................................................................................102ROMP of the Compound 2-22 ......................................................................................103Diacetone D-mannose (3-25) ........................................................................................104Carbonate of diacetone (D)-mannose 3-26 ...................................................................104Metathesis of the carbonate of D-mannose 3-27 ...........................................................105Hydrogenation of the metathesis product of carbonate of diacetone (D)-mannose 328............................................................................................................................. ...106Esterification of diacetone D-mannose 3-29 .................................................................107Metathesis of the ester of D-mannose 3-30 ...................................................................108Ester of diacetone D-glucose 3-32 ................................................................................109Metathesis of the glucose ester 3-33 .............................................................................110Synthesis of diacetone D-galactose 3-35 .......................................................................111Ester of protected D-galactose 3-36 ..............................................................................112Metathesis of the ester of (D)-galactose 3-37 ................................................................113Protected monoacetone -D-ribose 3-39 .........................................................................114TBDMS protected monoacetone-D-ribose 3-40 ...........................................................114Esterification of monoace tone (D)-ribose 3-41 .............................................................115Esterification of TBDMS protec ted monoacetone-D-ribose 3-45 .................................116Monobenzylation of monoacetone (D)-ribose 3-44 ......................................................117Esterification of benzylated monoacetone-D-ribose 3-46 .............................................118Metathesis of the monoa cetone (D)-ribose 3-47 ...........................................................119Metathesis of benzylated monoacetone (D)-ribose 3-49 ...............................................120Metathesis of the diester of monoacetone (D)-ribose 4-14(HH/HT) ............................121Benzylation of D-isomannide 3-51 ...............................................................................122Esterification of monobenzylat ed (D)-Isomannide 3-52 ...............................................123Metathesis of the ester of be nzylated (D)-Isomannide 3-53 .........................................124Benzylation of D-isosorbide ( exo ) 3-55 ........................................................................125Esterification of benzyl ated (D)-isosorbide ( exo ) 3-56 .................................................125

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6 Metathesis of the ester of benzylated (D)-isosorbide ( exo ) 3-57 ..................................127Ester of phloroglucinol 3-62 ..........................................................................................128CM of the ester of phloroglucinol and glucose 3-63 .....................................................129Formation of diacetone D-mannitol (4-5) .....................................................................130Esterifiction of diacetone D-mannitol 4-9 .....................................................................131Diester of the monoacetone (D)-ribose 3-43 or 4-10 ....................................................132Esterification of D-isomannide 4-11 .............................................................................133Diesterification of (D)-Isosorbide 4-12 .........................................................................134ADMET of the diacetone (D)-mannitol 4-13 ................................................................135ADMET of the diester of (D)-ribose 4-15 .....................................................................136ADMET of the diester of (D)-isomannide 4-16 ............................................................137ADMET of the diester of (D)-isosorbide 4-17 ..............................................................138APPENDIX A SELECTED NMR SPECTRAL DATA ...............................................................................140LIST OF REFERENCES ............................................................................................................ .154BIOGRAPHICAL SKETCH .......................................................................................................165

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7 LIST OF TABLES Table page 1-1 Potential application of different dynamic process in DCC systems. ................................32 2-1 t-Boc Cleavage of the compound 2-14 .............................................................................50 2-2 Deprotection of Fmoc group to get the compound 2-15 ...................................................51 3-1 Olefin self-metathesis of alkenyl O and C -glycopyranosides. .........................................61 3-2 Yields, and optical proper ties of carbohydrate derivatives. ...............................................64 3-3 Yields, and optical properti es of the metathesis products. .................................................65 3-4 Comparison of the optical property of the esters of (D)-mannose and (D)-glucose. ........69 4-1 Yield of diene from the protected carbohydrates. ..............................................................86 4-2 ADMET of the carbohydrates. ...........................................................................................87 4-3 Mn of the ADMET polymer. ..............................................................................................93

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8 LIST OF FIGURES Figure page 1-1 Alkoxy imidomolybdenum-based Schrock’s catalyst. ......................................................18 1-2 Ruthenium catalysts. ..................................................................................................... .....19 1-3 Schematic representation of the concept involved in DCC. ..............................................29 1-4 Molding and casting processes in dynamic combinatorial libraries. .................................30 1-5 Templating of hydrazone-based library (a) in (b) the absence and (c) the presence of acetylcholine. ................................................................................................................ .....33 1-6 Structures of natural glycopolymers: ( 1 ) Starch; ( 2 ) Chitin; ( 3 ) Cellulose. ......................34 1-7 Physical cross-linking by noncovalent interactions. ..........................................................40 1-8 Acyclic diene metathes is (ADMET) polymerization. .......................................................42 3-1 Tungsten aryloxo complex used by Descotes ...................................................................59 4-1 Head-to-Tail, Head-to-H ead, Tail-to-Tail arrangement. ....................................................84 4-2 Hydrogels with carbohydrates le ngthwise, crosswise or rings. .........................................85 4-3 Schematic representation of the HH or HT cyclic dimer of diacetone (D)-ribose. ...........91 A-1 Proton NMR of diacetone (D)-mannitol. .........................................................................140 A-2 Proton NMR of the ADMET of diacetone (D)-mannitol. ................................................141 A-3 Proton NMR of the t-Boc amino acetate of norbornene. .................................................142 A-4 Proton NMR of ketoester of norbornene. ........................................................................143 A-5 Proton NMR of diazo-ket oester of norbornene. ..............................................................144 A-6 Proton NMR of the homodimer of diacetone (D)-mannose. ...........................................145 A-7 Proton NMR of the homodimer of diacetoned (D)-glucose. ...........................................146 A-8 Proton NMR of the homodimer of the diacetoned (D)-galactose. ...................................147 A-9 Proton NMR of the homodimer of th e benzylated monoacetoned (D)-ribose. ................148 A-10 Proton NMR of the homodimer of monoacetoned (D)-ribose. ........................................149

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9 A-11 Proton NMR of the dieste r of monoacetoned (D)-ribose. ................................................150 A-12 Proton NMR of the homodimer of benzylated (D)-isomannide. .....................................151 A-13 Proton NMR of the dies ter of (D)-isomannide. ...............................................................152 A-14 Proton NMR of the diester of (D)-isosorbide. .................................................................153

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10 LIST OF SCHEMES Scheme page 1-1 Olefin metathesis. ....................................................................................................... .......16 1-2 Proposed intermediates for olefin metathesis. ...................................................................17 1-3 Chauvin proposed metallacyclobutane intermediate. ........................................................17 1-4 Dissociative substitution of ruthenium catalyst. ................................................................20 1-5 Proposed mechanism of olefin metathesis. ........................................................................20 1-6 Quenching of ruthenium catalys t with ethyl vinyl ether (EVE) ........................................21 1-7 Different types of olefin metathesis. ..................................................................................22 1-8 Utilizing RCM for the synthesis of Epoth ilones using different alcohol protection and different solvents ........................................................................................................ .23 1-9 Application of ROMP to synthesize new materials. ..........................................................23 1-10 Cross-metathesis of asymmetric internal olefins. ..............................................................24 1-11 Primary and secondary CM reactions. ...............................................................................25 1-12 Cross-metathesis of O and C allyl galactopyranoside derivatives ..................................25 1-13 Ring opening metathesis polymerization of norbornene. ..................................................25 1-14 Mechanism of the ROMP of norbornene using Grubbs’ catalyst. .....................................27 1-15 Representative ADMET polymerization cycle. .................................................................43 2-1 Nitrogen aerosol through elimination. ...............................................................................46 2-2 ROMP to synthesize polymer scaffold. .............................................................................47 2-3 Other nitrogen-releasing products. .....................................................................................47 2-4 Synthesis of norbornene diazoester. ..................................................................................48 2-5 Synthesis of norbornenemethanol. .....................................................................................48 2-6 Deprotection of t-Boc protecte d ester carbamate of norbornene. ......................................49 2-7 Deprotection of Fmoc group. .............................................................................................5 0

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11 2-8 Synthesis of norbornene amino acetate using Fmoc protecting group. .............................51 2-9 Synthesis of norbornene ketoester 2-17 ............................................................................52 2-10 Synthesis of diazoester 2-19 .............................................................................................52 2-11 Attempt to make polymer by ROMP. ................................................................................52 2-12 ROMP of the ketoester of norbornene. ..............................................................................53 2-13 Unsuccessful attempt to ma ke co-polymer using ROMP. .................................................53 2-14 ROMP of the monomer 2-22 ............................................................................................54 2-15 Synthesis of co-polymer 2-27 ...........................................................................................55 2-16 Diazotization of the co-polymer 2-27 ...............................................................................55 3-1 Illustration of the structural diversity in pyranose scaffolds ..............................................57 3-2 Homodimerization of O -acetyl-D-galactopyranoside 3-2 ..............................................60 3-3 General scheme for the self-metathesis of O -pentenoate of a furanose. ............................62 3-4 Protecting group and hydr oxyl reactivity strategy. ............................................................63 3-5 Synthesis of the carbonate of diacetone (D)-mannose. ......................................................65 3-6 Metathesis followed by hydrogenati on to obtain saturated homodimer. ...........................67 3-7 Metathesis of the ester of (D)-mannose. ............................................................................68 3-8 Metathesis of the ester of diacetone (D)-glucose. ..............................................................69 3-9 Metathesis of the protected (D)-galactose. ........................................................................71 3-10 Monoesterification of the monoacetone (D)-ribose. ..........................................................72 3-11 Metathesis of compound 3-41 ...........................................................................................72 3-12 Synthesis of TBDMS and benzyl protected monoacetone (D)-ribose. ..............................73 3-13 Synthesis of esters of TBDMS and benzyl protected monoacetone (D)-ribose. ...............74 3-14 Metathesis of the ester of TB DMS protected monoacetone (D)-ribose. ...........................75 3-15 Metathesis of the ester of benz yl protected monoacetone (D)-ribose. ...............................75 3-16 Synthesis of metathesis produc t of benzylated (D)-isomannide. .......................................76

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12 3-17 Metathesis of the benzyl ated (D)-isosorbide in the exo position. ......................................77 3-18 Schematic representation of the cr oss-metathesis betw een carbohydrate and phloroglucinol esters. ........................................................................................................ .78 3-19 Tri-ester of phloroglucinol 3-62 ........................................................................................78 3-20 Cross-metathesis of phlorogluc inol ester and glucose ester. .............................................79 4-1 General scheme for the ADMET polym erization of functionalized carbohydrate derivatives with terminal double bond. ..............................................................................83 4-2 Diacetone D-mannitol as a hydrogel precursor. ................................................................85 4-3 Synthesis of the dieste r of diacetone (D)-mannitol. ...........................................................88 4-4 Synthesis of the diester of the monoacetone (D)-ribose. ...................................................88 4-5 Synthesis of the diester of monoacetone (D)-isomannide. ................................................89 4-6 Synthesis of the diester of monoacetone (D)-isosorbide. ..................................................89 4-7 ADMET of the diester of (D)-mannitol. ............................................................................90 4-8 ADMET of the diester of (D)-ribose. ................................................................................92 4-9 ADMET of the diester of (D)-isomannide. ........................................................................92 4-10 ADMET of the dieste r of (D)-isosorbide. ..........................................................................92

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13 Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy OLEFIN METATHESIS IN CARBOHYDR ATE AND NORBORNENE APPLICATIONS By Kalyan Mondal December 2007 Chair: Eric J. Enholm Major: Chemistry Olefin metathesis is a convenient route for the synthesis of functi onalized higher alkenes from simple alkene precursors. Our research goals are comprised of developing olefin metathesis in ring opening metathesis polym erization (ROMP) of norbornene scaffold, in self-metathesis reactions of carbohydrates, which can be used as precursors for the generation of dynamic combinatorial libraries (DCLs), and in employing for the first time to study the acyclic diene metathesis (ADMET) polymerization of carbohydrates. Functionalized norbornene monomers have been the subject of interest due to facile preparation and high reactivity in ROMP. We choose norbornene aldehyde as the starting material for synthesizing the nor bornene polymer scaffold, which can later be crosslinked using a diyl and by the release of nitrogen gas. Olefin metathesis is an important methodology for the generation of library members in dynamic combinatorial chemistry. We have s ynthesized a series of carbohydrate based homodimers by self metathesis reaction using Gr ubbs’ second generation catalyst. Sophisticated products were observed beari ng a variety of functional a nd protecting groups on the carbohydrates. The carbohydratelinked alkenes were trans with several versions examined. Products yields were dependent on the type of carbohydrate groups, and whether the ester group

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14 possessed an allyl or pentenyl moiety at the carboxylate side. In addi tion, several carbohydrate derivatives were made containi ng diene functionality. When subj ected to the self-metathesis condition, such diene carbohydrate system generated cyclic dimer. The utility of ADMET chemistry for the pol ymerization of dienes containing silyl, aromatic, and ester functional groups have been investigate. We ha ve synthesized the diesters of carbohydrates (D)-mannitol, (D)-rib ose, (D)-isomannide, and (D)-isosorbide. We performed the ADMET chemistry for those carbohydrat es. To our best knowledge, we are the first to report the ADMET chemistry of carbohydrates.

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15 CHAPTER 1 HISTORICAL BACKGROUND 1.1 Olefin Metathesis Throughout the history of chemistry, any r eaction that has the ability to form carbon-carbon bonds receives a significant amount of attention; and olefin metathesis is not an exception to it. Olefin metathesis is a powerful synthetic tool that has found its way into the vast array of scientific disc iplines, starting from the development of small molecular drug candidates to the industrial sized sy nthesis of petrochemicals.1-7 The word, “metathesis”, derived from the Greek words meta (change) and tithemi (place), means an exchange; thus the term “olefin metathesis”, originally introduced by Calderon in 1967,9 refers to the interchange of carbon atoms (with their substituents) between a pair of alkene bonds.10 This catalytic organic reaction is unlike other carbon-carbon bond forming strate gies due to the versatility of synthetic transformations it promotes, such as the synthesis of various sized cycloalkenes from dienes and specialized polymers by the ring opening metathesis polymerization of the cyclic molecules. Olefin metathesis has opened efficient synthetic routes for the synthesis of complex natural products, medicinal drugs, and new materi als as demonstrated by the explosion of the metathesis related applications found in literature during the past decade. In 2005, the importance of this organic reaction was prestigious ly recognized by the Nobel Prize Award in Chemistry to the major contributors of olefin metathesis–Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock. 1.1.1 Development of Olefin Me tathesis and Catalyst Olefin metathesis was first discovered acci dentally by researchers in petrochemical companies in the 1950s when they were searchin g for heterogeneous catalyst to produce highoctane gasoline products from olefins.7, 8 Instead of their expected products, the chemists

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16 observed newly developed olefins. It was not unt il the 1960s, when researchers at Goodyear Tire & Rubber determined that these new products we re the result of exchange of substituents on different olefins, which they officially refe rred to as “olefin metathesis” (Scheme 1-1).11 Scheme 1-1. Olefin metathesis. For several years, chemist tr ied to explain the mechanism involved in this novel reaction that involves a skeletal transf ormation of olefins. Calderon,12 Pettit,13 and Grubbs and Brunck14 initially suggested cyclobutane, tetramethylen e complex, and a rearrang ing metallacyclopentane intermediate as part of the m echanism, respectively, but all of the proposals were later found to be incorrect (Scheme 1-2).8 It was in the year 1971 when French chemist Yves Chauvin proposed a metal-carbene mechanism, which i nvolved the formation of a metallacyclobutane intermediate (Scheme 1-3).8, 15 However, the mechanism for the olefin metathesis was not to be established for years yet. The independent wo rks of Katz, Schrock, and Tebbe supported the mechanism proposed by Chauvin and is now accepted widely.1, 8 Several groups had tried to develop transi tion metal carbene complexes. These include Fischer carbenes (involving low oxidation state metals and electron deficiency at the carbon center) and Schrock carbenes (invo lving high oxidation state metals and electron deficiency at the metal center).1, 8 The Fischer carbenes involved little ac tivity for the olefin metathesis, while Schrock’s tantalum and niobium metal co mplexes were also proved unsuccessful.1, 8 The propagating species could not be obtained, isolated, or structural ly characterized and the metal catalysts involved in the olefin metathesis are often referred as “class ical” or “ill-defined”

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17 catalysts. However, all these initial studies he lped to improve the synthesis of alkylidene complexes that eventually demonstrated improved reactivity for olefin metathesis. B A D C B D C A M A C B D + + B A D C A C B D + + B A D C A C B D + + M D B A C M B A C D +M -M M=metal Rearrangementof metallacyclopentane M C D B A Tetramethylene complex -M +M +M -MCyclobutane intermediate Scheme 1-2. Proposed intermediates for olefin metathesis.8 Scheme 1-3. Chauvin proposed metallacyclobutane intermediate. Despite of all these early developments, Ol efin metathesis did not find any practical application due to the following reasons: 1. Low reactivity of the metal catalyst.

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18 2. Lack of stability a nd tolerance toward th e functional group of the alkene involved. In the 1990s, Schrock introduced first a well-defined alkoxy imidomolybdenum-based catalytic system 1-1 which allowed successful applic ation of olefin metathesis (Figure 1-1).16, 17 In contrast to the earlier develo ped catalysts, the molybdenum alkylidene complex is highly reactive and leads to the desired product with higher percentage of yield including starting materials with sterically hindered alkenes.1, 18 However, the catalyst was found to be ineffective for the starting material s containing polar functi onal groups like alcohols and carboxylic acids. Also, this catalyst is highl y air and moisture sensitive and needs absolute dry condition s to carry out the olefin reaction.5 Shrock’s catalyst Figure 1-1. Alkoxy imidomolybdenum-based Schrock’s catalyst. To improve the moisture-air and the func tional group sensitivity, Grubbs and coworkers examined ruthenium based catalysts having an ox idation state higher than the Fischer carbenes but lower than Schrock’s catalyst.1, 19 The first Grubbs’ catalyst [(PPh3)2Cl2Ru=CHCH=C(Ph)2] ( 1-2 ) was developed in 1992 and was stable in protic and aqueous solvents. However, the catalyst exhibited limited reactivity in comparis on with Schrock’s carbene complex (Figure 1-2).1, 20, 21 In 1996 Grubbs and coworkers introduced a m odified form of th eir earlier ruthenium based catalyst (Figure 1-2, Grubbs’ catalyst 1-3) and is commonly known as Grubbs’ first generation catalyst. It not only di splayed better functional group tolerance but also was observed

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19 to be 20–10,000 times more react ive than the earlier versi on of the ruthenium catalyst 1-2 (Figure 1-2).22 Based on Herrmann’s studies on N-heterocyclic carbenes23 Grubbs replaced one of the tricyclohexyl phosphine (PCy3) ligands with a mesityl N -heterocyclic ligand to afford a more stable ruthenium catalyst 1-4 which is commonly referred as “Grubbs’ second generation catalyst”. This second generation ca talyst shows far more superiority in terms of its tolerance towards moisture, air, and a wide vari ety of functional groups (Figure 1-2).1, 18, 24, 25 As a result of this enhanced reactivity our research effort s were focused on olefin metathesis using Grubbs’ second generation catalyst 1-4 along with the use of Grubbs ’ first generation catalyst 1-3 Ru PCy3 Ph PCy3 Cl Cl Ru Ph PCy3 Cl Cl N N Mes Mes Grubbs'Second GenerationCatalyst Grubbs'First GenerationCatalyst 1-4 1-3 Ru PCy3 PCy3 Cl Ph Ph 1-2 Cl Figure 1-2. Ruthenium catalysts. 1.1.2 Mechanism of Ol efin Metathesis The commercial availability of ruthenium catalysts 1-3 and 1-4 has made them a practical and standard organic tool. The synthesis of this metal alkylidene complexes will not be discussed here. However, to better apply ol efin metathesis towards the synt hesis of target compounds and polymers, it is helpful to examine the mechan ism that was first introduced by Chauvin. When utilizing Grubbs’ catalysts 1-3 and 1-4 the first step of the mech anism involves the dissociation of the PCy3 ligand, followed by the binding of the alkene to the carbene (Scheme 1-4).26, 27 The next step is a [2+2] cycloaddition with the metal catalyst to form the metallacyclobutane intermediate, which can then undergo a cycl oreversion process to produce a new metal

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20 alkylidene complex (Scheme 1-5).4, 27 The mechanism proceeds as a catalytic cycle where the metal alkylidene undergoes another [2+2] cycloa ddition with a second alkene, followed by the cycloreversion leaving the newly formed olefin with R1 and R2 groups and the metal alkylidene for further catalytic use. Scheme 1-4. Dissociative substi tution of ruthenium catalyst. R1 LnM R2 R1 +LnM LnM R1 +LnM R1 R 2 H2CCH2 cycloreversion-2 + 2 c y c l o ad d i t i o n 2 + 2 c y c l o a d d i t i o n R1 R2 cycloreversion Scheme 1-5. Proposed mechan ism of olefin metathesis. Because ethylene gas is released as a byproduct,6 it is possible to shift the equilibrium towards the desired products by deliberately evacuating or flushing the headspace with argon to remove ethylene.28 The cycle continues until the reaction is quenched. Ethyl vinyl ether (EVE) reacts with the ruthenium catalyst and forms the Fischer carbene L(PCy3)(Cl)2 Ru=CHOEt

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21 (Scheme 1-6).26 This new, electron rich carbene co mplex formed by the reaction between ruthenium catalyst and EVE is virtually irreversib le in nature and significantly less reactive than the ruthenium alkylidenes.26, 29 Scheme 1-6. Quenching of ruthenium catalyst with ethyl vinyl ether (EVE).29 1.1.3 Important Types of Metathesi s Reactions and Applications As highlighted many times, olefin meta thesis is a versatile technique which includes ring-closing metathesis (RCM), ring-opening meta thesis (ROM), cross-metathesis (CM), ringopening metathesis polymerization (ROMP), and acyclic diene metathesis (ADMET) (Scheme 1-7).6 The three main metathesis reactions, used in our studies, RCM, ROMP, and ADMET will be discussed in greater detail. RCM is olefin metathesis involving the cycliz ation of a diene to generate various sized cycloalkenes, from small 5-membered rings to macrocycles.18 The stereochemistry of the cycloalkene products are dependent on the substrates; for example, small and medium sized rings formed from RCM are in a less strained cis conformation while in contrast, the stereochemistry of the non-rigid RCM derived macrocyclic compounds is difficult to predict and can encompass a mixture of cis and trans stereoisomers.30 RCM reactions are conducted under highly dilute conditions to prevent ADMET polymerization. In addition, heat is often employ ed to improve ring closures due to the entropy of activation required to bring the two ends of the chain together.31 However, higher temperatures can cause the catalyst to decompose, thus a greater cataly st loading is required.5

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22 Despite this requirement, RCM has provided a shorter, more effici ent synthetic route to natural products,184 medicinal drugs,32 and new materials185 compared to conventional methods, as attested by the numerous st udies found in literature.59, 83, 89, 123 An example is shown in Scheme 1-8 in which Danishefsky and coworkers utilized RCM to synthesize Epothilones using different alcohol protection groups.32 n -C2H4RCM +C2H4ROM ROMP ADMET -nC2H4 R1 R2 R1 R2 R1 R2 R2 R1 ++ + cross-metathesis -H2CCH2 Scheme 1-7. Different t ypes of olefin metathesis. The reverse reaction of the RCM is called ROM, where the cycloalkene breaks open to form terminal diene, which can be followed by a CM reaction with other acy clic alkenes to form new products.5 Similar to RCM, ROM requires dilute c onditions due to the resulting dienes undergoing polymerization, referred to as ROMP. The polymerizati on is quite practical and is more widely used than the ROM itself. Cycl oalkenes, which possess ring strain, such as norbornene, cyclopentene and cyclooctene, favor ROMP.16 Removing ring st rain leads to a reversible reaction that is driven fo rward, and is not reversible anymore.

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23 S N O O O OR2 OR1 3 7 S N O O O OR2OR1 S N O O O OR2OR1 10 11 + Grubbs'IICatalyst CH2Cl2/toluene 0.002M 1-5aR1=TES,R2=Troc35%/58%b15%/6%b1-5bR1=H,R2=Troc41%/57%0%/0% 1-5cR1=TES,R2=H57%/n.d.c0%/n.d.c1-5dR1=H,R2=H64%/55%0%/0% Epo490(R1,R2=H) aReactioninCH2Cl2wererunfor5.5hat35oC;reactionsintoluenefor25minat110oC.bDone with20mol%catalystat0.0005Mdilution.cNotdetermined.(10%) Scheme 1-8. Utilizing RCM for the synthesis of Epothilones using different alcohol protection and different solvents a.32 Grubb’s second generation catalyst 1-4 has high functional group tolerance and has been demonstrated in ROMP to generate functiona lized, telechelic and tr isubstituted polymers.33 ROMP is responsible for the synthesis of a variety of new materials, starting from the development of nonlinear optics to biologically rele vant polymers.32 A recent application of this polymerization is shown in Scheme 1-9, where a pol ymer was synthesized to create biomaterials that can undergo a [2+2] cycloadditi on when irradiated with UV light.35 Scheme 1-9. Application of ROMP to synthesize new materials. RCM and ROMP started as the most popular t ypes of metathesis re actions, but due to recent studies and a better understanding of the se lectivity and stereoselect ivity of CM, the later

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24 has become a more useful and versatile syntheti c technique over the years. The concerns over selectivity arise from the mixture of heterodimers, homodimers, cis and trans stereoisomers that can be generated from CM reactions. In addition, employing internal olefins in CM can also lead to a greater number of product mixtures (Scheme 1-10). Factors such as steric and electronic effects may also affect CM reactivity and sele ctivity, and must be considered when planning reactions. For example, olefins possessing electron withdrawing or bulky substituents often lead to little or no CM products because of the poor reactivity with the cataly st, but steric effects nearly always favor trans selectivity.34 R1 R1 R2 R2 R3 R4 R3 R4 R1 R2 R3 R4 R 1 R2 R3 R4 R1 R3 R4 R2 cross-metathesis + + + + + + + Heterodimers Homodimers Scheme 1-10. Cross-metathesis of asymmetric internal olefins. Fortunately, new models and me thodology were developed to improve selective CM. For instance, Grubbs categorized olefin metathesis as Type I, II, III and IV based on their reactivity to form homodimers by CM with catalyst 1-3 and 1-4 Primary allylic alcohols, protected amines and esters are the examples of Type I alkenes (sterically unhi ndered, and electron-rich) because they readily form homodimers by CM and also undergo secondary metathesis reactions.28, 36, 37 The more sterically hindered Type II al kenes (i.e., secondar y alcohols and vinyl ketones) are less reactive and T ype III alkenes are nonreactive (i.e ., tertiary allylic carbons). Type IV alkenes (i.e., protected trisubstituted ally l alcohols) are spectators and do not participate in the CM reaction. The examples given above are based on the uti lization of catalyst 1-4 One strategy towards selective CM involves a two step s procedure in which homodimers of Type I

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25 alkenes are generated, followed by a secondary meta thesis reaction with Type II / III alkenes to preferentially form the heterodimer product with trans favored in the presence of selected functional groups (Scheme 1-11).36 CM is more widely used now and an example of a recent application of CM is shown in Scheme 1-12, wh ere Roy and coworkers we re able to carry out cross-metathesis of O and C galactopyranosides in good to excel lent yields with predominantly trans selectivity.38 R1 R1 R1 R1 R1 R2 R 1 + catalyst catalyst R2 + Scheme 1-11. Primary and secondary CM reactions. Scheme 1-12. Cross-metathesis of O and C allyl galactopyra noside derivatives.38 1.2 Ring Opening Metathesis Polymerization (ROMP) Ring opening metathesis polymerization (ROM P) (Scheme 1-13) involves a chain growth process resulting in the formation of linear high molecular weight polymers. Norbornene is often used in these studies, due to a small strain release. Scheme 1-13. Ring opening metathes is polymerization of norbornene. Like all olefin metathesis reactions, ROMP is governed by competing equilibrium. The thermodynamics of the ring-chain equilibrium dict ate the polymerizability of cyclic olefins:49

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26 G = RT ln Keq = H T S (1) Polymerization is govern ed by the enthalpy ( H) since with the polymerization the ring strain of the monomer un it gets released. The bond-angle strain in 3, 4, and 8-membered rings as well as in bicyclic monomers like norborne ne provides the necessary energy for the polymerization process. The inherent ring strain in these monomer units allow the equilibrium to be shifted from the cyclic monomer towards the li ner polymer. The polymerization of the strain free (i.e., H = 0) macrocyclic olefin is an entropically ( S) driven process as a result of the formation of linear polymer. The ROMP of 5, 6, and 7-membered rings, however, presents a thermodynamic uncertainty. Due to comparable entropy and enthalpy ( H T S 0) values, such stable cyclic olefin monomers can undergo polymerization at Tc, the polymerization ceiling temperature (the temperature above which no pol ymerization can take place for any cyclic monomer).50, 51 Patton and McCarthy demonstrated that at a temperature of -23oC cyclohexene could polymerize.51 In general, monomers with greater ring strain (i.e., larger negative value of H of the reaction) are more prone to undergo ring-opening polym erization reactions. The mechanism of ROMP chemistry is outline d in Scheme 1-14 using norbornene as the monomer and Grubbs’ catalyst. The catalyst, M, is a transition metal carbene complex. The first step of polymerization involves coordination of th e monomer unit to the meta l to form an initial -complex [A]. The monomer th en undergoes an insertion pr ocess through a [2+2]-like cycloaddition to form the metallacyclobutane inte rmediate [B]. The double bond of the cyclic intermediate is highly strained and is energetic ally unfavorable. The successive cleavage of the metallacyclobutane by a retro [2+2] addition generates a chain extended -complex [C]. The final step involves th e dissociation of the -complex. This whole process repeats itself and

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27 thereby creating potentially high molecular weight polymers, until the reaction is halted by the addition of a capping reagent like EVE. Scheme 1-14. Mechanism of the ROMP of norbornene using Grubbs’ catalyst. Ring opening polymerization is controlled by a chain growth mechanism, as shown in the above mentioned mechanism (Scheme 1-14). Poly merization or chain propagation continues at the reactive, growing chain end unt il secondary metathesis reacti ons, called chain transfer or cyclization, become significant. When this se condary reaction predomin ates over the primary chain propagation reaction, the thermodynamics of the polymeri zation is controlled by the ringchain equilibria.52 1.3 Dynamic Combinatorial Chemistry For the discovery of biologically active substa nces, especially drugs, it is necessary to find molecules that react selectively with the given biological targets. Within less than one decade, combinatorial chemistry has established itself as a versatile and attrac tive approach for the synthesis of libraries of compounds that are able to be tested for their biological activities and desirable properties.54, 55 It was first developed for the synthe sis of peptide libraries for screening against antibodies or receptors. However, the technology has evolved rapidly to become a

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28 powerful technique primarily in the drug discovery processes.56 The goal of combinatorial chemistry is to synthesize a large number of products via condensation of a small numbers of starting materials in all possible combinations. Fo r example, let us consider a chemical reaction in which there are three different reactants: A, B, C. If we start with only one type of each reagent, and then the reaction will result in 1 x 1 x 1 = 1 product as the re sult of a total of three reactions. On the other hand, if we use 10 types of each reagent, then there will be a total 30 reactions which would result in the formation of 10 x 10 x 10 = 1000 products, while 100 types of each reagent would result in the formati on of 1,000,000 products as a result of 300 total reactions only. Traditional combinatorial chemistry involve s sequential and irreversible syntheses irrespective of whether they are performed individually in parallel or concertedly in the same compartment. Another characteristic feature is that all constituents of the lib rary are more or less robust molecules. The major disadvantage of this process is the lack of flexibility or limited flexibility in the generation of the library, sin ce almost all structures have to be designed distinctly and synt hesized separately.57 In contrast to the static approaches involved in traditional combinatorial chemistry, the library may be pr oduced from a set of reversibly interchanging reactants. This technique introduces a dynamic equilibrium into the system. The interesting feature of dynamic combinatorial chemistry (DCC) is that each library member affects all other surrounding constituents and components.58 Also, DCC combines the generation of the library and the screening processes in a single step. There is a continuous interchange of building blocks between different members, and hence the co mposition of a dynamic combinatorial library (DCL) is governed by thermodynamics rather than kinetics. The major advantage of DCC over the traditional or static combinatorial chemistry is that the desired com pound is amplified at the

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29 expense of the undesired compounds. This is due to the fact that the molecular recognition events are specific for a particular memb er, and thus will stabilize that particular substance only. This induces a shift in equilibrium towards the formation of recognized species at the expense of unrecognized species.59 Figure 1-3. Schematic representation of the concept involved in DCC.73 In the simplest fashion, we can describe th e principle involved in dynamic combinatorial chemistry by means of Emil Fisc her’s lock-and-key metaphor.74 The whole process can be divided into three steps. The fi rst step involves selection of in itial building blocks, which are capable of interacting with each other in a re versible fashion. The second step involves the development of the conditions for the generation of the library, where the building blocks can form interchanging, individual molecular “keys” (f or example, ligands). In the last step, the library is subjected to a selection process, wh ich results from binding strength to a molecular “lock” (for example, a receptor).73 With this concept, two situati ons can arise. In the first case, the receptor can itse lf act as the trap for the given liga nd. Under this condition the ensemble of candidates will be forced to rearrange in orde r to produce that species. In the second case, a

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30 specific synthetic receptor is selected from a seri es of interconverting receptors by addition of a certain ligand. These two cases have been term ed as “substrate casting” and “receptor molding” respectively. Figure 1-4 shows the schematic representation of the casting and the molding process. Figure 1-4. Molding and casting processe s in dynamic combinatorial libraries.75 Thus, in DCC, there are two concepts, dependi ng on whether a recepto r or a substance acts as a target-template for the assembly of the ot her partners. Casting invo lves the receptor-induced assembly of a substrate that f its the receptor; whereas, the mold ing involves substrate-induced assembly of a receptor that fits the substrate.76 There are three steps involved in a dyna mic combinatorial approach. These are: (1) synthesis of a mixture of inter-converting mol ecules; (2) amplification of the best binder(s) through non-covalent interactions with a template; and (3) isolation (or re-s ynthesis) of the best binder(s). The success of each step depends upon the type of reversible reaction used to connect the building blocks. Under ideal conditions, we look for a rapid reversib le reaction which is tolerant towards a wide-range of functional groups, proceeds under mild conditions, and does not interfere with the recognition events.59 A series of different types of reversible reactions have

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31 been studied for their use in DCC. Table 1-1 sh ows a series of such reactions. These include disulfide exchange,77 metal-ligand coordination,78 exchange of oximes,79 and hydrazones,80 and olefin metathesis.81, 82 There are two basic procedures invo lved in the implementation of the DCC approach, depending on whether library gene ration and screening are performed in a single step or in two steps. This result in two types of dynamic libraries : adoptive combinatorial libraries and pre-equilibrated dynamic combinatorial libraries.77 Earlier using the reversible chemistry, divers e libraries were genera ted. However, recent emphasis in combinatorial chemistry is to shif t the equilibrium towards templating by exposing those libraries to targets.59 These targets can either be a recep tor or ligand molecules. The most significant examples of templating have been observ ed when a molecule selects its best receptor from small dynamic libraries of macrocycles of different sizes.80, 86, 87 Figure 1-5 shows an example of hydrogen-bond based dyna mic system prepared from a building block derived from L-proline. Acid catalyzed cyclization results in the formation of 15 macr ocycles initially, which changes mainly into cyclic dimers. At equilibri um, the library comprises 88% of the dimers and 11% of trimers. Addition of template acetylcho line to the reaction mixture significantly changes the equilibrium to produce a 50-fold am plification of the cyclic trimer.59

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32 Table 1-1. Potential application of di fferent dynamic process in DCC systems.59

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33 Figure 1-5. Templating of hydrazone-b ased library (a) in (b) the ab sence and (c) the presence of acetylcholine.59 1.4 Carbohydrate chemistry The study of carbohydrates began in the late ni neteenth century with the work of Emil Fischer. Carbohydrate ring struct ure was elucidated in the 19 30s by Haworth and colleagues. Polysaccharides were discovered soon after and a ppeared to be present in every living organism, such as vegetables and animals. In addition to determining the structure of this new category of molecules, chemists and biologists focused on the functions of these ubiquitous polymers. Polysaccharides display a very wide range of biol ogical functions from acting as nature’s source of energy (such as starch and glycogen), to pr oviding structural materials (cellulose, chitin, collagen, and proteoglycans) 1-3 (Figure 1-6).62 Carbohydrates are now k nown to assume wider variety of biological roles. For example, the sulfated polysacchar ide, heparin plays an essential role in blood coagulation,70 while hyaluronan acting as a lubrican t in joints has been used in the implantation of plastic intraocular lenses in the 1980s.71

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34 O O O OH O HO HO OH O OH HO nO O OH O HO NHAc NHAc HO n O HO O 2 1 O O OH O HO OH OH HO n O HO O 3 Figure 1-6. Structures of natural glycopolymers: ( 1 ) Starch; ( 2 ) Chitin; ( 3 ) Cellulose.62 Moreover, hyaluronan, as well as another sulf ated polysaccharide, chondroitin sulfate, exhibit anti-inflammatory activity and were inves tigated for the treatment of osteoarthritis and rheumatoid arthritis.72 A large number of syntheses i nvolving carbohydrate chemistry are directed increasingly toward the preparation of artificial glycoconjugate s. Such glycoconjugates contain sugars and/or na turally occurring compounds.58, 88 However, it has been recognized that it is not necessary to have actual glycoconj ugates in order to study and understand various biological processes. Several ar tificial carbohydrate compounds exhibiting parallel or even improved biological interact ions can be synthesized.58 Carbohydrate recognition plays an important role in many biological processes lik e, cell-cell interacti on, cell communication, and others. They are also used as ligands for endoge nous lectins, used to me diate various regulatory processes.58, 77 Therefore, carbohydrate groups are highly attractive tools for the generation of mimics and analogues. Eventually, by identify ing and tailoring potent new ligands, medicinal application in drug designing and gl ycohistochemistry can be accomplished.58

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35 Unlike other compound groups, synthesis of carb ohydrate libraries using classical methods have never witnessed identical rapid progress. In spite of suffering identical problems, DCC still offers a complementary route for the synthesis of carbohydrate libraries, es pecially, the synthesis of dynamically interchangi ng carbohydrates “clusters”.58 Only a few examples of DCLs containing carbohydrates are reported a nd none of them involve metathesis.58, 77, 88-91 Multicovalent neoglycoconjugates have been extensively utilized to probe and enhance carbohydrate-protein interactions at the molecular level.92-94 Moreover, glycoclusters92 and dendrimers93 are also emerging as potential carbohydrates therapeutic agents.94 Several examples exist in which ligand-induced receptor and protei n dimerization occurred as a general mechanism for signal transduction.95 It is conceivable that signal transduction and receptor shedding could be triggered by carbohydrate oligomers.96 Cross-metathesis of a hydrocarbon chain havi ng terminal double bond involves elimination of ethylene gas. If elimination of the ethylene gas can shift the equilibriu m towards the product side, then the addition of the gas can shift the eq uilibrium towards the reactant side. This is the basic concept involved in developing carbohydrat e based dynamic combinatorial library using the cross-metathesis method. We examined the reac tivity of various types of sugars in the selfmetathesis reactions. Roy and coworkers employe d Grubbs’ catalyst based cross-metathesis for O and C allyl and O -pentenyl galactopyranosides.150 Considering the growing importance of carbohydrates in the study of carbohydrate-protein inte ractions, our research goal is to generate a series of O -esters of furanose and pyranose with pe ndant terminal double bonds and examine their applications in the olefin metathesis reaction.

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36 1.5 Tissue Engineering Peppas and Langer defined biomedical engi neering as an extension of chemical engineering towards biomaterials.39 Tissue engineering is one of its main branches. Various disciplines, such as materials science, cell bi ology, chemistry, reactor engineering, as well as clinical research contribute to tissue engineeri ng. It requires a balan ced combination of cell culture growth with biomaterials to support it a nd with bioactive molecules to enhance and direct it.40 A quite successful approach in tissue engineeri ng involves replacement or repair of damaged or failed tissues with viable ones by creation of an environment, which promotes the native capacity of cell to integrate, differentiate, and proliferate.41-43 Every year, millions of patients suffer the loss, or failure of an organ or tissue as a result of accidents or disease. Similarly, traumatic injuri es, cancer treatment, and congenital abnormalities are often associated with abnormal bone shape or segmental bone loss. Restoration of normal structure and function in these cases require s replacement of the missing bone that may be accomplished by surgical transfer of natural tissu e from an uninjured location elsewhere in the body. However, these approaches are extremely limited and have several drawbacks including shortage of donor, infection or pain of patients due to sec ond surgery for the removal of implanted metal plate, inadequate blood supply, and secondary deformities at the donor site.44 Recently, tissue engineering ha s found enormous applications in generating artificial constructs to direct tissue regeneration.45 Scaffolds made from synt hetic and natural polymers and ceramics have been investigated extensivel y for orthopedic treatment This approach has several advantages including ability to generate desired pore structures with matching size, shape and mechanical properties. The major disadvantages it has include shaping them to fit in cavities or defects, bonding to the bone tissues, and requirement of an open surgery to get rid of it.46

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37 A material that can be employe d as a scaffold in tissue engineering must satisfy a number of requirements. These include biocompatibility, biodegr adation to non toxic products within the time frame required for the application, processab ility to complicated shapes with appropriate porosity, ability to support cell growth and prol iferation, and appropriate mechanical strength during the major part of the ti ssue regeneration process. Biodegr adable synthetic polymers offer a number of advantages over other materials for developing scaffolds in tissue engineering. The ideal biomaterial must be biocompatible, promot e cellular interaction and tissue development, and possess proper physical and mechanical properti es. The key advantages include the ability to tailor mechanical properties and degradation kine tics to suite various applications. However, in addition to the main requirements mentioned earlie r, an injectable polymer composition must be in liquid or paste form, steril izable without causing any chemi cal change, and must have the capacity to incorporate biological matrix components. Upon injection the prepolymer composition should bond to the biol ogical surface and cure to th e solid and porous structural form with appropriate mechanical properties. The curing process should take place with minimum heat generation and chemical reactions involved in curing should not damage the cells and adjacent tissues. The cured polymer while fa cilitating the cell-in-growth proliferation and migration should ideally be degraded into biocompatible materials that are either absorbed within the body or released from the body without any side reaction or damage to the body.46 Among the families of synthetic polymers, polyesters have been found attractive due to the ease of degradation by hydrolys is of ester linkage (degrada tion products being reabsorbed through the metabolic pathways in some cases) and the potential to tailor the structure to alter degradation rates. Biodegradable synthetic pol ymers such as polyglycolides, polylactides, polycaprolactone (PCL) and their copolymer s, poly(p-dioxanone), and copolymers of

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38 trimethylene carbonate and glycolide have been used in a number of clinical applications for the preparation of the scaffolds.40, 47-48 However, the hydrophobicity of such polyester based biodegradable polymers, acidity of the decomposed material; and se lf acceleration of degradation are the major drawbacks they have.40 Attempts to find tissue-engineered materials to cure orthopedic injuri es/diseases have made necessary the development of new polymers that meet a number of demanding requirements. Such requirements include ability of scaffold to provide mechanical support during tissue growth and gradually degrade to biocom patible products, to withstand several requirements including ability to incorporate cells, gr owth factors etc. and to provide osteoconductive and osteoinductive environments. Recent studies in tissue engi neering involve development of in-situ polymerization of the biocompatible compositions. This can function as cell delivery systems in the form of an injectable liqui d/paste. Many of the currently available degradable polymers do not comply with all of these necessary requi rements and significant chemical changes are required to their structure to achieve th eir role for the desired applications.46 One strategy to overcome these problems is to develop living tissu e substitutes based on s ynthetic biodegradable polymers. We hope our research efforts to synt hesize the biomaterials for tissue engineering from norbornenemethanol will sati sfy the criteria mentioned above. 1.6 Hydrogels A hydrogel is a network of polymer chains that are water-insoluble, sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are su perabsorbent (they can contain over 99% water) natural or synthetic polymers. Hydrogels possess also a degree of flexibility very similar to natural tissue, due to their significant water content. Common uses of hydrogels are--

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39 Currently used as scaffolds in tissue engineer ing. When used as scaffolds, hydrogels may contain human cells in order to repair tissue. Environmentally sensitive hydrogels. These hydroge ls have the ability to sense changes of pH, temperature, or the concentration of metabolite and release th eir contents as result of such a change. As sustained-release delivery system. Hydrogels that are responsive to specific mol ecules, such as glucose or antigens, can be used as biosensors as well as in DDS. In disposable diapers where they "captu re" urine, or in sanitary towels. Contact lenses (silicone hydr ogels, polyacrylamides). Medical electrodes using hydrogels composed of cross linked polymers (polyethylene oxide, polyAMPS and pol yvinylpyrrolidone). Water gel explosives. Other, less common applications include--Breast implants. Granules for holding soil mo isture in arid areas. Dressings for healing of burn or other hard -to-heal wounds. Wound GEL are excellent for helping to create or maintain environment. Common ingredients are e.g., pol yvinyl alcohol, sodium poly acrylate, acrylate polymers and copolymers with an abundance of hydrophilic groups. Natural hydrogel materials are being investigated for tissue engin eering. These materials include agarose, methylcellulose, hyaluronan, and other naturally derived polymers. Hydrogels swell strongly in aqueous media, and are composed of hydrophilic organic polymer components that are crosslinked into a three-dimensional network either by covalent or non-covalent interactions. The cross-linking natu re of hydrogels provides it with dimensional stability, whereas the high solvent content gives rise to fluid-like tr ansportation properties. Physical properties of hydrogels ma ke it suitable for various applica tions. Initially it was used as

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40 superabsorbent where it can act as an absorber entrapping water and are used where a large volume of aqueous media needs to be removed from a localized source. With an eye to applying those in several areas like in vivo diagnostics, drug/gene delivery, chemical separations, and chemical and biological sensors scientists have now started to synthesize more complex polymer architectures. Such materials must satisfy conditions like biocompa tibility, biodegradation, encapsulation, and biorecognition etc. Based on the type of cross-links hydrogels ar e classified into two different categories— (a) Physically cross-linked hydrogels, a nd (b) Chemically cross-linked hydrogels.108 Physically Cross-linked Hydrogels This class of hydrogels is classified by its reversibility or by its degradation properties. These hydrogels are mostly used to encapsulate proteins,109 cells,110 or drugs,111 followed by dissolution of the structure to release them. The noncovalent attr active forces like hydrophobic interactions, hydrogen bonding, or i onic interactions between the pol ymer chains are responsible for the cross-linking here (Figure 1-7). YCross-link CoordinationBond HydrogenBond HydrophobicInteraction IonicInteraction Protein-LigandAssociation HydrogelNetwork Figure 1-7. Physical cross-linking by noncovalent interactions.108 Hydrogel formation is based on the pH value of the medium as the hydrogen bonds, the main source of such noncovalent bonding, ar e formed only when the acid groups are protonated.112, 113

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41 Chemically Cross-linked Hydrogels These kinds of hydrogels are more stable because the cross-links are covalent bonds.114 They have permanent structures unlike the physi cally cross-linked hydrogel s. Such hydrogels are made by polymerizing monomers containing the cross-linking agent. One example is the chemically cross-linked hydrogel poly(2-hydroxyethyl methacrylate). It is typically synthesized by polymerizing 2-hydroxy methacrylate (H2C=C-(CH3)COOCH2CH2OH) with ethylene glycol dimethacrylate (CH2=C(CH3)COOCH2CH2OCO(CH3)C=CH2) as the cross-linking agent. Hydrogels can also be formed by cross-linking of the various functiona l groups present on the polymer backbone. 1.7 Acyclic Diene Met athesis (ADMET) The introduction of the well-defined alkylid ene metal catalysts by Schrock and Grubbs continues to have profound impact on the viabil ity of ring opening metathesis polymerization (ROMP) reactions. However, it was the early co ntributions made specifically by Schrock that introduced a new metathesis polymerization reaction. Acyclic diene metathesis (ADMET) polymerization has been an area of intermittent study for the last 30 years. However, the discovery of Schrock’s alkylidines was the first practical reality. Acyclic diene metathesis (ADMET) polymerizati on (Figure 1-8) has proven to be a viable synthetic route for the synthesis of high molecula r weight unsaturated polymers and copolymers, including polymers possessi ng various functionalities.98 ADMET represents a unique equilibrium step condensation route for the synthesis of polyalkenylenes. The ADMET condensation, like the cross metathesis, is a reversible reaction wh ich is driven by the continuous production and removal of ethylene gas.100

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42 R Cat. R R n + H2CCH2 n Figure 1-8. Acyclic diene meta thesis (ADMET) polymerization. In order to understand the ADMET chemistry, st ructure-reactivity stud ies have been done. The mechanism of ADMET chemistry is shown in Scheme 1-15.98, 100 By examining the mechanism of both the ADMET and ROMP chemistr y, it is found that the reaction intermediate, the metallacyclobutane ring, is common to both a nd this is the only common feature between them as one is a chain growth polymerization an d the other is step growth polymerization. In ADMET chemistry, two metallacyclobutane rings must be proposed in a propagation step (whereas only one is needed in ROMP chemistr y). The first metallacyclobutane ring is the result of joining two monomers together followed by cleavage of methylidine carbene, which becomes the active catalyst entity during the polymerizatio n itself. The methylidine carbene continues to react with either monomer or polymer, leading to a new metallacyclobutane ring acting as the precursor of ethylene evolution. Once the ethyle ne is evolved and removed from the reaction system, the cycle repeats itself, and further connec tion with monomers results in the formation of high molecular weight polymer. The utility of ADMET chemistry for the pol ymerization of dienes containing silyl, aromatic, and ester functional groups has been investigated.98, 100-101 ADMET has been shown to be an efficient technique for the pr eparation of unsatur ated polyethers,103 unsaturated polyesters,104 as well as variety of functionalized polyethylenes105 and polyalkenylenes containing heteroatoms (N106, Si98) in the polymer main chain.

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43 Scheme 1-15. Representative ADMET polymerization cycle. To our best knowledge no ADMET chemistry has been reported for th e polymerization of dienes containing carbohydrates. Shown later in this dissertati on, we have for the first time, synthesized a number of carbohydr ate based dienes, which can be subjected to the ADMET chemistry. 1.8 Scope of the Thesis Olefin metathesis is a powerful organic synt hetic tool, as attested by the large volume of research found in literature. Grubbs’ second generation catalyst 1-4 and its tolerance for functional groups have made this methodology even more useful. However, there are still areas

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44 of olefin metathesis that require more studi es: peptidomimetics and carbohydrates. The work presented here will examine the use of ol efin metathesis in several applications. 1. Development of ROMP reactions on a norbornene scaffold as a means to later crosslink the polymers using a diyl and release of nitrogen gas. 2. Self-metathesis of carbohydrates to make hom odimers could be prepared and used as precursors of DCLs bearing a variety of functions and protecting groups on the carbohydrates. The carbohydratelinking alkene was trans with several versions examined. 3. ADMET reactions of carbohydrates. The preliminar y work is seen in this dissertation for the first time. Very complex products w ith new protecting group, strategies, and numerous asymmetric centers are produced.

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45 CHAPTER 2 RING OPENING METATHESIS POLYMERIZATION OF NORBORNENE DERIVATIVES 2.1 Introduction Synthetic biopolymers are desi gned with unique properties and biodegradability. A vast majority of biodegradable polymers belongs to the polyester family, in cluding polyglycolides, and polylactides. Biodegradable synthetic polymers offer a number of advantages over the other materials in respect to developing scaffolds in tissue engineering. Key advantages include ability to modify the mechanical propert ies, and the degradation kinetics facilitating their application in different fields.46 Another major advantage of syntheti c polymers include fabrication to the different shapes with desired pore morphology. Ma jor disadvantages of such polymers include poor biocompatibility, poor proces sability, release of acidic de gradation product, and loss of mechanical properties during the early stages of degradation.46 Major research efforts have b een directed to the developm ent of medically applicable biomaterials.169 Photopolymerization of multifunctional m onomers allows the synthesis of highly cross-linked polymer networks, which is usef ul for applications like contact lenses, dental restorative materials, and coatings for optical fibers.170-172 Numerous groups are involved in developing advanced experimental technique s and models in orde r to understand the polymerization of such multifunctional monomers to develop biomaterials.173-177 Of particular interest discussed here is an exploration into the use of multif unctional monomers for orthopedic biomaterial applications. One of the traditional tr eatments of many fractures is the application of metal plates for fixing the joints. However, it has several drawbacks like surgery for removing the plates, stress shielding duri ng healing, fatigue, loosening of implants etc. Synthesis of degradable polymers as biologically useful materials is an area of great interest. The major advantage of using a degradable polymer is its ability to provide temporary mechanical support

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46 as well as the elimination of the requirement of second surgery. Our research group was interested in synthesizing new biomater ials with increased mechanical strength.77 Our goal is to apply ring opening metathesis polymerization (ROMP) as a tool to photocrosslink a polymer. Since this cross-linking is covalent, better mechanical strength is possible. Earlier work done by previous group member Aarti Joshi had developed new biomaterials using cinnamate esters and coum arin esters as functional groups and ROMP, combined with [2+2] cross-linking as the me thodology. The advantages include flexibility caused by the mild polymerization and ability to accommodate different functional groups giving better mechanical strength obtained by the li near ladder-like cross-linking throughout the polymer chain length. Our approach is to incorporate the elimina tion of nitrogen into the photo-crosslinking reaction to prepare a porous architecture within the hard polymers that should permit the flow of water, nutrients, and other biomolecules throughout the new artificial tissue. We aim to use a free radical nitrogen release reaction to introduce the holes and open architecture. Our research group had developed the following novel approach (Schem e 2-1, 2-2) to developing a cross-link while simultaneously releasing nitrogen gas to synthesize the desired cross-linked polymer. Scheme 2-1. Nitrogen aerosol through elimination.

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47 O O ROMP O O O O H N N 3 n m Grubbs'II Traceamount ofBHT + 2-5 2-1 2-4 N N H O O Scheme 2-2. ROMP to synthesize polymer scaffold. We extend our research in order to increas e the size of pores within the cross-linked polymers in order to allow passage of tissue fl uid and achieving the goal with fewer numbers of steps, thus minimizing the time and cost factor for the synthesis of such biomaterials. Scheme 2-3 shows several other nitrogen releasing methods that c ould be investigated. Each example lead to slightly different intermediate with 2-7 2-8 2-9 leading to a carbine, nitrene, and diradical species, respectively. Scheme 2-3. Other nitrogen-releasing products.

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48 We used the method (a) for the synthesis of nitrogen-releasing system. Scheme 2-4 shows the basic concept of the development of diazoes ter, which when exposed to light can undergo nitrogen elimination. Thus a polymer of norbor nene diazoesters can un dergo photocross-linking to generate the hard polymer with pores for the flow of the fluid. Scheme 2-4. Synthesis of norbornene diazoester. 2.2 Results and Discussion We started with commercially available norbornene aldehyde 2-12 which was a mixture and exo and endo isomers. First step involves the synt hesis of norbornenemethanol by treating the aldehyde in methanol with sodium borohydride and sodium hydroxide at 0oC with an overall yield of 80% (Scheme 2-5). This gives a mixture of exo and endo isomers of norbornenemethanol. Scheme 2-5. Synthesis of norbornenemethanol.

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49 The norbornene alcohol was then treated with N t-Boc glycine in dichloromethane (CH2Cl2) in presence of diisopr opylcarbodiimide (DIC) and 4N, N -dimethylaminopyridine (DMAP) to generate the correspond ing ester carbamate of norbornene 2-14 with a yield of 71%. The next step was the deprotection of the am ine group to generate the amino acetate of norbornene 2-15 (25% yield one time only) (Scheme 2-6) t-BOC Deprotection was carried out in the presence of acid trifluoroacetic acid (TFA ) using different concentration and different solvents. Table 3-1 shows the t-BOC cleav age using different reaction conditions. Scheme 2-6. Deprotection of t-Boc pr otected ester carbamate of norbornene. However, the deprotection work of 2-14 to generate the corresponding amino acetate of norbornene did not proceed as expected. The TLC of the reaction showed several spots and purification of the crude product re sulted in a very poor yield (less than 10%). Presence of acid like TFA might be responsible for the poor recovery of the deprotected product 2-15 Also the deprotected amino acetate is highly reactive a nd can undergo a possible r eaction with each other to generate the dimer. This factor might also be responsible for having undesired results during the acid catalyzed deprotection of 2-14.

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50 Table 2-1. t-Boc Cleavage of the compound 2-14 Sl. No. Starting Material (SM) SM : TFA Solvent % Yield 1 2-14 1:8 Several spots 2 1:4 Several spots 3 1:3 CH2Cl2 (0.5 equiv) 25% 4 1:2.5 CH2Cl2 (0.5 equiv) 10% 5 1:2.0 CHCl3 (1 equiv) 10% 6 1:1.4 CH3CN (0.5 equiv) 15% Our aim was to synthesize the amino acetate of norbornene, which could be converted to the corresponding diazoester. Consid ering the fact that acid deprot ection of a t-Boc group lead to either several products or a poor yield, we changed the path to generate 2-16 (yield 75%) by treating the norbornenemethanol with Fmoc glyc ine in anhydrous tetrah ydrofuran (THF) using DIC, and DMAP as the catalyst. Fmoc functi onal group is stable unde r acidic condition, but undergoes deprotection under basi c condition. The Fmoc protected ester carbamate can be subjected to the base catalyzed deprotec tion to generate the desired amino acetate 2-15 (Scheme 2-8). Table 2-2 shows a series of reactions involved in the deprot ection of the Fmoc group to get 2-15 In one method, 2-16 was added to the solution of piperidine in DMF (20%).179, 180 In another method 2-16 was treated with 0.10 M TBAF in DMF (10 equiv). Scheme 2-7 shows the possible product of the deprotection of Fmoc pr otecting group in presence of TBAF in DMF along with the side product dibenzofulvene.181 2-16 2-15 0.1MTBAF DMF + R.T. O O NH2 O O H N O O Scheme 2-7. Deprotection of Fmoc group. However, the deprotection of Fmoc did not provide the necessary results. The possible reason for the failure of piperidine catalyzed Fmoc deprotection is that the piperidine prefers to

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51 attack at the ester carbonyl comp ared to the attack to the amide carbonyl as the former (ester carbonyl) is more reactive than the later. The 1H NMR of the deprotecte d product showed mostly the norbornenemethanol and not the desired compound 2-15 Scheme 2-8. Synthesis of norbornene amino acetate using Fmoc protecting group. Table 2-2. Deprotection of Fm oc group to get the compound 2-15 Sl. No. Starting Material Reagent QuenchingProduct 1 2.16 0.1 TBAF in DMF CH2Cl2 Major yield was Norobornenemethanol 2 0.1 TBAF in DMF H2O 3 50% piperidine in DMF H2O 4 20% piperidine in DMF H2O The base catalyzed deprotection of Fmoc es ter carbamate of norbornene did not work either. So we changed the route of making the diazoester from the amino acetate of norbornene. We use a new intermediate ketoester for this purpose. In this met hod, we synthesized the ketoester 2-17 from norbornenemethanol (Scheme 2-9) with an overall yield of 75%.

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52 Scheme 2-9. Synthesis of norbornene ketoester 2-17 Ketoester 2-17 was then subjected to diazotization by treating it with p -TsN3 to make the corresponding diazoester 2-18 with an overall yield of 70% (Scheme 2-10).182, 183 This diazoacetate product is potentially explosive mate rial and proper care was taken in making the product as well as preserving it for future use. Scheme 2-10. Synthesis of diazoester 2-19 The next step was the synthesis of the polym er containing the diazo functional group using ROMP methodology (Scheme 2-11). However, th e reaction was unsuccessful employed under several reaction conditions due to the formation of insoluble polymer of the diazoester of norbornene. O O N2 n Grubbs'IICatalyst,CH2Cl2 2-19 2-20 O O N N Scheme 2-11. Attempt to make polymer by ROMP.

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53 The reason behind the formation of the insol uble polymer is the possible cross-linking reaction was the diazoketone likely reacted faster than the ROMP with the catalyst. Also there could be a possibility that th e release of nitrogen can cause the formation of new metalalkyledene with the ru thenium catalyst causing a complicated ring opening metathesis reaction. Similar kind of cyclization reaction was observed by Padwa for a series of -diazo ketones in presence of rhodium catalyst. We checked whether the norbornene with ketoester pendent functional group (compound 2-17 ) is capable of undergoing polymerization or not (Scheme 2-12). The reaction took place successfully giving the corresponding ROMP product. In our next step we tried to make copolymer using differe nt ratio of norbornene and norbornene diazoester without any success (Scheme 2-13). We have also successfully polymerized the keto hexanoate of norbornene using Grubbs’ first generation catalyst (Scheme 2-14). Scheme 2-12. ROMP of the ketoester of norbornene. O O N2 Grubbs'IICatalyst,CH2Cl2 2-19 2-23 2-25 n m + O O N N n m Scheme 2-13. Unsuccessful attempt to make co-polymer using ROMP.

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54 Scheme 2-14. ROMP of the monomer 2-22 2.3 Conclusion We successfully synthesized the monomer 2-19 for the synthesis of the polymer 2-20 However, polymerization of 2-19 was not successful as the resultant polymerization using ROMP generated an insoluble cross-linked polym er. We have synthesized the polymer of the norbornene ketoesters, both the compound 2-17 and the compound 2-24 We have now observed the diazoketone group is not compatible with the Grubbs’ catalyst and metathesis. Compound 2-19 will need to be modified. So we proposed the polymerization of the compound 2-17 followed by the incorporation if the diazo functional group into the polymer (Scheme 2-15 and 2-16). This approach wi ll be studied later.

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55 Scheme 2-15. Synthesis of co-polymer 2-27 Scheme 2-16. Diazotization of the co-polymer 2-27

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56 CHAPTER 3 METATHESIS OF CARBOHYDRATES 3.1 Introduction In the current era of proteomics, genomics, a nd glycomics, there is an exponential increase in potential therapeutic targets, which in turn increases the demand to access novel and diverse chemical libraries.130 Molecular diversity131, 132 is based on the “similar property principle”133, which suggests that structurally similar mo lecules should have si milar physiological and biological properties. One way to interpret the mol ecular diversity is to split it into the functional and structural parts, and then re duce the structural part into the rigid portion of the scaffold. For example, some libraries can be described in te rms of (a) functional di versity, (b) structural diversity, (c) type of side chains and/or substituents, or (d) re lative orientation of the side chains.134, 135 Such orientations are de fined by the carbon-carbon (C-C) bonds linking the side chain to the backbone. A variety of scaffolds have been examined. These scaffolds are basically controlled by the orientation of the functional group and have lower impact on the biological properties of the compound.130 Monosaccharide-based scaffolds that contain seve ral chiral centers were targeted in this work. In principle we can incorporate various alkoxy substituents at each position and not alter the chirality at that center. Sugar scaffolds provide an unparalleled opportunity to generate libraries of high functional and structural dive rsity. For example, three different pharmacophore groups in glucose generates up to 60 unique prod ucts of similar molecular properties but with different orientations of the pharmacophore groups (Scheme 3-1).130

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57 A A AO C O A C O B C 1,2,4 3,2,4 2,1,6 Someofthe60uniquepresentations foronescaffold(5x4x3) O BA C O BA C O B Glucose Galactose Altrose Someofthe8uniquepresentations foronesubstituentpattern(2x2x2) C B B Scaffold Substitutionpatterns Scheme 3-1. Illustration of the stru ctural diversity in pyranose scaffolds.130 A great deal of synthesis in carbohydrate chemistry is incr easingly directed towards the synthesis of artificial glyc oconjugates containing the sugars and/or natura lly occurring compounds instead of the natural compounds itself.117, 118 The artificial ca rbohydrate compounds can be synthesized to exhibit parallel or even improved biological inte ractions. Many biological interactions require two or more carbohydrate moieties.118 Many combinatorial approaches involving carbohydrates have been investigated. For example th e structural diversity of carbohydrates has been coupled with the Ugi f our component condensation reactions in both solid and solution phase.130, 160 There are no DCL libraries that use solid phase synthesis. In spite of this drawback solid phase organic synthesis is still an attractive and powerful tool for the development of compound libraries. Little is kno wn about static librari es using sugars. Sofia et al .136 demonstrated this by generating a large lib rary of disaccharide -based moenomycin mimetics and identified several compounds whic h displayed high activity against Gram-positive bacteria. Orthogonally protected scaffolds of D-glucose137 and D-galactose138 have been used by Kunz’s group to exploit the concept of regiosel ective introduction of a va riety of substituents

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58 using solid support chemistry. However, none are used to make dynamic combinatorial libraries and none use metathesis. It is therefore clear that s ugars possess a great deal of potential as medical compounds. However, the application of co mbinatorial chemistry to the carbohydrate class of biomolecules has arrived “late to the party” with only rece nt consideration of these compounds as potential therapeutic agents.121-123 Carbohydrates are biologi cal information molecules with the possibility of dense functionalization and stereochemistry, thereby potentia lly could lead to excellent libraries.124 Only a few example of DCLs containi ng carbohydrates are av ailable and none of them involves a metathesis method.57, 117-118, 125-126, 162 A few classes of biomolecules have been used with DCLs, including lectins, enzymes, polynucleotides, etc., and libraries have been constructed using a variety of el ements. Most of these are associ ated with non-natural cores and connectors. Efforts are now being made to develop strategies th at can join the carbohydrates through this synthetic linkages.118, 127 Several chemical reactions including the aldol condensation,128 and free-radical couplings129, 162 are used to synthesize these connectors. Such linkages are more resistant towards acids and enzymes. The concept of employing homodimeric compounds139 to increase th e ligand-binding affinity140 and ultimately shed light on enzymatic and cellular processes has generated considerable interest in the drug discovery arena.141, 142 Such homodimeric compounds prepared by metathesis are discussed below. The use of naturally occurring compounds like peptides,143 steroids,144 and carbohydrates145 as scaffolds in combinator ial synthesis has received considerable attenti on. In spite of their good qualities, carbohydrate molecules have an unfortunate drawback of being water soluble.

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59 Olefin metathesis has emerged as a versatil e technology for the synthesis of combinatorial libraries in respect to scaffold creation and embellishment.146 The advantages of olefin metathesis over the other transition-metal-catalyzed reactions can be seen in catalyst efficiency, accessibility and functional group compatibility.116 Cross-metathesis also opens the door to DCLs. In spite of having advantages like unique properties, high reactivit y, stability to air and remarkable functional group tolera nce, ruthenium carbene cata lysts (Grubbs’ first and second generation catalyst) have scarcely been used in carbohydrate chemistry.148 The example of carbohydrate homodimerization wa s reported by Descotes et.al.149 in his sugar syntheses using a tungsten aryloxo complex such as 3-1 (Figure 3-1). O W OAr Cl OEt2 3-1 Figure 3-1. Tungsten aryloxo complex used by Descotes .150 However, such tungsten-catalyzed alkenyl gl ycoside homodimerizations were unsuccessful with O -allyl glycosides as well as benzyl-protected sugar derivati ves. Roy and coworkers first prepared a range of “homodimers” starti ng from peracetylate d or perbenzylated Oand Callyl as well as O -pentenyl galactopyranosides usi ng ruthenium benzylidene complex 1-3 (Scheme 32).150 Table 3-1 shows a series of Oand Callyl and Opentenyl (entry 3-6 ) galactopyranosides using ruthenium catalyst 1-3 .150 Such carbohydrate dimers represen t appealing tools to quickly titrate distances between carbohydr ate binding sites in polyvalen t recognition. Moreover, they can represent potent noncovale nt cross-linking reagents.163

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60 OAc AcO AcO O OAc O OAc AcO AcO O OAc O O OAc OAc AcO AcO 10mol%1-3 CH2Cl2,reflux H2CCH2 1' 2' 3-2 3-3 Scheme 3-2. Homodimerization of O -acetyl-D-galactopyranoside 3-2 .150 The examples above demonstrate the importan ce of ruthenium catalyzed cross-metathesis reaction in carbohydrate chemistry. As part of the continuing intere st in the application of crossmetathesis in carbohydrates we envisioned ring clos ing metathesis (RCM) as a means to generate the homodimer 3-19 (Scheme 3-3). We envisioned the self-metathesis products possessing several anchoring groups where pharmacophoric groups can be attached. Also some carbohydrates can have two hydroxyl groups (primary, and secondary hydroxyl groups), which can be protected in different ways. Such carbohydrat es can also be subjected to different olefin metathesis reactions.

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61 Table 3-1. Olefin sel f-metathesis of alkenyl O and C -glycopyranosides.150 R R R 10mol%, 1-3 CH2Cl2,reflux,6h 3-2,3-4, 3-6-3-9,3-12 3-3,3-5, 3-7-3-11,3-13 Entry Substrate R Product (E/Z) Yield (%) 1 3-2 OAc AcO AcO O OAc 3-3 (5/1) 92 2 3-4 OAc AcO OAc OAc O 3-5 (4/1) 95 3 3-6 OAc AcO OAc OAc O 3-10 (5/1) 85 4 3-7 O AcO OAc OAc OAc O O AcO OAc OAc O 3-11 (4/1) 89 5 3-8 O OAc OAc AcO AcO 3-12 (2/1) 82 6 3-9 O OAc OAc OAc AcO 3-13 (1/1) 75 7 3-12 O OBn OBn O BnO OBn 3-15 (3/1) 76

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62 O O O O O H3C H3C HO O O O O O H3C H3C CH3 CH3 O DIC,DMAP,CH2Cl20oC-R.T.,71% O HO O Grubbs'I,CH2Cl2 3-19 3-17 3-16 O O O O O O O CH3 CH3 H3C H3C O O O O O O O CH3 CH3 CH3 CH3 Reflux,18h,83% 3-18 Scheme 3-3. General scheme for the self-metathesis of O -pentenoate of a furanose.

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63 O OH OO OH O O OO OH O O OH OO O O O O OO O O O O HO (1-equiv.) + O HO (2equiv) 3-20 3-18 3-21 3-22 3-23 3-18 Scheme 3-4. Protecting group a nd hydroxyl reactivity strategy. 3.2 Results and Discussion 3.2.1 Metathesis of the monoester of carbohydrates In order to study the viability of olefin metath esis for DCC, we first required synthesis of the various monomers and ester derivatives. It wa s then necessary to react the monomers with Grubbs’ second generation catalyst 1-4 to study the selectivity a nd reactivity of olefin metathesis. A series of 5and 6member carboh ydrate derivatives (furanosides and pyranosides) were synthesized by coupling acetone, benzyl, and TBDMS protected ca rbohydrates with allyl chloroformate and 4-pentenoic aci d using DIC, DMAP, or/and HOB T. The starting material was typically consumed within the next 3 h as indicated by TLC. Purification by column

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64 chromatography gave the 4-pentenoic esters of the 5and 6member carbohydrates in moderate to high yield (Table 3-2) with the exception of 3-41 (26% only). Table 3-2. Yields, and optical pr operties of carbohydrate derivatives. Entry Carbohydrates Protec ting group Product Yield (%) [ ]25 D 1 D-Mannose Acetone protected 3-26 71 +59.82 o (C=1.57, MeOH) 3-29 76 + 49.55 o (C = 1.19, MeOH) 2 D-Glucose Acetone protected 3-32 71 -27.50 o (C = 1.19, MeOH) 3 D-Galactose Acetone protected 3-36 87 -48.22 o (C = 2.71, MeOH) 4 D-Ribose Acetone protected 3-41 26 -60.34 o (C = 1.46, MeOH) TMS protected 3-45 89 -51.16 o (C = 2.05, MeOH) Benzyl protected 3-46 81 -71.55 o (C = 1.57, CH2Cl2) 5 D-Isomannide Benzyl protected 3-52 84 +168.51 o (C = 1.66, CH2Cl2) 6 D-Isosorbide Benzyl protected 3-56 71 +74.19 o (C = 1.87, CH2Cl2) The resultant 4-pentenoate monomers of the protected carbohydrates were then subjected to olefin metathesis in presence of Grubbs ’ second generation catalyst in anhydrous CH2Cl2 or CHCl3 under reflux condition. Table 3-3 shows the olefin metathesis of the monomers of different carbohydrates. We started with commercially available D-mannose ( 3-24) The first step was the protection of four out of five hydroxyl groups available in the fu ranose form of the sugar. The protection of the D-mannofuranose ( 3-24 ) (mannose) was performed in presence of acetone and 2, 2-dimethoxy propane (2, 2 DMP). Catalytic amount of p -toluenesulfonic acid ( p -TsOH) was added to facilitate the reaction, resulting in the formation of 71% of the diacetone D-mannose ( 325 ). This protected mannose was then treated with allylchloroformate in presence of DMAP to obtain the corresponding carbonate 3-26 with an overall yield of 67%. Scheme 3-5 shows the

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65 synthesis of 3-26 the carbonate of the protected D-ma nnose. The carbonate, thus formed, was subjected to metathesis reaction using Gr ubbs’ first and second generation catalyst. Table 3-3. Yields, and optical prop erties of the metathesis products. Entry Carbohydrates Protecting group Product Yield (%) mp (oC)[ ]25 D 1 D-Mannose Acetone protected 3-27 61 Oil + 15.6 (C = 1.04, CH2Cl2) 3-30 72 88.590.0 + 28.88 o (C = 1.04, CH2Cl2) 2 D-Glucose Acetone protected 3-33 83 Oil 0 o (C = 1.28, CH2Cl2) 3 D-Galactose Acetone protected 3-37 74 86.087.0 4 D-Ribose Acetone protected 3-44 81 Oil -1.35 o (C = 1.11, CH2Cl2) TBDMS protected 3-48 0 Benzyl protected 3-49 81 Oil -6.60 o (C = 1.51, CH2Cl2) 5 D-Isomannide Benzyl protected 3-53 82 Oil +0.13 o (C = 1.68, CH2Cl2) 6 D-Isosorbide Benzyl protected 3-57 80 Oil +0.23 o (C = 1.87, CH2Cl2) Scheme 3-5. Synthesis of the carbonate of diacetone (D)-mannose.

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66 The metathesis of the carbonate of (D)-ma nnose was carried out in presence of Grubbs’ first and second generation catalysts. Prior to the addition of Grubbs’ catalyst (both first and second generation), butylated hydroxytoluene (B HT) was added to prevent any possible atom transfer radical polymerizati on (ATRP). All reactions were refluxed either in anhydrous chloroform or in anhydrous methylene chloride overnight. The reaction was quenched with EVE. EVE reacts with the catalyst (both first and second generation) in an irreversible manner, making it inactive to othe r kind of olefins.152 Metathesis of compound 3-26 resulted in the formation of metathesis product 3-27 with an overall yield of 61%. Use of methylene chloride as the solvent helps to maintain the reactivity of Grubbs’ catal yst during the reflux. The reaction was expected to result in the formation of both E and Z isomer, with the E isomer having a well-known preference over the Z due to steric hindrance. Once the me tathesis product was formed, it was subjected to hydrogenation via Pd on activated carbon (10% Pd) under H2 atmosphere to give compound 3-28 in good yield (90%). Scheme 3-6 show s the formation of the saturated metathesis product 3-28 To increase the yield of the metathesis product, we had increased the chain by one methylene and removed the carbonate. Instead of allyl chloroformate, th e diacetone (D)-mannose 3-25 was treated with 4-pentenoic acid in the pr esence of DIC and DMAP to give the ester 3-29 with a yield of 76%. The ester of mannose was then subjected to metathesis with Grubbs’ first generation catalyst (10 mol%) in anhydrous dichloromethane (0.50 M) resulting in the formation of the self-metathesis product 3-30 with a yield of 72%. A series of self metathesis of (D) mannose carbonate were done and everytime th e yield was around 74% (varying from 72% 76%).

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67 O O O O O O O O H3C CH3 H3C H3C Grubbs'II,CHCl3Reflux,18h,61% O O O O O O H3C H3C CH3 H3C O O O O O O O O O O CH3 CH3 H3C CH3 3-26 3-28 O O O O O O H3C H3C CH3 H3C O O O O O O O O H3C CH3 3-27 H2(g),PdCatalyst,90% O O CH3 CH3 Scheme 3-6. Metathesis followed by hydr ogenation to obtain saturated homodimer. Thus, with the use of new terminal alke ne with longer chain length, there is an improvement in the overall metathesis yield. Scheme 3-7 shows the metathesis reaction involving the longer terminal alkene chain. Only a single trans isomer was produced.

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68 Scheme 3-7. Metathesis of the ester of (D)-mannose. The next sugar used for the metathesis wa s glucose. The diacetone D-glucofuranose (3-31) is commercially available. It was subjected to es terification with 4-pentenoic acid in presence of DIC and catalytic amount of DMAP. The yield was 70%. The metathesis of ester 3-32 under identical conditions to those us ed for the mannose derivative 3-29 resulted in the formation of compound 3-33 with a yield of 83%. Scheme 3-8 show s the overall reactions involved in the metathesis of glucose. Both the sugars, (D)-mannose and (D)-glucose are chiral in nature and the esterification may lead to possible isomerization of the pr oduct. In order to find out whether actual racemization took place during the esterification or not, we did the esterification of both (D)-mannose and (D)-glucose in presence and absence of hydroxybenzotriazole (HOBT). The C1 of the ester compound is particular ly labile, especially in the presence of acids or HOBT. Since no change in the NMR as well as the optical rotational properties was observed, we were

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69 convinced that C1 epimerization had not occurred. Table 34 shows the optical properties of the ester of sugars in presen ce and absence of HOBT. Table 3-4. Comparison of the optical prope rty of the esters of (D)-mannose and (D)-glucose. Type of ester [ ]25 D of the ester without HOBT [ ]25 D of the ester with HOBT O O H3C H3C O O O O CH3 H3C O +49.55o +49.25o O O O O O H3C H3C CH3 CH3 O O -27.50o -27.03o O O O O O H3C H3C HO O O O O O H3C H3C CH3 CH3 O DIC,DMAP,CH2Cl20oC-R.T.,71% O HO O Grubbs'I,CH2Cl2 3-33 3-32 3-31 O O O O O O O CH3 CH3 H3C H3C O O O O O O O CH3 CH3 CH3 CH3 Reflux,18h,83% Scheme 3-8. Metathesis of th e ester of diacet one (D)-glucose.

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70 The NMR of the metathesis of D-mannose indicates that the product is mostly trans isomer. However, in the case of D-glucos e, the metathesis product contains both cis and trans isomers. Considering the steric factor, the trans isomer is expected to predominate over the cis isomer. However, a combination of 1H NMR and 2-D NMR of the product give the ratio of cis and trans isomers. The third sugar we used was D-galactose. Like mannose, the commercially available D-galactose was first protected by treating it with acetone in the presence of a catalytic amount of anhydrous copper sulfate to give compound 3-34 with an overall yield of 43%.153 However, the protected D-galactopyaranose is also available commercially. This protected galactose was then subjected to esterification with 4 pentenoic acid ( 3-18 ) to give the ester with a yield of 87%. It was subjected to metathesis with 10 mo l% of Grubbs’ first generation catalyst, using anhydrous methylene chloride (0.5 0 M), resulting in the formation of 74% of the metathesis product 3-37 In fact, we noticed some double bond is omerization with the galactose system when the ester of the D-galactopyranose was su bjected to the metathesis with Grubbs’ second generation catalyst using chloroform during refl ux. We used Grubbs’ sec ond generation catalyst and the chloroform system for th e metathesis of the ester of D-mannose and the D-glucose also without any evidence of double bond isomerizat ion. Again, a single geometric isomer of 3-37 was observed and it was trans As a result we have shifted to the Grubbs’ first generation catalyst and dichloromethane system for all metathesis r eaction conditions applied in later part of the project. Scheme 3-9 shows the formation of the metathesis product of (D)-galactose 3-37

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71 Scheme 3-9. Metathesis of the protected (D)-galactose. The fourth sugar we used was D-ribose. Unlike the first three sugars, D-mannose, Dglucose, and D-galactose, prot ection of the D-ribose resulted in the formation of compound 3-39 which has two hydroxyl groups. One of the hydroxyl groups is 1o (primary), while the other hydroxyl group is 2o (secondary). From the steric hi ndrance point of view, a primary alcohol is expected to be more reactive than a secondary one. However, when the monoacetone D-ribose was subjected to monoest erification with 4-pentenoic acid, using the same conditions, the esterification took place not only at the desired 1o alcohol to give 3-41 but also at the other available position 3-42 3-43 resulting into an overall poor yield (26%) of the desired sugar derivative 3-41 We changed the concentration of the reaction medium using 0.50 M, 1.0 M, and 0.10 M of dichloromethane without any significant improvement in the percentage yield of the desired product 3-41

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72 Scheme 3-10. Monoesterificati on of the monoacetone (D)-ribose. Metathesis of compound 3-41 using standard reaction conditions resulted in the formation of compound 3-47 with an overall yield of 81% (Scheme 3-11). Scheme 3-11. Metathesis of compound 3-41 Even the less reac tive alcohol site (20 hydroxyl site) of the monoacetone D-ribose took part in esterification (compound 3-42 ), yet the overall yield was low (no significant amount was recovered after column chromatography each time). So, our next attempt was to protect the most reactive alcohol site, so that the esterificati on of the corresponding ri bose would lead to the incorporation of the ester gr oup exclusively in the less r eactive site. We used both tert -butyl

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73 dimethylsilyl chloride, (TBDMSCl)154 and benzyl chloride for the protection of the primary hydroxyl site of monoacetone (D)-ribose. Scheme 3-12 shows the synthesis of TBDMS protected monoacetone (D)-ribose 3-40 (52%), and benzyl protected monoacetone (D)-ribose 3-44 (47%). O OH O O H3C CH3 O Ph O OH O O H3C CH3 HO NaH,CH2Cl2,TBAI BnCl,R.T.,47% O O O OH O H3C CH3 Si CH3 H3C H3C H3C H3C TBSCl,DMF Imidazole,R.T. 3-39 3-40 3-44 52% Scheme 3-12. Synthesis of TBDMS and benzyl protected monoacetone (D)-ribose. Compounds 3-40 and 3-44 were then subjected to the esterification reaction with 4-pentenoic acid, using DIC and cat alytic amount of DMAP. Este rification of TBDMS protected monoacetone (D)-ribose resulted in the formation of compound 3-45 with an 89% yield. Esterification of the benzyl protected monoacet one (D)-ribose resulted in the formation of compound 3-46 with an overall yield of 81%. Scheme 3-13 shows the esters of the two diprotected (D)-ribose 3-45 (benzyl protected) and 3-46 (TBDMS protected).

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74 Scheme 3-13. Synthesis of esters of TBDM S and benzyl protected monoacetone (D)-ribose. When the ester of TBDMS pr otected monoacetone (D)-ribose 3-45 was subjected to the metathesis reaction, no significant result was obt ained. Our attempt of the metathesis of compound 3-45 did not yield the desired self-metat hesis product. The ester of benzyl monoacetone (D)-ribose, 3-46 was then subjected to the metathesis reaction with Grubbs’ first generation catalyst using methylene chloride as the reflux solvent with a concentration of 0.50 M. Scheme 3-15 shows the metathesis of the compound 3-46 which resulted in the formation of the self-metathesis compound 3-49 with an overall yield of 81%. The last two sugars we used are commer cially available (D)-isomannide and (D)-isosorbide, which are diastereoisomers. In the case of (D)-isomannide ( 3-50 ), both the hydroxyl groups are cis whereas for (D)-isosorbide ( 3-54 ), they are trans with respect to each other.

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75 O O O O O H3C CH3 Si CH3 H3C H3C H3C H3C O O O O O O H3C CH3 Si CH3 H3C H3C H3C H3C O O O O O O O Si CH3 CH3 CH3 CH3 CH3 Grubbs'I, CH2Cl2,Reflux,18h 3-45 Self-metathesisproduct 3-48 Scheme 3-14. Metathesis of the ester of TBDMS protected m onoacetone (D)-ribose. O O O O O CH3 H3C Ph O O O O O O CH3 H3C Ph O O O O O Ph O O CH3 CH3 Grubbs'CatI CH2Cl2,Reflux,81% 3-46 3-49 Scheme 3-15. Metathesis of the ester of benzyl protected monoacetone (D)-ribose. Scheme 3-16 shows the metathesis of the es ter of benzyl protecte d (D)-isomannide, where the first step involved the synthesi s mono benzylated (D)-isomannide 3-51 by following the literature procedure.124 This was then subjected to esterification to get 3-52 (84%) followed by metathesis reaction using Grubbs’ first generatio n catalyst to get the self-metathesis product 3-53 (82%).

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76 Scheme 3-16. Synthesis of metathesis product of benzylated (D)-isomannide. However, in case of (D)-isosorbide the two hydroxyl groups are trans to each other. Due to the cis -fused bicyclic system, one hydroxyl group is in the exo position while the other one is in the endo position. From a steric point of view, the hydroxyl group in the exo position is expected to be more reactiv e than the hydroxyl group in the endo position. Benzylation of the (D)-isosorbide with KOH, water, and benzyl br omide resulted in the formation of mostly exo protected (D)-isosorbide 3-55 following the literature procedure.155 It was then subjected to the esterification reaction to give the product 3-56 followed by the self-metathesis reaction in presence of Grubbs’ first generation catal yst to give the metathesis product 3-57 with an yield of 80%. Scheme 3-17 shows the metathesis of the exo -benzylated (D)-isosorbide.

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77 O O HO OH O O HO O Ph KOH,H2O,Reflux,30min. PhCH2Cl,Reflux,3hr. H H H H O O O O Ph O 4-PentenoicAcid DIC,DMAP,CH2Cl2, H H O O O O H H O O O O O O H H Ph Grubbs'I,CH2Cl2,Reflux,18h,80% P h 3-54 3-55 3-56 3-57 0oC-R.T.,71% 40% Scheme 3-17. Metathesis of the benzylated (D)-isosorbide in the exo position. Table 3-3 shows the all the homodimers made from esters of different o -oligosaccharides 3.2.2 Metathesis of Tri-esters of Phloroglucinol We diversify the concept of making library of metathesis produc ts of carbohydrates. In this approach we tried the cross metathesis reac tion between the ester of phloroglucinol with the ester of different carbohydrates to ge nerate a second library (Scheme 3-18). The first step involves the synthesis of the tri-ester of phloroglucinol 3-62 using the usual esterification reaction conditi ons between phloroglucinol 3-61 and 4-pentenoic acid 3-18 (Scheme 3-19). The second step involves the cr oss-metathesis reaction between the ester of diacetone (D)-glucose and the ester of phlorogl ucinol using Grubbs’ fi rst-generation catalyst (Scheme 3-20). The reaction gives a whole bunch of possible cross-metathesis as well as selfmetathesis products as observed from the TLC of the crude product. However, the major product

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78 isolated from the crude mixture was the compound 3-63 with a yield of 58%. Using a preparative column chromatography, it is possible to separate each fraction as well as identify them by NMR Scheme 3-18. Schematic representation of th e cross-metathesis between carbohydrate and phloroglucinol esters. OH OH HO HO O DIC,DMAP,CH2Cl20oC-R.T.,70% O O O O O O 3-61 3-62 3-18 Scheme 3-19. Tri-es ter of phloroglucinol 3-62

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79 Scheme 3-20. Cross-metathesis of ph loroglucinol ester and glucose ester. 3.4 Conclusion Our main objective in this project was to exam ine the olefin self-metathesis reactivity and selectivity of the esters of pentose and fructose. The extension of carbon skeletons by the construction of carbon-carbon bonds represents one of the most important areas in synthetic organic chemistry. We applied this self-metathe sis technique on different carbohydrates in their 5-membered as well as 6-membered ring forma tions. We synthesized the olefin metathesis products of functionalized car bohydrate derivatives in good yiel ds with the Grubbs’ first

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80 generation catalyst used mostly. It is considered that having the olefin moiety further from the ester functional groups in creased the yields of the homodime r products. The stereochemistry of the homodimers was found to be predominantly trans The flexibility of our route is illustrated by the different types of Oglycoside that have been prepared from the commercially available monosaccharides (Table 3-2). Our metathesis-based approach to O -saccharide formation allows for structural diversity in the olefin.

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81 CHAPTER 4 ACYCLIC DIENE METATHESIS RE ACTIONS OF CARBOHYDRATES 4.1 Introduction Hydrogels have increased popularity as scaffold s for tissue engineering due to their high water content, good biocompatibility, and consis tency similar to soft tissue. Natural and synthetic hydrogels retain water in a thre e-dimensional network of polymer chains.83 Examples of such degradable polymers include series of polyesters such as pol y(lactic acid) (PLA), poly(glycolic acid) (PGA), and th eir copolymers. But these have their own problems like early loss of mechanical properties, generation of acidic products during degr adation creating harsh environments that are not compa tible with cells and tissues. Carbohydrates are mostly present in nature in the form of glycoconjugates (glycoproteins and glycolipids).60 Their role is unambiguously importa nt but remains often vague. If the understanding of the biological ro le of carbohydrates is to appro ach that of nucleic acids and proteins, access to well-defined pure oligosaccharide structures will have to be improved. While the sequencing of samples of oligonucleotides a nd proteins is routine and has been automated, carbohydrate sequencing has been particularly challenging.61 Glycopolymers, synthetic sugarcontaining macromolecules, are attracting ever -increasing interest from the chemistry community due to their role as biomimetic analogues and their potential for commercial applications. Recent developments in polymeriza tion techniques have enabled the synthesis of glycopolymers featuring a wide range of c ontrolled architectures and functionalities.62 Condensation polymers and the corresponding monomers and macrocycles can generally be interconverted by a seri es of closely related reactions, wher e the nature of the major reaction product(s) depends greatly on the concentration of reactants.63-65 Acyclic Diene Metathesis chemistry is used to produce polymers of unique and fixed architecture utilizing diene

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82 monomers. ADMET is a condensation polymeriza tion reaction that connects molecules through terminal alkenes with the rel ease of small molecules ethylene. The release of this gaseous molecule is the driving force for this reaction an d allows high molecular weight to be reached with a variety of monomers. Essentially this is an example of self-metathesis with a diene. The use of monosaccharides in hydrogels for soft tissues has not been investigated. This is somewhat unusual because sugars are nontoxic food to most animal forms and highly hydroxylated. Absorption with time as new tissu e grows into the biomaterial will not be problematic in this case. Traditionally, carbohydrat e substituted polymers have been synthesized by polymerization of acrylamide derivatives. Th e naturally occurring car bohydrates are chiral molecules. The racemizations of chiral centers are of great concern wh en polymerization method requires the use of basic or hi ghly thermal conditions. ADMET is a thermally and chemically neutral polymerization method. These conditions make ADMET an ideal candidate for studying polymers that are sensitive to harsher polymerization methods. These polymers ( 4-14 4-15 4– 16 and 4-17 ) made by ADMET chemistry therefore represent an opportunity to develop hydrogel from them. In connection with our intere st in the potential applic ations of such reactions,64, 66-69 in particular the preparation of combinatorial librari es of either macrocycle s and/or polymers, we decided to polymerize a series of carbohydrate ba sed pentenoic ester with pendent terminal double bond by ADMET polymerization method using Grubbs’ first generation catalyst. Scheme 4-1 shows the basic idea behi nd the ADMET of functionalized carbohydrate derivatives.

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83 O OO OH HO H3C CH3 O OO O O H3C CH3 O O n n OO O O O O O H3C CH3 n n m Grubbs'firstgene rationcatalyst O HO n DIC,DMAP 4-1 4-2 4-3 Scheme 4-1. General scheme for the ADMET polymerization of func tionalized carbohydrate derivatives with terminal double bond. Another interesting feature of ADMET chemistry is the regiochemistry of the polymer, i.e., the structural arrangements of the monomer units. When ethylene is polymerized into linear chains, only one arrangement of atoms is possible. However, the incorporation of substituents into the olefin monomer introduces the opportunity for some structural variability. For example, when propylene is polymerized, the monomers can arrange themselves along the chain in three different ways. If we call the CH2 end of the propylene th e "head" and the CH(CH3) end the "tail", then a head-to-tail (HT) polymerization would lead to a polymer chain with a methyl group (CH3) located on every other carbon (Figure 4-1). On the ot her hand, if the polymerization occurred in a head-to-head (HH), tail-to-tail (TT) fashion, methyl gr oups would be located on adjacent carbons in pairs.

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84 Figure 4-1. Head-to-Tail, Head-t o-Head, Tail-to-Tail arrangement. A third possibility involves random orientati on of monomer units along the polymer chain. These three different structural forms of polypr opylene would be expected to have different physical properties. Generally, th e head-to-tail polymer is produced using heterogeneous ZieglerNatta or homogeneous cyclopentadienyl-zirco nium catalysts. Ring closing metathesis polymerization of the diester of (D)-ribose results in the formati on of a cyclic structure with a possibility of the formation of the HH/TT or HT structure pattern (Figure 4-3). If the H and T monomer units are equally reactive the repeat units would be linked statistically. In that case the expected proportions of HT: HH: TT linkages are 50:25:25. On the other if the head groups are much more reactive than the tail group, then HH link would be formed first, followed later by TT linkages and polymer would c ontain only HH and TT linkages.178 Scheme 4-2 shows an example how the carbohydrate D-mannitol 4-4 might be incorporated into the backbone of a metathesis polymer. Instead of placing the sugar into the polymer lengthwise where it is a major structural unit, this time the polymer is placed across the carbohydrate (Figure 4-2).

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85 Scheme 4-2. Diacetone D-ma nnitol as a hydrogel precursor. Figure 4-2. Hydrogels with carbohydrates lengthwise, crosswise or rings.

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86 Adding two alkenes as ester li nkages for the construction of 4-9 serves two purposes. First, it allows for the ADMET reaction to occur by providing two alkenes to build on. Secondly, the esters provide a point for natural degr adation in time by esterases in the cells. 4.2 Results and Discussion In order to study the viability of olefin metathesis for ADMET, we first required to synthesize a number of monomers–e ster derivatives with pendent di ene. It was then necessary to allow the monomers to undergo metathesis re action in presence of Grubbs’ first generation catalyst 1-3 A series of carbohydrate deri vatives were synthesized by coupling acetone protected carbohydrates with 4-pentenoic aci d using DIC, DMAP. The star ting material was typically consumed within 3 h as indicated by TLC. Puri fication by column chromatography gave the 4-pentenoic esters of the prot ected carbohydrates in moderate to high yield (Table 4-1). Table 4-1. Yield of diene fr om the protected carbohydrates. Enter Carbohydrate Product Yield (%) [ ]25 D 1 D-Mannitol 4-9 71 +13.88 o (C = 2.33, MeOH) 2 D-Ribose 4-10 72 -44.25 o (C = 2.13, MeOH) 3 D-Isomannide 4-11 65 +142.68 o (C = 2.20, CH2Cl2) 4 D-Isosorbide 4-12 70 +87.39 o (C = 2.06, CH2Cl2) The resultant monomers with two pendent alkene groups were then subjected to ADMET in presence of Grubbs’ first gene ration catalyst in anhydrous CHCl3 under vacuum condition resulting in the formation of the polymers in high yield. Table 4-2 shows the acyclic diene metathesis polymerization of different carbohydrates monomers.

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87 Table 4-2. ADMET of the carbohydrates. Enter Carbohydrate Product Yield (%) 1 D-Mannitol 4-13 90 2 D-Ribose 4-15 92 3 D-Isosorbide 4-16 90 4 D-Isomannide 4-17 94 Monoacetone protected sugars, used for the prep aration of dynamic combinatorial libraries, like (D)-ribose (4-6) (similar to th e compound earlier named as ( 3-38 )), (D)-isomannide ( 4-7 ) (similar to the compound earlier named as ( 3-50 )), (D)-isosorbide ( 4-8 ) (similar to the compound earlier named as ( 3-54 )) have two hydroxyl groups and ther efore, can be subjected to diesterification reaction, resulti ng in the synthesis of dienes. Also we have synthesized the diester of diacetone (D)-mannitol ( 4-9 ). All these dienes can be subjected to ADMET chemistry. Depending on the reaction condition available, it is possible to obtain either a ring closing metathesis product or an ADMET product as obser ved with the diene of monoacetone D-ribose 4-10 (similar to the compound earlier named as 3-39 ). A high concentration of catalyst (monomer: catalyst, 10:1) can lead to RCM product 4-14 whereas a much lower concentration of catalyst (monomer: catalyst, 100:1) gives rise to the formation of the ADMET polymer 4-15 The first diene subjected to ADMET was based on the sugar (D)-mannitol ( 4-4 ). Scheme 4-3 shows the synthesis of the diester of diacetone D-mannitol 4-9. The first step involves the protection of the (D)-mannitol us ing the literatu re procedure126 4-5 with an overall yield of 51%. Compound 4-5 was then been subjected to esterificat ion using the normal esterification reaction conditions to make the compound 4-9 with an overall yield of 70%.

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88 Scheme 4-3. Synthesis of the diester of diacetone (D)-mannitol. The monoacetone (D)-ribose ( 4-6 ) has two hydroxyl groups. Ther efore, esterification of the monoacetone D-ribose ( 4-6 ) with 4-pentenoic acid (using 2.10 e quivalents with respect to the moles of the carbohydrate 4-6) results in the formation of the diester of the monoacetone (D)ribose 4-10 with an overall yield of 72%. Scheme 44 shows the synthesis of the diester of monoacetone (D)-ribose. Scheme 4-4. Synthesis of the di ester of the monoacetone (D)-ribose. The other two carbohydrates used for ADMET polymerization are (D)-isomannide ( 4-7 ) and (D)-isosorbide ( 4-8 ). Scheme 4-5 shows the synthetic route for the synthesis of compound

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89 4-11 (65%). Scheme 4-6 shows the synthe sis of diester of (D)-isosorbide 4-12 with a yield of 70%. O O H H OH HO O O H H O O O O 4-PentenoicAcid DIC,DMAP,CH2Cl20oC-R.T.,65% 4-74-11 Scheme 4-5. Synthesis of the diester of monoacetone (D)-isomannide. Scheme 4-6. Synthesis of the di ester of monoacetone (D)-isosorbide. First ADMET chemistry was performed with diester of (D)-mannitol following the usual ADMET reaction condition (Scheme 4-7). First atte mpt resulted in the formation of expected polymer product, which was insoluble in almo st all common organic solvents. No further characterization of the highly viscous, gluey mate rial could be done. In our second attempt, we carried out the ADMET polymeri zation in presence of BHT. The product so obtained was soluble in dichloromethane. It appeared to be highly viscous liquid and could not be precipitated, unlike usual ADMET products.

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90 CHCl3,Grubbs'II R.T.-55oC,90% H O O H O O H3C H3C O O CH3 CH3 4-9 H O O H O O H3C H3C O O CH3 CH3 4-13 O O O O n Scheme 4-7. ADMET of the diester of (D)-mannitol. Carbohydrates with two terminal double bonds ca n undergo either self-m etathesis (like the one mentioned earlier in chapte r 3) to make a homodimer w ith linear structure or ADMET polymerization reaction to give a polymer depending upon the reaction conditions employed. However, when the diene of monoacetone (D) ribose 4-10 was subjected to the metathesis reaction condition using 10 mol% of Grubbs ’ first generation catalyst in anhydrous dichloromethane (0.50 M), a new compound 4-14 was synthesized. In case of the diester of Dribose 4-10 the 1H NMR shows specific peak at = 5.0 ppm for the hydrogen at the terminal double bond and a peak at = 5.8 ppm due to hydrogen at the internal double bond, whereas for the ADMET product of the diester of monoacetone D-ribose 4-15 there is no peak either at = 5.8 ppm or at = 5.0 ppm, instead a new broa d multiplate has appeared at = 6.0-5.0 ppm. The 1H NMR of the compound 4-14 shows two multiplates at = 5.52-5.42 ppm (2H) and at = 5.38-5.26 ppm (2H). If the compound 4-14 is a regular self-metat hesis product then we would see the peak for the hydrogens at the terminal carbon of the double bond. The HRMS analysis shows that it is a dimer [cal cd 653.2809 against found 653.2783). The absence of any peak corresponding to the terminal double bond hydrogen suggests that it is a cyclic dimer product (Figure 4-3) and not a polymer or linear dimer.

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91 Figure 4-3. Schematic representation of the HH or HT cyclic dimer of diacetone (D)-ribose. Such a variation in the possible structure of the cyclic dimer 4-14(HH) / 4-14(HT) is due to the presence of two different hydroxyl groups as the two ester functional groups are not equivalent. In the Figure 4-3 the pe ntenoate end att ached to the 1o hydroxyl end is assumed to be the head whereas the pentenoa te end attached to the 2o hydroxyl end is assu med to be the tail. Further analysis of the product 4-14(HH) / 4-14(HT) by 2-D NMR, and crystallography will help to determine the actual st ructure of the compound. The next carbohydrate used for ADMET is (D)ribose. It is the concentration of the catalyst used for the reaction which determines whether the reaction wo uld be ADMET type or

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92 RCM. ADMET polymerization requires much le ss amount of ruthenium catalyst compared to that for the RCM reaction. The usual ratio of m onomer to catalyst ratio for ADMET is 100:1 or even less than that, whereas the ratio for th e RCM reaction is 10:1. Scheme 4-8 shows the synthesis of the ADMET polymer for the carbohydr ate (D)-ribose. Scheme 4-9, and 4-10 show the synthesis of the ADMET of carbohydrates (D)-i somannide and (D)-isosorbide respectively. Scheme 4-8. ADMET of the diester of (D)-ribose. O O H H O O O O 4-11 O O H H O O O O n 4-16 CHCl3,Grubbs'II R.T.-55oC,80% Scheme 4-9. ADMET of the diester of (D)-isomannide. O O H H O O O O 4-12 O O H H O O O O n CHCl3,Grubbs'II R.T-55oC,85% 4-17 Scheme 4-10. ADMET of the diester of (D)-isosorbide.

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93 Also for the carbohydrate (D)-isosorb ide, the two hydroxyl groups are trans to each other. Even though the hydroxyl groups fo r (D)-isosorbide are not of 1o/2o type, but their reactivity are different. One of the hydroxyl groups occupies the exo orientation while the other occupies the endo orientation. From the steric point of view hydroxyl group at exo orientation is more reactive than the hydroxyl group at the endo orientation. Hence the polymer 4-17 formed by ADMET polymerization method will be of di fferent type compared to the polymer of (D)-mannitol or (D)isomannide. Thus we have a possibility of ha ving a mixture of HH/TT as well as HT polymer linkages in both polymers 4-15 and 4-17 The molecular weight of the polymers (Mn) was determined by GPC with respect to polystyrene as the standa rd. Table 4-3 shows the Mn of the polymers 4-13 4-15 4-16 and 4-17 Table 4-3. Mn of the ADMET polymer. Sl. No. ADMET Mn DPI 1 4-13 5000 1.11 2 4-15 4500 1.10 3 4-16 7000 1.14 4 4-17 6250 1.13 4.3 Conclusion We have successfully developed ADMET chemis try for carbohydrates for the first time. This opens up a new field of chemistry. Of the four carbohydrates we used, monoacetone (D)ribose has two different reactive sites, prim ary and secondary hydroxyl groups. Similarly the hydroxyl groups of (D) isosorbide are different in reactivity base d on the steric factor. So we expect to get polymers with a mixture of head-tohead or tail-to-tail and head-to-tail linkages.

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94 CHAPTER 5 EXPERIMENTALS METHODS 5.1 General Methods and Instrumentation All moisture and air-sensitive reactions were performed under argon atmosphere in flamedried glassware. Solvents were distilled under N2 from appropriate drying agents according to the established procedures. Rf values were obtained by usi ng thin-layer chromatography. Analytical thin-layer chromatography (TLC) was performed using Kiesel gel 20 F-254 precoated 0.25 mm silica gel plates. UV light, phosphomolybdic acid in ethanol, anisaldehyde in ethanol, permanganate, and vanil lin were used as indicators for spot identification in TLC. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Gemini, VXR, and Mercury 300MHz spectrometer. Carbon nuclear magnetic resonance (13C) spectra were recorded at 75 MHz on the same spectrometers. Some of the chemical shifts were reported in ppm downfield with respect to trimethylsilane (TMS) as an internal standard, while in other cases the chemical shift of the solvent (for exam ple, the chemical shift of solvent CDCl3 is 7.27 ppm) was used for standardization. Infrared spectra were ob tained from KBr-pellets using a Bruker Vector 22 IR and are reported in wavelength (cm-1). Unless reported all yields refer to the isolated materials, determined by TLC and NMR. High-resolution mass spectroscopy (HRMS) was performed by the Mass Spectroscopy Laboratory at the University of Florida. Optical rotations were recorded on a Perkin-Elm er 241 digital polarimeter (10-1degcm2 g-1). Melting points were obtained on a Thomas-Hoover capill ary melting point apparatus.

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95 5.2 Experimental Procedure and Data Norbornenemethanol 2-13 A solution of norbornene-1-carboxaldehyde (11.67 gm, 96 mmol) in MeOH (58 mL) was added dropwise over 1 h to a suspension of NaBH4 (1.74 gm, 46 mmol) in 2N NaOH (20 mL) at 0oC under Ar. The reaction mixture was stirred at r oom temperature for further 3 h, monitored by TLC. The pH of the reaction medium was brought back to 6 at 0oC with 30% H2SO4 (30 mL). The methanol was evaporated, and the resulting re sidue was extracted with diethyl ether (3 x 70 mL). The combined organic layers were washed with saturated NaHCO3 and brine (3 x 100 mL with each), dried over anhydrous MgSO4, and concentrated under re duce pressure, affording 213 as a white liquid (9.50 g, 80%).35 2-13 : Rf = 0.71 (CH2Cl2/MeOH, 9:1); IR (film) max 3333, 2967, 1682, 1570, 1337, 1252, 1146 cm-1; 1H NMR (300MHz, CDCl3) 6.20-5.90 (m, 2H, C H =C H ), 3.70-3.20 (m, 2H, C H2OH), 2.90–2.70 (m, 2H, C=CC H C=CC H ), 2.40–2.20 (m, 1H), 2.10-1.90 (s, 1H, O H ), 1.851.70 (m, 1H), 1.50-1.40 (m, 1H), 1.40-1.10 (m, 2H); 13C NMR 137.3, 136.8, 136.6, 132.3, 64.2, 66.2, 49.5, 44.9, 43.6, 43.3, 42.2, 41.74, 41.6, 41.6, 29.6, 28.9. This compound is commercially available from Aldrich. Ester carbamate of norbornene 2-14 A solution of N -tertiary-butoxycarbonyl-glycine ( N -tBoc) (1.34 g, 0.01 mol) in anhydrous CH2Cl2 (3 mL) was added to a solution of the norbornenemethanol 2-13 (1 g, 8 mmol), catalytic amount of DMAP, and DIC ( 1.10 g, 9 mmol) in anhydrous CH2Cl2 (13 mL) over a period of 20 min at 0oC under Ar. The reaction mixture was then stirred for an addi tional 3 h at room

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96 temperature monitored by TLC. The precipitate was filtered and the organic phase was washed with saturated NaHCO3 and brine (3 x 30 mL each), dried over anhydrous MgSO4 and concentrated under reduce pressu re. The crude product was then pur ified by silica gel column chromatography using hexane and ethyl acetate (9 0:10) as eluent to afford the pure product 2-14 as colorless oil (1.60 g, 71%). 2-14 : Rf = 0.52 (CH2Cl2/MeOH, 9:1); IR (film) max 3067, 2978, 1692, 1575, 1347, 1258, 1146 cm-1; 1H NMR (300MHz, CDCl3) 6.20-5.85 (m, 2H, C H =C H ), 5.22-5.00 (s, 1H,-N H ), 4.25-3.72 (m, 4H, C H2OH, OCOC H2NH), 2.90–2.70 (m, 2H, C=CC H C=CC H ), 2.45–2.30 (m, 1H ), 1.90-1.80 (m, 1H), 1.50-1.40 (s, 9H, C(C H3)3), 1.30-1.10 (m, 3H); 13C NMR 170.6, 170.5, 155.9, 137.9, 137.1, 136.3, 132.2, 80.0, 69.5, 68.8, 49.5, 45.0, 43.9, 43.7, 42.6, 42.3, 41.7, 38.0, 37.9, 31.7, 29.6, 29.1, 28.5, 22.8, 14.3. Amino acetate of norbornene 2-15 In a 5 mL round bottom flask under argon, 0.26 g (0.93 mmol) of 2-14 in 1 mL of anhydrous CH2Cl2 was taken. 0.10 mL of TFA was added into it at 0oC under Ar over 15 min. The reaction mixture was stirre d for an additional 2 h at 0oC and was followed by overnight stirring under Ar at room temperature. The volat ilities were removed unde r reduced pressure and the residue was treated with saturated NaHCO3, and extracted with ethyl acetate (3 x 10 mL). The pooled organic extracts were then dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexane and ethyl acetate (40:60) as el uent to afford the pure product 2-15 (45 mg, 25% yields) as colorless oil. Possible reason for the low yield co uld be the use of high concentrated acid TFA. Also a possible dimerization of the amino acetate of norbornene 2-15 may also be responsible for

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97 the low yield. Reaction conditions had been change d with the change in concentration of acid TFA and the solvent (Table 2-1) without any significant change in yield. 2-15 : Rf = 0.52 (CH2Cl2/MeOH, 9:1); IR (film) max 3054, 2975, 1698, 1625, 1578, 1378, 1244, 1048 cm-1; 1H NMR (300MHz, CDCl3) 6.80-6.20 (m, 2H, C H =C H ), 4.60-3.90 (m, 2H), 3.40-3.20 (m, 2H), 3.00-2.80 (m, 1H), 2.60-2.40 (s, 2H), 2.40-2.30 (m, 1H), 2.10-1.90 (m, 1H), 1.90-1.60 (m, 2H); 13C NMR 170.8, 170.4, 170.3, 137.9, 137.1, 136.3, 132.2, 69.5, 68.9, 49.5, 45.1, 43.9, 43.7, 42.3, 41.7, 41.5, 38.0, 37.8, 29.6, 29.1, 22.94. Fmoc protected ester carbamate of norbornene 2-16 A solution of N -Fmoc-glycine (3.95 g, 13 mmol) in a nhydrous THF (13 mL) was added at 0oC under Ar over a period of 20 min into a solu tion of norbornenemethanol (1.50 g, 12 mmol) in anhydrous THF (9 mL) along with DIC ( 1.59 g, 13 mmol) and DMAP (0.14 g, 1.10 mmol). After completion of addition, the reaction mixture was warmed to room temperature and stirred for an additional 3 h. The reaction was monitore d by TLC (hexane/EtOAc, 6:4). The product was then filtered to remove the precipitate. Th e organic phase was then washed with aqueous saturated NaHCO3 and brine solution (3 x 50 mL each), dried over anhydrous MgSO4, and concentrated over reduced pressu re. The crude product was then pur ified by silica gel column chromatography using hexane and ethyl acetate (90: 10) as eluent to afford the pure product as highly viscous oil (3.82, 79%). 2-16 : Rf = 0.72 (hexane/EtOAc, 6:4); IR (film) max 3033, 2967, 1685, 1572, 1347, 1250, 1151 cm-1; 1H NMR (300MHZ, CDCl3) 7.8-7.2 (m, 8H, C H =C H of benzene ring part), 6.2-5.8 (m, 2H, C H =C H of norbornene part), 4.42-4.34 (d, J = 8.1 Hz, 2H), 4.26-4.16 (t, J = 7.2 Hz,

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98 2H); 4.06-3.86 (m, 3H), 3.78–3.66 (t, J = 7.2 Hz, 1H), 2.88–2.74 (m, 2H), 2.44-2.28 (m, 1H), 1.88-1.76 (m, 1H), 1.48-1.18 (m, 2H); 13C NMR 170.2, 156.5, 147.3, 143.9, 141.4, 137.9, 1372, 136.2, 132.2, 127.8, 127.1, 125.2, 120.1, 69.7, 69.0, 67.3, 49.5, 47.2, 45.0, 43.9, 43.7, 42.9, 42.3, 41.7, 38.0, 37.8, 29.6, 29.0. Deprotection of the Fmoc group 2-16 (1.61 g, 2.75 mmol) was added to a solutio n of piperidine in DMF (20%). The mixture was heated for 30 min or until disappearance of star ting material by TLC (CHCl3/MeOH, 9:1). The solution was cooled back to room temperature and poured into cold water (50 mL). The white solid of dibenzofulve ne was removed by vacuum filtration. The filtrate was then extracted with diethyl ether (3 x 50 mL), washed with water, dried under anhydrous MgSO4, and concentrated under reduced pressure to get the deprotected compound, which is mostly the norbornenemethanol (0.12 g, 25%). 2-13 : Rf = 0.71 (CH2Cl2/MeOH, 9:1); IR (film) max 3333, 2967, 1682, 1570, 1337, 1252, 1146 cm-1; 1H NMR (300MHZ, CDCl3) 6.20-5.90 (m, 2H, C H =C H ), 3.70-3.20 (m, 2H, C H2OH), 2.90–2.70 (m, 2H, C=CC H C=CC H ), 2.40–2.20 (m, 1H), 2.10-1.90 (s, 1H, O H ), 1.851.70 (m, 1H), 1.50-1.40 (m, 1H), 1.40-1.10 (m, 2H); 13C NMR 137.3, 136.8, 136.6, 132.3, 64.2, 66.2, 49.5, 44.9, 43.6, 43.3, 42.2, 41.74, 41.6, 41.6, 29.6, 28.9. Norbornene ketoester 2-17 5.30 g of the norbornenemethanol 2-13 (43 mmol) was taken in a round bottom flask under Ar and was dissolved in 86 mL of anhydrous benzene. 7.82 g of DMAP (64 mmol, 1.50 equiv)

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99 was added into it. 14.87 g of methyl acetoacetate (13 mmol, 3 equiv) was added and the reaction mixture was refluxed overnight under Ar. The cr ude product was then washed with water and brine (3 x 50 mL each) and dried over anhydrous MgSO4. The pooled organic layers were then concentrated under reduced pressure and purif ied by silica gel column chromatography using hexane and ethyl acetat e (70:30) as eluent affording the pure compound 2-17 (6.67g, 75%) as a colorless oil. 2-17 : Rf = 0.54 (hexane:EtOAc, 4:6); IR (film) max 3053, 2965, 1715, 1655, 1568, 1357, 1256, 1149 cm-1; 1H NMR (300MHZ, CDCl3) 6.18-5.86 (m, 2H, C H =C H ), 4.22-3.64 (m, 2H, C H2O), 3.46-3.40 (s, 2H, COCH2CO), 2.87-2.64 (d, 2H, C=CC H C=CC H ), 2.26–2.22 (s, 3H, COC H3), 1.90-1.60 (m, 1H), 1.50-1.10 (m, 3H); 13C NMR 200.9, 167.2, 137.8, 137.0, 136.2, 132.1, 69.5, 68.8, 50.2, 49.4, 44.9, 43.9, 43.6, 42.3, 41.6, 37.9, 37.7, 30.2, 29.6, 28.9. p -Toluene sulfonyl azide (2-18) S O O N H3C N N Sodium azide (3.34 g, 51 mmol) was added into a 20 mL of ethanol. To this solution was added 8.89 gm (50 mmol) of p -toluene sulfonyl chloride in 40 mL acetone. A precipitate of NaCl was formed. The reaction mixture was then sti rred for an additional 15 h and then filtered. Acetone was removed by rotary evaporation an d the organic phase was separated and diluted with CH2Cl2. The solution was then washed with di stilled water (3 x 50 mL) and dried over anhydrous MgSO4. Removal of the solvent was left 8.24 gm of p -toluene sulfonyl azide ( 2-18) (90% yields) as colorless o il. Spectral data are in agreement with literature.182 Necessary precautions were taken to preserve this highly explosive compound in a sealed vial.

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100 2-18 : Rf = 0.21 (hexane/CH2Cl2, 6:4); IR (film) max 3238, 3067, 2927, 2100, 1595, 1494, 1451.5 cm-1; 1H NMR (300MHZ, CDCl3) 7.90-7.20 (d, J = 8.4 Hz, 4H), 2.60-2.40 (s, 3H, tosyl C H3); 13C NMR 141.2, 139.5, 128.3, 125.6, 14.4. Diazo-ester of norbornene 2-19 To a stirred solution of the norbornene keto ester 2-17 (1.33 g, 6 mmol) in 7 mL of anhydrous acetonitrile and p -TsN3 (1.52 g, 8 mmol), triethyl am ine (3.60 mL, 4 equiv) was added at 0oC under Ar over 10 min. The reaction mixture was stirred for additional 2 h at 0oC. It was then warmed to room temperature and was stirred for another additional 5 h. Then 1M NaOH (60 mL) was added to the st irred solution. The r eaction mixture was s tirred for additional 12 h. It was extracted with dichloromethane (3 x 50 mL). The combined extracts were washed with 1M NaOH (3 x 75 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain a yellow crude oil. The product was purified by silica gel column chromatography using hexane and ethyl acetate (60:40) as eluent to afford a pure product 2-19 (0.93 g, 81%).183 2-19 : Rf = 0.56 (hexane/EtOAc, 6:4); IR (film) max 3123, 2968, 2111, 1696, 1549, 1363, 1241, 1185 cm-1; 1H NMR (300MHZ, CDCl3) 6.18-5.88 (m, 2H, C H =C H ), 4.82-4.66 (s, 1H, COC H N2), 4.24-3.66 (m, 2H, C H2O), 2.92-2.72 (m, 2H, C=CC H C=CC H ), 2.44-2.28 (1H), 1.86-1.74 (m, 1H), 1.48-1.10 (m, 3H); 13C NMR 177.1, 166.4, 137.3, 136.6, 135.8, 131.8, 68.9, 68.5, 37.9, 49.0, 45.7, 44.6, 43.6, 43.5, 43.2, 41.9, 41.2, 38.0, 37.8, 37.6, 37.4, 36.5, 29.1, 28.5;

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101 Norbornene oxohexanoate 2-22 To an ice-cooled solutio n of norbornenemethanol 2-13 (6.13 g, 50 mmol), DIC (9.64 g, 74 mmol) and catalytic amount of DMAP (0.86 g, 7 mmol) in 99 mL anhydrous CH2Cl2, 4-acetyl butyric acid (9.64 g, 70 mmol) was added over 20 min. After comple tion of addition, the reaction mixture was stirred at room temperature for an additional 4 h until there was no more starting material monitored by TLC (hexane/EtOAc, 6:4). It was then filtered and washed with water (2 x 75 mL) and brine (1 x 50 mL). The or ganic layer was dried over anhydrous MgSO4 and concentrated under reduced pr essure. The crude was then purified by silica gel column chromatography using hexane and ethyl acetate (90:10) as eluent affording the pure product 2-22 (8.50 g, 73%) as colorless oil. 2-22 : Rf = 0.65 (hexane/EtOAc, 6:4); IR (film) max 3053, 2967, 2667, 1714, 1669, 1573, 1424, 1343, 1266, 1158 cm-1; 1H NMR (300MHZ, CDCl3) 6.20-5.60 (m, 2H, C H =C H ), 4.203.50 (m, 2H, C H2O), 2.80-2.68 (m, 2H, C=CC H C=CC H ), 2.45-2.38 (m, 2H), 2.35-2.20 (m, 3H), 2.10-2.05 (s, 3H, C H3), 1.85-1.70 (m, 3H), 1.40-1.00 (m, 3H); 13C NMR 207.8, 172.9, 137.6, 136.9, 136.1, 132.1, 68.4, 67.7, 49., 44.9, 43.8, 43.6, 42.4, 42.2, 41.5, 37.9, 37.8, 33.2, 29.8, 29.54, 28.96, 18.9, 18.9.

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102 ROMP of the Compound 2-17 O O O n A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was flushed with Ar and charged with 0.61 g (2.90 mmol) of the keto-ester of the norborne nemethanol and 4-acetyl butyric acid 2-17 catalytic amount of BHT and 20 mg of the Grubbs’ first-generation catalyst (0.01 equiv.) in 15 mL of anhydrous CH2Cl2 (0.20 equiv). The mixture was stirred ra pidly for an additional 15 min at the room temperature and then quenched with et hyl vinyl ether to afford the ROMP product 2-23 (0.51g). 2-26 : Rf = 0.21 (CHCl3/MeOH, 9:1); IR max 3015, 2985, 2678, 1725, 1661, 1575, 1428, 1353, 1265, 1163 cm-1; 1H NMR (300MHz, CDCl3) 5.80-5.40 (m, 2H), 4.60-4.20 (m, 2H), 3.80-3.60 (m, 2H), 3.50-2.50 (m, 6H), 2.40-2.20 (m, 2H), 2.20-1.60 (m, 12H); 13C NMR 205.6, 205.3, 172.7, 172.3, 137.5, 136.3, 135.9, 133.1, 69.5, 68.6, 67.3, 50.2, 49.5, 45.3, 44.8, 43.7, 43.5, 42.8, 42.6, 41.8, 38.2, 37.9, 33.7, 30.2, 29.7, 29.2.

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103 ROMP of the Compound 2-22 A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was flushed with Ar and charged with 0.51 g (2.10 mmol) of the keto-ester of the norborne nemethanol and 4-acetyl butyric acid 2-22 catalytic amount of BHT and 18 mg of the Grubbs’ first-generation catalyst (0.01 equiv.) in 10 mL of anhydrous CH2Cl2 (0.20 equiv). The mixture was stirred ra pidly for the next 15 min at the room temperature and then quenched with ethyl vinyl ether to afford the ROMP product 2-24 (0.44g) as a highly viscous oil. 2-24 : Rf = 0.23 (CHCl3/MeOH, 9:1); IR max 3013, 2965, 2678, 1725, 1669, 1573, 1423, 1344, 1264, 1157 cm-1; 1H NMR (300MHz, CDCl3) 5.30-5.20 (m, 2H), 4.05-3.70 (m 2H), 2.55-2.40 (m, 4H), 2.30-2.15 (m, 4H), 2.10-2.05 (m, 5H), 1.95-1.70 (m, 6H); 13C NMR 207.6, 172.7, 137.5, 136.3, 135.9, 133.1, 68.4, 67.3, 49.5, 44.8, 43.7, 43.5, 42.8, 42.6, 41.8, 38.2, 37.9, 33.7, 30.2, 29.7, 29.2, 19.5, 19.2.

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104 Diacetone D-mannose (3-25) O O O OH O O H3C H3C CH3H3C A solution of D-mannose (3-24) (10 g, 0.06 mol) and 2,2 DM P (31 mL) in acetone (74 mL) was placed in a round bottom flask under Ar. Catalytic amount of p -toluenesulfonic acid ( p TsOH) (80 mg, 0.46 mmol) was added. The reaction mixture was stirred at r.t. overnight. The reaction was monitored by TLC (hexane/EtOAc, 6: 4). After 10 h of r eaction, the solvent was removed under reduced pressure to affo rd a pure white solid product (m.p. 119.0 – 121.0 oC) of diacetone D-mannose (3-25) (10.11g, 71% yield). 3-25: Rf = 0.25 (hexane/EtOAc, 6:4); m.p. 119.0-121.0 oC (lit 123-124 oC); 25 D +17.16 o (C = 1.35, MeOH); IR (KBr) max 3435, 2988, 2948, 2901, 1459,1439, 1319 cm-1; 1H NMR (300MHz, CDCl3) 5.39-5.36 (d, J = 5.84 Hz, 1H), 4.83-4.78 (dd, J = 5.88 Hz, 3.69 Hz, 1H), 4.63-4.58 (d, J = 5.88 Hz, 1H), 4.44-4.37 (m, 1H), 4.21-4.16 (dd, J = 6.99 Hz, 3.72 Hz, 1H), 4.20-4.02 (m, 2H), 3.14-3.18 (d, 1H, hydroxyl O H ), 1.48-1.44 (s, 6H), 1.4.-1.30 (s, 3H, 3H); 13C NMR 112.8, 109.3, 101.4, 85.7, 80.4, 79.8, 73.5, 66.1, 26.9, 26.0, 25.3, 24.6. Spectral data and m.p. are in agreem ent with literature.159 Carbonate of diacetone (D)-mannose 3-26

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105 To a solution of the diacetone-D-mannose (3-25) (4 g, 15 mmol) together with DMAP (5.63 g, 46 mmol) in CHCl3 (31 mL, 0.5 M), allyl chloroformate (5.57 g, 46 mmol) was added. The reaction mixture was then refluxed for an additional 3 h under Ar until the complete consumption of the starting material. Reaction was monitored by TLC (hexane/EtOAc, 6:4). The crude product was filtered, washed with water (3 x 100 mL) and brine (3 x 100 mL). The organic layer was then dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography using hexane and ethyl acetate (90:10) to afford the product 3-26 (3.55 g, 67%) as a colorless oil. 3-26: Rf = 0.51 (hexane/EtOAc, 6:4); [ ]25 D +59.82 o (C = 1.57, MeOH); IR (neat) max 3643, 3087, 2987, 2338, 1754, 1640, 1456, 1381, 1296 cm-1; 1H NMR (300MHz, CDCl3) 6.025.99 (s, 1H), 5.98-5.84 (ddt, J = 17.33 Hz, 10.28 Hz, 7.34 Hz, 1H), 5.40-5.24 (m, 2H), 4.86-4.80 (dd, J = 5.88 Hz, 3.69 Hz, 1H), 4.76-4.72 (d, J = 5.88 Hz, 1H), 4.65-4.60 (m, 2H), 4.42-4.34 (m, 1H), 4.10-3.98 (m, 3H), 1.48-1.44 (s, 3H), 1.44-1.40 (s, 3H), 1.36-1.34 (s, 3H), 1.34-1.30 (s, 3H); 13C NMR (CDCl3) 153.3, 131.3, 119.6, 113.5, 109.6, 103.9, 84.9, 82.5, 79.4, 72.9, 68.9, 66.9, 27.1, 26.1, 25.3, 24.8; HRMS (CI pos) for C16H25O8 [M+H]+, calcd 345.1549, found 345.1539. Metathesis of the carbon ate of D-mannose 3-27 A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was flushed with Ar and charged with 0.50 g (2

PAGE 106

106 mmol) of the carbonate of protected (D)-mannose 3-26 167 mg of the Grubbs’ first-generation catalyst (10 mol %) in 4.0 mL of CH2Cl2 (0.50 M). The reaction mixtur e was stirred and refluxed for 18 h. Ethyl vinyl ether (1 mL) was added to quench the metathesis reaction. The crude product was then concentrated under reduced pressure, and purified by silica gel column chromatography using hexane and ethyl acetate (70/ 30) as eluent to afford the metathesis product 3-27 (0.41 g, 61%) as a highly viscous oil. 3-27 : Rf = 0.35 (hexane/EtOAc, 6:4); IR (neat) max 3643, 3087, 2987, 2338, 1754, 1640, 1456, 1381, 1296 cm-1; 1H NMR (300MHz, CDCl3) 6.04-6.00 (s, 2H), 5.96-5.90 (m, 2H), 4.88-4.82 (dd, J = 5.85 Hz, 3.67 Hz, 2H), 4.78-4.74 (dd, J = 5.98 Hz, 2.19 Hz, 2H), 4.70-4.64 (m, 4H), 4.44-4.36 (m, 2H), 4.14-4.02 (m, 6H), 1.50-1.42 (two s, 6H, 6H), 1.38-1.32 (two s, 6H, 6H); 13C NMR (CDCl3) 187.8, 183.7, 173.2, 154.3, 154.5, 131.3, 131.5, 113.7, 109.8, 103.9, 103.4, 84.9, 82.5, 79.4, 72.9, 68.9, 66.9, 27.1, 26.1, 25.3, 24.8, 24.6. Hydrogenation of the metathesis product of carbonate of diacetone (D)-mannose 3-28 O O O O O O H3C H3C CH3H3C O O O O OO O O O O CH3CH3H3C CH3 Metathesis product of car bonic acid allyl ester 3-26 (102 mg, 0.15 mmol) was hydrogenated in presence of Pd catalyst. The product 3-28 was used directly for the NMR analysis in CDCl3. 3-28 : Rf = 0.56 (hexane/EtOAc, 6:4); IR (neat) max 3087, 2987, 2338, 1754, 1640, 1456, 1381, 1296 cm-1; 1H NMR (300MHz, CDCl3) 6.06-6.02 (s, 2H), 4.90-4.84 (dd, J = 5.81 Hz,

PAGE 107

107 2.13 Hz, 2H), 4.80-4.74 (dd, J = 6.32 Hz, 1.9 Hz, 2H), 4.46-4.36 (m, 4H), 4.26-4.18 (m, 2H), 4.12-4.02 (m, 6H), 1.60-1.54 (m, 4H), 1.50-1.42 (two s, 6H, 6H), 1.38-1.32 (two s, 6H, 6H); 13C NMR (CDCl3) 154.3, 154.5, 131.3, 131.5, 113.7, 109.8, 103.9, 103.4, 84.9, 82.5, 79.4, 72.9, 68.9, 66.9, 27.1, 26.1, 25.3, 24.8, 24.6, 23.6, 23.8. Esterification of dia cetone D-mannose 3-29 O O H3C H3C O O O O CH3H3C O To a solution of the diacetone D-mannose (3-25) (5.17 g, 0.02 mol) was added DIC (3.01 g, 24 mmol) and a catalytic amount of DMAP (0.49 g, 4 mmol) in anhydrous CH2Cl2 (40 mL, 0.50 M) in a round bottom flask under Ar. 4-Pentenoic acid ( 2.39 g, 24 mmol) at 0oC over the 10 min. After completion of the addition, the reaction mixture was warmed to the room temperature and stirred for an additional 3.5 h. Reaction was monitored by TLC (hexane/EtOAc, 6:4). After the completion of the reaction, the pr oduct was filtered, and washed with water (2 x 100 mL) and brine (1 x 75 mL). The crude product was then dried over anhydrous MgSO4, concentrated under reduced pre ssure, and purified by silica gel column chromatography using hexane and ethyl acetate (90:10) as eluent to a fford the desired product 3-29 (5.12 g, 76 %) as a colorless oil. 3-29 : Rf = 0.47 (hexane/EtOAc, 6:4); [ ]25 D + 49.55 o (C = 1.19, MeOH); IR (neat) max 3080.17, 2987.39, 1747.39, 1642.32, 1455.96, 1373.83, 1071.79 cm-1; 1H NMR (300MHz, CDCl3) 6.14-6.08 (s, 1H), 5.86-5.72 (ddt, J = 17.33, Hz, 10.28, 7.34, 1H), 5.08-4.97 (m, 2H), 4.85-4.80 (dd, J = 5.88 Hz, 2.69 Hz, 1H), 4.69-4.64 (d, J = 5.88 Hz, 1H), 4.42-4.32 (m, 1H), 4.10-3.96 (m, 3H), 2.44-2.30 (m, 4H), 1.46-1.44 (s 3H), 1.44-1.41 (s, 3H), 1.36-1.32 (s, 3H),

PAGE 108

108 1.32-1.28 (s, 3H); 13C NMR (CDCl3) 171.5, 136.4, 115.9, 113.4, 109.5, 100.9, 85.2, 82.4, 79.5, 73.0, 66.9, 33.6, 28.7, 27.1, 26.1, 25.3, 24.8; HRMS (CI pos) for C17H27O7 [M+H]+, calcd 343.1757, found 343.1762. Metathesis of the ester of D-mannose 3-30 A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was fl ushed with argon and charged with 0.63 g (1.80 mmol) of the ester of diacetoned (D)-mannose 3-29 150 mg of the Grubbs’ first-generation catalyst (10 mol %) in 4.0 mL of CH2Cl2 (0.50 M). The reaction mixtur e was stirred and refluxed for 18 h. Ethyl vinyl ether (1 mL) was added to quench the metathesis reaction. The crude product was then concentrated under reduced pressure, and purified by silica gel column chromatography using hexane and ethyl acetate (70: 30) as eluent to afford the solid metathesis product 3-30 (0.43 g, 72%) (m.p. 88.5 – 90.0 oC). 3-30 : Rf = 0.26 (hexane/EtOAc, 6:4); m.p. 88.5 oC – 90.0 oC ; [ ]25 D + 28.88 o (C = 1.04, CH2Cl2); IR (KBr) max 2987, 2671, 1742, 1459, 1382, 1250 cm-1; 1H NMR (300MHz, CDCl3) 6.02-6.00 (s, 2H), 5.48-5.34 (m, 2H), 4.88-4.80 (dd, J = 7.55 Hz, 4.63 Hz, 2H), 4.704.64 (dd, J = 5.49 Hz, 3.69 Hz, 2H), 4.42-4.34 (m, 2H), 4.12-4.06 (m, 6H), 2.40-2.24 (m, 8H), 1.50-1.46 (s, 6H), 1.46-1.42(s, 6H), 1.38-1.34 (s, 6H), 1.34-1.30 (s, 6H); 13C NMR (CDCl3) 171.5, 171.5, 129.5, 129.0, 113.4, 109.4, 100.9, 100.9, 85.2, 82.4, 79.5, 73.0, 66.9, 34.2, 27.6,

PAGE 109

109 27.1, 26.1, 25.3, 24.8, 22.6; HRMS (CI pos) C32H49O14 [M+H]+, calcd 657.3122, found 657.3118. Ester of diacetone D-glucose 3-32 O O O O O O CH3 CH3 H3C H3C O To a solution of th e diacetone-D-glucose (3-31) (6 g, 0.02 mol) at 0oC was added DCC (2.30 g, 0.02 mol) and a catalytic amount of DMAP (0.47 g, 4 mmol) in anhydrous CH2Cl2 (40 mL, 0.50 M) taken in a round bottom flask under Ar. 4-Pentenoic acid (2.31 g, 0.02 mol) was then added at 0 oC over the 10 min. After completion of the addition, the reaction mixture was warmed to the room temperature and stir red for 3.5 h. Reaction was monitored by TLC (hexane/EtOAc, 6:4). At the end of the reaction, the product was filtered, and washed with water (2 x 50 mL) and brine (1 x 50 mL). The crude product was then dried over anhydrous MgSO4, concentrated under reduced pre ssure, and purified by silica gel column chromatography using hexane and ethyl acetate (95:5) as eluent to afford the desired product 3-32 (5.60 g, 71 %) as a colorless oil. 3-32 : Rf = 0.51 (hexane/EtOAc, 6:4); [ ]25 D -27.50 o (C = 1.19, MeOH); IR (neat) max 3080, 2988, 1748, 1642, 1455, 1374, 1163, 1076 cm-1; 1H NMR (300MHz, CDCl3) 5.85-5.70 (m, 2H), 5.30-5.20 (m, 1H), 5.10-4.90 (m, 2H), 4.45-4.35 (d, J = 7.1 Hz, 1H), 4.20-4.10 (m, 2H), 4.10-4.00 (m, 1H), 4.00-3.90 (m, 1H), 2.50-2.30 (m 4H), 1.50-1.40 (s, 3H), 1.40-1.30 (s, 3H), 1.20-1.30 (s, 6H); 13C NMR (CDCl3) 171.4, 136.3, 115.7, 112.2, 109.3, 105.1, 83.4, 79.9, 76.0, 72.4, 67.2, 33.4, 28.7, 26.8, 26.7, 16.2, 25.3; HRMS (CI pos) for C16H23O7 [M-CH3]+, calcd 327.1444, found 327.1448.

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110 Metathesis of the glucose ester 3-33 O O O O O O O CH3 CH3 H3C H3C O O O O O O CH3 CH3 CH3 CH3 A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was fl ushed with argon and charged with 0.56 g (2 mmol) of the monoester of diacetone (D)-glucose 3-32 0.25 g of the Grubbs’ first-generation catalyst (10 mol %) in 6 mL of anhydrous CH2Cl2 (0.5 M). The reaction mixture was stirred and refluxed for 18 h. The metathesis reaction was then brought back to room temperature and quenched with ethyl vinyl ether (1 mL). Th e crude product was con centrated under reduced pressure, and purified by silica gel column ch romatography using hexane and ethyl acetate (70:30) as eluent to afford the desired metathesis product 3-33 (0.45 g, 83%) as a highly viscous oil. 3-33 : Rf = 0.34 (hexane/EtOAc, 6:4); [ ]25 D 0 o (C = 1.28, CH2Cl2); IR (neat) max 3627, 2988, 2254, 1952, 1747, 1455, 1374, 1075 cm-1; 1H NMR (300MHz, CDCl3) 5.85-5.78 (m, 2H), 5.48-5.34 (m, 2H), 5.24-5.18 (m, 2H), 4.60-4.40 (m, 2H), 4.22-4.12 (m, 4H), 4.06-3.92 (m, 4H), 2.42-2.22 (m, 8H), 1.50-1.46 (s, 6H), 1.38-1.34 (s, 6H), 1.29-1.24 (s, 12H); 13C NMR (CDCl3) 171.5, 129.5, 129.0, 112.3, 109.4, 105.1, 83.5, 79.9, 79.9, 76.1, 72.5, 67.3, 37.1, 34.0, 27.7, 26.9, 26.9, 26.8, 26.3, 25.4, 25.4, 22.7; HRMS (CI pos) for C31H45O14 [M-CH3]+, calcd 641.2809, found 641.2824.

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111 Synthesis of diacetone D-galactose 3-35 O O O O O HO CH3 CH3 H3C CH 3 Anhydrous CuSO4 (3.0 g, 19 mmol) (dried at 110 oC for 24 h) and (D)-galactose (3-34) (1.35 g, 7 mmol) were suspended in dry acetone (30 mL) in a 50 mL round bottom flask under Ar, and were treated with catalytic amount of conc. H2SO4 (0.50 mL). The resulting mixture was stirred at room temperature for 24 h. The cupric sulfate was then removed by filtration and washed with acetone. The combined organic phas es were then neutralized by addition of K2CO3. The resulting mixture was then filtered, washed with brine (3 x 50 mL) and dried over anhydrous MgSO4. The organic layer was then evaporated under reduced pressu re, and purified by silica gel column chromatography using hexane and ethyl a cetate (40:60) affording the desired diacetone D-galactose (3-35) (0.83 g, 43 % yield). Spect ral data are in agreement with literature.153 3-35 : Rf = 0.18 (hexane/EtOAc, 6:4); [ ]25 D -48.22 o (C = 2.71, MeOH); IR (neat) max, 3489, 2996, 1713, 1645, 1458, 1388, 1309, 1260 cm-1; 1H NMR (300MHz, CDCl3) 5.50-5.44 (d, J = 5.1 Hz, 1H), 4.60-4.52 (dd, J = 7.8 Hz, 2.4 Hz, 1H), 4.28-4.24 (dd, J = 5.1 Hz, 2.4 Hz, 1H), 4.24-4.18 (dd, J = 8.1 Hz, 1.8 Hz, 1H), 3.80-3.65 (m, 3H), 2.45-2.25 (br s, 1H, hydroxyl O H ), 1.48-1.42 (s, 3H), 1.38-134 (s, 3H), 1.28-1.24 (s, 6H); 13C NMR (CDCl3) 109.6, 108.9, 96.5, 71.7, 70.9, 70.8, 68.3, 62.4, 26.2, 26.1, 25.1, 24.5.

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112 Ester of protected D-galactose 3-36 O O O O O O CH3 CH3 H3C CH3 O To a solution of the diacet one D-galactose (3-35) at 0oC (1.85 g, 7 mmol) was added DIC (1.35 g, 11 mmol) and a catalytic amount of DMAP (0.12 g, 1 mmol) in anhydrous CH2Cl2 (15 mL, 0.50 M) taken in a round bottom flask under Ar. 4-Pentenoic acid (1.10 g, 11 mmol) was added at 0oC over the next 10 min. After completion of the addition, the reaction mixture was brought back to the room temperature and stirre d for an additional 3 h. Reaction was monitored by TLC (hexane/EtOAc, 6:4). At the end of the 3 h, the product was filtered, and washed with water (2 x 50 mL) and brine (1 x 50 mL). Th e crude product was then dried over anhydrous MgSO4, concentrated under reduce pressure, and purified by silica gel column chromatography using hexane and ethyl acetate (90:10) as eluent to give the desired product 3-36 (2.11g, 87 %) as a colorless oil. 3-36 : Rf = 0.51 (hexane/EtOAc, 6:4); [ ]25 D -38.03 o (C = 2.08, MeOH); IR (neat) max 3080, 2988, 2937, 1738, 1642, 1455, 1383, 1071 cm-1; 1H NMR (300MHz, CDCl3) 5.86-5.70 (m, 1H), 5.52-5.46 (d, J = 5.1 Hz, 1H), 5.06-4.90 (m, 2H), 4.62-4.54 (d, J = 7.2 Hz, 1H), 4.324.02 (m, 4H), 4.02-3.92 (m, 1H), 2.46-2.27 (m, 4H ), 1.48-1.44 (s, 3H), 1.42-1.38 (s, 3H), 1.321.25 (s, 6H); 13C NMR (CDCl3) 172.86, 136.7, 115.5, 109.6, 108.7, 96.4, 71.1, 70.8, 70.5, 66.1, 63.4, 33.5, 28.9, 26.1, 26.0, 25.0, 24.5; HRMS [CI pos] for C17H27O7 [M+H]+, calcd 343.1757, found 373.1748.

PAGE 113

113 Metathesis of the ester of (D)-galactose 3-37 A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was flushed with argon and charged with 0.48 g (0.001 mol) of the ester of pr otected diacetone-D-galactose 3-36 115 mg of the first-generation Grubbs’ catalyst (10 mol %) in 3.mL of anhydrous CH2Cl2 (0.50 M). The reaction mixture was stirred and refluxed for next 18 h. Ethyl vinyl ether (1 mL) was added to quench the metathesis. The crude product was concentrated under reduce d pressure, and purifie d by silica gel column chromatography using hexane and ethyl acetate (7 0:30) as eluent to afford the desired solid metathesis product 3-37 (0.34 g, 74%) (m.p. 86-87 oC). 3-37 : Rf = 0.34 (hexane/EtOAc, 6:4); m.p. 86-87 oC ; [ ]25 D 43.81 o (C = 1.00, CH2Cl2); IR (KBr) max 2994, 2943, 1736, 1451, 1381, 1250 cm-1; 1H NMR (300MHz, CDCl3) 5.565.51 (d, J = 8.1 Hz, 2H), 5.50-5.36 (m, 2H), 4.65-4.58 (dd, J = 9.2 Hz, 2.5 Hz, 2H), 4.36-3.99 (m, 10H), 2.44-2.26 (m, 8 H), 1.52-1.48 (s, 6H ), 1.46-1.42 (s, 6H), 1.36-1.31 (dd, 12H); 13C NMR (CDCl3) 172.7, 129.2, 128.8, 109.4, 108.5, 96.1, 70.9, 70.5, 70.3, 65.8, 63.2, 63.1, 33.8, 27.5, 25.8, 25.7, 24.8, 24.3, 22.5; HRMS (CI pos) for C32H49O14 [M+H]+, calcd 657.3122, found 657.3099.

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114 Protected monoacetone -D-ribose 3-39 O O O O H HO CH 3 H3C Catalytic amount of conc. H2SO4 was added to a stirring mixture of D-ribose (3-38 ) (5 g, 33 mmol) in dry acetone (33 mL, 1M) at room temperature under Ar. A clear solution was obtained within 10 minutes. Stirring was continue d for the next 5 minutes. The reaction medium was then neutralized by adding NaHCO3, filtered, and extracted with ether. The combined organic medium was then washed by water (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous MgSO4, and concentrated under reduced pr essure. The crude product was then purified by silica gel column chro matography using hexane and ethyl acetate (60:40) as eluent affording a pure product of 3-39 (4.20 g, 67%) as a colorless oil. 3-39 : Rf = 0.38 (CH2Cl2/MeOH, 9:1); [ ]25 D -35.57 o (C = 1.69, MeOH); IR (neat) max 3385, 2942, 1736, 1643, 1459, 1377, 1325 cm-1; 1H NMR (300MHz, CDCl3) 5.68-5.5.62 (d, J = 6 Hz, 1H), 5.38-5.32 (d, J = 6 Hz, 1H), 4.79-4.73 (d, J = 6.0 Hz, 1H), 4.56-4.50 (d, J = 6.0 Hz, 1H), 4.38-4.26 ( br m, 2H, two hydroxyl O H ), 3.3.72-3.62 (m, 2H), 1.56-1.42 (s, 3H), 1.30-1.24 (s, 3H); 13C NMR (CDCl3) 112.3, 102.8, 87.7, 86.8, 81.7, 63.5, 26.4, 24.8. TBDMS protected monoacetone-D-ribose 3-40 O O O OH O H3C CH3 Si CH3 H3C H3C H3C H3C To a solution of 2,3-o-is opropylidine-D-ribofuranose (3-39) (2.25 g, 12 mmol) and imidazole (2.25 g, 33 mmol) in anhydrous DMF (6 mL, 2M) was added TBDMS chloride (2.05

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115 g, 14 mmol) in one portion. The resulting solution was then stirred at room temperature for 3.5 h and was subsequently diluted in water (30 mL ). The product was then extracted with ethyl acetate (3 x 30 mL). The combined extract was wash ed with water (2 x 50 mL) and brine (1 x 50 mL), dried over anhydrous MgSO4, and purified by silica gel co lumn chromatography with hexane and ethyl acetate (90:10) as eluent afford ing the pure white solid 3-40 (1.86g, 52% yield) (m.p. 54-57oC). Spectral data and melting point are in agreement with literature.154 3-40 : Rf = 0.51 (hexane/EtOAc, 6:4); m.p. 54.0-55.0 oC (lit 55.0-57.0 oC)24 [ ]25 D -14.02 o (C = 1.64, MeOH), lit C = -13.4 o (C = 1.0, CHCl3); 24 IR (neat) max 3422, 2935, 2859, 1472, 1374 cm-1; 1H NMR (300MHz, CDCl3) 5.20-5.12 (d, J = 12 Hz, 1H), 4.70-4.62 (d, J = 6.2 Hz, 1H), 4.62-4.56 (d, J = 6 Hz, 1H), 4.42-4.36 (d, J = 8.1 Hz, 1H), 4.24-4.18 (m, 1H, hydroxyl O H ), 3.65-3.62 (d, 2H), 1.80-1.34 (s, 3H), 1.24-1.20 (s 3H), 0.85-0.80 (s, 9H), 0.01-0.05 (s, 6H); 13C NMR (CDCl3) 111.9, 103.4, 87.5, 86.9, 81.9, 64.8, 26.5, 26.1, 25.9, 25.8, 25.6, 24.9, 24.7, 18.3, -5.6, -5.7. Esterification of monoacetone (D)-ribose 3-41 O O O OH O CH3 O H3C To a solution of the monoacetone-D-ribose (3-39) (3.00 g, 16 mmol) at 0oC was added DIC (2.39 g, 19 mmol) and a catalytic amount of DMAP (0.48 g, 4 mmol) in anhydrous CH2Cl2 (32 mL, 0.50 mol) taken in a round bottom flas k under Ar. 4-Pentenoic acid (1.58 g, 16 mmol) was added at 0oC over the next 20 min. After completion of the addition, the reaction mixture was warmed to the room temperature and st irred for 4 h. Reaction was monitored by TLC (hexane/EtOAc, 6:4). The crude product was filt ered, and washed with water (2 x 50 mL) and

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116 brine (1 x 50 mL). It was then dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column ch romatography using hexane and ethyl acetate (60:40) as eluent to give the desired product 3-41 (1.15 g, 26 %). Majority of the product is the diester of the monoacetone (D)-ribose. All products were colorless oil. 3-41 : Rf = 0.28 (hexane/EtOAc, 6:4); [ ]25 D -60.34 o (C = 1.46, MeOH); IR (neat) max 3494, 3080, 2986, 1744, 1642, 1417, 1382 cm-1; 1H NMR (300MHz, CDCl3) 6.20-6.15 (s, 1H), 5.82-5.68 (m, 1H), 5.06-4.94 (m, 2H), 4.73-4.68 (d, J = 8.1 Hz, 1H), 4.65-4.60 (d, J = 8.1 Hz, 1H), 4.36-4.28 (t, J = 7.1 Hz, 1H), 3.62-3.52 ( m, 2H ), 2.64-2.54 (br s, 1H, hydroxyl O H ), 2.40-2.26 (m, 4H), 1.46-1.42 (s, 3H), 1.28-1.24 (s, 3H); 13C NMR (CDCl3) 171.3, 136.2, 115.9, 112.9, 102.6, 88.8, 85.5, 81.2, 63.4, 33.6, 28.5, 26.5, 24.9; HRMS [CI pos] for C13H21O6 [M+H]+, calcd 273.1338, found 273.1336. Esterification of TBDMS protect ed monoacetone-D-ribose 3-45 O O O O O H 3 C CH 3 Si CH3 H3C H3C H3C H3C O To a solution of the TBDMS protected monoacetone-D-ribose 3-40, (1.20 g, 4 mmol) was added DIC (0.60 g, 5 mmol) and DMAP (0.14 g, 12 mmol) in anhydrous CH2Cl2 (8 mL, 0.50 M) taken in a round bottom flask under Ar. 4-Penten oic acid (0.47 g, 5 mmol) was added at 0oC over the next 10 minutes. After completion of the a ddition, the reaction mixture was warmed to the room temperature, and stirred for an a dditional 3 h. Reaction was monitored by TLC (hexane/EtOAc, 6:4). At the end of 3 h, the product was filtered, washed with water (2 x 50 mL) and brine (1 x 50 mL). The crude pro duct was then dried over anhydrous MgSO4, concentrated

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117 under reduce pressure, and purifie d by silica gel column chromat ography using hexane and ethyl acetate (95:5) as eluent to give the desired product 3-45 (1.36 g, 89 %) as a colorless oil. 3-45 : Rf = 0.65 (hexane/EtOAc, 6:4); [ ]25 D -51.16 o (C = 2.05, MeOH); IR (neat) max 3081, 2956, 1752, 1472, 1417, 1374, 1105 cm-1; 1H NMR (300MHz, CDCl3) 6.18-6.14 (s, 1H), 5.84-5.70 (m, 1H), 5.08-4.94 (m, 2H), 4.78-4.72 (d, J = 5.1 Hz, 1H), 4.66-4.62 (d, J = 5.1 Hz, 1H), 4.30-4.22 (dd, J = 8.1 Hz, 2.3 Hz, 1H), 3.68-3.60 (dd, J = 8.1 Hz, 2.3 Hz, 1H), 3.56-3.46 (dd, J = 8.1 Hz, 2.3 Hz, 1H), 2.38-2.32 (m, 4H), 1.48-1.44 (s, 3H), 1.32-1.28 (s, 3H), 0.90-0.86 (s, 9H), 0.06--1.02 (s, 6H); 13C NMR (CDCl3) 171.4, 136.4, 115.8, 112.9, 102.7, 88.2, 85.3, 81.8, 63.7, 33.8, 28.6, 26.6, 25.9, 25.2, 18.4, -5.3, -5.3; HRMS [CI pos] for C18H31O6Si [MCH3]+, calcd 371.1890, found 371.1882. Monobenzylation of monoacetone (D)-ribose 3-44 O OH OO H3C CH3O Ph In a 100 mL oven-dried round bottom flask, 4.06 g of acetone D-ribose (3-39) (21 mmol) was taken in 11 mL of anhydrous CH2Cl2 (2M) and was stirred for the next 10 min. 0.90 g of NaH (60% in oil dispersion) was added to it a nd the reaction mixture was stirred for the next 15 min under Ar, till no more hydrogen gas was eva porated, as noticed by the absence of an bubbling. This was followed by the addition of TBAI (0.80 g, 2 mmol). Then 2.70 g of benzyl chloride (21 mmol) was added over the next 15 min under Ar. The reaction mixture was stirred for overnight. At the end of 12 h stirring it was quenched with water and the organic layer was extracted with CH2Cl2. The combined organic medium were then washed with water (3 x 20 mL) and brine (3 x 20 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure.

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118 The crude product was then purified by silica gel column chromatography using hexane and ethyl acetate (80:20) as elue nt affording the pure product 3-44 (2.80 g, 47 %) as a white solid (m.p. 98.5 – 100.0 oC). 3-44: Rf = 0.35 (hexane/EtOAc, 6:4); [ ]25 D -82.08 o (C = 1.08, CH2Cl2); m.p. 98.5 – 100.0 oC; IR (neat) max 3476, 3032, 2930, 1947, 1892, 1498 cm-1; 1H NMR (300MHz, CDCl3) 7.387.28 (m, 5H), 5.22-5.16 (s, 1H), 4.88-4.84 (d, J = 6 Hz, 1H), 4.80-4.73 (d, J = 6 Hz, 1H), 4.704.64 (d, J = 6 Hz, 1H), 4.60-4.53 (d, J = 7.1 Hz, 1H), 4.47-4.42 (t, J = 7.1 Hz, 1H), 3.75-3.56 (m, 2H), 3.20-3.12 (dd, J = 10.1 Hz, 5.1 Hz, 1H), 1.50-1.46 (s, 3H), 1.34-1.28 (s, 3H); 13C NMR (CDCl3) 136.5, 128.8, 128.4, 128.4, 112.3, 108.2, 88.6, 86.1, 81.7, 70.3, 64.2, 26.5, 24.8; HRMS (ESI FT-ICR) for C15H20O5Na [M+Na]+, calcd 303.1203, found 303.1210. Esterification of benzylated monoacetone-D-ribose 3-46 O O O O O CH3H3C Ph O To a solution of the benzylated monoacetone-D-ribose 3-44 (2.20 g, 8 mmol) was added DIC (1.19 g, 9 mmol) and a catalytic amount of DMAP (0.29 g, 2 mmol) in anhydrous CH2Cl2 (79 mL, 0.10 M) taken in a round bottom flas k under argon atmosphere, 4-pentenoic acid (0.94 g, 9 mmol) was added at 0oC over the next 15 min. After completion of the addition, the reaction mixture was warmed to the room temperature and stirred for 3 h. Reaction was monitored by TLC (hexane/EtOAc, 6:4). At the end of 3 h, the product was filtered, and washed with water (2 x 50 mL) and brine (1 x 50 mL). The crude product was then dried over anhydrous MgSO4, concentrated under reduce pre ssure, and purified by silica gel column chromatography using

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119 hexane and ethyl acetate (70:30) as eluent to give the desired product 3-46 (2.30 g, 81 %) as a colorless oil. 3-46: Rf = 0.61 (hexane/EtOAc, 1:2); [ ]25 D -71.55 o (C = 1.57, CH2Cl2); IR (neat) max 3067, 3033, 2941, 1740, 1642, 1498, 1455, 1374, 1078 cm-1; 1H NMR (300MHz, CDCl3) 7.37-7.24 (m, 5H), 5.87-5.72 (m, 1H), 5.18-5.16 (m, 1H), 5.09-4.96 (m, 2H), 4.72-4.66 (t, J = 7.1 Hz, 3H), 4.46-4.37 (m, 2H), 4.24-4.12 (m, 2H), 2.46-2.30 (m, 4H), 1.49-1.46 (s, 3H), 1.331.29 (s, 3H); 13C NMR (CDCl3) 172.7, 137.2, 136.8, 128.7, 128.4, 128.2, 115.9, 112.8, 107.6, 85.6, 84.7, 82.2, 69.5, 64.9, 33.6, 28.9, 26.7, 25.2; HRMS (ESI FT-ICR) for C20H26O6Na [M+Na]+, calcd 385.1622, found 385.1623. Metathesis of the monoacetone (D)-ribose 3-47 A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was fl ushed with argon and charged with 0.51 g (1 mmol) of the ester of monoacetone (D)-ribose 3-41, 0.15 g of the Grubbs’ first-generation catalyst (10 mol %) in 4 mL of anhydrous CH2Cl2 (0.50 M). The reaction mixture was stirred and refluxed for 18 h. The metathesis reaction wa s then brought back to room temperature and quenched with ethyl vinyl ether (1 mL). The crude product was concen trated under reduced pressure, and purified by silica gel column ch romatography using hexane and ethyl acetate (40:60) as eluent to afford the desired metathesis product 3-47 (0.39 g, 81%).

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120 3-47: Rf = 0.23 (hexane/EtOAc, 1:2); [ ]25 D -1.35 o (C = 1.11, CH2Cl2); IR (neat) max 3492, 2941, 1743, 1377, 1111 cm-1; 1H NMR (300MHz, CDCl3) 6.22-6.18 (s, 2H), 5.46-5.14 (m, 2H), 4.77-4.4.72 (dd, J = 8.1 Hz, 2.1 Hz, 2H), 4.70-4.62 (m, 2H), 4.40-4.32 (t, J = 7.1 Hz, 2H), 3.68-3.54 (m, 4H), 2.72-2.52 (br s, 2H), 2. 40-2.22 (m, 8H), 1.48-1.44 (s, 6H), 1.32-1.26 (s, 6H); 13C NMR (CDCl3) 171.5, 171.4, 129.4, 129.1, 113.0, 102.7, 88.8, 85.5, 85.5, 81.3, 63.5, 34.3, 34.2, 27.4, 26.5, 24.9, 22.5; HRMS (ESI FT-ICR) for C24H36O12Na [M+Na]+, calcd 539.2099, found 539.2102. Metathesis of benzylated mo noacetone (D)-ribose 3-49 O O O O O CH3H3C Ph O O O O O Ph O O CH3CH3 A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was fl ushed with argon and charged with 0.66 g (2 mmol) of the ester of benzylated monoacetone (D)-ribose 3-46, 0.15 g of the Grubbs’ firstgeneration catalyst (10 mol %) in 4 mL of anhydrous CH2Cl2 (0.50 M). The reaction mixture was stirred and refluxed for 18 h. The metathesis reaction was then br ought back to room temperature and quenched with ethyl vinyl et her (1 mL). The crude product was concentrated under reduced pressure, and purified by silica gel column ch romatography using hexane and ethyl acetate (70:30) as eluent to afford the desired metathesis product 3-49 (0.51 g, 74%). 3-49: Rf = 0.64 (hexane/EtOAc, 1:2); [ ]25 D -6.60 o (C = 1.51, CH2Cl2); IR (neat) max 3065, 3032, 2940, 1952, 1739, 1607, 1498, 1455 cm-1; 1H NMR (300MHz, CDCl3) 7.38-7.28 (m, 10H), 5.46-5.32 (m, 2H), 5.18-5.16 (s, 2H), 4.72-4.66 (t, J = 7.3 Hz, 6H), 4.47-4.41 (d, J =

PAGE 121

121 8.1 Hz, 2H), 4.40-4.36 (m, 2H), 4.20-4.15 (dd, J = 7.1 Hz, 2.1 Hz, 4H), 2.42-2.22 (m, 8H), 1.491.46 (s, 6H), 1.34-1.30 (s, 6H); 13C NMR (CDCl3) 172.3, 136.7, 129.0, 128.2, 127.9, 127.7, 112.3, 107.1, 85.1, 84.2, 81.7, 69.1, 64.4, 64.3, 33.6, 27.4, 26.2, 24.7; HRMS (ESI FT-ICR) for C38H48O12Na [M+Na]+, calcd 719.3055, found 719.3038. Metathesis of the diester of mo noacetone (D)-ribose 4-14(HH/HT) O O O O O O O O O O H3C H3C O O CH3CH3O O A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was fl ushed with argon and charged with 0.51 g (2 mmol) of the diester of monoacetone (D)-ribose 3-43, 0.12 g of the Grubbs’ first-generation catalyst (10 mol %) in 15 mL of anhydrous CH2Cl2 (0.10 M). The reactio n mixture was stirred and refluxed for 18 h. The metathesis reaction wa s then brought back to room temperature and quenched with ethyl vinyl ether (1 mL). The crude product was concen trated under reduced pressure, and purified by silica gel column ch romatography using hexane and ethyl acetate (70:30) as eluent to afford the desired metathesis product 4-14 (HH/HT) (0.47 g, 74%). 4-14: Rf = 0.34 (hexane/EtOAc, 6:4); [ ]25 D -59.47 o (C = 1.48, CH2Cl2); IR (neat) max 2989, 2863, 1736, 1427, 1357 cm-1; 1H NMR (300MHz, CDCl3) 6.18-6.12 (s, 2H), 5.52-5.42 (m, 2H), 5.38-5.26 (m, 2H), 4.76-4.70 (d, J = 5.1 Hz, 2H), 4.60-4.44 (m, 4H), 4.00-3.80 (m, 4H), 2.44-2.34 (m, 8H), 2.32-2.22 (m, 4H), 2.18-2.02 (m, 4H), 1.50-1.40 (s, 6H), 1.32-1.24 (s, 6H);

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122 13C NMR (CDCl3) 173.6, 172.1, 129.8, 129.5, 113.5, 102.6, 85.1, 84.3, 81.4, 64.9, 34.4, 33.5, 28.1, 28.0, 26.5, 25.3; HRMS (CI pos) for C32H45O14 [M+H]+, calcd 653.2809, found 653.2783. Benzylation of D-isomannide 3-51 O OHO H H O Ph D-Isomannide (3-50) (5.20 g, 36 mmol), potassium hydr oxide (5.20 g, 36 mmol) were dissolved in water (18 mL) and the resulting so lution was heated to reflux for 20 min. the mixture was cooled to room temperature, benz yl chloride (4.51 g, 36 mmol) was added. The solution was refluxed for additional 3h. The reac tion was quenched with acid (HCl, 2N, 15 mL), followed by extraction with ethyl acetate (3 x 15 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under vacuum. Th e crude product was then purified by silica gel column chromatography using hexane and ethyl acetate (30:70) as eluent to afford the pure product 3-51 with a yield of 3.36 g (40% yi eld) as a white solid (m.p. 90-92.oC). Spectral data and m. p. are in agreement with literature.155 3-51: Rf = 0.22 (hexane/EtOAc, 6:4); m.p. 90-92 oC (lit. reported m.p. 93 oC), [ ]25 D +122.25 o (C = 1.03, CH2Cl2) (lit reported [ ]20 D +138 o (C = 1.00, CHCl3)); IR (neat) max 3423, 3063, 3031, 2875, 1496, 1455, 1405 cm-1; 1H NMR (300MHz, CDCl3) 7.34-7.16 (m, 5H), 4.70-4.62 (d, J = 11.8 Hz, 1H), 4.50-4.40 (dd, J = 8.5 Hz, 5.5 Hz, 2H), 4.38-4.32 (t, J = 7.1 Hz, 1H), 4.20-4.10 (dq, J = 8.5 Hz, 5.5 Hz, 1H), 4.14-3.94 (m, 3H), 3.77-3.66 (m, 2H), 3.00-2.84 (dd, J = 8.5 Hz, 2.1 Hz, 1H); 13C NMR (CDCl3) 137.6, 128.4, 127.9, 81.7, 80.5, 79.0, 74.5, 72.5, 72.3, 71.3.

PAGE 123

123 Esterification of monobenz ylated (D)-Isomannide 3-52 O O O H H O Ph O To a solution of benzylated-D-isomannide (3-51) (0.53 g, 2 mmol) was added DIC (0.34 g, 2.70 mmol) and catalytic amount of DM AP (70 mg, 6 mmol) in anhydrous CH2Cl2 (6 mL, 0.5 mol) taken in a round bottom flask under Ar. 4-Pe ntenoic acid (0.28 g, 3 mmol) was added at 0oC over the next 5 min. After completion of the addition, the reaction mixture was warmed to the room temperature, and stirred for an a dditional 2.5 h. Reaction was monitored by TLC (hexane/EtOAc, 6:4). After the completion of the reaction, the product was filtered, washed with water (2 x 20 mL) and brine (1 x 20 mL). Th e crude product was then dried over anhydrous MgSO4, concentrated under reduce pressure and purified by silica gel column chromatography using hexane and ethyl acetate (90:10) as eluent to afford the pure product 3-52 with a yield of 3.24 g (84%). 3-52: Rf = 0.31 (hexane/EtOAc, 6:4); [ ]25 D +168.51 o (C = 1.66, CH2Cl2); IR (neat) max 3067, 3031, 2879, 1740, 1642, 1500, 1455, 1367 cm-1; 1H NMR (300MHz, CDCl3) 7.40-7.20 (m, 5H), 5.90-5.74 (m, 1H), 5.12-5.07 (m, 2H), 5.06-4.96 (m, 2H), 4.78-4.71 (d, J = 8.1 Hz, 1H), 4.70-4.65 (t, J = 7.1 Hz, 1H), 4.50-4.45 (t, J = 7.1 Hz, 1H), 4.08-3.98 (m, 2H), 3.96-3.88 (dd, J = 8.5 Hz, 5.5 Hz, 2H), 3.68-3.60 (t, J = 7.1 Hz, 1H), 2.52-2.44 (m, 1H), 2.42-2.34 (m, 2H); 13C NMR (CDCl3) 172.4, 137.6, 136.5, 128.4, 127.9, 115.5, 80.7, 80.2, 78.8, 70.5, 38.1, 28.7; HRMS (ESI FT-ICR) for C18H22O5Na [M+Na]+, calcd 343.1359, found 343.1359.

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124 Metathesis of the ester of be nzylated (D)-Isomannide 3-53 O O O O H H O Ph O O O O O H H Ph A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was fl ushed with Ar and charged with 0.52 g (16 mmol) of the ester of benzylated (D)-isomannide 3-52, 0.13 g of the Grubbs’ first-generation catalyst (10 mol %) in 5 mL of anhydrous CH2Cl2 (0.50 M). The reaction mixture was stirred and refluxed for 18 h. The metathesis reaction wa s then brought back to room temperature and quenched with ethyl vinyl ether (1 mL). The crud e product was then concentrated under reduced pressure, and purified by silica gel column ch romatography using hexane and ethyl acetate (70:30) as eluent to afford the desired metathesis product 3-53 (0.41 g, 82%) as a highly viscous oil. 3-53: Rf = 0.35 (hexane/EtOAc, 1:2); [ ]25 D +0.13 o (C = 1.68, CH2Cl2); IR (neat) max 3031, 2878, 1739, 1657, 1497, 1455, 1367 cm-1; 1H NMR (300MHz, CDCl3) 7.40-7.26 (m, 12H), 5.50-5.36 (m, 2H), 5.16-5.06 (dd, J = 5.1 Hz, 2.1 Hz, 2H), 4.78-4.72 (d, J = 7.1 Hz, 2H), 4.70-4.64 (t, J = 7.1 Hz, 2 H), 4.60-4.54 (d, J = 7.2 Hz, 2H), 4.51-4.46 (t, J = 7.1 Hz, 2H), 4.103.98 (m, 4H), 3.96-3.88 (m, 4H), 3.68-3.59 (t, J = 7.1 Hz, 2H), 2.46-2.26 (m, 8H); 13C NMR (CDCl3) 172.7, 137.7, 129.4, 129.0, 128.6, 128.1, 80.8, 80.3, 78.9, 74.3, 74.2, 72.7, 71.2, 70.6, 33.8, 27.8, 22.7; HRMS (ESI FT-ICR) for C34H40O10Na [M+Na]+, calcd 631.2514, found 631.2518.

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125 Benzylation of D-isosorbide ( exo ) 3-55 O O OH OPh H H D-Isosorbide (3-54) (5.20 g, 36 mmol), potassium hydroxide (2 g, 36 mmol) were dissolved in water (18 mL) and the resulting so lution was heated to reflux for 20 min. the mixture was cooled to r.t., benzyl chloride (4.51 g, 36 mmol) was added. The solution was refluxed for an additional 3h followed by an aci d quench (HCl, 2N, 15 mL), and extraction with ethyl acetate (3 x 25 mL). The combined or ganic layers were dr ied over anhydrous MgSO4 and concentrated under vacuum. The crude product was th en precipitated in co ld diethyl ether (30 mL) to obtain the final product 3-55 with a yield of 40%. Spectral data are in agreement with literature.155 3-55: Rf = 0.18 (hexane/EtOAc, 6:4); [ ]25 D +29.76 o (C = 1.32, CH2Cl2), (lit, [ ]27 D +27.60 o (C = 0.51, CHCl3) 26; IR (neat) max 3489, 2996, 1713, 1645, 1458, 1388, 1309, 1260 cm-1; 1H NMR (300MHZ, CDCl3) 7.38-7.26 (m, 5H), 4.65-4.60 (t, J = 7.1 Hz, 1H), 4.60-4.55 (d, J = 8.1 Hz, 2H), 4.54-4.48 (d, J = 8.1 Hz, 1H), 4.32-4.21 (m, 1H), 4.14-4.04 (m, 2H), 3.92-3.80 (m, 2H), 3.58-3.50 (m, 1H), 2.84-2.76 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3) 137.6, 128.6, 128.0, 127.8, 86.1, 83.6, 81.9, 73.5, 73.5, 72.4, 71.6. Esterification of benzylated (D)-isosorbide ( exo ) 3-56 O O O OPh H H O

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126 To a solution of benzylated (D)-isosorbide (exo) 3-55 (1.2 g, 0.005 mol) at 0oC was added DIC (0.69 g, 5 mmol) and a catalytic amount of DMAP (0.21 g, 2 mmol) in anhydrous CH2Cl2 (50 mL, 0.10 M) taken in a round bottom flask under Ar. 4-Pentenoic acid (0.55 g, 6 mmol) was added at 0oC over the next 10 min. After completion of the addition, the reaction mixture was warmed to the room temperature, and stirred for an additional 3 h. Reaction was monitored by TLC (hexane/EtOAc, 6:4). At the end of 3h, the product was filtered, washed with water (2 x 35 mL) and brine (2 x 35 mL). The crude product was then dried over anhydrous MgSO4, concentrated under reduce pre ssure and purified by silica gel column chromatography using hexane and ethyl acetat e (90:10) as eluent to afford the pure product 3-56 with a 71 % yield (1.15 g) as a colorless oil. 3-56: Rf = 0.47 (hexane/EtOAc, 6:4); [ ]25 D+74.19 o (C = 1.87, CH2Cl2); IR (neat) max 3489, 2996, 1713, 1645, 1458, 1388, 1309, 1260 cm-1; 1H NMR (300MHz, CDCl3) 7.36-7.22 (m, 5H), 5.88-5.72 (m, 1H), 5.14-5.04 (m, 2H), 5.02-4.94 (m, 2H), 4.83-4.74 (t, J = 7.1 Hz, 1H), 4.58-4.54 (s, 2H), 4.54-4.49 (d, J = 5.1 Hz, 1H), 4.10-4.06 (m, 1H), 4.06-3.98 (m, 1H), 3.95-3.82 (m, 2H), 3.77-3.69 (dd, J = 5.1 Hz, 1.9 Hz, 1H), 2.49-2.42 (m, 2H), 2.41-2.34 (m, 2H); 13C NMR (CDCl3) 172.6, 137.6, 136.5, 128.4, 127.8, 127.6, 115.5, 86.1, 83.2, 80.5, 73.9, 73.0, 71.3, 69.9, 33.1, 28.7; HRMS (ESI FT-ICR) for C18H22O5Na [M+Na]+, calcd 343.1359, found 343.1369.

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127 Metathesis of the ester of benzylated (D)-isosorbide ( exo ) 3-57 A 25 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was fl ushed with argon and charged with 0.47 g (15 mmol) of the ester of benz ylated (D)-isosorbide (exo) 3-56, 0.12 g of the Grubbs’ first-generation catalyst (10 mol %) in 5 mL of anhydrous CH2Cl2 (0.30 M). The reaction mixture was stirred and refluxed for 18 h. The metathesis reaction wa s then brought back to room temperature and quenched with ethyl vinyl ether (1 mL). The crude product was concen trated under reduced pressure, and purified by silica gel column ch romatography using hexane and ethyl acetate (70:30) as eluent to afford the desired metathesis product 3-57 (0.37 g, 82%) as a colorless oil. 3-57: Rf = 0.35 (hexane/EtOAc, 1:2); IR (neat) max 3031, 2878, 1739, 1657, 1497, 1455, 1367 cm-1; 1H NMR (300MHz, CDCl3) 7.38-7.26 (m, 10H), 5.52-5.38 (m, 2H), 5.16-5.09 (m, 2H), 4.84-4.78 (t, J = 7.1 Hz, 2H), 4.58-4.55 (m, 2H), 4.54-4.51 (d, J = 7.1 Hz, 2H), 4.12-4.06 (m, 2H), 4.05-3.99 (m, 2H), 3.96-3.85 (m, 4H ), 3.77-3.70 (m, 2H), 2.47-2.28 (m, 8H); 13C NMR (CDCl3) 172.9, 138.1, 129.9, 129.4, 128.9, 128.4, 128.2, 86.7, 86.7, 81.1, 74.5, 74.4, 73.6, 71.89, 70.5, 34.3, 28.2, 23.2.

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128 Ester of phloroglucinol 3-62 O O O O O O To a solution of the phloroglucinol 3-61 (2.30 g, 0.018 mol) taken in a round bottom flask was added DIC (7.10 g, 56 mmol) and DMAP (2 .97 g, 24 mmol) in anhydrous THF (37 mL, 0.50 M) under Ar. 4-Pentenoic acid (5.65 g, 56 mmol) was added at 0 oC over the next 15 minutes. After completion of the addition, th e reaction mixture was warmed to the room temperature and stirred for an additional 3 h. Reaction was monitored by TLC (hexane/EtOAc, 6:4). After the completion of the reaction, the pr oduct was filtered, and washed with water (2 x 50 mL) and brine (1 x 50 mL). As observed fr om the TLC plate, a si gnificant portion of the crude product was the di-ester of phlorogluc inol. The crude product was then dried over anhydrous MgSO4, concentrated under reduce pressure and purified by silica gel column chromatography using hexane and ethyl acetate (9 5:5) as eluent to afford the desired product 362 (5.03 g, 75 %) as a colorless oil. 3-62: Rf = 0.62 (hexane/EtOAc, 6:4); IR (neat) max 3081, 2981, 2922, 1767, 1642, 1608, 1457, 1363, 1126, 1004 cm-1; 1H NMR (300MHz, CDCl3) 6.84-6.81 (m, 3H), 5.96-5.81 (m, 3H), 5.18-5.04 (m, 6H), 2.68-2.62 (t, J = 7.1 Hz, 6H), 2.53-2.44 (q, J = 12.1 Hz, 6H); 13C NMR (CDCl3) 170.8, 151.3, 136.2, 116.2, 112.7, 33.6, 28.8; HRMS [ESI-FTICR-MS] for C21H24O6Na [M+Na]+, calcd 395.1465, found 395.1459.

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129 CM of the ester of phlor oglucinol and glucose 3-63 A 50 mL round bottom flask, equipped with a magnetic stirring bar under Ar, was flame dried and cooled under vacuum. The flask was fl ushed with argon and charged with 0.16 g (0.43 mmol) of the ester of phloroglucinol 3-62 and 0.51 g (1.49 mmol) of the ester of diacetone-Dglucose 3-32), 37 mg of the first-generation Grubbs’ catalyst (10 mol %) in 17 mL of anhydrous CH2Cl2 (0.50 M). The reaction mixture was stirred a nd refluxed for 18 h. The cross metathesis reaction was then brought back to room temperatur e and quenched with ethyl vinyl ether (1 mL). The crude product was concentrated under reduce d pressure, and purifie d by silica gel column chromatography using hexane and et hyl acetate (70:30) as eluent to afford the desired metathesis product 3-63 (0.11 g, 58%) as a highly viscous oil. 3-63: Rf = 0.35 (hexane/EtOAc, 1:2); [ ]25 D +0.15 o (C = 1.68, CH2Cl2); IR (neat) max 3081, 2981, 2922, 1767, 1748, 1642, 1608, 1457, 1363, 1126, 1004 cm-1; 1H NMR (300MHz, CDCl3) 7.40-7.26 (m, 3H), 5.90-5.80 (m, 4H), 5.7-5. 0 (m, 12H), 4.5-4.4 (m, 4H), 4.3-4.1 (m,

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130 8H), 4.1-3.9 (m, 8H), 2.5-2.2 (m, 18H), 1.6-1. 4 (s, 12 H), 1.4-1.3 (s, 12H), 1.30-1.25 (m, 12 H); 13C NMR (CDCl3) 172.7, 137.7, 129.4, 129.0, 128.6, 128.1, 80.8, 80.3, 78.9, 74.3, 74.2, 72.7, 71.2, 70.6, 33.8, 27.8, 22.7. Formation of diacetone D-mannitol (4-5) H OH HO H O O H3C H3C O O CH3 CH3 Anhydrous zinc chloride (28.0 g) was placed in an oven-dried 500 mL round bottom flask and 141 mL of acetone was added. The mixture wa s stirred under argon atmosphere until the salt had dissolved completely. The suspension was filtered into another round-bottom flask containing 16.0 g of D-mannitol (4-4) and stirred in a bath of cool water until it had just dissolved (several hours). The solution was poured with stirring into a beaker containing a solution of 35 g of potassium carbonate in 35 mL of water. The suspension was filtered with suction and the precipitate was stirred several times with dich loromethane. The aqueous layer was also extracted with dichloro methane two times. The combined organic extracts were dried over anhydrous MgSO4, evaporated to dryness under redu ced pressure. The crude product was then recrystallized with dichloromethane/n-hexane (1:10) resulting in the formation of 11.75 g (51%) of the pure product 4-5. Spectral data are in ag reement with literature.126 4-5: Rf = 0.09 (hexane/EtOAc, 6:4); m.p. 117.0-119.0 oC (lit 118.0 – 120.0 oC); 126 25 D +2.09 o (C = 1.46, MeOH); IR (KBr) max 3319, 2986, 2893, 1457, 1418, 1372, 1214, 1159, 1065 cm-1; 1H NMR (300MHz, CDCl3) 4.20-4.10 (m, 4H), 4.00-3.94 (dd, J = 8.4 Hz, 5.4 Hz, 2H), 3.78–3.70 (d, J = 6.7 Hz, 2H), 3.00-2.62 (br s, 2H, OH), 1.44-1.40 (s, 6H), 1.38-1.34 (s, 6H); 13C NMR 109.6, 76.4, 71.3, 66.9, 26.9, 25.4.

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131 Esterifiction of diacetone D-mannitol 4-9 H O O H O O H3C H3C O O CH3 CH3 O O To a solution of the diacetone D-mannitol (4-5) (4 g, 15 mmol) taken in a 100 mL round bottom flask was added at 0oC DIC (5.77 g, 45 mmol) and DMAP (0.53 g, 0.28 mol) in anhydrous CH2Cl2 (30 mL, 0.50 equiv.) under Ar. 4-Penten oic acid (4.60 g, 0.05 mol) was added at 0oC over the next 10 minutes. After completion of addition the reaction mixture was warmed to room temperature and stirred for the ne xt 3.5 h. The reaction was monitored by TLC (hexane/EtOAc, 6:4). At the end of 3.5h, the prod uct was filtered, and washed with water (2 x 50 mL) and brine (1 x 50 mL). The crude product was then dried over anhydrous MgSO4, concentrated under reduced pre ssure; and purified by silica gel column chromatography using hexane and ethyl acetate ( 100:0 to 90:10) as eluent to give the desired product 4-9 (4.60 g, 71%). 4-9 : Rf = 0.53 (hexane/EtOAc, 6:4); 25 D +13.88 o (C = 2.33, MeOH); IR (KBr) max 3081, 2987, 1747, 1642, 1455, 1418, 1372, 1156 cm-1; 1H NMR (300MHz, CDCl3) 5.95-5.85 (m, 2H), 5.40-5.30 (m, 2H), 5.10-4.90 (m, 4H), 4.20-4.10 (dd, J = 8.2 Hz, 5.4 Hz, 2H), 3.94-3.84 (dd, J = 9.5 Hz, 5.4 Hz, 2H), 3.82-3.76 (dd, J = 12.5 Hz, 4.5 Hz, 2H), 2.50-2.30 (m, 8H), 1.38-1.30 (s, 6H), 1.28-1.20 (s, 6H); 13C NMR 171.8, 136.4, 115.9, 109.5, 74.4, 71.5, 68.1, 33.5, 28.8, 26.6, 25.3.

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132 Diester of the monoacetone (D)-ribose 3-43 or 4-10 O O O O O O H3C CH3 O To a solution of monoacetone (D)-ribose 3-39 (or 4-6) (2.10 g, 0.011 mol) at 0oC was added DIC (2.30 g, 25 mmol) and a catalytic am ount of DMAP (0.34 g, 3 mmol) in anhydrous CH2Cl2 (22 mL) taken in a round bottom flask under Ar. 4-Pentenoic acid (2.54 g, 25 mmol) was added dropwise at 0 oC over the next 15 minutes. After comp letion of the addition, the reaction mixture was warmed to the room temperature and stirred for the next 3.5 h. Reaction was monitored by TLC (hexane/EtOAc, 6:4). At the end of 3.5 h, the product was filtered, and washed with water (2 x 50 mL) and brine (1 x 50 mL). The crude product was then dried over anhydrous MgSO4, concentrated under reduce pressure and purified by silica gel column chromatography using hexane and ethyl acetate (9 0:10) as eluent to give the desired product 3-43 (or 4-10) (2.83 g, 72 %). 4-10: Rf = 0.52 (hexane/EtOAc, 6:4); [ ]25 D -44.25 o (C = 2.13, MeOH); IR (neat) max 3079, 2979, 2881, 1743, 1703, 1642, 1520, 1419, 1366, 1066 cm-1; 1H NMR (300MHz, CDCl3) 6.20-6.18 (s, 1H), 5.84-5.70 (m, 2H), 5.06-4.94 (m, 4H), 4.68-4.64 (s, 2H), 4.44-4.38 (t, J = 7.1 Hz, 1H), 4.14-4.02 (m, 2H), 2.46-2.26 (m, 8H ), 1.48-1.44 (s, 3H), 1.32-1.28 (s, 3H); 13C NMR (CDCl3) 172.9, 171.7, 136.9, 136.8, 116.3, 116.2, 113.7, 102.6, 85.8, 85.6, 82.1, 64.5, 34.1, 33.8, 29.2, 28.9, 26.9, 25.5; HRMS [CI pos] for C18H26O7 [M]+, calcd 354.1679, found 354.1691.

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133 Esterification of D-isomannide 4-11 O O O O O O H H To a solution of D-isomannide (4-7) (or compound 3-50) (6 g, 0.04 mol) in anhydrous THF (82 mL, 0.50 equiv) was added DIC (11.41 g, 0.09 mol) and DMAP (3.80 g, 31 mmol) at 0oC under Ar. 4-Pentenoic acid (8 .65 g, 90 mmol) was added at 0oC under Ar over the next 20 min. The reaction mixture was warmed to room temperature and stirred for the next 4h. The crude product was then filtered, washed with water (2 x 50 mL) and brine (1 x 50 mL). The combined organic layer were then dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column ch romatography using hexane and ethyl acetate (90:10) as eluent to afford the pure product 4-11 (8.28 g, 65%) as a colorless oil. 4-11: Rf = 0.39 (hexane/EtOAc, 6:4); [ ]25 D +142.68 o (C = 2.20, CH2Cl2); IR (neat) max 3079, 2979, 2881, 1743, 1703, 1642, 1520, 1419, 1366, 1066 cm-1; 1H NMR (300MHz, CDCl3) 5.80-5.64 (m, 2H), 5.02-4.94 (m, 3H), 4.94-4.88 (m, 2H), 4.88-4.84 (dd, J = 10.1 Hz, 5.1 Hz, 1H), 4.60-4.54 (m, 2H), 3.94-3.86 (dd, J = 8.1 Hz, 2.1 Hz, 2H), 3.71-3.64 (dd, J = 5.1 Hz, 2.1 Hz, 2H), 2.42-2.34 (m, 4H), 2.32-2.22 (m, 4H); 13C NMR (CDCl3) 172.4, 136.5, 115.6, 80.4, 73.7, 70.4, 22.1, 28.8; HRMS (ESI FT-ICR) for C16H22O6Na [M+Na]+, calcd 333.1309, found 333.1310.

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134 Diesterification of (D)-Isosorbide 4-12 O O H H O O O O To a solution of (D)-isosorbide (4-8) (or compound 3-54) (2.06 g, 0.01 mol) at 0oCwas added DIC (3.73 g, 0.03 mol), and DMAP (1.03 g, 8 mmol) in anhydrous THF (30 mL, 0.50 M) taken in a round-bottom flask under Ar. 4-Pentenoi c acid (3.03 g, 0.03 mol) was added over the next 10 min at 0oC. After completion of addition the r eaction medium was warmed to room temperature and was stirred for the next 6h. Th e reaction was monitored by TLC (hexane/EtOAc, 6:4). At the end of 6h, the reaction medium was diluted with EtOAc (30 mL), and washed with water (2 x 30 mL), and brine (2 x 30 mL). Th e combined organic layer were then dried over anhydrous MgSO4, and concentrated under reduced pressu re followed by purification by column chromatography, using ethyl acet ate and hexane as el uent (90:10) to afford the pure product 4-12 (3.06 g, 70%) as a colorless oil. 4-12: Rf = 0.42 (hexane/EtOAc, 6:4); [ ]25 D +153.71.39 o (C = 2.10, CH2Cl2); IR (neat) max 3060, 2980, 2877, 1741, 1703, 1642, 1520, 1419, 1365 cm-1; 1H NMR (300MHz, CDCl3) 5.86-5.68 (m, 2H), 5.17-5.14 (m, 1H), 5.14-5.08 (m, 1H), 5.07-5.03 (m, 1H), 5.01-4.97 (m, 2H), 4.97-4.94 (m, 1H), 4.81-4.76 (t, J = 7.2 Hz, 1H), 4.44-4.40 (d, J = 5.1 Hz, 1H), 3.94-3.91 (m, 1H), 3.91-3.86 (m, 1H), 3.79-3.72 (dd, J = 8.1 Hz, 5.1 Hz, 1H), 2.48-2.28 (m, 8H); 13C NMR (CDCl3) 172.3, 172.0, 136.5, 136.3, 115.8, 115.6, 85.9, 80.8, 78.0, 73.9, 73.4, 70.4, 33.4, 33.2, 31.6, 28.8, 22.7, 14.1.

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135 ADMET of the diacetone (D)-mannitol 4-13 A 25 mL round bottom flask equipped with st ir-bar was placed under argon atmosphere. Ester of diacetone protected (D)-mannitol 4-9 (2.86 g, 7 mmol) in anhydr ous chloroform (7 mL) was added to it. Grubb’s second-generation cataly st (56.93 mg) was added to the monomer and stirred (monomer: catalyst ratio 100:1). The re action system was placed under argon atmosphere and vacuum alternatively. With the first additi on of the catalyst, there was little evolution of ethylene gas as observed from the bubbles form ed. As the reaction progressed the medium became more and more viscous and it had been changed from alternate argon vacuum state to total vacuum condition. It was kept under th is condition for next 48 hours with two more addition of 1 e quivalent CHCl3 and subsequent vacuuming. Afte r 48 hours of reaction, half of the amount of Grubbs’ second generation catalyst used initially was a dded. With the second addition of catalyst, there were formation huge bubbles and the system was kept under total vacuum for the next 24 hours. The reaction was monitored by taking NMR of the crude time to time, as there was no significant information av ailable from the TLC monitoring. The NMR of the crude taken after first 24, 48 and 72 hours showed disappe arance of the hydrogen of the terminal double bond. The polymerization was te rminated by adding ethy l vinyl ether. Any further purification of the polymer could not be performed due its in ability to be precipitated in an appropriate cold solvent.

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136 4-13: Rf = 0.22 (CHCl3/MeOH, 9:1); [ ]25 D +15.65 o (C = 2.02, MeOH); IR (neat) max 3071, 2977, 1767, 1647, 1465, 1438, 1382, 1186 cm-1; 1H NMR (300MHz, CDCl3) 6.0-5.2 (m, 11H), 4.2-4.0 (m, 7H), 4.0-3.7 (m, 14 H), 3.2-3.0 (m, 14H), 2.6-2.2 (m, 16H), 1.4-1.2 (m, 45H); 13C NMR: 172.3, 130.1, 110.0, 109.5, 74.5, 74.2, 71.7, 71.5, 65.9, 65.6, 34.9, 34.0, 33.7, 30.42, 29.0, 27.7, 26.6, 26.2, 25.7, 25.3. ADMET of the diester of (D)-ribose 4-15 A 25 mL round bottom flask equipped with stir-bar was placed under Ar. Diester of diacetone protected (D)-ribose 4-10 (2.86 g, 7 mmol) in anhydrous chloroform (8 mL) was added to it. Grubb’s second-generation catalyst ( 57 mg) was added to the monomer and stirred (monomer: catalyst ratio 100:1). The reaction system was placed under argon atmosphere and vacuum alternatively. With the first addition of th e catalyst, there was lit tle evolution of ethylene gas as observed from the bubbles formed. As th e reaction progressed the medium became more and more viscous and it had been changed from alternate argon vacuum state to total vacuum condition. It was kept under this condition for next 48 hours with two more addition of 1 equivalent CHCl3 and subsequent vacuuming. After 48 hour s of reaction, half of the amount of Grubbs’ second generation catalyst used initially was added. With the second addition of catalyst, there were formation huge bubbles and the system was kept under total vacuum for the next 24 h. The reaction was monitored by taking NM R of the crude time to time, as there was no significant information available from the TLC monitoring. The NMR of the crude taken after first 24, 48 and 72 hours showed disappearance of the hydrogen of the terminal double bond. The

PAGE 137

137 polymerization was terminated by adding ethyl vinyl ether. Any further purification of the polymer could not be performed due its inability to be precipitated in an appr opriate cold solvent. 4-15: Rf = 0.21 (CHCl3/MeOH, 9:1); [ ]25 D +141.65 o (C = 1.76, MeOH); IR (neat) max 3058, 2983, 1745, 1646, 1523, 1420, 1375, 1123 cm-1; 1H NMR (300MHz, CDCl3) 6.20-6.18 (m, 6H), 5.0-4.0 (m, 22H), 2.462.26 (m, 30H), 1.5-1.1 (m, 10H); 13C NMR: 172.9, 172.7, 172.3, 171.5, 136.9, 136.7, 136.2, 136.1, 135.9, 134.7, 102.1, 101.9, 101.5, 85.8, 85.7, 85.5, 85.3, 85.1, 84.9, 82.7, 82.5, 82.1, 64.5, 64.3, 64.2, 63.9, 34.5, 33.7, 27.4, 26.3, 25.3, 24.9. ADMET of the diester of (D)-isomannide 4-16 A 25 mL round bottom flask equipped with sti r-bar was flamed dried and placed under Ar. Ester of diacetone protected (D)-isomannide 4-10 (2.56 g, 8 mmol) in anhydrous chloroform (10 mL) was added to it. Grubb’s second-generation catalyst (58 mg) was added to the monomer and stirred (monomer: catalyst ratio 100:1). The re action system was placed under argon atmosphere and vacuum alternatively. With the first additi on of the catalyst, there was little evolution of ethylene gas as observed from the bubbles form ed. As the reaction progressed the medium became more and more viscous and it had been changed from alternate argon vacuum state to total vacuum condition. It was kept under th is condition for next 48 hours with two more addition of 1 e quivalent CHCl3 and subsequent vacuuming. Afte r 48 hours of reaction, half of the amount of Grubbs’ second generation catalyst used initially was a dded. With the second addition of catalyst, there were formation huge bubbles and the system was kept under total

PAGE 138

138 vacuum for the next 24 hours. The reaction was monitored by taking NMR of the crude time to time, as there was no significant information av ailable from the TLC monitoring. The NMR of the crude taken after first 24, 48 and 72 hours showed disappe arance of the hydrogen of the terminal double bond. The polymerization was te rminated by adding ethy l vinyl ether. Any further purification of the polymer could not be performed due its in ability to be precipitated in an appropriate cold solvent. 4-16: Rf = 0.23 (CHCl3/MeOH, 9:1); [ ]25 D +148.39 o (C = 2.01, MeOH); IR (neat) max 3078, 2971, 2885, 1763, 1698, 1632, 1523, 1423, 1316 cm-1; 1H NMR (300MHz, CDCl3) 5.35.0 (m, 6H), 4.4-4.0 (m, 6H), 4.0-3.5 (m, 16H), 3.4-3.0 (m, 16H), 2.50-2.20 (m, 32H), 1.6-1.1 (m, 32H); 13C NMR: 109.1, 74.0, 71.2, 65.6, 34.5, 33.7, 27.4, 26.3, 25.3, 24.9. ADMET of the diester of (D)-isosorbide 4-17 A 25 mL round bottom flask equipped with sti r-bar was flame dried and placed under Ar. Ester of diacetone prot ected (D)-isosorbide 4-11 (2.76 g, 9 mmol) in anhydrous chloroform (8 mL) was added to it. Grubb’s second-generation catalyst (57 mg) was added to the monomer and stirred (monomer: catalyst ratio 100:1). The re action system was placed under argon atmosphere and vacuum alternatively. With the first additi on of the catalyst, there was little evolution of ethylene gas as observed from the bubbles form ed. As the reaction progressed the medium became more and more viscous and it had been changed from alternate argon vacuum state to total vacuum condition. It was kept under th is condition for next 48 hours with two more

PAGE 139

139 addition of 1 e quivalent CHCl3 and subsequent vacuuming. Afte r 48 hours of reaction, half of the amount of Grubbs’ second generation catalyst used initially was a dded. With the second addition of catalyst, there were formation huge bubbles and the system was kept under total vacuum for the next 24 hours. The reaction was monitored by taking NMR of the crude time to time, as there was no significant information av ailable from the TLC monitoring. The NMR of the crude taken after first 24, 48 and 72 hours showed disappe arance of the hydrogen of the terminal double bond. The polymerization was te rminated by adding ethy l vinyl ether. Any further purification of the polymer could not be performed due its in ability to be precipitated in an appropriate cold solvent. 4-17: Rf = 0.25 (CHCl3/MeOH, 9:1); [ ]25 D +154.39 o (C = 2.26, MeOH); IR (film) max 3061, 2988, 2857, 1743, 1709, 1644, 1412, 1375 cm-1; 1H NMR (300MHz, CDCl3) 5.3-5.0 (m, 6H), 4.4-4.0 (m, 6H), 4.0-3.5 (m, 18H), 3.4-3.0 (m, 18H), 2.50-2.20 (m, 28H), 1.6-1.1 (m, 34H); 13C NMR: 172.3, 172.0, 171. 6, 170.9, 136.4, 135.8, 135.4, 135.2, 86.9, 86.5, 81.2, 80.8, 78.5, 78.3, 77.8, 77.4, 73.9, 73.6, 73.1, 70.6, 70.3, 69.8, 69.5, 69.1, 68.8, 33.7, 33.3, 33.1, 32.9, 31.9, 31.7, 31.5, 31.3, 28.9, 28.7, 28.3, 27.9, 22.9, 22.5, 22.2, 21.7.

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140 APPENDIX A SELECTED NMR SPECTRAL DATA The 1H NMR spectra of selected compounds from Chapter 2-4 are illustrated in this appendix. The spectra along with th e proposed structure are shown. Figure A-1. 1H NMR of diacetone (D)-mannitol. H O O H O O H3C H3C O O CH3 CH3 O O

PAGE 141

141 Figure A-2. 1H NMR of the ADMET of diacetone (D)-mannitol. H O O H O O H3C H3C O O CH3 CH3 O O n

PAGE 142

142 Figure A-3. 1H NMR of the t-Boc amino acetate of norbornene.

PAGE 143

143 Figure A-4. 1H NMR of ketoester of norbornene.

PAGE 144

144 Figure A-5. 1H NMR of diazo-ketoest er of norbornene.

PAGE 145

145 Figure A-6. 1H NMR of the homodimer of diacetone (D)-mannose.

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146 Figure A-7. 1H NMR of the homodimer of diacetoned (D)-glucose. O O O O O O O CH3 CH3 H3C H3C O O O O O O CH3 CH3 CH3 CH3

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147 Figure A-8. 1H NMR of the homodimer of the diacetoned (D)-galactose.

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148 Figure A-9. 1H NMR of the homodimer of the benzylated monoacetoned (D)-ribose.

PAGE 149

149 Figure A-10. 1H NMR of the homodimer of monoacetoned (D)-ribose.

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150 Figure A-11. 1H NMR of the diester of monoacetoned (D)-ribose.

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151 O O O O H H O Ph O O O O O H H Ph Figure A-12. 1H NMR of the homodimer of be nzylated (D)-isomannide.

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152 O O H H O O O O Figure A-13. 1H NMR of the diester of (D)-isomannide.

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153 Figure A-14. 1H NMR of the diester of (D)-isosorbide. O O H H O O O O

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154 LIST OF REFERENCES (1) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140. (2) Furstner, A. Adv. Synth. Catal. 2002, 344, 567-567. (3) Ivin, K. J. J. Mol. Cat. A: Chemical 1998, 133,1-16. (4) Randall, M. L.; Snapper, M. L. J. Mol. Cat. A: Chemical 1998, 133, 29-40. (5) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (6) Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3013-3043. (7) Mol, J. C. J. Mol. Cat. A: Chemical 2004, 213, 39-45. (8) Rouhi, A. M. Chem. Eng. News 2002, 80, 34-38. (9) Calderon, N. et al. Chem. Eng. News 1967, 45, 51. (10) Ivin, K. J.; Mol, J. C. Olefin Metathesis and Polymerization; Academic Press: San Diego, CA, 1997. (11) Calderon, N.; Chen, H. Y.; Scott, K. W. Tetrahedron Lett. 1967, 3327-3329. (12) Calderon, N.; Ofstead, E. A.; Ward, J. P.; Judy, W. A.; Scott, K. W. J. Am. Chem. Soc. 1968, 90, 4133-4140. (13) Lewandos, G.S.; Pettit, R. J. Am. Chem. Soc. 1971, 93, 7087-7088. (14) Grubbs, R. H.; Brunck, T. K. J. Am. Chem. Soc. 1972, 94, 2538-2540. (15) Herisson, J. L.; Chauvin, Y. Makromol. Chem. 1971, 141, 161-176. (16) Bazan, G. C.; Oskam, J. H.; Cho, H. N.; Park, L. Y.; Schrock, R. R. J. Am. Chem. Soc. 1991, 113, 6899-6907. (17) Schrock, R. R.; Murdzek, J. S.; Basan, G. C.; Robbins, J.; Dimare, M.; Oregan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886 (18) Furstner, A. Topics in Organometallic Chemistry: Alkene Metathesis in Organic Synthesis; Springer; New York, 1998; Vol. 1. (19) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem. Int. Ed. 1995, 34, 2039-2041. (20) Nguyen, S. T.; Johnson, L. K.; Grubbs, R.H.; Ziller, J. W. J. Am. Chem. Soc. 1992, 114, 3974-3975.

PAGE 155

155 (21) Rouhi, A. M. Chem. Eng. News 2002, 80, 29-33. (22) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110. (23) Herrmann, W. A.; Elison, M.; Fischer, J.; Kocher, C.; Artus, G. R. J. Angew. Chem. Int. Ed. 1995, 34, 2371-2374. (24) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 22472250. (25) Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem. 2002, 74, 7-10. (26) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem. Soc. 2001,123, 749-750. (27) Dias, E.L.; Nguyen, S.T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887-3897. (28) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58-71. (29) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153-2164. (30) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 2, 371-388. (31) Smith, M. B.; March, J. March’s Advanced Organic Chemistry; John Wiley & Sons, Inc.: New York, 2001. (32) Rivkin, A.; Cho, Y. S.; Cho, Gabarda, A. E.; Yoshimura, F.; Danishefsky, S. J. J. Nat. Prod. 2004, 67, 139-143. (33) Bielawski, C.W.; Grubbs, R. H. Angew. Chem. Int. Ed. 2000, 39, 2903-2906. (34) Frenzel, U.; Nuyken, O. J. Polym. Sci. Part A: Polym. Chem 2002, 40, 28952916. (35) Enholm, E.; Joshi, A.; Wright, D. Tetrahedron Lett. 2004, 45, 8635-8637. (36) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360-11370. (37) Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187-190. (38) Roy, R.; Dominique, R.; Das, S. K. J. Org. Chem. 1999, 64, 5408-5412. (39) Peppas, N. A.; Langer, R. Origins and deve lopment of biomedical engineering within chemical engineering. AICHE J. 2004, 50, 536-545. (40) Jagur-Grodzinski, J. Polyme. Adv. Technol. 2006, 17, 395-418.

PAGE 156

156 (41) Lavik, E.; Langer, R. Tissue engineer ing: current state and perspectives. Appl. Micrbiol. Biotechnol. 2004, 65, 1-8. (42) Cao, Y.; Carol, T. I., et.al. Scaffolds, stem cells, and tissue engineering: a potent combination. Aust. J. Chem.i 2005, 58, 691-703. (43) Wang, Y. K.; Yong, T.; Ramakrishna, S. Nanof ibers and their influence on cells for the tissue engineering. Aust. J. Chem. 2005, 58, 704-712. (44) Langer, R.; Vacanti, J. P. Science, 1993, 260, 920. (45) Vacanti, J. P.; Langer, R. Lancet, 1999, 354, 32-34. (46) Gunatillake, P. A.; Adhikari, R. Euro. Cells and Materials, 2003, 5, 1-6. (47) Harris, L. D.; Kim, B. S.; Mooney, D. Biomed. Master. Res 1998, 42, 396. (48) Thomson, R. C.; Mikos, A. G.; Beahm, E.; Lemo n, J. C.; Satterfield, W. C.; Aufdemorte, T. B.; Miller, M. J. Biomaterials, 1999, 20, 2007. (49) Ivin, K. J.; Olefin Metathesis, Academic Press: London, 1983. (50) Patton, P. P.; McCarthy, T. J. Macromolecules 1987, 20, 778. (51) Patton, P. P.; Lillya, C. P.; McCarthy, T. J. Macromolecules 1986, 19, 1266. (52) Jacobson, H.; Stockmayer, W. H. J. Chem. Phys. 1950, 18, 1600. (53) Wagener, K. B.; Nel, J. G.; Konzelman, J.; Boncella, J. M. Macromolecules 1990, 23, 5155-5157. (54) Ballkenhol, F.; Bussche-Hunnefeld, C.V.; Lansky, C.; Zachel, C. Angew. Chem. Int. Ed 1996, 35, 2288. (55) Czarnik, A. W. Acc. Chem. Res. 1996, 79, 112. (56) Terrett, N. K. Combinatorial Chemistry, Oxford Univ. Press, Oxford, 1998. (57) Ramstrom, O.; Lehn, J. M. Chembiochem 2000, 1, 41-48. (58) Ramstrm, O.; Bunyapaiboonsri, T.; Lohmann, S.; Lehn, J. M. Biochimica et Biophysica Acta 2002, 1572, 178-186. (59) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Combinatorial Chemistry 2002, 7, 117-125. (60) Varki, A.; Cummins, R.; Freeze, H.; Hart, G.; Marth, J. Essentials of Glycobiology, 1999, Cold Spring Harbor Laborato ry, Cold Spring Harbor, NY.

PAGE 157

157 (61) Rudd, P. M.; Guile, G. R.; Kuster, B.; Harv ey, D. G.; Oppendaker, G.; Dwek, R. A. Nature, 1997, 388, 205. (62) Ladmiral, V.; Melia, E.; Haddleton, D. M. Eu. Polymer J. 2004, 40, 431. (63) Wang, Y. F.; Chan, K. P.; Hay, A. S. React. Funct. Polym. 1996, 30, 205. (64) Hodge, P.; Colquhoun, H. M. Polym. Adv. Technol. 2005, 16, 84. (65) Hodge, P. React. Funct. Polym. 2001, 48, 15. (66) Hodge, P.; Kamau, S. D. Angew. Chem. Int. Ed. 2003, 42, 2412. (67) Ivin, K. J.; Mol, J. C. (Eds) Olefin metathesis and Metathesis Polymerization, Academic Press, London, 1997. (68) Grubbs, R. H. (Ed) Handbook of Metahthe sis, vols 1-3, Wiley-VCH, 2003. (69) Ben-Haida, A.; Colqhoun, H. M.; Hodge, P.; Stanford, J. L. Macromol. Rapid Commun. 2005, 26, 1377. (70) Linhardt, R. J.; Toida, T. Carbohydrates in drug design. New York: Marcel Dekker, 1997. (71) Goa, K. L.; Benfield P. Drugs, 1994, 47, 536-566. (72) McAlindon, T. E.; LaValley, M. P.; Gulin, J. P.; Felson, D. T. Jama-J. Am. Med. Assoc. 2000, 283, 1469-1475. (73) Ramstrm, O.; Lehn, J. M. Nature 2001, 1, 26-36. (74) Fischer, E. Enzyme. Chem. Ber. 1894, 27, 2985-2993. (75) Lehn, J. M.; Eliseev, A. V. Science. 2001, 5512, 2331-2332. (76) Lehn, J. M. Chem. Eur. J. 1999, 9, 2455-2463. (77) Ramstrom, O.; Lehn, J. M. Chembiochem 2000, 1, 41-48. (78) Kubota, Y.; Sakamato, S.; Yamaguchi, K.; Fujita, M. Proc. Natl. Acad. Sci. USA. 2002, 99, 4854-4856. (79) Nazarpack-Kandlousy, N.; Zweigenbaum, J.; Henion, J.; Eliseev, A. V J. Comb. Chem. 1999, 1, 4854-4856. (80) Furlan, R. L. E.; Ng, Y. F.; Otto, S.; Sanders, J. K. M. J. Am. Chem. Soc. 2001, 123, 8876-8877. (81) Giger, T.; Wigger, M.; Audetat, S.; Benner, S. A. Synlett 1998, 688-691.

PAGE 158

158 (82) McNaughton, B. R.; Bucholtz, K. M.; Camaano-Moure, A.; Miller, B. L. Org. Lett. 2005, 7, 733-736. (83) Ramstrom, O.; Lehn, J.M. Nature Rev. Drug Discov.; 2002, 1, 26-36. (84) Reprinted from Publication: Nature Rev. Drug Discov.; Vol 1, R., O.; Lehn, J. M.; Drug Discovery by Dynamic Combinatorial Librar ies; 26-36; Copyright 2002, with permission from nature publishing Group. (85) Nazarpack-Kandlously, N.; Zweigenbaum J.; Henion, J.; Eliseev, A. V. J. Comb. Chem. 1999, 1, 199-206. (86) Cousins, G. R. L.; Furlan, R. L. E.; Ng, Y. F.; Redman, J. E.; Sanders, J. K. M. Angew. Chem. Int. Ed. 2001, 40, 423-428. (87) Furlan, R.L.E. et al. Chem. Commun. 2000, 1761-1762. (88) Ramstrom, O.; Lohmann, S.; Bunyapaiboonsri, T.; Lehn, J. M. Chemistry-A European Journal 2004, 10, 1711-1715. (89) Otto, S. Current Opinion in Drug Discovery & Development 2003, 6, 509-520. (90) Almogren, A.; Koury, S.; Rittenhouse-Diakun, K. FASEB JOURNAL 1999, 13, A646A646. (91) Fukuda, M.; Ohyama, C.; Lowitz, K.; Matsuo, O.; Pasqualini, R.; Ruoslahti, E. CANCER RESEARCH 2000, 60, 450-456 (92) Roy, R. Carbohydrate Chemistry, ed. G. J. Boons, Chapman & Hall, UK, 1998, 243; Roy, R. Curr. Opin. Struct. Biol., 1996, 6, 692; Kiessling, L. L.; Pohl, N. L. Chem. Biol. 1996, 3, 71; Bovin, N. V.; Gabius, H.-J. Chem. Biol. 1995, 24, 413. (93) Lee, Y. C.; Lee, R. T. Acc. Chem. Res. 1995, 28, 322; Lubineau, A.; Escher, S.; Alais, J.; Bonnaff, D. Tetrahedron Lett. 1997, 38, 4087; Patch, R. J.; Chen, H.; Pandit, C. R. J. Org. Chem. 1997, 62, 1543; Pag, D.; Roy, R. Bioorg. Med. Chem. Lett. 1996, 6, 1765; DeFrees, S. A.; Kosch, W.; Way, W.; Pauls on, J. C.; Sabesan, S.; Halcomb, R. L.; Huang, D. -H.; Ichikawa, Y.; Wong, C. –H. J. Am. Chem. Soc. 1995, 117, 66. (94) Roy, R. Top. Curr. Chem. 1997, 187, 241; Zanini, D.; Roy, R. Carbohydrate Mimics: Concepts and Methods. ed.; Chapleur, Y.; Chemie, Verlag; Weinheim, Germany, 1998, p. 385; Jayaraman, N.; Nepogodiev, S. A.; Stoddart, J. F. Chem. Eur. J. 1997, 3, 1193. (95) Yarema, K. J.; Bertozzi, C. R. Curr. Opin. Chem. Biol. 1998, 2, 49; Roy, R. Carbohydrates in Drug Design, ed.; Witczak, Z. J.; Nieforth, K. A.; Dekker, Marcel, NY, 1997, p. 83.

PAGE 159

159 (96) Wells, J. A. Curr. Opin. Cell Biol., 1994, 6, 163; Heldin, C. –H. Cell., 1995, 80, 213; Boger, D. L.; Chai, W. Tetrahedron, 1998, 54, 3955; Diver, S. T.; Schreiber, S. L. J. Am. Chem. Soc., 1997, 119, 5106. (97) Velupillai, P.; Harn, D. A. Proc. Natl. Acad. Sci. U.S.A., 1994, 91, 18; Takata, I.; Chida, K.; Gordon, M. R.; Myrvik, Q. N.; Ricardo, M. J.; Jr.; Kucera, L. S. J. Leukocyte., 1987, 41, 248; Gordon, E. J.; Sanders, W. J.; Kiessling, L. L. Nature, 1998, 392, 30. (98) Wagener, K. B.; Smith, Jr.., D. W. Macromolecules 1991, 24, 6073-6078. (99) Odian, G. G.; Principles in Polymerization, 3rd Ed., John Wiley & Sons, Inc.: New York, 1991 (100) Wagener, K. B.; Wolf, A. Polymer Preprints (American Ch emical Society, Division of Polymer Chemistry) 1991, 32, 535-536. (101) Bauch, C. G. Wagener, K. B.; Boncella, J. M. Polymer Preprints (American Chemical Society, Division of Polymer Chemistry) 1991, 32, 377-378. (102) Wagener, K. B; Boncella, J. M. Macromolecules, 1991, 24, 2649. (103) Wagener, K. B.; Brzezinska, K. Macromolecules, 1991, 25, 5273. (104) Patton, J. T.; Boncella, J. M.; Wagener, K. B. Macromolecules, 1992, 25, 3862. (105) Watson, M. D; Wagener, K. B. Macromolecules, 2000, 33, 8963. (106) Portmess, J. D.; Wagener, K. B. J. Polymer Sci., Polymer Chem. 1996, 24, 6073. (107) Corkhill, P. H.; Trevett, A. S.; Tighe, B. J. Proc Inst Mech Eng, 1990, 204, 147-155. (108) Nayak, S.; Lyon, L. A. Angew. Chem. Int. Ed. 2005, 44, 7686 – 7708. (109) Gombotz, W. R.; Wee, S. Adv. Drug Delivery Rev. 1998, 31, 267. (110) Goosen, M. F. A.; OEShea, G. M. H.; Gharapetian, M.; Chou, S.; Sun, A. M. Biotechnol. Bioeng. 1985, 27, 146. (111) Lutolf, M. P.; Raeber, G. P.; Zisch, A. H.; Tirelli, N.; Hubbell, J. A. Adv. Mater. 2003, 15, 888. (112) Eagland, D.; Crowther, N. J.; Butler, C. J. Eur. Polym. J. 1994, 30, 767. (113) Mathur, M.; Hammonds, K. F.; K lier, J.; Scranton, A. B. J. Controlled Release 1998, 54, 177. (114) Hennink, W. E.; van Nostrum, C. F. Adv. Drug Delivery Rev. 2002, 54, 13. (115) Dusek, K.; Patterson, K. J. Poly. Sci. Poly. Phys. Ed. 1968, 6, 1209.

PAGE 160

160 (116) Staudinger, H.; Husemann, E. Ber. Dtsch. Chem. Ges. A 1935, 68, 1618. (117) Ramstrom, O.; Lohmann, S.; Bunyapaiboonsri T.; Lehn, J. M., Dynamic Combinatorial Carbohydrate Libraries: Probi ng the Binding Site of the Concanavalin a Lectin. Chemistry-A European Journal 2004, 10, (7), 1711-1715. (118) Ramstrom, O.; Bunyapaiboonsri, T.; Lohmann, S.; Lehn, J. M., Chemical Biology of Dynamic Combinatorial Libraries. Biochimica Et Biophysica Acta-General Subjects 2002, 1572, (2-3), 178-186. (119) Bloodworth, A. J.; Davies, A. G., The A ddition of Tin Alkoxides to Isocyanates. J. Chem. Soc. 1965, 5238-5244. (120) Amaya, T.; Tanaka, H.; Takahashi, T., Comb inatorial Synthesis of Carbohydrate Cluster on Tree-Type Linker with Orthogonally Cleavable Parts. SYNLETT 2004, (3), 497-502. (121) Hummel, G.; Jobron, L.; Hinds gaul, O., Solid-Phase Synthesis of a 1-Thio-Beta-DGlcnac Carbohydrate Mimetic Library. J. OF CARBOHYDRATE CHEM. 2003, 22, (7-8), 781-800. (122) Lohse, A.; Schweizer, F.; Hindsgaul, O., Synt hesis of a 56 Component Library of Sugar Beta-Peptides. COMB. CHEM. & HIGH THROUGHPUT SCREENING 2002, 5, (5), 389-394. (123) Nilsson, U.; Fournier, E.; Fryz, E.; Hindsga ul, O., Parallel Solution Synthesis of a "Carbohybrid" Library Desi gned to Inhibit Galact ose-Binding Proteins. COMB. CHEM. & HIGH THROUGHPUT SCREENING 1999, 2, (6), 335-352. (124) Marcaurelle, L.; Seeberger, P., Co mbinatorial Carbohydrate Chemistry. CURRENT OPINION IN CHEM. BIO. 2002, 6, (3), 289-296. (125) Kerckhoffs, J.; Ishi-i, T.; Paraschiv, V.; Ti mmerman, P.; Crego-Calama, M.; Shinkai, S.; Reinhoudt, D. N., Complexation of Pheno lic Guests by Endoand Exo-HydrogenBonded Receptors. Organic & Biomolecular Chemistry 2003, 1, (14), 2596-2603. (126) Lins, R. J.; Flitsch, S. L.; Turner, N. J.; Irving, E.; Brown, S. A., Generation of a Dynamic Combinatorial Librar y Using Sialic Acid Aldolas e and in Situ Screening against Wheat Germ Agglutinin. Tetrahedron 2004, 60, (3), 771-780. (127) Bunyapaiboonsri, T.; Ramstrom, O.; Lohmann, S.; Lehn, J. M.; Peng, L.; Goeldner, M., Dynamic Deconvolution of a Pre-Equilibra ted Dynamic Combinatorial Library of Acetylcholinesterase Inhibitors. Chembiochem 2001, 2, (6), 438-444. (128) Misske, A.; Hoffmann, H., High Stereochemi cal Diversity and Applications for the Synthesis of Marine Natural Products: A Li brary of Carbohydrate Mimics and Polyketide Segments. CHEMISTRY-A EUROPEAN JOURNAL 2000, 6, (18), 3313-3320.

PAGE 161

161 (129) Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser, R., Serial Radical Cyclization of Branched Carbohydrates. Part 1. Simple. J. Org. Chem. 1989, 54, 5350-5356. (130) Le, G. T.; Abbenante, G.; Becker, B.; Grathw ohl, M.; Halliday, J.; Tometzki, G.; Zuegg, J.; Meutermans, W. Drug discovery today, 2003, 8, 701-709. (131) Martin, E. J. et al. Measuring diversity: e xperimental design of comb inatorial libraries for drug discovery. J. Med. Chem. 1995, 38, 1431-1436. (132) Dean, P. M. Molecular Similarity in Drug Design, Champman & Hall. (133) Johnson, M. A.; Maggiora, G. M. Concepts and Application of Molecular Similarity, 1990, Wiley-Interscience. (134) Bourne, G. T. et al.b-turn nomenclature: a topographi cal classification system. In Peptides: Chemistry. Structure and Biology (kaumaya, P. T. P. and Hodges, R. S., eds) 354-355. (135) Tran, T. T. et al. The side-chain classification of loops from high-resolution protein crystal structures. In Peptides for the New Millenium (Fields, G. B. et al., eds), 320-321. (136) Sofia, M. et al. Discovery of novel disaccharide antibacterial agents using a combinatorial library approach. J. Med. Chem. 1999, 42, 3193-3198 (137) Opatz, T. et al. D-Glucose as a pentavalent chiral scaffold. Eur. J. Org. Chem. 2003, 8, 1527-1536. (138) Kallus, C. et al. Combinatorial solid-pha se synthesis using D-Galactose as a chiral fivedimension-diversity scaffold, Tetrahedron Lett. 1999, 40, 7783-7786. (139) Clemons, P. A. Curr. Opin. Chem. Biol. 1999, 1, 112-115. (140) Nicolaou, K. C.; Hughes, R.; Cho, S. Y.; Wi nssinger, N.; Smethurst, C.; Labischinski, H.; Endermann, R. Angew. Chem. Int. Ed. Engl. 2000, 39, 3823-3828. (141) Nicolaou, K. C.; Pfefferkorn, J. A.; Schuler, F. ; Roecker, A. J.; Cao, G. Q.; Casida, J. E. Chem. Biol. 2000, 12, 979-992. (142) Burgess, L. E.; Newhouse, B. J.; Ibrahim, P.; Kashem, M. A.; Hartman, A.; Brandhuber, B. J.; Wright, C. D.; Thomson, D. S.; Vigers, G. P. A.; Koch, K. Proc. Natl. Acad. Sci. USA. 1999, 96, 8348-8352. (143) Dolle, R. E.; J. Comb. Chem. 2002, 4, 369-418. (144) Hirschmann, R.; sprengeler, P. A.; Kawasaki, T.; Leahy, J. W.; Shakespeare, W. C.; Smith, A. B. III. Tetrahedron, 1993, 49, 3665-3676.

PAGE 162

162 (145) Hirschmann, R.; Nicolau, K. C.; Pietranico, S.; Leahy, E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors, P. G.; Shakespeare, W. C. J. Am. Chem. Soc. 1993, 115, 1255012568. (146) Piscopio, A.; Robinson, J. E.; Curr. Opion. In Chem. Bio. 2004, 8, 245-254. (147) Reetz, M. T. Comp. Coord. Chem II. 2004, 9, 509-548. (148) Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett., 1996, 37, 547; Furstner, A.; Muller, T. J. Org. Chem. 1998, 63, 424; Van Hooft, P. A.; Leeuwenburgh, M. A.; Overkleeft, H. S.; Van der Marel, G. A.; Boeckel, C. A. A. van; Boom, J. H. van. Tetrahedron Lett. 1998, 39, 6061; Feng, J.; Schuster, M.; Blechert, S. Synlett, 1997, 129; Schuster, M.; Lucas, N.; Blechert, S. Chem. Commun. 1997, 823; Mortell, K. H.; Gingras, M.; Kiessling, L. L. J. Am. Chem. Soc. 1994, 116, 12053; Fraser, C.; Grubbs, R. H. Macromolecules, 1995, 28, 7248; Nomura, K.; Schrock, R. R. Macromolecules, 1996, 29, 540. (149) Descotes, G.; Ramza, J.; Basset, J.M.; Pagano, S. Tetrahedron Lett., 1994, 35, 7379; Ramza, J.; Descotes, G.; Basset, J. M.; Mutch, A. J. Carbohydr. Chem., 1996, 15, 125. (150) Dominique, R.; Das, S. K.; Roy, R. Chem. Commun. 1998, 8, 2437-2438. (151) Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115, 9858; Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887; Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100; Schuster, M.; Blechert, S. Angew. Chem., Int. Eng 1997, 36, 2036; Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413; Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446 (152) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 749-750. (153) Burkart, M. D. V.; Stphane. P.; Dffels, A.; Murry, B. W.; Ley, S. V.; Wong, C. Bioorganic & Medicinal Chemistry 2000, 8, 1937-1946. (154) Kaskar, B.; Heise, G. L.; Michal ak, R. S.; Vishnuvajjala, B. R. Synthesis 1990, 10311032. (155) Loupy, A.; Monteux, D. A. Tetrahedron 2001, 58, 1541-1549. (156) Bauch, C. G. Wagener, K. B.; Boncella, J. M. Polymer Preprints (American Chemical Society, Division of Polymer Chemistry) 1991, 32, 377-378. (157) Danielmeier, K.; Steckhan, E. Tetrahedron Asymmetry 1995, 6, 1181-1190. (158) Loupy, A.; Monteux, D. A. Tetrahedron 2001, 58, 1541-1549. (159) Vonlanthen, D.; Leumann, C. J. Synthesis 2003, 1087-1090. (160) D mling, A.; Ugi, I. Angew. Chem. Int. Edu. Engl. 2000, 39, 3168-3210.

PAGE 163

163 (161) Sando, S.; Narita, A.; Aoyama, Y. Bioorganic & Medicinal Chemistry Letters 2004, 14, (11), 2835-2838. (162) Enholm, E. J.; Jiang, S., Highly Stereosele ctive Couplings of Ca rbohydrate Lactones with Terpene. Tetrahedron Lett. 1992, 33, 6069-72. (163) (a) Roy, R. In carbohydrate Chemistry; Boons, G. J., Ed.: Chapman & Hall: London, UK, 1998; p 243. (b) Roy, R. In Toipcs in Current Chemistry Thiem, J., Driguez, H., Eds.: Springer: Heidelberg, 1997; Vol. 187, p 241. (164) Dai, W. S.; Barbari, T. A. J. Membr. Sci. 2000, 171, 79 (165) Peppas, N. A.; Benner, Jr. R. E. Biomaterials, 1980, 1, 158. (166) Gehrke, S. H. Adv. Polym. Sci. 1993, 110, 82. (167) Hoffman, A. S. Adv. Drug. Delivery Rev. 2002, 54, 3. (168) Yeomans, K. Chem. Rev. 2000, 100, 2. (169) Pit, C. G.; Schindler, A. In Biodegradati on of Polymers. Controlled Drug Delivery; Bruck, S. D. Ed.; CRC Press: Bocaraton, FL, 1983, Vol I, 53. (170) Anseth, K. S.; Newman, S. M.; Bowman, C. N. iAdv. Polym. Sci. 1995 122, 177. (171) Kloosterboer, J. G. Adv. Polym. Sci. 1998, 84, 1. (172) Mathias, L. J.; Kusefoglu, S. H.; kress, A. O.; Lee, S.; Wright, J. R.; Culberson, D. A.; Warren, S. C.; Warren, R. M.; Huang, S.; Lop ez, D. R.; Ingram, J. E.; Dickerson, C. W.; Jeno, M.; Halley, R.J.; Colletti, R. F.; Cei, G.; Geiger, C. C. Makromol. Chem. Macromol. Symp. 1991, 51, 153. (173) Zhu, S.; Tian, Y.; Hamielec, A. E.; Eaton, D. R. Macromolecules, 1990, 23, 1144. (174) Decker, C. Polym Int. 1998, 45, 133. (175) Matsumoto, A. Adv. Polym. Sci. 1995, 123, 41. (176) Anseth, K. S.; Decker, C.; Bowman, C. N. Macromolecules, 1995, 28, 403. (177) Nelson, E. W.; Scranton, A. B. J. Polym. Sci., Polym. Chem. 1996, 34, 403. (178) Hall, A. J.; Hodge, P.; Kamau, S. D.; Ben-Haida, A. J. Organometallic Chem. 2006, 691, 5431-5437. (179) Chang, C. D.; Waki, M.; Ahmed, M.; Meie nhofer, J.; Lundell, E. O.; Hang, J. D. Pept. Prot. Res. 1980, 15, 59. (180) Atherton, E.; Logan, C. J.; Sheppard, R. C. J. Chem.Soc. Perkin Trans I. 1981, 538.

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164 (181) Ueki, M.; Amemiya, M. Tetrahedron Letter. 1987, 28, 6617-6620. (182) McElwee-White, L.; Dougherty, D. A. J. Am. Chem. Soc. 1984, 106, 3466-3474. (183) Jung, M. E; Min, S.J.; Houk, K. N.; Ess, D. J. Org. Chem. 2004, 69, 9085-9089. (184) F rstner, A.; Kindler, N. Tetrahedron Letters, 1996, 117, 5855. (185) Houri, A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem.Soc. 1996, 118, 10926.

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165 BIOGRAPHICAL SKETCH Kalyan Mondal was born in 1974, in Calcutta India. He completed his schooling from Taki High School, Calcutta with Science as major. He received his bachelor’s degree from the University of Calcutta. Dr. S. P. Basak in spired him in organic chemistry throughout his teaching. Kalyan gladly recognizes his contribut ion for his basic chemistry knowledge. He then joined B.Tech course under University of Ca lcutta and studied about Reverse Engineering on Rubber based products. This Graduation course in troduced him with new prospects of study in Polymer Science. Dr. S. N. Gupta, Advisor had helped him to enrich his knowledge in Polymer Science. After graduation, he decided to do furt her research work in synthesizing of Prostate specific Antigen field and thus did his M.Tech fr om the same University under the guidance of Dr. P. Sarkar. He always wanted to carry on hi s research work to develop his knowledge. This passion of knowledge brought him to USA and open ed new scopes and opportunities before him. He received his second M.S. degree in chemistry from East Tennessee State University under the guidance of Dr. Tammy Davidson, working on the synthesis of Chiral Surfactants for Enantioselective Organic Synthesi s. He always wanted to be innovative and ve rsatile and get every possible knowledge from various fields of s ynthesis. He joined Dr. Eric Enholm’s group to enrich his knowledge on synthetic chemistry for Ph D program at University of Florida. Kalyan has learned much about the field of synthetic organic chemistry, especially chemistry related to developing new methodology and multi-step synthesi s. His graduate career is reached to a pinnacle from where he is eager to step forwar d to apply his knowledge in practical field of various industries engaged in differe nt research & development works.