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Studies on the ring-opening/cross metathesis of 8-Oxabicyclo [3.2.1]Octene derivatives and its application toward the synthesis of Latrunculin B

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Studies on the ring-opening/cross metathesis of 8-Oxabicyclo [3.2.1]Octene derivatives and its application toward the synthesis of Latrunculin B
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Estrella-Jimenez, Maria E
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x, 194 leaves : ill. ; 29 cm.

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Acetates ( jstor )
Alcohols ( jstor )
Alkenes ( jstor )
Catalysts ( jstor )
Ethers ( jstor )
Hexanes ( jstor )
Metathesis ( jstor )
Pyrans ( jstor )
Silica gel ( jstor )
Spectroscopy ( jstor )
Chemistry thesis, Ph. D ( lcsh )
Dissertations, Academic -- Chemistry -- UF ( lcsh )
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Thesis (Ph. D.)--University of Florida, 2005.
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Includes bibliographical references.
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Printout.
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Vita.
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by Maria E. Estrella-Jimenez.

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STUDIES ON THE RING-OPENING/CROSS METATHESIS OF 8-
OXABICYCLO[3.2.1 ]OCTENE DERIVATIVES AND ITS APPLICATION
TOWARDS THE SYNTHESIS OF LATRUNCULIN B














By

MARIA E. ESTRELLA-JIMENEZ


A 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


2005































Copyright 2005

by

Maria E. Estrella-Jim6nez

































Dedicated to my family, the most important thing in my life, and to all of those who have
taught me in some way














ACKNOWLEDGMENTS

I need to thank my big and wonderful family; they are my life's engine. Especially,

I thank my parents, Sheila Jim~nez and FMlix A. Estrella, my brother FMix A. Estrella Jr.,

and my sister Johanna Estrella for their unconditional love and support. In addition, a

special thank you goes to Wilfredo Ortiz, who has always been there to give me his love,

help, support and positive input. Without him, everything would have been

overwhelming. I would like to thank my friends for keeping my social life in healthy

status.

Professionally, I would like to thank my undergraduate advisor, Dr. John A.

Soderquist. I am very grateful for the trust he gave me as a student and for giving me the

opportunity to start organic chemistry in his research group. I also thank him for his help

in numerous opportunities and fellowships.

I thank my advisor, Dr. Dennis L. Wright, for giving me the opportunity of being

part of his research group and for respecting my decision of staying at the University of

Florida, after he moved to Dartmouth College for a new faculty position. I also thank

him for his advices and exciting chemistry discussions.

I offer special thanks to Professor Merle A. Battiste. He was a key person in my

final year at University of Florida. I could not be more grateful of his support, positive

input, confidence and friendship. I really appreciated the concern and interest he took in

me. He always had the time to listen, regardless of the matter.








I would like to thank the other members of my committee, Professor William R.

Dolbier, Professor Ken Sloan and Professor David H. Powell, for taking their time to be

part of my professional development. Dr. Ion Ghiviriga needs to be given special thanks

for all his help with the NMR and for his friendship. He was a great collaborator and

friend. No matter how busy he was, he would always take some time to help me. In

addition, the mass spectroscopy team needs to be thanked for their suggestions and work

in getting the molecular weight of my compounds. I am very grateful for my former and

present colleagues for offering me their knowledge and friendship, especially Lynn

Usher, Chris Whitehead and Ravi Orogunty. Lynn Usher trained me during my first year

as a graduate student and offered me tremendous help through the years with her advice,

friendship and, I need to add, the English lessons. I will always remember Chris

Whitehead; he mentored me on many occasions with lab techniques. I appreciate Ravi

Orogunty for sharing his wisdom with me many times. In addition, I would like to thank

Chris Baker for his friendship during this past year.

Furthermore, I would like to express my thanks to my colleagues and friends,

Theodore Martinot and Jed Hasting. I thank Theodore Martinot for all the help and

advice he offered me this past year. Jed Hasting is truly appreciated for his wonderful

friendship, help and patience in listening to me during stressful times. Dave Pirman, the

undergraduate that worked with me during my last year, also deserves special mentioning

for all the help he provided in the lab. Last, but not least, for all the non-research-related

work, I am very grateful for secretaries Lori Clark and Gwen McCann from the

Department of Chemistry. They are efficient, friendly and wonderful secretaries.








Finally, I would like to thank the University of Florida for giving me the

opportunity of coming here to pursue my graduate studies and for the fellowship

provided.














TABLE OF CONTENTS

p e

ACKNOW LEDGM ENTS ............................................................................................ iv

ABSTRA CT ....................................................................................................................... ix

CHAPTER

IN TRODUCTION ........................................................................................................ 1

Ring-Opening of 8-Oxabicyclo[3.2. 1 ]Octene Derivatives and its Application in
Synthesis .................................................................................................................. 3
Cleavage of the Unsaturated Double Bond, C6-C7, of the Oxabicyclo[3.2.1]
System .......................................................................................................... 4
Cleavage of the Carbonyl and the a-Carbon, C3-C4, of the Oxabicyclo[3.2.1]
System .......................................................................................................... 8
Cleavage of the Carbon-Oxygen Bridgehead Bond. C 1-C2, of the
Oxabicyclo[3.2.1 ] System ............................................................................. 9
Olefin M etathesis ................................................................................................... 13
Types of Olefin M etathesis Reactions ............................................................. 16
Ring-opening metathesis polymerization ............................................... 16
Acyclic diene metathesis .......................................................................... 17
Cross metathesis ..................................................................................... 18
Ring-closing metathesis .......................................................................... 19
Ring-opening cross m etathesis ............................................................... 23
Tandem M etathesis ........................................................................................ 26
Catalytic Asym metric Olefin M etathesis ....................................................... 29
The Latrunculins ................................................................................................... 36
Total Syntheses of Latrunculin B ................................................................... 37
Sm ith's total synthesis ............................................................................ 37
Ftirstner's total synthesis ........................................................................ 39
Total Syntheses of Latrunculin A ................................................................... 40
Sm ith's total synthesis ............................................................................ 40
W hite's total synthesis ............................................................................ 41
Kashman's Approach to the Latrunculin Synthon ......................................... 44
Kashman's Synthesis of Latrunculin M and C ............................................... 45








2 RESULTS/DISCUSSION ..................................................................................... 47

Intermolecular Ring-Opening Cross Metathesis (ROCM) ................................... 47
K inetic Studies ............................................................................................... 49
Bridgehead Substituted 8-Oxabicyclo[3.2.1 ]Octene Derivatives .................. 59
Intramolecular Ring-Opening Cross Metathesis (ROCM) ................................... 65
Approaches Towards Latrunculin B from Ring-Opening Metathesis of 8-
Oxabicyclo[3.2.1 ]Octene Derivatives ............................................................... 71

3 CONCLUSIONS AND FUTURE WORK ............................................................. 80

4 EXPERIMENTAL PROCEDURES ...................................................................... 82

APPENDIX

A SELECTED SPECTRA ............................................................................................ 118

B LIST OF TABLES FOR KINETIC STUDIES ........................................................ 151

C LIST OF GRAPHS FOR KINETIC STUDIES ........................................................ 157

LIST O F REFER EN C ES ................................................................................................. 188

BIOGRAPHICAL SKETCH ........................................................................................... 194














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

STUDIES ON THE RING-OPENING/CROSS METATHESIS OF 8-
OXABICYCLO[3.2.l]OCTENE DERIVATIVES AND ITS APPLICATION
TOWARDS THE SYNTHESIS OF LATRUNCULIN B

By

Maria E. Estrella-Jim6nez

May 2005

Chair: Dennis L. Wright
Cochair: Merle A. Battiste
Major Department: Chemistry

The pyran moiety is a common structural feature found in many natural products,

and often seen as an integral part of carbohydrates and macrolides of marine origin. This

work discloses the use of ring-opening cross metathesis (ROCM) of 8-

oxabicyclo[3.2. 1 ]octene derivatives for the preparation of substituted pyrans, using

Grubbs' ruthenium-based metathesis catalyst. The oxabicyclic systems were synthesized

using F6hlish conditions, which involve the [4+3] cycloaddition between furan and an

oxallyl cation. An unusual influence in the reactivity and selectivity of the ROCM

reactions was discovered upon substituent variation at the C3 position of the oxabicyclo.

These results led to further investigations that involved the synthesis of a series of 8-

oxabicyclo[3.2. 1 ]octene derivatives with different substituents at C3. Kinetic

experiments were conducted with the substrates, using NMR to monitor the reactions.

These experiments provided relative rates of ring-opening metathesis polymerization for








the series of oxabicyclic derivatives when compared with 4,10-dioxa-tricyclo[5.2.1.0
2,6]dec-8-ene-3,5-dione (adduct of furan and maleic anhydride). The relative rate trend

observed among the substrates showed that their reactivity is affected by the combination

of electronic and steric effects. The knowledge obtained can be used to accelerate

sluggish ROCM reactions in the synthesis of pyrans from these types of substrates.

Substitution at the bridgehead position of the oxabicycle decreases the reactivity of the

system and brings into focus the problem of regioisomers. However, the careful

consideration of the substituent at the C3 position gave good yields of the pyrans, and

excellent regioselectivity was obtained having an endo-alcohol as a substituent at that

position. In addition, the intramolecular ROCM of oxabicyclic system having a tethered

alkene at the C2 position was studied and led to linear-fused pyrans.

Furthermore, preliminary work was done towards the synthesis of latrunculin B

using the ROCM approach.













CHAPTER 1
INTRODUCTION

Polycyclic systems can be seen as a method to achieve stereoselectivity in organic

synthesis. The ring strain contained in some polycyclic compounds fixes them in a

conformation that accesses contiguous stereocenters as well as helps in the control of

stereocenters from successive reactions. Oxabicyclic compounds are polycyclic systems

that possess an oxygen atom as part of the cyclic framework. The developments of ring

cleavage reactions of oxabicyclic compounds have made them attractive starting

materials in organic synthesis. Ring-opening of oxabicyclic derivatives can lead to a

wide variety of compounds by selective cleavage of specific bonds. These compounds

are frequently highly substituted ethers, particularly tetrahydrofurans and

tetrahydropyrans. 1 A large number of natural products and sugars have been synthesized

from oxabicyclic compounds. '

A particular substrate is 8-oxabicyclo[3.2.1 ]oct-6-en-3-one 1, which allows the

construction of different oxygen-containing compounds by specific bond disconnections.

Cleavage between the bridged-carbon, C 1, and the oxygen (path a) generates a

cycloheptenol, whereas cleavage between the carbonyl, C3, and the adjacent (x carbon,

C2, (path b) gives a 2,4 dihydrofuran moiety, and cleavage of the unsaturated double

bond, C6-C7, (path c) produces a pyrone derivative (Scheme 1-1).








0
3'
4 '2

6' 7
0 path c _p 1 ath a 0

R Rpath b
R O HO.

COOH OH



Scheme 1-1. Different oxygen-containing compounds by specific bond disconnections of
8-oxabicyclo[3.2.1 ]oct-6-en-3-one

The availability of this oxabicyclo, which can be synthesized by a [4+3]

cycloaddition with protocols amenable to large scale preparations,2 and the availability of

alternative ring-opening reactions make this compound an interesting starting unit in

organic synthesis.'

Our research focused on the cleavage of the double bond (path c) of 1 and its

derivatives using ruthenium-based olefin metathesis to generate a pyran moiety. To

prove the efficiency of the method, it was also applied in an approach to latrunculin B.

The precursors were readily obtained by a [4+3] cycloaddition, employing Fohlish's

conditions, which involves the [4+3] cycloaddition of furan and trichloroacetone in the

presence of sodium trifluorethoxide, and subsequent reduction using zinc/copper couple

in methanol saturated with ammonium chloride.3 The presence of the pyran moiety in

many natural products (Figure 1-1) sparked our interest in developing this methodology.




















Forskolin Milbemycin SCH351448

......[, ',- 00 Me02C :"


0 0 OH
'"'t ...... 0i. ... ..





Latrunculin A Latrunculin B Bryostatin 7

Figure 1-1. Natural products displaying the pyran moiety

This dissertation will present the studies on the ring opening cross metathesis of 8-

oxabicyclo[3.2. 1 ]octene derivatives and its application in an approach to latrunculin B.

Relevant to this dissertation is to mention different types of ring-opening of 8-

oxabicyclo[3.2. 1]octene derivatives and their application to the synthesis of a variety of

natural products, as well as a background on the olefin metathesis reaction. In addition, a

brief history of the latrunculins is included.

Ring-Opening of 8-Oxabicyclo[3.2.1lOctene Derivatives and its Application in
Synthesis

This section is devoted to demonstrating the versatility of 8-

oxabicyclo[3.2. 1 ]octene derivatives in the synthesis of natural products via different ring

openings. 8-oxabicyclo[3.2.1 ]octene derivatives present some advantages that make








them excellent precursors in organic synthesis. Among these, specific bond

disconnections in the system allow for the construction of different oxygen-containing

moieties that are commonly seen in natural products. Moreover, the system is readily

accessible in large scale from a [4+3] cycloaddition.4 The defined conformation and

rigidity of the system allows access to multiple stereocenters in one step from the

cycloaddition reaction. Furthermore, methods have been developed towards asymmetric

[4+3] cycloadditions.4'5 In addition, chiral derivatives can be accessed from

desymmetrization of meso 8-oxabicyclo[3.2. 1 ]octene compounds.6

Cleavage of the Unsaturated Double Bond, C6-C7, of the Oxabicyclo[3.2.1] System

Tetrahydropyrans are common features in many natural products and sugars. They

can be accessed by cleavage of the unsaturated bond of the oxabicyclo[3.2. 1] system.

Yadav and coworkers elaborated a strategy of asymmetric hydroboration for the

desymmetrization and subsequent opening of 8-oxabicyclo[3.2. 1 ]octene 2 in the

asymmetric synthesis of the C(19)-C(25) polypropionate unit of Rifamycin.7 Cleavage of

the double bond, C6-C7, of bicyclic ketone 2 was performed in several steps. The

sequence involves reduction and protection of 2, asymmetric hydroboration of ether 3

with (+)-Ipc2BH (Bis (isopinocampheyl) borane), PCC oxidation of the resulting alcohol

4, and Baeyer-Villiger oxidation of ketone 5. After a diastereoselective a-methylation,

the system was opened by an exhaustive reduction that lead to the resolved acyclic

compound 8, which is relevant to 9, the C(1 9)-C(25) segment of Rifamycin (Scheme 1-

2). The sequence elaborated by Yadav et al. was exploited by Hoffmann et al., who

proved the efficacy of the methodology in the enantioselective synthesis of various 6-

valerolactones and polyacetate segments of natural products (Scheme 1-3).8










0 1

2


a, b 0

OBn


OBn OBn




0 0


C


OBn


0
/ OB n
0
5


e


h25 19
OH OBn 0 0
OH 0Bn OH OH l9)C2
C(1 9)-C(25
segment
8 9


Scheme 1-2. Yadav's asymmetric synthesis of the C(19)-C(25) unit of Rifamycin. a)
DIBAL-H, CH2C12, -10C b) NaH, BnBr, THF, 650C c) (+)-Ipc2BH, -20'C,
24h, 96% (>99% ee) d) PCC, CH2C12, rt, 95% e) H202, Se02, tBuOH, reflux,
40% f) LDA, Mel, THF, -78C g) LiA1H4, THF, 0C, h) 2,2-
dimethoxypropane, P-TsOH, acetone, r.t.


OBn
C(3)-C(9) segment
0 Bryostatins

/ O~n16
0 12 0 ------ .B
OBn


0\-.r0


V IOBn


OBn


rac-I1


i. (-)-Icp2BH, Et2O, PCC[O]
ii. (+)-Icp2BH, Et20, PCC[O]


rOE
0 13





0 E
14



00kOE


0
0
0
OBn


0

In 18
-- 0
OBn



0
0
0 i


C( 10)-C( 17) segment
Pederin; C(12)-C(19)
segment disorazoles

17



C(1)-C(7) segment
epothilones





C(1)-C(9) segment
aurisides

9


Scheme 1-3. Structural and stereochemical diversity from racemic oxabicyclo 10


rac-lO


3n








Hoffmann and coworkers demonstrated the utility of 8-oxabicyclo[3.2. 1 ]octene

derivatives as versatile scaffolds in the approach to numerous natural products containing

the tetrahydropyran unit. These include Bryostatins,9 Phorboxazoles,10 Discodermolide,"

Lasonolide A, 12 Spongistatin 1,13 and mevinic acids14 among others. They approached

the tetrahydropyran unit by oxidative cleavage of the unsaturated double bond, C6-C7, of

the system. In the approach to the Bryostatins, two strategies that involved the cleavage

of the unsaturated double bond were employed. The C(1)-C(16) segment of the molecule

was synthesized starting from 8-oxabicyclo[3.2. 1 ]oct-6-en-3-one 1 and racemic 2,2-

dimethyl-8-oxabicyclo[3.2.1 ]oct-6-en-3-one 10.9b

To synthesize the C(1)-C(9) unit, Hoffmann et al. started with racemic 2,2-

dimethyl-8-oxabicyclo[3.2. I]oct-6-en-3-one 10. The synthesis of that segment involves

the preparation of lactone 16 using the strategy developed by Yadav et al. (Scheme 1-3).7

This protocol prepared the system for cleavage under standard basic conditions that

resulted in the asymmetric tetrahydropyran 20. Further manipulations including ring-

opening with borontrifluoride and Claisen condensation afforded 23, the C(1)-C(9)

segment of the Bryostatins (Scheme 1-4).

OBn
OBn
0 a ~S OBnOH 0 e
a b
HO O OeS OMe
0HO 0 OMe
0 20 21
16
>98% ee O
cOBnOHO S OBn 0

S OtBu S OTPS
C(1)-C(9)
22 23
Scheme 1-4. Synthesis the C(1)-C(9) segment of the Bryostatins. a) K2CO3, MeOH, rt,
99% b) 2 equiv HS(CH2)3SH, 3 equiv BF3-Et2O, MeNO2, -20 to -15C, 95%
c) 5 equiv CH3CO2But, LDA, -78 to 0C, 94%








For the synthesis of the C(l 0)-C(I 6) fragment, ring-opening of the meso

oxabicyclic ketone 1 was performed by ozonolytic olefin cleavage. Tetrahydropyran 25,

the key intermediate in Hoffmann's synthesis of the C(10)-C(16) unit, was obtained in 5

steps in 35% overall yield from 1 (Scheme 1-5). The enantioselectivity of 25 was

achieved by enzymatic desymmetrization of ketal 24.


0AcO jo OAc H HI0
a, b,c d,e HO Ac
/ e.e. > 98%
0 O (35% from 1)

24 25
H H lo H H16
7 0 0
TrO O OH TfO OTIPS
I C(1o)-C(16)
OEt segment

26 0 27 TBDPS

Scheme 1-5. Synthesis of the C(10)-C(16) unit of the Bryostatin. a) 2,2,5,5-tetramethyl-
1,3-dioxane, cat. p-TsOH, 35-45 mm Hg, 50% b) i. 03, MeOH/CH2CI2, -780C
ii. NaBH4, -200C, 98% c) Ac20, cat 4-DMAP, py, r.t. 91% d) lipase PS,
toluene/phosphate buffer (1:4) pH 7, r.t. 88% e) Acetone, cat. Pd(CH3CN)2C12
r.t. 89% f) Trityl chloride, Et3N, cat. 4-DMAP, CH2CI2, r.t. g) K2CO3 5% H20
in MeOH (79% two steps) h) ethyl diisopropoxyphosphonoacetate, NaH,
toluene, -50 to -35 C then -25C (72%)

After various transformations including protection, deprotection and Homer-

Wadsworth-Emmons olefination, tetrahydropyrone 25 was converted to 27, the C(I 0)-

C(16) fragment of the Bryostatins, (Scheme 1-5). Finally, coupling of the C(l)-C(9)

segment 23 and the C(1 0)-C(16) unit 27 achieved the northern hemisphere of the

Bryostatins 28 (Scheme 1-6).









ioH H16 i
ZO OTIPS + S OnO 0
S S OTPS



27 23
TBDPS


0 S S OTBSO 0 OTPS

28 C(1)-C(16) segment


Scheme 1-6. Synthesis of the C(1)-C(16) segment of the Bryostatins

Cleavage of the Carbonyl and the a-Carbon, C3-C4, of the Oxabicyclol3.2.1I System

Tetrahydrofurans can also be derived from oxabicyclo[3.2. 1] systems.

Tetrahydrofuran 33, a key intermediate in the synthesis of the C-nucleoside

showdomycin,'5 was synthesized by Simpkins and coworkers by cleavage of the C2-C3

bond of the bicyclic ketone 1 (Scheme 1-7).16

0 OTMS
Ph N Ph
0 a 0 3O Li 0 b
TMSCI



29 31

0
,,OH HO OH
0 0

0 0' OH
0 0 MeO2C OH HN 0 Showdomycin


32 33

Scheme 1-7. Cleavage of C2-C3 of an oxabicyclo[3.2.l] from a chiral silyl enol ether. a)
Os04, tBuOH, Et20, H202, acetone b) PhIO, BF3"OEt2, H20, 67% c)
Pb(OAc)4, MeOH; then NaCNBH3, 93%








The protocol involves the preparation of a chiral enol silane 31 with homochiral

lithium amide 30. Enol silane 31 was oxidized with PhIO (iodosobenzene) producing a-

hydroxyketone 32 with the hydroxyl group in an equatorial position. Oxidative cleavage

of recrystallized a-hydroxyketone 32 was effected by treatment with lead tetraacetate in

methanol, followed by reduction with NaCNBH3, in the same pot, yielding the C-

nucleoside 33 with high enantiomeric excess (>98% ee).

Cleavage of the Carbon-Oxygen Bridgehead Bond, C1-C2, of the Oxabicyclo[3.2.11
System

Cleavage of the carbon-oxygen ether bond allows the access to functionalized

seven-membered rings, avoiding entropically disfavored cyclization approaches to it. In

addition, further cleavage of the seven-membered ring provides an efficient route to

polysubstituted acyclic chains.

Also involving enolate formation, Grieco and Hunt performed opening at the

bridgehead of an oxabicyclo[3.2. 1] system.7 Thus, enol ether 34, generated from

treatment of bicyclic ketone 2 with LDA, THF, HMPA and TBSCI, was mixed with 2.0

equiv. of 1 -methoxy- I -(tert-buthyldimethylsiloxy)-ethylene 35 in a 4.0 M solution of

lithium perchlorate in diethyl ether (LPDE) at room temperature affording

cycloheptadienes 36 and 37 in a ratio of 4:1 in quantitative yields (Scheme 1-8).

MeO TBSO TBSO
TBSO / OTBS /OTBS
OTBS 4.0 M LPDE, 0C _

TCOOMe COOMe
4:1
34 36 37

Scheme 1-8. Ring opening of oxabicyclo[3.2.1 ] system with a silyl ketene acetal








Cycloheptadiene 36 was transformed into the C(I 9)-C(27) fragment 41 of

Rifamycin S (Scheme 1-9). Grieco and Hunt also applied the protocol in the synthesis of

the chiral C(I 9)-C(26) and C(27)-C(32) fragments of Scytophycin. 18


TBSO TBSO
OTBS a,b,c,d 2 "OH
0
19


36 "-COOMe 0/ \ 31



efg,h,i 21
MeQOC -1
OH OBn OH OH

40


'"Bn


8 HO '39

27 19

-'OH 00 0 0


41 C(1 9)-C(27)
segement


Scheme 1-9. Synthesis of C(1 9)-C(27) fragment of Rifamycin. a)TBAF,THF,HOAc b)
LiAI(OtBu)3H, THF, -20'C c ) i. NaOH, THF, MeOH, H20 ii. CO2 iii. KI/I2,
0C d) Bu3SnH, THF, AIBN, 60'C e) TESCi, 2,4,6-collidine, CH2CI2, -78C
t) TPAP, NMO, CH2C12, 4h g) TBAF, HOAc, THF h) MCPBA, absolute
EtOH i) K2CO3, MeOH, 0C, lh

Lautens'9 and Cha et al.2325have also proven the utility of cleaving the carbon-

oxygen bridgehead bond, C 1-C2, of the oxabicyclo[3.2.1 ] system in the synthesis of

natural products. Lautens and co-workers explored the reactivity of oxabicyclo[3.2. ]

compounds toward nucleophilic addition, demonstrating that they can be opened with


Rifamycin S








reagents such as aluminum hydrides,20 high order cuprates, and organolithium22 type-

nucleophiles by an SN2' mechanism. Examples are illustrated in Scheme 1-10.

OBn OBn
O 0 D IB A L H '.
Hexnes

OBn reflux OH OH
3 42 43
50% 27%

0 0
0 (t-Bu)2CUCNLi2 t-Bu
/ O THF, 0C to RT OH t-Bu"" OH OH
92%
2t-Bu
1 44 45 46


n-BuLi, HO: \,OH
OH Et20, -785C Bu
92%
47 48

Scheme 1 10. Ring opening of oxabicyclo[3.2. 1] compounds by nucleophilic additions.

Minor products derived from anti SN2, such as 45 were also obtained when

organocuprates were used as the nucleophile. Subsequent manipulations of

cycloheptanol 42, including ozonolytic cleavage, afforded the C(1 7)-C(23) unit of

ionomycin (Scheme 1-11).









OBn
-~ 1. Swern [0]

2. DIBAL-H, -780C
OH 3. NaH, PMBBr
72%
42

PMP

OBn 0"t0
17 7
HO 23

50


OBn 1.03, MeOH, -780C
2. NaBH4
"'OPMB 3. DDQ, 00C
49 72%


Scheme 1-11. Synthesis of the C(17)-C(27) segment of ionomycin

Cha et al. took advantage of the [4+3] cycloaddition to synthesize phorbol26 and

tropone-containing natural products, such as imerubrine23, colchicine24, and hinokitiol2

from complex oxabicyclo[3.2. 1] systems. Cha et al. employed F6hlish 27 and Mann28

methods to cleave the carbon-oxygen ether bond of the oxabicyclic compounds. In his

synthesis of the tropolone, hinokitiol, Moriarty's oxidation of cycloadduct 51 produced

alcohol 52, which was subjected to double elimination according to the procedures of

Fbhlish et al.27 and Mann et al.28 (Scheme 1-12).


PhI(OAc)2
MeOH-KOH
59%


0
OH
TMSOTf \

52 OHO Et3N, 63%

52 /k--
hinokitiol


Scheme 1-12. Cha's synthesis of hinokitiol


lonomycin








The value of oxabicyclo[3.2.1] compounds in organic synthesis has been

demonstrated by the examples presented above. This dissertation focuses on the use of

olefin metathesis to cleave the unsaturated bond, C6-C7, of the 8-oxabicyclo[3.2.1 ]octene

derivatives to generate a cis-2,6-disubstituted pyran moiety with two differentiated ends

that can be useful to synthesize pyran-containing natural products.

Olefin Metathesis

Olefin metathesis29 is a method that allows a redistribution of olefins. During the

reaction two olefin partners are exchanged to give a new unsaturated carbon-carbon bond

in the presence of a metal carbene complex. Since the discovery of the olefin metathesis

in the mid 1950's, a large number of catalyst systems have been reported to initiate this

reaction. However, it was not until the accepted metal carbene mechanism proposed by

Chauvin that scientists were provided with a basis for the design and development of

well-defined catalysts. Chauvin and Herisson proposed a [2+2] cycloaddition between

an olefin 53 and a metal alkylidine catalyst 54 to generate a metallocyclobutane

intermediate 55. The metallocyclobutane intermediate 55 undergoes cycloreversion

resulting in a new olefin 56 and a new metal alkylidine 57. A second [2+2] cycloaddition

between 57 and 58, followed by cycloreversion yields the metathesis product 60 and the

turnover of the catalyst 61 (Scheme 1-13).

The development of well-defined catalysts promoted the steady increase of the

olefin metathesis usage in organic and polymer chemistry. Some well-defined catalysts

are presented in Figure 1-2.





14

+ MLn [2 + 2] retr______+ ML,
+I MLn [2 + 2] Rj

53 54 55 56 57


[2+ 2] R2 retro R2 + MLn
z 1 1
=7 MLn [2 + 2] R,
58R2 R
59 60 61

Scheme 1-13. Olefin metathesis mechanism



i-Pr -~i-Pr i-Pr -~i-Pr
HC N Ph ICN Ph-

F3C FO CF F3C C3 CF3 PPh

H3C CF3 H3C CF3
62 63 64



CI, PC31 Ph l"PYNYN
CI',Ru CI PCY3Ph CI//Ru
PCy3 CI'I Ph
PCY3
65 66 67

Figure 1-2. Selected olefin metathesis catalysts

Molybdenum and tungsten catalysts 62, 63, and 64 were proven to be very

effective for this reaction. Basset and coworkers's catalyst 64 was tolerant to various

functional groups such as silicon, phosphorous and tin; however, its efficiency varied

according to the steric demand of the substrate.31 Tungsten 62 and molybdenum 63

(Schrock's catalysts) presented high reactivity toward a broad range of substrates.32

Catalyst 62 is a very useful catalyst for olefin metathesis; however, despite its high

reactivity, 62 presents some drawbacks. These are extremely high sensitivity to air, and








moderate to poor functional group tolerance. Ruthenium catalysts 65-67 developed by

Grubbs and coworkers33"35 and co-workers overcame those problems. They were more

tolerant to functional groups, reacting mainly with olefins in the presence of alcohols,

aldehydes, amides and carboxylic acids. Metal alkylidine 65 was the first ruthenium

catalyst developed by Grubbs et al.33 Besides its stability and tolerance toward many

functional groups, it was not as reactive as Schrock's molybdenum catalyst. Shortly after

catalyst 65, ruthenium catalyst 66 was reported to present a higher reactivity.34 In the

aim of finding a better catalyst, Grubbs et al. reported another ruthenium catalyst 67 in

1999.35 Catalyst 67 exhibited higher reactivity, thermal stability and a lower rate of

decomposition compared to metal alkylidine 66. For this reason, 67 is commonly

referred as "Super Grubbs" catalyst.36 Today, metal alkylidines 62, 66 and 67 are the

most widely used catalysts for the olefin metathesis reaction. Our research involves

mainly the usage of Grubbs catalyst 67. Its mechanism of activity has been demonstrated

to proceed by a "dissociative" pathway as depicted in scheme 1-14.37
cL/ +, _,,Phn PhiL PhL Ph
_l ph jY~ ci1, L~P _____ PhI c,
Cl 1 y3 + PCy3 Cl' u -O -efin CI U_ CI l __ ii
PCY3 -

68 69 70 71

Scheme 1-14. Dissociative olefin metathesis mechanism

The 16-electron specie 68 generates a 14-electron complex 69 by the loss of a

phosphine. This complex then associates with an olefin as in intermediate 70 that

promotes the metallocyclobutane formation of 71 that will eventually generate the

metathesis product and the catalyst turnover. One of the most fascinating aspects of the

olefin metathesis is that several types of chemistry can be performed with the same

catalyst depending on the reaction conditions and the nature of the substrate.








Types of Olefin Metathesis Reactions

There are five main variants on the olefin metathesis reaction. These are: a) ring-

opening metathesis polymerization (ROMP) b) acyclic diene metathesis (ADMET) c)

cross metathesis (CM) d) ring-closing metathesis (RCM) e) ring-opening cross metathesis

(ROCM) (Scheme 1-15).


a) ROMP_



b) ADMET


c) _, Rj+ ; R2 M R2




d) j*L RCM_



e) + ROMP- R

Scheme 1-15. Different types of olefin metathesis reactions

Ring-opening metathesis polymerization

Ring-opening metathesis polymerization (ROMP) marked the beginning of olefin

metathesis, since olefin metathesis was discovered while examining the polymerization

of olefins. In this reaction, driven by the release of ring strain, a monomer is opened by a

metal alkylidine and the resulting intermediate reacts with another monomer initiating the

propagation for polymerization. The success of this reaction has been described in

several reviews.38 The main advantage in the polymer chemistry is that well-defined

catalysts allow for the realization of living polymerization. Thus, control of the








architecture and length of the polymer can be obtained.39-4 This has many applications

for the development of new materials.41-42

An area of research that has been growing in the last decade is the use of

functionalized polymers as scaffolds for the delivery of drugs. ROMP provides a viable

route to prepare polymeric scaffolds for the delivery of drugs by attaching the drug to a

substrate that can undergo polymerization, such as norbornene. The anti-inflammatory

and cancer preventive indomethacin 72 was attached to exo-5-norborneol 73 to form

monomer 74 which can undergo polymerization (Scheme 1-16).4

0 0
1. (COC)2 ,, jO

"N2. N NEt3
/ __:OH ) N
0 Cl 73 Cl
72 74

Scheme 1- 16. Monomer preparation toward a functionalized polymeric scaffold for drug
delivery

Acyclic diene metathesis

Acyclic diene metathesis (ADMET) is the acyclic cross metathesis of dienes or

the acyclic version of ROMP. In this reaction the elimination of gaseous ethylene from

the polymerization is believed to be the driving force of the reaction. In an example,

biopolymers were created by Wagner and coworkers using ADMET in dienes that

incorporated amino acid units in the backbone (Scheme 1-17).44

O R O R

Reflux n + A
H H 0 X
75 76


Scheme 1-17. Biopolymers from ADMET








Cross metathesis

Another type of olefin metathesis is the cross metathesis reaction (CM). In this

reaction, the rearrangement of two olefins results in a new carbon-carbon double bond

incorporating one carbon from each partner. The CM reaction is advantageous since it

allows the synthesis of highly substituted olefins. One disadvantage, however, is the

formation of unwanted self metathesis products. Another challenge is the control of

geometry of the newly formed olefin (Scheme 1-18).

R R{ [Catalyst] R2 + R R2 + R -.R2
R"z + lyt R1

desired self-metathesis product
product undesired

Scheme 1-18. Possible cross metathesis products

To overcome these problems it is necessary to determine a way to minimize self-

metathesis, thus maximizing cross-coupling as well as improve the stereoselectivity of

the reaction. Over the years researchers have worked on these problems. With the

development of well-defined catalysts, cross metathesis has gained more attention as a

viable tool in organic chemistry. In 1995, Crowe and coworkers showed the viability of

acrylonitrile to undergo cross metathesis with a molybdenum based catalyst.45 Although,

the cross metathesis product was obtained in moderate yield, high cis selectivity was

obtained and no self-metathesis product was observed (Scheme 1-19, entry 1). Crowe

also showed that addition of steric bulk at the allylic position of the olefin promoted trans

selectivity. This was demonstrated with a series of allyl silanes (Scheme 1-19, entries 2,
3).46 Blechert et al. observed the same with substituted allylic amines, reporting the first

example of exclusively trans selective CM (Scheme 1-19, entries 4, 5).47 The

homodimerization was controlled by the electronic and steric parameters of one of the








alkene partners in the CM reaction. Furthermore, the high reactivity and tolerance to

functional groups allowed catalyst 67 to give CM products of disubstituted olefins

(Scheme 1-19, entry 6)48 and a,B-unsaturated carbonyls49 or acrylic amides50 (Scheme 1-

19, entries 7, 8). One important application of the CM reaction is that it allows for the

preparation of reagents by providing different highly functionalize olefins. Products

derived from CM of allyl silanes (Scheme 1-19, entries 2, 3) are useful for silane addition

to carbonyl compounds (Sakurai reaction). Also, products from the CM reaction of vinyl

boronates51 with alkenes are useful for Suzuki couplings (Scheme 1-20, entries 1, 2),

while CM of allyl boronates52 with alkenes are analogous to allyl silane compounds, and

can be added to aldehydes and ketones (Scheme 1-20, entries 3, 4).

Ring-closing metathesis

A well-recognized type of metathesis reaction is the ring-closing metathesis

(RCM). RCM has found the widest application in synthesis, being a key step in various

total syntheses. The release of volatile ethylene is believed to drive this reaction. Its

value consists in being a reliable method for the formation of small, medium and large

membered-rings. Examples of RCM abound in literature. RCM have been employed in

the synthesis of carbohydrates,53 numerous heterocycles, and peptides.54 Perhaps, the

major utility of this application has been found in the synthesis of natural products. RCM

was used at the early stage of the synthesis of a marine natural product dysinosin A

(Scheme 1-21).55 Meyers and co-workers reported the first successful synthesis of (-)-

griseoviridin using RCM strategy in a macrocyclization that led to the 20-membered ring

antibiotic (Scheme 1-22).56









Entry

1



2




3


Blechert:
0 .OTr

4 CI3C J N
H


CO2Me
Cbz N\,,H
H H


Grubbs:


BzO






0


0

H2N


Crowe:
OBn




PhO
3



PhO, ,w
3


62 10 mol%
,, SiMe3
1.5 equiv



62 10 mol%
,-, SiMe3
1.5 equiv


67 5 mol%
qAc
2 equiv


67 5 mol%
TBSO -r2-
7


67 5 mol%
AcO
I-3


62 5 mol%
NC' 2 equi


62 5 mol%
SiMe3
2 equiv


62 5 mol%

.eSi(i-Pr)3
2 equiv


All trans, 98%


CO2Me
Cbz 'N\, \ SiMe3

H H
All trans, 92%


BzO 3OAc

trans:cis 4: 1
81%

TBSO co2cH3

trans:cis 20: 1
62%
0

H2N "Ac
All trans, 89%


Scheme 1- 19. Examples of intermolecular Cross Metathesis


OBn
v CN cis:trans 7.6: 1
60%
PhO I.-SiMe3
3
trans:cis 2.6: 1
72%

Pho 'Si(i-Pr)3

trans:cis 7.6: 1
77%

0 .OTr

C13C N SiMe3









0-
Bzo Bo

66%, 8:1 E/Z

I0-
AcO B O
65%, 13:1 E/Z


Cl --Ci +


0
B -0


1. 67 (2.5 mol%)
400C, 12h
2. PhCHO (1.5 equiv)


OH



CI


79%, 3.6: 1 anti/syn


0--
+1


1. 67 (2.5 mol%)
400C, 12h
2. PhCHO (2 equiv)


OH

Ph
Ph


88%, 99: 1 anti/syn


Scheme 1-20. Cross metathesis of vinyl and allyl boronates


64

N Co2Me
Boc


6 (1 mol%j


H\
Boc' N
C02Me


Scheme 1-21. Application of RCM in the synthesis of Dysinosin A


Entry


I BzO-




2 AcO 3


0


0


67 (5 mol%)
400C, 12h


67 (5 mol%)
400C, 12h


4 I


H 0 G+NH2
HO N .
N NH2
HO H NH


O Dysinosin A


MeO
OS03















66 (30 mol%/)


PPTS, 68%
acetone/H20


Scheme 1-22. Application of RCM in the synthesis of (-)-Griseoviridin

In addition, RCM involving alkynes has been reported. One example is presented

in scheme 1-23. Pyroglutamic acid 81 was converted to the enyne 82, which underwent

RCM with ruthenium carbene 66. Compound 83 was further elaborated to yield the

alkaloid (-)-Stemoamide.57

MeOOC
HOC"N-e-CO 66 (5 mol%) 0U N
HOC N 0 MeOOC" ...

H

81 82 83


(-)-Stemoamide


Scheme 1-23. RCM with an alkyne at the early stage of the synthesis of (-)-stemoamide


Me
0
o
0 H,, S
N H
r4-(-)Griseoviridin
0 0 NH



OH OH








Ring-opening cross metathesis

Ring-opening cross metathesis (ROCM) is a variant of cross metathesis where one

of the olefin partners is a cyclic olefin. In this type of metathesis, the release of ring

strain drives the reaction. ROMP is avoided by performing the reaction under diluted

conditions with excess of the acyclic olefin partner. This olefin metathesis variant has

not received as much attention as the RCM. This is because it is necessary to have

efficient control of the regio- and stereoselectivity in order to make this strategy

synthetically useful. Therefore, ROCM has been limited to unsubstituted or symmetric

cyclic olefins. Regiochemical issues arise when the starting cyclic olefin is not

symmetrically substituted. For example, whereas ROCM of symmetric bicyclic alkene

84a with a terminal alkene can produce only one product (85 = 85', X = H), an

unsymmetrical bicyclic alkene such as 84b can produce two regioisomers 86 and 87 (X

H) (Scheme 1-24).

X x
x / ROCM /R R- /_
"R

84a x = H 85 85'
84b x H 86 87

Scheme 1-24. Possible regioisomers from unsymmetrical bicyclic alkenes

Early successful examples using well-defined olefin metathesis catalyst were

disclosed by Snapper et al. in 1995. He reported the ROCM of various cyclobutenes with

a series of terminal alkenes, using vinylidene catalyst 65 (scheme 1-25).58 His studies

included the first examples of regioselectivity in the ROCM of unsymmetrical bicylic

systems. Whereas symmetric cyclobutenes gave a ratio of stereoisomers favoring the Z-

alkene, asymmetric cyclobutenes gave two regioisomers, where the more hindered alkene








was preferred (scheme 1-25, entry 2 and 3). Snapper explained that the products

distribution was consistent with an alternating alkylidene mechanism, where the

alkylidene A, generated from the reaction of the terminal olefin and the catalyst, was

preferred over the methylidene B as the active catalyst in the reaction (path I was favored

over Path II, scheme 1-26). In addition, Blechert et al.59 and Arjona et al.60 reported

regioselective ROCM examples of bicyclic alkenes (Scheme 1-25, entries 4-6). In their

studies, the less hindered alkenes were obtained. Furthermore, Szeimies and Feng

disclosed a highly regioselective ROCM of various 1 -arylcyclobutenes with

allyltrimethylsilane and 1 -octene. In this case, the less hindered regioisomer was

obtained as the only product (Scheme 1-25, entries 7-8).61





> Path I1> Path 11

RuLn -RuLn

R



R

R R
R

Scheme 1-26: A selective ROCM process based on the identity of the propagating
alkylidene









Entry
Snapper




Et

2 HO'"



OMe

3 A


1 -octene Hex
65 Hex


1 -decene
65


1 -octene
65


Et,

HO'" Oct

88 2.3:1 Z/E

OMe

Hex

90 1:8.8 Z/E


Et,
HOI,-.-
H" ,/,, Oct

89 1.7:1 Z/E


OMe

d Hex

91 2.1:1 Z/E


Blechert


4O/
OTBDMS


5 N B N0
Boc


66Sie3


EtEt

!--OTBS


"' >- CH2Si(CH3)3
N
Boc O


Plumet


0 OAc --"(O. CH2OAC
6 ,O
OAc 66 OAc


Szeimies


0 ,,z-zCH2OAc
H' __75%
Acd 92:93
93 19:81


02N


8
S


,SiMe3

66




1-octene
66


02N

O CH2SiMe3




SHex


Scheme 1-25. Examples of ROCM reaction on symmetric and unsymmetrical bicyclic
systems


63%
2.3:1 Z/E


56%
88:89
1.3:1


81%
90:91
4.1:1


85%
2:1 E/Z


83%
2:1 E/Z


81%
1.3:1 E/Z


54%
1.9:1 E/Z








Although regiochemical issues have limited the use of ROCM to symmetrical

cyclic systems in organic synthesis, examples have demonstrated the possibility of

obtaining good regioselectivity in the ROCM reactions. However, additional efforts are

required to evaluate the steric and electronic influence of this issue.

Tandem Metathesis

Tandem or domino metathesis reactions involve more than one transformation in a

sequential order in one pot. They are desired because they can provide complex

structures in fewer steps. Tandem metathesis can be defined as the combination of two or

more consecutive metathesis operations. The driving force for these consecutive

operations is attributed to either the loss of ethylene or ring-strain release. These

reactions need to be carried out at high dilution to promote intramolecular rearrangement

over olygomer formation.

Grubbs et al. reported double ring-closing metathesis of dienynes, catalyzed by

ruthenium metal complex 65, producing fused bicyclic [n.m.0] rings.62 In an example,

reaction of compound 94 with catalyst 65 produces the metal alkylidine 95, which

undergoes RCM, forming a new metal alkylidine 96 which is able to undergo a second

RCM yielding the fused ring 97 (Scheme 1-27). Bulky substituents at the triple bond can

significantly slow down the reaction or cause no reaction to occur.









OSiEt3 OSiEt3
65 Q3 moffL.
8h, RT, 0.06M kn[Ml

CH3 CH3
94 95

OSiEt3 OSiEt3



CH3 CH3
96 97

Scheme 1-27. Tandem metathesis with a dienyne

Blechert et al. reported the first total synthesis of (-)-halosaline using domino

metathesis with ruthenium catalysts 66.63 Employing the combination of

RCM/ROM/RCM operations, compound 101 was built in a single operation from 100

(Scheme 1-28).


OH 0'
66 (5moI%)

Aco / TsN N
Ts H

99 100 101
OH
-~N N

(-)-Halosaline

Scheme 1-28. Total synthesis of (-)-halosaline

In another example, Arjona and Plumet et al. reported the combination of

ROM/RCM!CM with 2-azanorbornenones 103 toward the synthesis of I -azabicyclic y-

lactam compounds 104 in modest yields 55-65% (Scheme 1-29).6 The domino

metathesis was catalyzed by ruthenium complex 66.









Br 66 (5mo1%) AN
N K2CO3, KOH H R n=1,2,3,4
H TEBA, CH3CN 'z )n 0
H H
102 103 104
R'= H, CH2OAc

Scheme 1-29. Tandem ROM/RCM/CM of 2-azanorbomenones

Cyclized product 104 was observed with n = 2 or 3. With n = 1,4 ROM/CM took

place affording 110. The distribution of the products is explained based on the

mechanisms depicted in scheme 1-30.

There are two different pathways (A and B) that lead to either product 104 or 110.

If the initial metathesis occurs at the terminal olefin (path A), the formed metal alkylidine

105 undergoes intramolecular RCM followed by CM yielding the desired lactam 104.

On the other hand, if initial metathesis occurrs at the internal olefin, two regioisomers can

be formed giving rise to alkylidines 109a and 109b. Alkylidine 109a can not undergo

RCM, but instead undergoes CM with a terminal alkene yielding 110, whereas alkylidine

109b can give rise to the lactam 104. Nonetheless, compound 110 can be converted to

104 by a separate RCM reaction.












Path B Path A
103

M 0 N N
N N N





)n ) M )n
M
10a 108b 105













C2C R = CH2=CH2,C=HHOc R ,C2'
S e 1 R o M v C M RO M
M

10 104 106
RH2C= CH2=CHR'C=HH2A;R= ,C2A







Catalytic Asymmetric Olefin Metathesis

The latest achievement in olefin metathesis is the possibility of getting chiral

molecules from racemic substrates with the development of chiral metathesis catalysts.

The first chiral catalysts were derived from Schrock molybdenum alkylidene 62 (Figure

1-3 ).65-67















/111a R = i-Pr .' 1
111bR Me CF3 112


i-Pr
i-Pr- M
R
i-Pr
-"0 //, N R
0 Mo\ Me
0 "Ph
I Me

i-Pr 113a R =i-Pr
113b R = Me
i-Pr

Figure 1-3. Some Asymmetric Olefin Metathesis Catalysts

In 1993, Schrock et al. reported the first asymmetric olefin metathesis catalyst 11 a

for the synthesis of chiral polymers by ROMP.65 In addition to that publication, reports

on the use of asymmetric olefin metathesis catalysts concentrated on the asymmetric ring-

closing metathesis (ARCM) reaction. The first report on ARCM was disclosed by

Grubbs and Fujimura on the kinetic resolution of various dienes using asymmetric

ruthenium catalyst 112.66 Poor enantioselectivity was observed by these workers; an

example is presented in scheme 1-31, entry 1. Starting with the pioneer work presented

by Grubbs, Hoveyda and Schrock studied a series of asymmetric molybdenum-based

catalysts, 111 and 113, in the kinetic resolution of dienes (Scheme 1-3 1, entries 2-5).67









Entry



1







2





3






4






5


Grubbs
OTES
Me

Me


Hoveyda and Schrock
OTES
Me

R




Me 1--R



OTES
Me





OTBS
Me


Scheme 1-31. Kinetic resolution of dienes with chiral Mo-based catalyst

Regardless of the good enantiocontrol observed with the chiral catalyst 111 a, they

concluded that it was not possible to generalize which catalyst provide the best

enantiocontrol. For compounds 120 and 121, catalyst 113a provided the highest

enantioselection. Thus, they highlighted the importance of testing a set of chiral catalysts

per substrate to decide which one gives the best enantiocontrol. The impact of ARCM in

organic synthesis was observed in the desymmetrization of achiral molecules. Two

examples are illustrated in scheme 1-32.


(S)-114;Kre = 2.2; catalyst 112







(R)-115; R = H; Krel=23; catalyst 111a
(R)-116; R = CH3; Krei >25; catalyst 111a


(R)-I 17; R = n-pentyl; Kre=1 0; catalyst 11 Ila
(R)-118; R = sec-butyl; Krel=23; catalyst 11 la
(R)-119; R = cyclohexyl; Kre=17; catalyst 111a



(R)-120; Kre < 5; catalyst 111a
Krej = 24; catalyst 113a
Kre, < 5; catalyst 113b




(R)-121; Kre < 5; catalyst 111a
Kre >25; catalyst 113a
Kre, < 5; catalyst 113b









0 111a 2 mol% 0 Me
Me Me no solvent (R)123
o e220C 5 min H Me 99% ee, 93%
Me Me Me
122


Si 113a 2 mol% (R)-125
Me Me no solvent >98% ee, 98%
600C 4h Me
Me
124

Scheme 1-32. Desymmetrization of achiral trienes

Thus, substrates 122 and 124 were transformed to optically enriched compounds

123 and 125 respectively without the need of solvent. The absence of homodimers when

these reactions were performed neat indicates the high degree of catalyst-substrate

specificity in these reactions.68 The ARCM strategy was utilized in the enantioselective

total synthesis of endo-brevicomin by the desymmetrization of achiral triene 126

employing chiral catalyst 11 la (Scheme 1-33).69


0 l1a(loi% 0 H2, Pd/C 0
Me 0 C6H6,22 0 o 7% -Me
126 127 (+) -endo-brevicomicin

Scheme 1-33. Application of Mo-catalyzed ARCM to the synthesis of endo-brevicomin

In addition to the ARCM, several examples on the tandem AROM/CM were

reported. Chiral catalyst 111 a gave excellent enantioselection (92-99% ee) in the tandem

AROM/CM of various substrates. Two examples are illustrated in scheme 1-34.










1DI a(5moo, 92% ee, 68%
& C6H6,220C

128 129


111a (5 mol%)
pentane 92% ee, 85%

131
130 0 132
10 mol%

Scheme 1-34. Mo-catalyzed tandem AROM/RCM

The reaction of 128 with catalyst 111 a generates the heterocycle triene 129 in 92%

ee and 68% yield. 70 To generate compound 132 from bicycle 130, diallyl ether 131 was

necessary.7' Based on earlier mechanisms, Schrock explained that reaction of 131 with

111 a led to the formation of the chiral Mo-methylidene complex (vs Mo-neophylidene),

which reacted with the sterically hindered norbornyl system 130 to initiate the catalytic

cycle.

Tandem AROM/CM has also been explored with a series of norbornyl substrates.

As depicted in scheme 1-35, chiral catalyst I11 a catalyzed the tandem AROM/CM

reaction of norbomene systems with allyl silane or styrene. Although the yields were

moderate, the enantioselectivity was high.72

To address the issue of a more practical and accessible chiral catalyst, in 2001

Hoveyda and Schrock et al. reported a new chiral molybdenum type catalyst 139 (scheme
1-36) .3








OTBS Ph OTBS



133 -134, >98% ee, >98% trans,
C6H6.220C 57%

OMOM
111a 5 mol% (MeO) OMOM
(MeO)3Si/ H' "/H

135 C6H6. 220C 136, >98% ee, >98% trans,

Scheme 1-35. Mo-catalyzed tandem AROM/CM toward enatioselective functionalized
cyclopentanes



MeOTf 138 i-Pr i-Pr
o NHAr N
Me .Me
K@ Me "'Ph --0, 0" M ,,\
OTf Me M
K 0______ Me
07 OTHF -50 -220C lh



137 139
MeMe 5 moI% in situ 139 0

22C, C6H6, 2h
Me
140 141
88% ee, 80%
93% ee, 86% using 1IIa

Scheme 1-36. In situ preparation and utility of chiral catalyst 139

This catalyst exhibited the properties of a biphenolate-based complex such as 111

and binaphtholate system such as 113, which were proven to be efficient earlier, thus

leading to the expection that catalyst 139 would be more suitable for a wide range of

substrates. The advantage of this catalyst relies on its easy preparation from

commercially available reagents. The catalyst can be used in-situ without the need of








purification, and is air stable. They also reported a supported chiral Mo-catalyst for

olefin metathesis that did not exhibit much activity.74

Chiral ruthenium-based olefin metathesis catalysts were also developed. Grubbs et

al. reported the first chiral Ru-based catalyst 144.75 As in the previous reports, the

enantioselection depended on the substrates. The highest ee reported in the study was

90% ee (scheme 1-37). They reported that the enantioselection was increased by the

addition of Nal.

Ph Ph
--- i-Pr,
N N

0---, --CI"Ru=-"H
Me Me 0' Ph 0
PCY3 144 Me -

R R THF, 38oC, lequiv Nal
Me R
142a R = H 143a 39% ee, 22%
142b R = Me 143b 90% ee, 82%

Scheme 1-37. ARCM with Grubbs's Ru-based chiral catalyst

More recently, Hoveyda and coworkers developed a new ruthenium chiral catalyst

145.76 This new catalyst was reported to be air stable and recyclable besides promoting

high enantioselectivity, up to 98% ee, (Scheme 1-38).

There is no doubt that the olefin metathesis will remain as an area of continuing

interest with the development of more olefin metathesis catalysts.



















OAr1

5 mol%145
THF, 220C, lh 147a
95% ee, 66%, >98% trans
SPh 86% recov cat. #

OAr OAr2
146 0.5 mol% 145 ,. Ph
a Arl = p-CF3C6H4 THF, 220C, 1.2h
b Ar2 = p-OMeC6H4 147b
96% ee, 76%, >98% trans
71% recov cat. #

Scheme 1-38: Air stable Ru-based catalyst in tandem AROM/CM

Since latrunculin B was the target chosen to apply our methodology of ring-

opening metathesis of 8-oxabicyclo[3.2. 1] systems to generate pyrans, the next segment

presents a brief history of the Latrunculins.

The Latrunculins

Two toxins, namely Latrunculin A and Latrunculin B, were isolated from the Red

Sea sponge Latrunculia Magnifica (keller) by Kashman et al. in 1980.77 The Latrunculia

Magnifica is sponge that enjoys freedom from predation because it secrets a reddish fluid

that causes fish to flee. Furthermore, squeezing this sponge in an aquarium is lethal to

fish. The fluid causes them agitation, followed by hemorrhage, loss of balance and the

death within 4 to 6 min.78 The interesting biological activities of this sponge lead to the

isolation, purification and characterization of the above mentioned toxins.








The structures of Latrunculin A and B were determined by spectroscopic methods

and X-ray difraction.77'9 The Latrunculins were the first marine macrolide known to

possess 14 and 16 membered-rings and the first natural products found to contain a 2-

thiazolidinone moiety. The biological interest of these molecules arises from the

reversible changes in the cell morphology, disruption of the microfilament organization

and inhibition of the cytoskeletal protein actin polymerization.78a

In 1985, Kashman et al. reported the first synthetic approach towards the synthesis of the

Latrunculin synthon by the preparation of the bicyclic 2-thiazolidinone-tetrahydropyran

90 (Scheme 1-50), as well as isolation of two new toxins from the same sponge,

Latrunculin C and Latrunculin D.79 In 1989, he reported the isolation of another

congener, Latrunculin M, and the preparation of Latrunculin C and M from Latrunculin

B.80 To date, two total syntheses of Latrunculin B as well as Latrunculin A have been

reported. The first total synthesis of Latrunculin B was reported by Smith and coworkers

in 1986.1 The other total synthesis was elaborated by Fiirstner and coworkers in 2003.82

Latrunculin A total syntheses were independently completed by Smith83 and White84 in

1990.

Total Syntheses of Latrunculin B

Smith's total synthesis

Smith's synthesis was achieved in a convergent and stereocontrolled route of 14

steps in 2% overall yield. 81 Smith's retrosynthetic analysis is depicted in Scheme 1-39.

Early in the synthesis, Smith connects the thiazolidinone moiety 152 to ortho ester 151 by

an aldol reaction that generates 150. An interesting structural reorganization occurs upon

exposure of the new ortho ester 150, to tosic acid which leads to the pyran 148.

According to Smith, the skeletal rearrangement involves hydrolysis of the ortho ester 150









to give a hydroxy ester intermediate 153, which in the presence of methanol forms the

mixed methyl ketal 154 (Scheme 1-40). Completion of the synthesis is accomplished by

reduction of ester 154 with DIBAL, a Wittig reaction that connects the advance

intermediate 148 with the northern hemisphere of the molecule 149, and an inverted

Mitsunobu macrolactonization. The northern hemisphere of the molecule, the Wittig

reagent 149, was prepared in 5 steps in 54% overall yield (Scheme 1-41).

0OH
0--

S0.1H Ph3P

O HOOC
H Meo H
HN BnN
S S 149
O 0
Latrunculin B 148

"0 HH "

_____ *0 H 0 0 0
0 OH 0 H BnN s

H
150 BnNfe-s 151 152
0

Scheme 1-39. Smith's retrosynthetic analysis of Latrunculin B


O 0 --OH 0 '"-O


0 O O\OOOH OH
0 OH 0 TsOH MeOH
H 0
HO :H Meo :H
N BnNI
150 B sBNS B
0 o


153 154

Scheme 1-40. Acid catalyzed formation of the pyran moiety in Smith's synthesis of
Latrunculin B








C1. nBuli, C1o2M C 1. 1N ,iOH, T.F
2. Me2CuLi,-78C "MeO2C 2. Nal, Me2CO
155 -8C MOC156
G@
I PPh3, PhH IPh3P
HO2C 53% overall H02C
157 149

Scheme 1-41: Synthesis of the northen hemisphere of the Latrunculin B molecule.7

Ffirstner's total synthesis

FHirstner assembled the molecule using aldol chemistry, esterification, ring-closing

82
alkyne metathesis and Lindlar reduction as the key reactions.



RCAM / Lindlar i Fe-catalyzed
0" 1[ cross-coupling

OH
OH1- Aldol E=* OR 159
O\ -Fe-catalyzed
acylation 158 o.
HN
s RN 160
Latrunculin B 0 S

Scheme 1-42. Firstner's retrosynthetic analysis of Latrunculin B

Reaction of building blocks 158 and 160 produces aldol product 161, which under

acid-catalyzed conditions rearranged to form pyran 162. Compound 162 was then

reacted with 159 to produce 163, which upon alkyne metathesis, Lindlar reduction, and

deprotection gave the target molecule, Latrunculin B (Scheme 1-43). The total synthesis

which comprised 16 steps as the longest sequence was performed in 6% overall yield.











TBSO OH 0
TSO H0aq HCI, THF ,~H
S
161 PMBN-H 162

PMBN

0

HO 0
159
159 Latrunculin B


H 163
OH
PMBN



Scheme 1-43. Fiirstner's synthesis of Latrunculin B

Total Syntheses of Latrunculin A

Smith's total synthesis

Smith's total synthesis of Latrunculin A involves the same common intermediate

150 previously used in his synthesis of Latrunculin B (Scheme 1-44). 83 However, the

nitrogen atom had to be protected as a PMB (para-methoxybenzyl) rather than a benzyl

group due to interference of the sensitive diene moiety not present in Latrunculin B at the

time of its deprotection. Latrunculin A was then completed in an analogous manner to

the synthesis of Latrunculin B by a Wittig reaction that connects the common

intermediate 150 with the northern hemisphere of the molecule following the inverted

Mitsonubu macrolactonization. The northern hemisphere of Latrunculin A and B is the

differing point in these molecules. The preparation of the northern hemisphere of

Latrunculin A (164) took 10 steps and was obtained in 34% overall yield (scheme 1-45).









0 H

0
oOH Ph : H
OHI + 3P2
H MeO :H
HN PMBN 164
S S
0 Latrunculin A
148
0








06 166 3. n1,ClOM
H +
OH. PMBN es
a ~ H0
1 PMBN 151 152









0
Scheme 1-44: Smith's retrosynthetic analysis of Latrunculin A





HO 1. Swern Oxidation 1. addtio -78n C
2. (EtO)2POCH2CO2Et rEtO2C 2. DHP, PPTS
165 166 3. nBuLi, CICO2Me

CO2Me 1. Me2CuLi, -780C HO >
PHDO 2. Amberlyst
3. LiOH H02C
167 168


1. NBS, Me2 S P -3
2. PPh3, MeON
169 HO2C

Scheme 1-45: Synthesis of the northern hemisphere of Latrunculin A molecule

White's total synthesis

White's total synthesis of Latrunculin A was designated to exemplify his

methodology towards (E,Z)-1,3-dienes that involves tandem addition of an enolate








dianion to a dienylphosphonium salt following a Wittig reaction of its derivative with an

aldehyde.84 The target was sectioned in three principal subunits presented in scheme 1-

46.



0
,,' 0

cNIV --PPh3
H
0
170 -S O R
R
O Latrunculin A

0---, H

H N
OS
172


Scheme 1-46. Principal subunits in White's total synthesis of Latrunculin A

Fragment 170 was derived from the union of epoxide 173 and sulfone 174

(scheme 1-47). Aldehyde 176 was employed in his novel methodology to form 183 in

scheme 1-48.

-,---OTBDMS
0 173 nBuLi Ph02S OH
+
THF-HMPA BnO OTBDMS

BnO -'-'SO2Ph 175
OSEM
174 o OTBDMS

176

Scheme 1-47. Construction of segment 170 in White's total synthesis of Latrunculin A










Br LDA (I equiv).
Ph3P THF, -500C
177


0 0 LDA (2 equiv)

L) o",TMS

179


G G
Br Ph3P
dienylphosphonium
salt 178


OLi CLI

Io 0 TMS]
enolate dianion 180


o OLi
Ph3P" "
181 0 TMS


0,,


OSEM

O0"- OTBDMS
176

THF OC


0

\10. 0 TMS


SEMa'

OTBDMS

182


0 TMS

SEMO""
H 183
0


Scheme 1-48. Construction of segment 171 in White's total synthesis of Latrunculin A

Condensation of intermediate 183 with the (R)-4-acetyl-2-oxothiazolidine 172

proceeded without the need to protect the nitrogen atom. This condensation produced an

epimeric mixture of the alcohols 184. Selective deprotection of the SEM ether and

exposure of the resulting diol to acidic methanol produced separable ketals 185 and 186

(Scheme 1-49). Cleavage of the ester of compound 185 followed by a Mitsonubu

reaction, and hydrolysis afforded the natural compound Latrunculin A in 26 steps as the

longer linear sequence in 0.9 % overall yield. In a parallel sequence, ketal 186 was

converted to 15-epilatrunculin A.










0
TMS + LDA, CeC OH

H TMS
SEMO o OEM"'
183 172 184 H



O +

H0 H TMS H0 H OM
O== OMe O:N OMe
S S
185 186

0 Latrunculin A + 15-epilatrunculin A

Scheme 1-49. Completion of White's total synthesis of Latrunculin A

Kashman's Approach to the Latrunculin Synthon79

Kashman's approach to the Latrunculin synthon started with L-cysteine 189, which

by reaction with phosgene afforded a thiazolidinone moiety. After protection of the

thiazolidinone nitrogen atom by benzylation, the ester moiety was converted to an acid

chloride with thionyl chloride affording 188. Stille coupling of the acid chloride with the

siloxy stannane yielded 189, which produced the bicyclic 2-thiazolidinone-

tetrahydropyran 190 after removal of the TBS protecting group and partial hydrogenation

over Lindlar's catalyst (Scheme 1-50).








CO2Et 1. COCI2 COCl
H2N 2.BnBr, Nai HN TBSO(H2C)2CCSnBu3
SH 3.H+, SOC12 Pd(PPh3)4
187 188

TBSO'] 0
I 1 1. H+ HO
PhH2C 2. H2 PhH2CN
N O
OzzO
S0
189 190

Scheme 1-50. Kashman's synthetic approach towards the Latrunculin synthon

Kashman's Synthesis of Latrunculin M and C79'80

From the same sponge from which Latrunculin A and B were isolated, three

additional marine toxins were obtained by Kashman. These toxins are Latrunculin C, D

and M, which are presented in Figure 1-4.


0 0 0
0 0 .. OCH3
OCH3 0 OH OH 0
0 0 OH
HN HN HN
/S S -S
O 0 0/

Latrunculin C5,6 Latrunculin D5 Latrunculin M6

Figure 1-4. Latrunculin C, D and M

Kashman et al. converted Latrunculin B to Latrunculin C and its 15-epilatrunculin

C by reduction with sodium borohydride.79 He also prepared Latrunculin M, a minor

component of the L. Magnifica sponge, from Latrunculin B in a four step sequence

(Scheme 1-51).













1. Et20-BF3 MeOH
2. Et3SiH, Et20-BF3
3. HOAc


Latrunculin B


Scheme 1-51 Kashman's synthesis of Latrunculin M from Latrunculin B


CH2N2


HN

S
0;


H


S
0


Latrunculin M













CHAPTER 2
RESULTS/DISCUSSION

Intermolecular Ring-Opening Cross Metathesis (ROCM)

Our research focused on the synthesis of the tetrahydropyran moiety using

ruthenium-based olefin metathesis on oxabicyclo[3.2. I ]octene derivatives. Initial

investigations centered on the study of the parent compound 8-oxabicyclo[3.2.1 ]oct-6-en-

3-one3 (1). The intermolecular ring-opening metathesis of 1 was explored with a series

of electronically different terminal alkenes (Scheme 2-1). 85-87

L
CI
C PCY3 Ph
: oR (5eq.) R
CHCl3 (0.3M) 192a-g

67 L = Mes-N -N-Mes
66 L = PCy3

Scheme 2-1. ROCM of 8-oxabyciclo[3.2. 1 ]oct-6-en-3-one 1 with terminal alkenes

Table 2-1. ROCM of 8-oxabyciclo[3.2. I]oct-6-en-3-one 1 with terminal alkenes85,86
Pyran Alkene -R Catalyst Yields (%)
192a Styrene -Ph 67 83
192b 2-bromostyrene -o-BrPh 67 65
192c 1 -hexene -(CH2)3CH3 66 89
192d allyl bromide -CH2Br 67 71
192e 4-bromo- I -butene -CHCH2Br 67 72
192f methylacrilate -CO2Me 67 33
192g acrylonitrile -CN 67 10

The reaction was highly selective for the formation of the E-alkene and

demonstrated the correlation between the alkene used and the reaction yields. The yields

were better when electron rich alkenes were used rather than electron poor alkenes.








Literature reports support the limited reactivity of electron poor alkenes in cross

metathesis.46'88 Thus, electron rich alkenes afforded the highest yields.

Another observation was the increment of reactivity of the system when the

hybridization of the carbonyl group was changed from sp2 to sp3.85"86 This was revealed in

attempts to improve the yield of the reaction. Though the yields were good (up to 83%

with styrene as the donor alkene), the reactions were not reaching completion. Studies

demonstrated that the reaction reached equilibrium after a certain amount of starting

material was consumed. To drive the reaction to completion, the addition of a set of 1,3-

diaxial interactions in the reaction intermediate (194) was proposed. This was done by

placing a bulky group at C3 in the endo position (Scheme 2-2). 85.86 The idea consisted

of creating unfavorable steric interactions between the bulky group and the two

appendices of the opened intermediate, thereby driving the reaction to product, and

avoiding reversibility.

HO x LnRu Y LnRU
H Y H
H H H Y
1 X =Y =O 194a =X =Y= 0 195a-c
192 = X = OTBS, Y = H 194b = X = OTBS, Y = H
193 = X = H, Y = OTBS 194c = X = H, Y = OTBS

Scheme 2-2. Reversibility of the ROCM reaction

As predicted, the consumption of the starting material was complete; however, the

yields decreased dramatically (Table 2-2).85,86 A competitive reaction was occurring,

namely the ring-opening metathesis polymerization.








L
CIYRu X .Y
J C!1
Cl. PCY3 Ph

R ( R
CHCl3 (0.3M)
192 = X = OTBS, Y = H H 196a-f= X OTBS, Y = H
193 = X = H, Y = OTBS 67 L = Mes-NN-Mes 197a-bV X H, Y = OTBS
66 L = PCy3

Scheme 2-3. ROCM of the reduced derivatives8586

Table 2-2. ROCM of the reduced derivatives85,86
Pyran Alkene -R Catalyst Yields (%)
196a Styrene -Ph 67 60
196b 2-bromostyrene -o-BrPh 67 18
196c 1-hexene -(CH2)3CH3 66 63
196d allyl bromide -CH2Br 67 62
196e 4-bromo- 1-butene -CHCH2Br 67 56
196f methylacrilate -CO2Me 67 0
197a Styrene -Ph 67 67
197b 1 -hexene -(CH2)3CH3 66 75

Exo-silyl ether 193 showed that despite the absence of the large group in the axial

position, the reactivity was enhanced. Thus, the exo-silyl ether gave results comparable to

the endo-silyl ether using styrene and 1 -hexene as the donor alkene in the metathesis

reaction (Table 2-2, last two entries).

Based on these observations it was understood that a change in hybridization at C3,

and not the position of the bulky silyl ether, was responsible for the change in reactivity.

In an attempt to provide a rationale for whether the hybridization, steric hindrance or

electronic effects were affecting the reactivity of the system, further studies were

undertaken.

Kinetic Studies

Kinetic experiments were conducted with a series of 8-oxabicyclo[3.2. 1 ]octene

derivatives differing by the functional group placed at C3. The substituent placed at C3

varied according to three categories: oxygen in the endo position (ether 192, alcohols 201








and 202, and ketal 203), hydrogen in the endo position (ether 193, methylene 204 and

alcohol 205), and sp2 hybridization (ketone 1, oxime 199 and exo-methylene 200). The

plan was to generate a relative trend of the reaction rate among the bicycle derivatives to

have a general idea of the effects of the remote substituents in the reactivity of the

system.

sp2 hybridized:
0N-0OCH3
O0 0
1 199 200

sp3 hybridized with electron rich oxygen in the endo position:

OTBS OH OH 0
H oCH3 OH 0
192 201 202 203

sp3 hybridized with hydrogen in the endo position:

H H OH3

Oj OTBSQ O H O OH
193 204 205

Figure 2-1. Substrates considered for the kinetics studies.

The substrates were derived from ketone 1 (Scheme 2-4). Substrates 1,3 192,89

202,89 203,90 and 19389 were known compounds and were prepared according to reported

procedures in the literature. Oxime 199 was made in 81% yield by condensation of 1

with methoxylamine hydrochloride in the presence of molecular sieves. The exo-

methylene 200 was prepared following a Peterson olefination protocol9' of 1, since

Wittig conditions produced low yields. Wolf-Kishner92 reaction of 1 afforded compound

204 in 68% yield. Grignard addition to ketone 1 in the presence of cerium chloride









yielded alcohol 201 in 74% yield; if cerium chloride was not present, aldol product was

isolated. Epoxidation of 200 with m-CPBA produced epoxides 207-210, and the opening

of epoxide 208 with lithium aluminum hydride gave alcohol 205.


0




0




0


0
20
0







0

200



208


Py, MeONH2.HCI
CH2CI2, MS 3A"-
81%


TMSMgCl, THF
CeC13o7H20, 76%



MeMgCI, THF
CeCI3.7H20, 74%


H2NNH2.H20,
KOH 1950C
HO/0-OH
68%

MCPBA, 0OC
CH2CI2


199


206 ete,8% 200

OH
2010

H


H
04
204


0


207
8%
CH3
LAH, THF, 80% OOH
205


--LO 0 0

) 0 09:
208 209 210
13% 32% 14%


(Scheme 2-4). Synthesis of the some substrates employed in the kinetic studies

The substrates were compared with 4,1 0-dioxa-tricyclo[5.2. 1.0 2'6]dec-8-ene-3,5-

dione (198), namely the standard, in a ring-opening metathesis polymerization reaction

(Scheme 2-5). The relative rate of the ring opening polymerization of the substrate

versus the standard was determined using a Varian inova 500 MHz NMR. This particular

standard was chosen because: (i) its alkene proton does not overlap with the alkene








proton of the substrates studied; (ii) the resulting polymer precipitates out of solution

most of the time and when it does not, the signals of the resulting polymer do not

interfere with the signals monitored; (iii) its reactivity in the ROMP reaction is

comparable with the substrate's reactivity; (iv) it is easily obtained by a Diels-Alder

reaction of furan and maleic anhydride. Thus, the standard (198) and each substrate were

mixed at different relative concentration with an internal standard to normalize their

integral area. These concentrations varied from 0.25 to 16 [standard/substrate] ratios.

The variation in concentration was done to observe how the rate was affected by

concentration. To the mixture, Grubbs' second generation catalyst (67) was added, and

the consumption of the compounds versus time was monitored by proton NMR. Thus,

spectra were acquired on automation (ca. 100 points for the course of the reaction), which

varied from 10 minutes to 1.5 h, and the integrals of the alkene protons of the substrate

and of the standard were normalized against the integral of a comparable amount of

internal standard, benzene or residual TMS from the deuterated solvent. The normalized

proton integral area was the concentration measurement during the course of the

reactions. The plot of concentration versus time does not follow first order kinetics,

displaying an induction period at the beginning of the reaction (Figure 2-2). Therefore

individual rates for the reactions of the substrate and the standard could not be obtained.

Thus, the data was obtained by plotting the natural logarithm of the substrate

concentration against the natural logarithm of the standard (ln [substrate] vs. In

[standard]), which showed linearity. Figure 2-3 is a representative example of the

linearity obtained and the generation of the data by the lineal regression equation.










Concentration vs Time
0.2

0.16

7 0.12
U
= 0.08
0

0.04 [A]

0
0 150 300 450 600 750 900
Time (sec)



Figure 2-2. The evolution of the normalized concentrations of the substrate [A] and the
standard [B]



Relative ksub/kStd Rate
-2.5

-3


y = 6.3871 x + 8.4834
-4.
-4.5-4 lR2 = 0.999

-4.5

-5
-2.06 -2.01 -1.96 -1.91 -1.86 -1.81 -1.76 -1.71
In [Std]


Figure 2-3. Representative example of the generation of the data with the linear
regression equation of the In[sub] vs ln[std]

This is consistent with the alkenes being consumed in a first order reaction, where

the concentration of the catalyst is included in the rate constant as established by the

following equations: d[sub]/dt = ksub[cat][sub], d[std]/dt = kstd [cat][ std], which leads to

In[sub] = pln[std] + const., where p = ksub / kstd and const. = ln[sub]init pln[std]init. In the









induction period, the active catalyst is formed, but by using the slope of In[sub] vs.

ln[std], the relative rates can be measured without considering the catalyst concentration.

Relative rates measured at different ratios [std]/[sub] are given in Table 2-3.

YY
-Y 0
C1.- R--1 h 67/
Yx oCIRU\6
S+ n n
Acetone 0/
Benzeneo/
1,192,193, 198 O
199-200


Scheme 2-5. Possible polymers from the ROMP of substrates and standard

Table 2-3. Relatives' rates k,,b/kstd of ring-opening metathesis polymerization of 8-
oxabicyclic[3.2.1 ] octene derivatives
Substrate X Ratio [Std/Sub]; nm=not meassured
0.25 1 4 8 16
1 X=Y=O nm 0.21 0.29 0.34 0.42
192 OTBS H 5.2 6.34 6.34 nm nm
193 H OTBS 1.46 1.38 1.55 nm nm
199 X = Y = N-OCH3 nm 0.34 0.49 0.56 0.55
200 X=Y=CH2 1.56 1.05 1.15 1.29 nm
201 OH CH3 4.12 4.25 4.55 nm nm
202 OH H 6.03 6.17 5.39 nm nm
203 X = Y = OCH2C(CH3)2CH20 3.18 3.83 4.21 4.66 4.62
204 X=Y=H 2.38 2.22 1.91 nm nm
205 CH3 OH 3.92 4.28 3.38 nm nm

The concern for the influence of the reagents ratio on the relative rates comes from

the fact that there are four reactions by which the polymers grows:

(1) sub + std-poly sub-std-poly (KI) where: sub =substrate

(2) std + std-poly std-std-poly K2) std = standard
poly = the growing polymer
(3) sub+sub-poly sub-sub-poly (K3) Y X oO o
(4) std + sub-poly std-sub-poly (K4) sub-poly Rutd-poly Ru


Scheme 2-6. Possible pathways for the reagents consumption in the ring-opening
metathesis polymerization








The substrate as a monomer can react with the living-growing polymer of the

standard, path (1), or with its living-growing polymer, path (3). In the same way, the

standard could react with its living-growing polymer, path (2), or via path (4), reacting

with the living-growing polymer of the substrate.

The measured relative rate is p = kub / kstd = (kl + k3) / (k2 + k4). By eliminating

the last two reactions, the rates in the reaction with the same polymer could be compared,

meaning Pideal = p = k 1 / k2. This could be achieved by making k3 and k4 closer to 0 at

high [std] / [sub] ratio. High [std] / [sub] ratio would make the substrate and the standard

compete for the same living-growing polymer, thus k3 and k4 will approach to 0.

However, ratios [std] / [sub] higher than 16 are impractical, because of the errors arising

from a small ratio substrate / internal standard. The same errors can be observed towards

the end of the reaction monitored period. Measurements become less precise as the

concentrations of substrate or standard become too small compared to the internal

standard, benzene or residual TMS, and a contiguous number of points at the end of the

reaction were discarded in order to improve the precision. Comparisons can be seen in

Figure 2-4.


-0.
1 6 74x 2 413
2 R =0. 9 97
-2 -2

-4 -2

-1 4 -12 -1 -0.8 -0+6 -04 12 1 -0.8 -0.6 -0.4
In[std] In~std]


Figure 2-4. Comparison of selected data points: (a) left total of 76 points (b) right total of
50 points








Since the data obtained (Table 2-3) showed no correlation with the concentration,

additional p values were taken for compounds 192,199, 202-204 at a ratio of [std]/[sub]

= 1. Table 2-4 presents all the values measured, the average of these values and the 95%

confidence interval.

Table 2-4. Relative rates ksuIb/kstd and confidence interval (95%) from the ROMP of 8-
oxabicyclic[3.2. 1] octene derivatives
Substrate X Mean Interval for
Y P 95%
P confidence
1 X = Y = 0 0.21 0.29 0.34 0.42 0.32 0.18 0.45
192 OTBS H 5.20 6.34 6.34 6.81 7.11 6.6 7.09 7.09 6.5 5.96 7.03
193 H OTBS 1.46 1.38 1.55 1.43 1.28 1.59
199 X = Y = N-OCH3 0.34 0.49 0.56 0.55 0.78 0.40 0.75 0.76 0.58 0.44 0.72
200 X = Y =CH2 1.56 1.05 1.15 1.29 1.26 0.90 1.61
201 OH CH3 4.12 4.25 4.55 4.31 3.76 4.86
202 OH H 6.03 6.17 5.39 6.03 5.49 5.24 5.60 5.53 5.56 5.25 5.87
X =Y
203 OCH2C(CH3=CH20 3.18 3.83 4.21 4.66 4.62 3.83 3.77 3.69 3.97 3.54 4.39
204 X=Y=H 2.38 2.22 1.91 2.29 1.91 1.98 1.95 2.04 2.07 1.94 2.21
205 CH3 F OH 3.92 4.28 3.38 1 3.85 2.79 4.92

All p values given in Table 2-3 and Table 2-4 correspond to an R2 greater than

0.98. For certain ratios, [std] / [sub], a R2 values greater than 0.98 could not be achieved.

This is because of an overlap between signals from polymer and signals from the

substrate or because the difference between the signals compared was too large. Those

cases were marked as nm (not measured) in table 2-3. Figure 2-5 presents a plot of the

average relative rates ksub / kstd and the 95% confidence interval for the substrates studied

in a decreasing order of reactivity.








8.0
7.0 -
6.0
x 5.0
4.0
"3.0
2.0
1.0
0.0
192 202 201 203 205 204 193 200 199 1
Substrates

Figure 2-5. Plot of the average relative rates ksub / kstd and the 95% confidence interval
for the substrates studied in order of reactivity
Based on the results, the order of reactivity is depicted in Figure 2-6.

Surprisingly, the results obtained do not show a large difference in the relative rate values

among the substrates. The major difference was observed between ketone I and ether

192. Nonetheless, whereas the exo silyl ether 193 demonstrated the same reactivity in the

intermolecular reaction with styrene (Table 2-2), the results showed that it is less reactive

than the corresponding endo silyl ether 192. This is in agreement with the hypothesis that

a bulky group in the endo position would make the oxabicyclic system more reactive

toward ring-opening metathesis.








OTBS OH OH 0

H M H CH3 a
192 202 201 203
6.50 +/- 0.5 5.56 +/- 0.3 4.31 +/- 0.5 3.97 +/- 0.4
CH3 H H

OH> H> OTBS
205 204 193
3.85 +/- 1.0 2.07 +/- 0.1 1.43 +/- 0.2

/N-OCH3\
0O 00
200 199 1
1.26 +/- 0.4 0.58+/- 0.1 0.32 +/- 0.1

Figure 2-6. Substrates arranged based on their order of reactivity from average relative
rates ksub / kstd and the 95% confidence interval

Though it was considered that oxygen in the endo position of the bicyclic substrates

would make the system more reactive from electrondensity donation to the double bond,

other factor such as steric hindrance play an important role in the reactivity of the

oxabicyclic compounds studied. This was exemplified by comparison of alcohols 201

and 205. Because 201 has an oxygen in the endo position, it was expected to be more

reactive than bicycle 205. Nonetheless, the alcohols displayed similar reactivity pattern,

indicating that sterics play a more important role than electronic, when the system is sp3

hybridized. Thus, a bulky group in the endo position would make the system more

reactive. On the other hand, the sp2 hybridized substrates showed a correlation between

electronegativity and reactivity. As a result, ketone 1 exhibited the lowest reactivity

when compared with the other sp2 hybridized derivatives 199 and 200. Although the

values obtained did not show a drastic difference among them, the knowledge obtained

can help improve sluggish reactions by tuning the reactivity of the system as well as








manipulating the system to avoid polymerization and provide the ROCM product.

Hence, the ROCM proceeds better (higher yield) with ketone 1 than with ether 192, but if

the interest is rather to obtain a polymer, ether 192 will be the preferred substrate for the

reaction.

As an expansion of the methodology to the construction of more substituted pyrans,

bridgehead substituted systems were studied. Though the olefin metathesis reaction has

been studied for a long time, little is known about the regioselectivity of this reaction.

Herein, our findings are reported on the intermolecular ROCM reactions of bridgehead

substituted oxabicyclic systems.

Bridgehead Substituted 8-Oxabicyclo[3.2.1]Octene Derivatives

Having reported the success of the ring-opening cross metathesis of 8-

oxabicyclo[3.2. 1 ]octene derivatives to generate the pyran moiety,8586 it was decided to

explore bridgehead substituted systems. As shown in scheme 2-7, two regioisomers are

expected from this reaction. This outcome makes the reaction unpractical from a

synthetic perspective. However, considering the impact of the olefin metathesis reaction

in organic synthesis, this issue needed additional investigations.

r---\
MCS-N N-e
o ,,, Y 67 o
206a: R=CH3 0cy C1Ri"
206b: R=CH2OCH3 O R NR + R
206c: R=CH2OCH2CH2CH 1.5=m0/o, CH212 0
-'ph 3 equiv.


Scheme 2-7: Attempted ring opening cross metathesis of substituted systems








In addition, interesting targets possess a substituent adjacent to the oxygen of the

pyran moiety. For example, Forskolin possesses two neighboring methyl groups, and

Latrunculin contains an adjacent alcohol (Figure 1- 1).

The reaction was first explored with 1 -methyl-8- oxabicyclo[3.2. 1 ]oct-6-en-3-one,

206a. After subjecting 206a to the reaction conditions that have proven favorable in the

unsubstituted cases, no reaction was observed. Various reaction conditions were tried

such as high catalyst loading (up to 10 mol %), elevated temperatures, and higher

concentrations; however, only trace amounts of product were obtained. The system did

not polymerize even at 11 0C in 1 M toluene. Ketones 206b and 206c also failed to react.

Considering the enhanced reactivity previously obtained by reduction/silylation of

ketone 1 towards ring opening, ketone 206a was reduced and converted to the

corresponding ether 207a. This dramatically increased the reactivity of the system under

the reaction conditions, producing the expected regioisomers in 83% yield using 1.5

mol% of 67 and 4 equivalents of styrene. The regioisomers were obtained in a ratio of

6:1, where the major isomer placed the cross metathesized olefin on the more hindered

side (Table 2-5). Initial attempt of this reaction using 5 mol % of 67 showed a decrease

in regioselectivity to 3:1. Additional trials with unprotected alcohol 207c gave surprising

results. Though the yield of the reaction was similar to the yield obtained with the endo

ether 207a, the regioselectivity increased significantly from 6:1 (208a: 209a) to 20:1

(208c: 209c).

Additional substituted substrates, 207b and 207d, were prepared and studied in

order to increase the regioselectivity by coordination of the oxygen with the catalyst;

however, the regioselectivity did not improve, and the yields decreased.








/--\
MesN NMes
Y. X ClI/,Ru=\ 7x
C, C Ph R + R
R PCY3 +
R CH2C12,0.03M 0 0
207a- Ph4 equiv.
207a-e Ph 208a-e 209a-e

Scheme 2-8: Intermolecular cross-metathesis of reduced derivatives

Table 2-5: Intermolecular cross-metathesis of reduced derivatives

Alkene R X Y Yield [%] Ratio (208:209)

207a Me OTBS H 83 6:1

207b CH2OMe OTBS H 65 1.6:1

207c Me OH H 85 20:1

207d CH2OMe OH H 66 20:1

207e Me H OH 15 6:1

Efforts made to optimize the reaction yield with 207d by increasing the

temperature, lowered the regioselectivity to 3:1. To study the effect of the remote

substituent stereochemistry, the exo alcohol 207e was prepared by reduction of the

corresponding ketone 206a with samarium diiodide. The exo alcohol gave poor yield.

Moreover, the regioselectivity decreased compared with the endo alcohol 207c to equal

the selectivity obtained with the ethers (6:1), again favoring the more hindered

regioisomer. This regioselectivity preference for the more hindered alkene is in

accordance with results obtained by Snapper58 on ROCM reactions. Thus, the

regioselectivity could be attributed to a high preference for the alkylidene formed with

styrene over the methylidene as the active catalyst as Snapper findings (Scheme 1-26).

Hence, the mechanism of the reaction could be as depicted in Scheme 2-9, where the

styryl unit is placed first, forming the alkylidene 211, which upon reaction with the








terminal alkene (styrene) produced the more substituted product. These reactions

represent one of the few successes with regioselective ROCM of unsymmetrical bicyclic

systems.58-61




R
210

LnRu
LnRu== 0
Ph y
Ph /R
211



x "Y
R Ph

0 ~Ph
212

Scheme 2-9. Proposed mechanism for the high regioselective ROCM of 8-
oxabicyclo[3.2. 1 ]octene derivatives with styrene

In addition, two other systems were investigated: see scheme 2-10. A 1:1 mixture

of trans and cis isomers of I -methyl-8-oxa-bicyclo[3.2. 1 ]oct-6-en-3-one-O-methyl-oxime

(213a, 213b) was obtained by condensation of 206a in refluxing dichloromethane with

methoxylamine hydrochloride salt. This example was made to have an additional case of

bridgehead substituted 8-oxabicyclo[3.2. I ]octene derivative with sp2 hybridization to

study the system. The system has similar electronic properties to the ketone but differs in

reactivity. When the mixture of isomers was subjected to the reaction conditions, no

reaction was observed. Increased temperatures did not help promote the reaction.









Mes-N N-Mes
MeO'N N OMe I
S I CI"IRu-P
CI lC Ph No Reaction
__"Ph CH2C12
213a 213b


Mes-N N-Mes
0CI y Ph 67% 215:216
phCH2C2 "- O Ph O Ph

214 215 216

Scheme 2-10: Additional examples of ROCM of C I substituted oxabicyclo derivatives

Ketal 214, prepared from transketalization with tetramethyl dioxane and p-toluene

sulfonic acid,90 mimics the ketone functionality, possessing the same electronic properties

of the parent ketone, but remaining sp3 hybridized at C3. The ROCM of 214 produces a

mixture of regioisomers in a 3:1 ratio and 67% yield. However, further investigation of

this case demonstrated that the regioselectivity of the reaction is dependant on the

reaction time; thus, at the early stage of the reaction, higher regioselectivity is observed

(Table 2-7). This is attributed to the reversibility of the reaction. In fact, when the

reaction was allowed to react for 1.5 hour one isomer was isolated in high yield, 90%

(Scheme 2-11). Though, ketal 214 was the only case monitored carefully by GCMS, it is

predictable that the substrates presented in Table 2-5, 207a-e, could exhibit the same

behavior and thus, high regioselectivity could be achieved if the reaction is allowed to

react for a specific amount of time, though the starting material never will be consumed

completely.









Mes-N YN-Mes l

Cy3 Ph 90%

NphCH2CI2 0ph
4 equiv. 0.3M
214 215
1.5 hr

Scheme 2-11. The regioselectivity ratio is dependent on time

Table 2-7. The regioselectivity ratio is dependent on time
Time (hrs) Regioselectivity Ratio (215:216)
1 >99:1
2 >99:1
3.5 16:1
24 3:1

Envisioning the synthesis of targets like Forskolin, a disubstituted bridgehead

substrate 217 was also explored (Scheme 2-12). The substrate was prepared in the same

fashion as the unsubstituted cases, using Fbhlish's method.3 No reaction was observed

upon exposure of the substrate to the reaction conditions.

Mes-N N-Mes
0 CI/u_ 67
CI P Uy3 Ph
0C Cah No Reaction
CH2C12 '"Ph
217

Scheme 2-12. Attempted ring opening cross metathesis of 1,5-dimethyl-8-
oxabicyclo[3.2. 1] oct-6-en-3-one.

Various sets of conditions were explored to make the reaction work. These

conditions varied from increasing the amount of catalyst to using high temperatures.

Despite our efforts, no reaction was observed. The reaction was also tried using the

molybdenum-based catalyst (Schrock catalyst), which has been reported to be more

reactive than Grubbs' catalyst;92 however the substrate still resisted reaction.

Considering the increment in the reactivity previously obtained converting the carbonyl








to the ether, the endo ether 218 was prepared from 217 and exposed to the same reaction

conditions (Scheme 2-13). However, our expectation was not met as no reaction was

observed. The disubstituted ether 218 did not undergo reaction or polymerization, even

at elevated temperatures and high concentrations.

Mes-N N-Mes
H OTBS 6
0 C 3I Ph
0H2l2 -h No Reaction
CH2C12 ,p

218

Scheme 2-13. Attempted ring-opening cross metathesis of the disubstituted ether 218

As an expansion of the methodology to the construction of highly substituted

pyrans an intramolecular process was attempted by tethering an alkene as a substituent in

the bicycle.

Intramolecular Ring-Opening Cross Metathesis (ROCM)

In principle, there are three types of fused pyrans that can be synthesized from 8-

oxabicyclo[3.2. 1 ]octene derivatives by varying the place of a tethered alkene in the

bicycle ( Scheme 2-14).93 A spiro-fused pyran is produced when it is placed at the

bridgehead position, C l, of the oxabicyclic system. If the tethered alkene is located at

C2, a linear-fused pyran is produced, while if the substituent is positioned at C3, a bridge-

fused pyran is generated. Previous work in our group has demonstrated the viability of

this domino metathesis toward fused pyrans.86,93 In that area, spiro-fused pyrans were

obtained in good yields and with high selectivity for the spiro-fused compound over

oligomers or dimers. 86,93









2 Cl tether
a) LnRu=CHPh


0 0
C2 tether
b) LnRu=CHPh 0

0 0
0 0
C3 tether
c)
LnRu=CHPh Nz o


Scheme 2-14. Fused-pyrans from intramolecular ROCM reaction

The fact that the intermolecular reaction of 206c with styrene did not generate

product raised interesting mechanistic questions involving the intramolecular cross

metathesis reaction in which the alkene is tethered at the C I bridgehead position (type a,

Scheme 2-14).93 The unreactive 206c is the saturated analog of 219, an example of an

oxabicyclic system with a tethered alkene at the bridgehead position that yielded a spiro-

fused pyran 220 (Scheme 2-15).93

One plausible mechanism involves an initial reaction with the terminal alkene

followed by cyclization (path A, scheme 2-16). An alternative path would involve a

regioselective opening of the bridged olefin followed by cyclization (path B, scheme 2-

16). The high regioselectivity and yields obtained for the spiro-fused pyrans support the

former pathway.93









0 Mes,-- Mes 0
,RU, Ph
C' PCY3 0 0 80%

2 mol %, 0.01M
219 CH2CI2, RT 220

Scheme 2-15. Formation of a spiro-fused pyran from an oxabicyclic system with a
tethered alkene at the bridgehead position

0

o o o

Path B\Path A

o 0 0



RuLn LnRu




o 0
0

x ~~ X n 0
RuLn A '~ LnRu X



o 0 0
r~~k ~Dimer ?? KH


Scheme 2-16. Possible mechanism for an intramolecular ROCM reaction

This section presents our efforts toward the linear-fused pyrans by placement of a

tethered alkene at the C2 position of the bicyclic system (type b, scheme 2-14). Two

examples of C2 alkylated system were studied; they were prepared by Mann's alkylation

protocol94 (Scheme 2-17). The reaction produced the C2-carbon tethered substituted








intermediates in poor yield and as an epimeric mixture of the alkyl group at the C2

position. The ratios of epimers for 222 ranged from 100:1 to 70: 30, and the ratios of

epimers for 223 ranged from 65: 35 to 50: 50 favoring the axial isomer in all cases.

Nonetheless yields were reproducible and not higher than 38% and 20% for 222 and 223

respectively. Unfortunately, the epimeric mixture could not be separated after many

trials. Consequently the intramolecular ROCM of compounds 222 and 223 to yield

linear-fused pyrans was attempted with the mixture. However, no reaction occurred and

the starting material was recovered unchanged for both cases.
0

O OTMS HrMPA 38%

1. DBU, CH2CI9 1. MeLi, -78C 222
2. TMSCI 96% 0
221 HMPA 2
20%
223
Scheme 2-17. Synthesis of the C2-carbon tethered substituted intermediates

To improve the reactivity of the system, as achieved earlier, and in an effort to

separate the epimeric mixtures, ketones 222 and 223 were reduced with L-Selectride, to

obtain their respective diasteromeric endo alcohols. The reduction proved to be more

complicated because the placement of the alkyl group in the axial position afforded exo

alcohol and endo alcohol from the reduction, thus making the mixture more difficult to

separate (Scheme 2-18).











O L-Selectride 0 HO 0 225a:225b
O THF, -780C 55: 45
91% OH
224 225a 225b




0
O0 226a
226a: 226b / L-Selectride
48:52 THF,-78JC 0 0
88% HO
226b OH4OH
0 13% 40% 47%
O 227a 227b 227c

ratios determined by NMR
Scheme 2-18. Reduction of the C2-alkylated oxabicyclo[3.2.1 ]octene derivatives

When ketone 224, obtained as a single isomer from the alkylation, was reduced

with L-selectride alcohols 225a and 225b were produced. When a mixture of 48: 52 of

the C2 epimeric ketones 226 were submitted to the reaction conditions (L-Selectride,

THF, -78C) afforded a mixture of alcohols 227a-c was obtained. The exo alcohols 225b

and 227b derived from ketones 224 and 226b respectively were obtained from an endo

attack of the hydride rather than the usual exo attack that provides the endo alcohols.

This is due to steric hindrance provided by the tethered alkene in the axial position. The

separation of alcohols 225a and 225b was possible. However, from the mixture

generated from ketone 226a-b, compound 227a was isolated, while alcohols 227b-c

remained as a mixture. Nevertheless with the alcohols in hand, the intramolecular

ROCM was attempted (Scheme 2-19).









OH
LnRu= 67
0 2 mol%/ Ph
CH2CI2
OH 0.01M
225a 13% 228
OH

LnRu=\ 67

HO CH2CI2 0

225b 8% 229



OH
LnRu= 67
O 2 rnol%P
CH2CI2
O.01M
OH227a 26% 230





OTBS
LnRu:=\ 67 ,,
0 2 moI% Ph
CH2CI2
O.01M
12%
231 232

Scheme 2-19. Intramolecular ROCM of the reduced C2-tethered systems

The yields for the linear-fused pyran products were low. During the first minutes

of reaction, the mixture becomes cloudy and all the starting material is consumed. After

evaporation of the solvent, a white precipitate is left, presumably some polymer. In an

attempt to improve the yield, the bulky silyl ether 231 was prepared from alcohol 227a.

Nonetheless, the system became more reactive toward polymerization and the yield

dropped compared to the results obtained with the respective alcohol 227a. Though the

intramolecular ROCM of the reduced C2-tethered systems was not successful, the








hypothesis of being able to form linear-fused pyrans from that type of system was

confirmed.

To prove the efficiency of the ROCM strategy of 8-oxabicyclo[3.2.1 ]octene

derivatives in natural products synthesis, an approach to Latrunculin B was attempted.

Approaches Towards Latrunculin B from Ring-Opening Metathesis of 8-
Oxabicyclo[3.2.1]Octene Derivatives

The marine macrolide Latrunculin B possesses interesting biological activity78

and a pyran-skeleton that is amenable using a ROCM approach. It was foreseen that

ROCM of an oxabicycle derivative would provide the differentiated cis-2,6-substituted

pyran. The rest of the target was envisaged to be completed by chiral alkylation, Wittig

olefination, where the formation of the cis olefin would be critical for the success of the

synthesis, a macrolactonization, oxidative decarboxylation or allylic oxidation, depending

on the substituent adjacent to the oxygen, and at the last stage of the synthesis,

construction of the thiazolidinone moiety. This approach differs from previous syntheses

in the initial formation of the pyran moiety from ROCM, and the last stage placement of

the thiazolidinone moiety, allowing for the preparation of analogs at that center. A

proposed fragmentation for a retrosynthetic analysis is presented in scheme 2-20.

Lactonization


6
Wittig Reaction 0 '- 0-
t1 f3 Oxidative
Alkylation ___ s-OH Decarboxylation
Al9ylatio 15?".
Olefin Metathesis :

Construction
of the thiazolidinone 0
from an aldehyde
Scheme 2-20. Possible fragmentation for a retrosynthetic analysis of Latrunculin B








Although various methods were formulated to choose which oxabicycle system

would lead to the desired pyran, two routes were tried to approach the target and thus will

be presented in this section. All the approaches were done with racemic mixture to study

the strategy.

Initial attempts to the target were based on the ROCM of methoxy bridgehead

substituted oxabicyclo 237 (Scheme 2-21). This route permits easy access to the pyran

moiety with the contiguous oxygen, protected as a methoxy acetal. This strategy presents

interesting possibilities for other natural products possessing this acetal type pyran such

as phorboxazole, callipeltosides and the bryostatins. However, this sequence presented

some drawbacks, such as the low yields obtained for the starting material, methoxyketone

235, and the poor efficiency of the intermolecular ROCM reaction. The low yield

obtained for methoxyketone 235 (30% over two steps, cycloaddition and reduction)

represents a problem due to the price of the 2-methoxyfuran, even though the reaction

could be performed on large scales. Nonetheless, with the bridgehead substituted

oxabicyclo 235 in hand, the ROCM with styrene was attempted. Surprisingly, the ketone

yielded 20% of the trisubstituted pyran 236 as a single regioisomer. This gave us some

basis to assume that the ROCM of the reduced derivative would provide a higher yield

and high regioselectivity. However the ROCM of the reduced derivative 237 was not as

successful as expected. The reaction was monitored by NMR to determine the time of

completion with the highest regioselectivity. The regioselectivity was high, one isomer

was observed by NMR, but the reaction proved to be highly reversible, favoring the

starting material. Product was formed up to a maximum of 65% (9 hours of reaction)

based on NMR. Prolonged reactions times favored the equilibrium to the starting








material, thus after 24 hours only traces of products were present along with the starting

material. At that point, there was less amount of stylbene (reaction byproduct) present,

probably taking part in the reversibility of the reaction.

O 0
mCa
Zn/Cu, MeOH
0OCH3 Na+OCH2CF3 ZnC, eH '
Cl2HCCOCIH2 OMe 30% over two steps OMe
233 234 235

0 0
LnRurrr 67
Ph OCH3
OMe >\Ph 4 eq. 0
235 CH2Cl2 0.3M 236
20%
O OH
0 OH LnaRL--\ 67 OH
L-Selectride Ph. OCH3
O 0 .p4 eq.
OMe THF, -780C OCH3 0 e.
86% CH2C12 0.3M 23
235 237 238

Scheme 2-21. Approach to the acetal type pyrans from the ROCM strategy

Consequently, another strategy was explored simultaneously. The new method

started with the ROCM of alcohol 242 (Scheme 2-22). Ketone 241 can be obtained on

large scale in good yield from the relatively cheap furfuryl alcohol 239. Ketone 241

failed to undergo ROCM with styrene. On the other hand, exo alcohol 242, which

provides the desired stereochemistry at the C 13 of latrunculin B, underwent ROCM;

however the alcohol gave low yields and poor regioselectivity. Further, ROCM of the

endo alcohol 245 gave a 79% yield of the more hindered alkene 246 as a single

regioisomer. None of the other regioisomer was observed by NMR or GCMS.

Nonetheless, high loads of styrene can provide the diphenyl cross metathesized product.








0
0 01 .Na+-OCH2CF3
2,6-Lutidine- Cl2HCCOCCIH2.
/ OH TBDMS-OTf / OTBS 2. Zn/Cu MeOH OTBS
95% 75-85 %
239 240 over 2 steps 241


OH
O H LnR ----\ 67 243:244
O2 0Ph R1 R2 1:1
O TSSml2 THF OH P4 eq. 0'
OTSReflux, 40% M'5P40
OTBS CH2Cl2 0.3M
241 242 13% 243; R1 = H, R2 = CH2OTBS
244; R1 = CH2OTBS, R2 = H
o OH
OH LnRLr---- 67 OH
L-Selectride, Ph OTBS
OTBS THF -780C o O H 0P4eq. 3M
92% OTBS CH2C12 0.3M
241 245 79% 246

Scheme 2-22. Initial approach to latrunculin B: generation of the pyran.

With the pyran 246 in hand, functionalization of the skeleton started with

protection of the free alcohol and hydroboration of the protected material; the two step

sequence gave a 74% yield of alcohol 247, which was then protected as a tert-butyl

dimethyl silyl ether 249 (Scheme 2-23). The hydroboration selectively oxidized the less

hindered alkene. The alcohol side chain was foreseen to be protected as a triflate to

undergo alkylation with an Evan's oxazolidinone enolate to set the center at C8.

Nonetheless, silyl ether 240 was used as a model compound to functionalize the pyran by

studying the oxidative decarboxylation to generate the C I5 alcohol, whose

stereochemistry was supposed to be set by the anomeric effect.95 After ozonolysis of

styryl compound 249 and oxidation to acid 251 with sodium chlorite, attempts were done

toward the oxidative decarboxylation of 251 (Scheme 2-23). It is interesting to mention








that acid 251 did not exhibit the characteristic OH stretch in the IR. Hence, an ester

derivative (263) was made by treatment of diazomethane for further confirmation.
OH OBn
OH O n 9-BBN-H,
OTBS 1. NaH, THF OTBS THF 0C-R.T.
2. BnBr, Reflux 74% over2
246 247 steps


2,6-Lutidine.
TBDMS-OTf
91%


OBn 1. 03, CH2CI2
OTBS -780C

TBSO 0 2. Me2S
78%


OBn

OTBS
H0 0248


OBn
/OTBS

TBSO' 0 I
250 H


NaOCIO, Na2H2PO4
2-methyl-2-butene
t-BuOH/H20
75%


Scheme 2-23. Functionalization of the pyran intermediate to approach Latrunculin B

Various conditions were attempted in an effort to promote the oxidative

decarboxylation of 251 as a strategy to install the C 15 alcohol of the target (Scheme 2-

24). The first thing tried was the use of lead tetraacetate (Pb(OAc)4). Lead tetraacetate is

commonly used for this type of transformation.96 Exposure of 251 to Pb(OAc)4 in

refluxing benzene gave an undefined mixture of compounds, though the starting material

was totally consumed. Presumably, the acetic acid present in the Pb(OAc)4 may have

deprotected the alcohols promoting further reactions with them that lead to a mixture of

compounds. Another possibility is that the starting material 251 decomposed under those

conditions. Another protocol, developed by Suarez et al. that was the simple oxidative

decarboxylation using the hypervalent iodine, diacetate iodobenzene (DIB), which has

been reported to react via a radical mechanism.97 Based on the proposed mechanism


OBn


-OTBS








reported in the literature, compound 251 was expected to undergo oxidative

decarboxylation as depicted in scheme 2-25.


251 Pb(OAc)4. undefined
PhH, reflux

251 DIB, 12, MeOH No Reaction


251 DIB, 12, CH3CN



251 DIB, 12, CH2Cl2


No Reaction


OBn


TBSO AO0


Scheme 2-24. Attempts of oxidative decarboxylation of the acid intermediate

The reaction of 251 with DIB was attempted in various solvents as reported in

successful examples from the literature. The product from oxidative decarboxylation

reaction was not observed in any of the cases. Interestingly, when dichloromethane was

used as solvent, lactone 253 was isolated as the only product. Although the yield was

moderate (49% yield), the reaction was clean: crude NMR showed only the new

compound 253 and excess of the DIB reagent. A proposed mechanism for the lactone

formation based on previous reported mechanism of this reagent with carboxylic acids is

presented in scheme 2-26.


49%









OBn


OBn


255


OBn

254
S TBSO 0 OTBS


Ph- -OAc


OBn

256TO O-

IBSO" 0 OTBS


OBn OBn

257 258

TBSO OTBS TBSO 0 OThS
GOAcOAc



Scheme 2-25. Proposed mechanism based on literature reports


OBn OBn OBn


TBSO O TBSO 0 OTBSO O
TBO~OAc OAc OAc
258 259 260


OBn OBn OBn



TBSO 0 0TBSO 0TBSO 0 0
261 .C 262 H3C( 253
H3C e
OAc

Scheme 2-26. Proposed mechanism for the lactone formation

It is proposed that compound 258 is a plausible intermediate for the lactone

formation. Compound 258 is predicted to be formed based on the mechanism depicted in








scheme 2-25. Thus, reaction of the carboxylic acid with DIB generates intermediate 254,

which fragments to the radical intermediate 256 by loss of C02, then radical oxidation by

the iodine gives carbocation 257, which eventually is quenched by an acetate group to

give 258. It is supposed that deprotection of the silyl ether of 258 generates the alcohol

259 which could form radical 260 by reaction with DIB, then loss of formaldehyde could

give rise to the new radical 261, that gave lactone 253.

Based on the results and the proposed mechanism for formation of lactone 253, it

was presumed that if compound 258 was formed, the reagent was performing the

oxidative decarboxylation. Hence, compound 265, would be able to form an oxygen

radical and loss CO (Scheme 2-26), and form a carbocation intermediate 262 stabilized

by an styryl unit that can lead to the C 15 alcohol. However, compound 266 appears to be

formed based on extensive NMR studies; this was not confirmed by mass spectrometry.

This may imply that the proposed mechanism is not taking place or that addition of the

iodine to the double bond, followed by cyclization is faster than the reaction of 265 with

DIB.

Ac20, Pyr, OBn
OBn DMAP, CH2Cl2 Oi.S ,_

OTBS Reflux, 90% OTB THE
HO An 1
248264
OBn
OBn
OHB D CH 0 X I1
AcO 0 1 c
266


Scheme 2-27. An alternative attempt to form the acetal type pyran








Some future work that may provide the desired oxygen at C 15 could be the use of

the Hunsdiecker reaction, with subsequent quench of with methanol in the presence of

catalytic acid. Nonetheless, preliminary results failed to give the desired alkyl halide.

Furthermore, Pb(OAc)4 could be tried with different protecting groups not as sensitive to

acid as the silyl ether case studied, and electrochemical oxidation, another common

procedure for the oxidative decarboxylation, should be also studied. In addition, if the

lactone could be obtained in higher yields, careful Grignard addition to the lactone could

provide the desired alcohol. Another route would be exploring the ROCM of other

oxabicycle systems, for example, ROCM of 1 and further allylic oxidation. Nevertheless,

ROCM has proven to be a useful strategy that may be employed in natural product

synthesis.













CHAPTER 3
CONCLUSIONS AND FUTURE WORK

The studies performed have proven that ring-opening cross metathesis reactions of

oxabicyclo[3.2.1 ]octene derivatives is a viable pathway toward the formation of highly-

substituted pyrans. The presence of a bridgehead substituent decreased the reactivity of

the system in the intermolecular ROCM. These findings disclosed mechanistic details in

the intramolecular ROCM reaction, implying that the intramolecular ROCM reaction

proceeds via initial reaction with the tethered vinyl group followed by cyclization rather

than initial regioselective opening of the bridged olefin.

The lack of reactivity in bridgehead substituted systems can be manipulated by

changes in remote substituents. The changes on remotes substituents can also affect the

regioselectivity of these reactions. However, it was observed that the regioselectivity

may depend on the reaction time. Thus, at the early stages of the reaction the

regioselectivity is higher.

Unfortunately, disubstitution at the bridgehead position of the oxabicyclo leads to

no reaction. Neither reduction/silylation had an effect on the reactivity of the system.

The kinetics studies performed on the unsubstituted oxabicyclic compounds lead

to a new hypothesis of how remote substituents affect the reactivity of the system. Based

on the results, it is suggested that the enhancement in reactivity is caused by the ability of

the substituent at C3 to donate electron density to the double bond through space rather

than by changes in hybridization as initially proposed.85 In addition, steric factor plays a

major role on the reactivity of the system. Although a small difference in the relative








rates was observed for the ROMP of the 8-oxabicyclo[3.2. 1 ]octene derivatives, the

differences manifest themselves in significant effects such as yield of ROCM products

versus polymers.

Our investigations have contributed to the expansion of the methodology towards

unsymmetrical cyclic compounds, as well as provided new insight into the factors that

can affect the valuable metathesis reaction.

The Intramolecular ROCM of the C2-tethered alkene oxabicyclic substrates was

sluggish, and rendering the direction of the reaction more to the production of polymer

rather than the linear-fused pyran.

The ROCM of of 8-oxabicyclo[3.2.1 ]octene derivatives proved to be an effective

way for the fast construction of the pyran moiety in Latrunculin B. Additional work

needs to be done to further functionalization of the pyran skeleton and obtain the acetal

type pyran.

In order for the ROCM 8-oxabicyclo[3.2. 1 ]octene derivatives to be useful and

appealing in synthesis, asymmetric intermediates need to be obtained. Thus it is

important to study the ROCM of chiral oxabicycles, and observe the effect on the

regioselectivity of asymmetric substituted bicycles. Another alternative is the

asymmetric ROCM with a chiral catalyst.98 Of interest could be the screening of various

chiral catalysts with a series of oxabicycle to determine a trend on which chiral catalyst is

better for specific functional groups and substitution of the system.













CHAPTER 4
EXPERIMENTAL PROCEDURES

General Methods. All the solvents used in the reactions were distilled prior to

use, unless reported. Thin-layer chromatography was performed using silica gel 60 F24

precoated plates (250 utm thickness). Column chromatography was performed using 230-

400 mesh silica gel 60. Melting points were obtained on a Thomas-Hoover Capillary

Melting point apparatus, and reported uncorrected. IR spectra were obtained on a FT-IR

spectrometer. NMR spectra were obtained on a Varian 300 MHz spectrometer; chemical

shifts are reported in 6 units relative to the tetramethylsilane (TMS) signal at 0.00 ppm.

Coupling constants are reported in Hz. High-resolution mass spectroscopy was provided

by the University of Florida Mass Spectroscopy Services.

Kinetic Studies. A 0.65 ml solution of acetone containing 4,1 0-dioxa-tricyclo[5.2. 1.0

2,6]dec-8-ene-3,5-dione (standard, 198), the substrate to be analyzed,

oxabicyclo[3.2.I]octene derivatives (1,192, 193, 199-200), in different ratios (1: 1, 1: 4,

4:1, and 8:1, 16:1 in some cases) and a drop of benzene as the internal standard was

prepared. To the mixture, 0.1 ml of a solution of 1.0 mg of Grubbs catalyst 67 in 1 ml of

CDC13 was added. The reactions were monitored by IH NMR at 500 MHz on a Varian

Inova spectrometer. The spectra were acquired on automation, ca. 100 points for the

course of the reaction, which varied from 10 minutes to 1.5 h, and the integrals of the

alkene protons of the substrate and of the standard were normalized against the integral of

a comparable amount of benzene. The plot of ln[substrate] vs ln[standard] afforded a

line, whose slope corresponded to the relative rate of the substrate versus the standard








(ksub/kstd) with a typical R2 of 0.98-0.99. In accordance with the following equations:

ln(A0/A) = kt, where k=[cat]*kA, the ratio of kA/kstd is the slope of ln[A]/ln[Std], where

[A] = [substrate] and [Std] = standard.

,0-..
N




Figure 4-1. 8-Oxa-bicyclo[3.2. 1 ]oct-6-en-3-one 0-methyl-oxime (199)

8-oxa-bicyclo[3.2. 1 ]oct-6-en-3-one 1 (0.100 g, 0.806 mmol) was dissolved in 2

ml of dry CH2C12 and mixed with methoxylamine hydrochloride ( 0.101 g, 1.210 mmol)

and 3A molecular sieves. Then 0.10 ml of pyridine was added, a condenser was fixed

and the reaction mixture was allowed to reflux for 5 hours. Upon completion of the

reaction by TLC, the reaction was diluted in CH2C12, the resulting powdering molecular

sieves were filtered. The filtered liquid was washed with brine and dried over MgSO4,

filtered trough a small plug of silica gel, eluting with 85:15 hexanes: ether and

concentrated to achieved a white solid (0.1003 g, 81%) of 199. Rf= 0.33 (85: 15 hexane:

ethyl acetate). Melting Point 55-56C. 'H NMR (300 MHz, CDCL3): 6 6.23-6.18 (2H,

m), 4.90(lH, dt, J= 4.7Hz, 1.2Hz), 4.85 (1H, dt, J= 4.7Hz, 1.2Hz), 3.78 (3H, s), 2.93

(1H, dd, J= 16.1Hz, 0.9Hz), 2.66 (1H, ddt, J= 15.2 Hz, 4.4Hz, 1.5 Hz), 2.36 (1H, ddt, J

= 16.1Hz, 4.4Hz, 1.5Hz), 2.26 (1H,dd, J= 15.2Hz, 0.9Hz). 3C NMR ( CDC13): 6 153.4,

133.4, 132.4, 78.0, 76.8, 61.4, 34.5, 30.4. HRMS (EI) calcd for C8H1 IN02 [M] 153.0790,

found 153.07889. IR (film): 2956, 2925, 2853, 2360, 1464, 1259, 1048, 994, 843 cm-1.

CH calcd for C8Hj IN02: C, 62.73; H, 7.24; found: C,62.74; H, 7.27.













Figure 4-2. 3-Methylene-8-oxa-bicyclo[3.2.1 ]oct-6-ene (200)

A flame dry 2-neck 25 ml flask was charged with 0.70 g of CeC13 heptahydrate

and stir bar. The solid was dried by heating at 1400C under vacuum for 3 hours. Then it

was allowed to cool to room temperature and a suspension was made by the addition of

THF (3 ml). The suspension was allowed to stir at room temperature for 2 hours, then it

was cooled to -780C and 1 M trimethylsilylmethyl magnesium chloride was added (0.97

ml, 97 mmol). The yellow suspension stirred for 30 min and oxabicyclic ketone 1 (0.10

g, 0.81 mmol) was added. The mixture was allowed to stir overnight and reach room

temperature slowly. The reaction was worked up by quenching with ice and adding a

solution of ammonium chloride for the emulsion formed. The layers were separated and

the aqueus layers were extracted with ether. The organic layers were dried with MgSO4,

filtered and concentrated to yield the crude alcohol in 84% yield as an orange oil. The

crude was added to a suspension of 35% wt. KH (1.1 g) in 6 ml of THF at 0C. The

mixture was allowed to stir at room temperature for 3 hours and then it was quenched

carefully with a saturated solution of ammonium chloride at I 0C. The aqueous layers

were extracted with ether, dried with MgSO4 and concentrated in a rotary evaporator.

The oil was purified by column chromatography eluting with 95: 5 (hexanes: ether)

affording 60% overall yield of the volatile, colorless oil 200. Rf= 0.71 (35: 65 ethyl

acetate: hexane). 'H NMR (300 MHz, CDCL3): 6 6.10 (2H, s), 4.79 (2H, d, J= 4.1Hz),

4.74 (2H, t, J = 2.2Hz), 2.61-2.54 (2H, m), 2.05 (2H, d, J= 14.6 Hz). 3C NMR (CDC13):

6 141.3, 131.7, 113.7, 78.7, 37.2. HRMS (El) calcd for C8H100 [M] 122.0732, found








122.0733. IR (film): 3072, 2951, 2897, 2820, 1645, 1418, 1342, 1045, 990, 890, 871cm







Figure 4-3. endo-3-Methyl-8-oxa-bicyclo[3.2.1 ]oct-6-en-3-ol (201)

In a 2 neck flask 3.84g of CeC13.7H20 were dried with stirring under vacuum at

1400C for 3 hours. The powdery white solid was cooled down under argon to room

temperature. Then 8 ml of dry freshly distilled THF were added and stirring was

maintained for two additional hours. The cloudy white suspension was cooled to -78C

and 2.8 ml, 3.84 mmol of 1.0 M solution of MgBrCH3 were added, where upon addition

the color of the suspension turned from white to a pale yellow color. After being kept at

the same temperature for 30 min, a solution of 8-oxa-bicyclo[3.2. 1 ]oct-6-en-3-one 1

(0.400 g, 3.2 mmol) in 4 ml of THF was added. The reaction mixture was allowed to

reach room temperature and stir under argon for 24 hours. Upon completion of the

reaction, it was quenched with ice and filtered through a pad of celite. The filtrated was

extracted with ethyl acetate, dried with Na2SO4, filtered and the solvent was evaporated

under reduced pressure. The dark orange residue was purified by silica gel

chromatography eluting with 85:15 hexane:ethyl acetate (residue previously adsorbed on

silica) producing 201 as a pale yellow oil (0.2500g, 56%) of 21. Rf= 0.14 (65: 35

hexane: ethyl acetate). 'H NMR (300 MHz, CDCL3): 6 6.48 (2H, s), 4.80 (2H, d, J

4.3Hz), 3.44 (1H, bs), 2.07 (2H, dd, J=14.9Hz, 4.0Hz), 1.74 (2H, d, J= 14.5 Hz), 1.15

(3H, s). 13CNMR (CDC13): 6 135.5, 77.8, 69.4, 41.6, 32.7. HRMS (EI) calcd for C8H1202

[M] 140.0837, found 140.0836. IR(film): 3429, 2947,1647, 1348, 1165, 1101, 857 cm1.










0

Figure 4-4. 8-Oxa-bicyclo[3.2.1 ]oct-6-ene (204)

In a sealed tube KOH (1.3g, 22mmol) was dissolved at 55C in diethylene glycol

(9 ml). To the yellow orange viscous solution (0.9025 g, 7.25 mmol) of 1 were added

followed by the addition of hydrazine monohydrate (0.9 ml, 18 mmol). Then the

mixtured was sealed and allowed to reflux to 195C. Upon completion by TLC the

reaction was worked up by adding water and a little amount of 2% HC1 solution. The

aqueous layer was extracted 4 times with small portions of ether. The ether layers were

dried with Na2SO4 and filtered. The solvent was removed by distillation. The residue was

purify by chromatography eluding with a mixture of 95:5 petroleum ether:ether. The

compound containing fractions were collected, and the solvent was removed by

distillation to afford 204 as a volatile pale yellow oil (0.5475g, 69% yield) of pungent

smell. Rf= 0.29 (95:5 hexane:ether). 1H NMR (300 MHz, CDCL3): 6 6.14 (2H, s)

4.67-4.71 (2H, m), 1.01-1.81 (6H,m). 13C NMR (CDC13): 8 130.6, 79.5.8, 41.6, 25.2.

HRMS (El) calcd for C7H,00 [M] 110.0732, found 110.0732. IR (film): 2930, 2854,

1029, 806, 701 cm-'.


0AjVJOH

Figure 4-5. exo-3-Methyl-8-oxa-bicyclo[3.2.1 ]oct-6-en-3-ol (205)

To a suspension of LiA1H4 (83mg, 2.18mmol) in THF (3 mL) was added epoxide

208 (40 mg, 0.29 mmol) as a solution in 2 ml of dry THF at 0C. After the addition, the

mixture was refluxed at 66C for 3hrs. The mixture was allowed to reach room

temperature and then was cooled to I0C and quenched with 0.25 ml of water follow by








0.25 ml of 2 M NaOH. Additional 0.5 ml of water was added and the mixture was

filtered. The aqueous layer was extracted with ethyl acetate, dried with MgSO4, and

concentrated in a rotary evaporator. The residue was purified by silica gel

chromatography and gave a colorless oil 205 (27 mg, 68%). Rf= 0.18 (40:60 hexane:

ethyl acetate). 'H NMR (300 MHz, CDCL3): 8 6.18 (1H, s), 4.82 (lH, d, J= 5.4 Hz),

2.05 (2H, d, J= 13.7 Hz), 1.69 (2H, d, J= 13.1 Hz), 1.27 (2H, s). 3C NMR (CDCI3):

8 133.2, 77.6, 69.4, 41.7, 33.6. IR (film): 3406, 2924, 2850, 1258, 1096, 1047, 711 cml.





Figure 4-6. 3-endo-spiro epoxide bicycle[3.2. 1]oct-6-ene (208)

To a solution of 3-Methylene-8-oxa-bicyclo[3.2. ]oct-6-ene (200) (0.4000g, 3.27

mmol) in methylene chloride (5 ml) was added NaHCO3 (0.35g, 3.89 mmol) of and m-

CPBA 77% (1.70g, 7.78 mmol) at 0C by portions. The reaction was allowed to stir for

6hrs at OoC then was allowed to reach room temperature and stir for additional 9hrs.

Upon completion of the reaction based on TLC the reaction was worked up by diluting

the mixture with water and washing it with 20% NaOH extracting with CH2C12. The

organic layer was dried with MgSO4, filtered and concentrated in a rotary evaporator.

The residue was then purify by silica gel chromatography using gradient elution (50g

silica gel: residue adsorbed on silica; 95:5 65:35 hexane: ethyl acetate) gave a white

semisolid 208 (58 mg, 13%). Rf= 0.34 (65:35 hexane: ethyl acetate). 'H NMR (300

MHz, CDCL3): 6 6.21 (1H, s), 4.87 (1H, d, J= 3.5 Hz), 2.5 (2H, s), 2.32 (2H, dd, J=

13.2, 3.8 Hz), 1.35 (2H, dt, J= 13.2, 1.2 Hz). '3C NMR (CDC13): 6 132.4, 78.3, 58.5,

54.8, 36.4. IR (film): 2958, 2924, 1394, 1245, 1048, 993 cml.








Other epoxides were isolated:





Figure 4-7. 3-exo-spiro epoxide bicycle[3.2.1]oct-6-ene (207)

Rf= 0.25 (65:35 hexane : ethyl acetate). 'H NMR (300 MHz, CDCL3): 6 6.37

(2H, s), 4.84 (2H,d, J= 3.33Hz), 2.54 (1H, d, J= 3.8 Hz), 2.49 (1H, d, J= 3.8 Hz), 2.38

(2H, s), 1.24 (2H, d, J= 14.1 Hz). 13C NMR (CDC13): 8 133.7, 78.3, 54.0, 48.1, 37.3.

Pale yellow oil (35 mg, 8%).





Figure 4-8. diepoxides (209)

Rf= 0.13 (65:35 hexane: ethyl acetate). 'H NMR (300 MHz, CDCL3) major: 6

4.33 (2H, d, J= 4.09 Hz), 3.76 (1H, s), 2.57 (2H, s), 2.44 (2H, dd, J= 15.2, 4.4 Hz), 1.22

(2H, d, J= 15.2 Hz). minor: 64.38 (2H, d, J= 4.4 Hz), 3.62 (2H, s), 2.61 (2H, s), 2.30

(2H, dd, J = 14.0, 4.09 Hz ), 1.38 (2H, d, J = 14.3 Hz). 13C NMR (CDC13) both: 6 71.9,

71.5, 57.3, 53.6, 53.2, 53.1, 50.5, 34.5. HRMS (El) calcd for C8H1003 [M]+ 138.0630,

found 154.0629. A yellow oil (0.16g, 32%).





Figure 4-9. 7-Methylene-3,9-dioxa-triciclo[3.3. 102'4]nonane (210)

Rf= 0.52 (65:35 hexane: ethyl acetate). 'H NMR (300 MHz, CDCL3): 8 4.79

(2H, t, J= 2.3 Hz), 4.26 (1H, d, J= 4.7 Hz), 3.5 (2H, s), 2.63-2.56 (2H, in), 2.23 (2H, d, J

= 15.5 Hz). 13C NMR (CDCI3): 6 132.4, 78.3, 58.5, 54.8, 36.4. HRMS (El) calcd for








C8H1002 [M]+ 138.0696, found 138.0696. IR (film): 2960, 2902, 1650, 1054, 854, 695

cm1. Pale yellow oil (62 mg, 14%).

0




Figure 4-10. 1 -methoxymethyl-8-oxa-bicyclo[3.2.1 ]oct-6-en-3-one (206b)

2-Methoxymethyl-furan prepared from furfuryl alcohol, sodium hydride and

methyl iodide in THF (4.90g, 44 mmol) was placed in a 500 ml round bottom flask

without purification and cooled to 00C. Via two separate syringes, trichloroacetone (6.0

ml, 9.21g, 57 mmol) was added, followed by the slow addition of trifluoroethoxide (2M,

33 ml). Upon completion of the addition, the solution was allowed to warm to room

temperature. The reaction was monitored by TLC using p-anisaldehyde as stain. After

12 hours, zinc/copper couple (8.8 g, 0.132 mmol) and a solution of methanol saturated

with ammonium chloride (75 mol) were added, and the mixture was allowed to reflux for

two days. Upon reaction completion, the mixture was filtered through celite washing

with ethyl acetate to remove the zinc/copper couple. The filtrate was then evaporated,

and the residue partitioned between dichloromethane and a saturated solution of EDTA.

The aqueous layers were extracted with dichloromethane. The organic layers were

combined and dried on MgSO4, filtered, and the solvent removed in vacuo. The brown

oil residue was then purified by chromatography using gradient elution (60: 1 silica gel:

residue adsorbed on silica; (95: 5- 60: 40 hexanes: ethyl acetate) to give 206b as a yellow

oil (3.0g, 40 % over 3 steps). Rf= 0.27 (70: 30 hexanes: ethyl acetate). IH NMR (300

MHz, CDC13) 6 6.27 (1 H, d, J = 5.9), 6.10 (1 H, d, J = 5.9), 5.11 (1 H, d, J = 4.5), 3.62

(2H, s), 3.45 (3H, s), 2.77-2.68 (2H, m), 2.36 (1H, d, J= 6.9 Hz), 2.30 (IH, d, J= 6.9








Hz). 3C NMR (300 MHz, CDC13): 6205.7, 134.2, 133.5, 86.0, 77.8, 74.6, 59.7, 47.8,

45.4. HRMS (El) m/z calcd for C9H1203 [M+H]+ 169.0865, found 169.0888. IR (film):

2923, 1716, 1455, 1406, 1343, 1183, 1108, 1020, 917, 854, 734 cm'.

0




Figure 4-11. 1-Propoxymethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-one (206c)

2-Propoxymethyl-furan (1.005 g, 7.1 mmol) was placed in a dry 100 ml round

bottom flask and cooled to 0C. Via two separate syringes, solutions of trifluoroethoxide

(2M, 15mL) and trichloroacetone (14.3 mmol, 1.5ml) in trifluoroethanol (7.5 ml) were

added drop wise simultaneously, and the solution was allowed to warm to room

temperature. The reaction was monitored by TLC using p-anisaldehyde as stain. Upon

completion of the reaction an equal volume of water and dichloromethane was added, and

the aqueous layers extracted 2 times with dichloromethane. The organic layers were

combined and dried on MgSO4, filtered, and the solvent removed in vacuo. The crude

dark orange/brown oil (7.39g) was placed in a 200 ml round bottom flask without

purification. To the crude, zinc/copper couple (10.23 g) and a solution of methanol

saturated with ammonium chloride (80 ml) were added, and the mixture was allowed to

reflux for two days. The mixture was then filtered through celite, washing with ethyl

acetate, to remove the zinc/copper couple. The filtrate was then evaporated, and the

residue partitioned between dichloromethane and a saturated solution of EDTA. The

aqueous layers were extracted with dichloromethane. The organic layers were combined

and dried on MgSO4, filtered, and the solvent removed in vacuo. The brown residue was

then purified by silica gel chromatography using gradient elution (60: 1 silica gel: residue




Full Text
STUDIES ON THE RING-OPENING/CROSS METATHESIS OF 8-
OXABICYCLO[3.2.1]OCTENE DERIVATIVES AND ITS APPLICATION
TOWARDS THE SYNTHESIS OF LATRUNCULIN B
By
MARÍA E. ESTRELLA-JIMÉNEZ
A 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
2005

Copyright 2005
by
María E. Estrella-Jiménez

Dedicated to my family, the most important thing in my life, and to all of those who have
taught me in some way

ACKNOWLEDGMENTS
I need to thank my big and wonderful family; they are my life’s engine. Especially,
I thank my parents, Sheila Jiménez and Félix A. Estrella, my brother Félix A. Estrella Jr.,
and my sister Johanna Estrella for their unconditional love and support. In addition, a
special thank you goes to Wilfredo Ortiz, who has always been there to give me his love,
help, support and positive input. Without him, everything would have been
overwhelming. I would like to thank my friends for keeping my social life in healthy
status.
Professionally, I would like to thank my undergraduate advisor, Dr. John A.
Soderquist. I am very grateful for the trust he gave me as a student and for giving me the
opportunity to start organic chemistry in his research group. I also thank him for his help
in numerous opportunities and fellowships.
I thank my advisor, Dr. Dennis L. Wright, for giving me the opportunity of being
part of his research group and for respecting my decision of staying at the University of
Florida, after he moved to Dartmouth College for a new faculty position. I also thank
him for his advices and exciting chemistry discussions.
I offer special thanks to Professor Merle A. Battiste. He was a key person in my
final year at University of Florida. I could not be more grateful of his support, positive
input, confidence and friendship. I really appreciated the concern and interest he took in
me. He always had the time to listen, regardless of the matter.
IV

I would like to thank the other members of my committee, Professor William R.
Dolbier, Professor Ken Sloan and Professor David H. Powell, for taking their time to be
part of my professional development. Dr. Ion Ghiviriga needs to be given special thanks
for all his help with the NMR and for his friendship. He was a great collaborator and
friend. No matter how busy he was, he would always take some time to help me. In
addition, the mass spectroscopy team needs to be thanked for their suggestions and work
in getting the molecular weight of my compounds. I am very grateful for my former and
present colleagues for offering me their knowledge and friendship, especially Lynn
Usher, Chris Whitehead and Ravi Orogunty. Lynn Usher trained me during my first year
as a graduate student and offered me tremendous help through the years with her advice,
friendship and, I need to add, the English lessons. I will always remember Chris
Whitehead; he mentored me on many occasions with lab techniques. I appreciate Ravi
Orogunty for sharing his wisdom with me many times. In addition, I would like to thank
Chris Baker for his friendship during this past year.
Furthermore, I would like to express my thanks to my colleagues and friends,
Theodore Martinot and Jed Hasting. I thank Theodore Martinot for all the help and
advice he offered me this past year. Jed Hasting is truly appreciated for his wonderful
friendship, help and patience in listening to me during stressful times. Dave Pirman, the
undergraduate that worked with me during my last year, also deserves special mentioning
for all the help he provided in the lab. Last, but not least, for all the non-research-related
work, I am very grateful for secretaries Lori Clark and Gwen McCann from the
Department of Chemistry. They are efficient, friendly and wonderful secretaries.
v

Finally, I would like to thank the University of Florida for giving me the
opportunity of coming here to pursue my graduate studies and for the fellowship
provided.
vi

TABLE OF CONTENTS
page
ACKNOWLEDGMENTS iv
ABSTRACT ix
CHAPTER
1 INTRODUCTION 1
Ring-Opening of 8-Oxabicyclo[3.2.1]Octene Derivatives and its Application in
Synthesis 3
Cleavage of the Unsaturated Double Bond, C6-C7, of the Oxabicyclo[3.2.1]
System 4
Cleavage of the Carbonyl and the a-Carbon, C3-C4, of the Oxabicyclo[3.2.1]
System 8
Cleavage of the Carbon-Oxygen Bridgehead Bond. C1-C2, of the
Oxabicyclo[3.2.1] System 9
Olefin Metathesis 13
Types of Olefin Metathesis Reactions 16
Ring-opening metathesis polymerization 16
Acyclic diene metathesis 17
Cross metathesis 18
Ring-closing metathesis 19
Ring-opening cross metathesis 23
Tandem Metathesis 26
Catalytic Asymmetric Olefin Metathesis 29
The Latrunculins 36
Total Syntheses of Latrunculin B 37
Smith’s total synthesis 37
Fiirstner’s total synthesis 39
Total Syntheses of Latrunculin A 40
Smith’s total synthesis 40
White’s total synthesis 41
Kashman's Approach to the Latrunculin Synthon 44
Kashman's Synthesis of Latrunculin M and C 45
vii

2RESULTS/DISCUSSION
.47
Intermolecular Ring-Opening Cross Metathesis (ROCM) 47
Kinetic Studies 49
Bridgehead Substituted 8-Oxabicyclo[3.2.1]Octene Derivatives 59
Intramolecular Ring-Opening Cross Metathesis (ROCM) 65
Approaches Towards Latrunculin B from Ring-Opening Metathesis of 8-
Oxabicyclo[3.2.1]Octene Derivatives 71
3 CONCLUSIONS AND FUTURE WORK 80
4 EXPERIMENTAL PROCEDURES 82
APPENDIX
A SELECTED SPECTRA 118
B LIST OF TABLES FOR KINETIC STUDIES 151
C LIST OF GRAPHS FOR KINETIC STUDIES 157
LIST OF REFERENCES 188
BIOGRAPHICAL SKETCH 194
viii

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
STUDIES ON THE RING-OPENING/CROSS METATHESIS OF 8-
OXABICYCLO[3.2.1]OCTENE DERIVATIVES AND ITS APPLICATION
TOWARDS THE SYNTHESIS OF LATRUNCULIN B
By
Maria E. Estrella-Jiménez
May 2005
Chair: Dennis L. Wright
Cochair: Merle A. Battiste
Major Department: Chemistry
The pyran moiety is a common structural feature found in many natural products,
and often seen as an integral part of carbohydrates and macrolides of marine origin. This
work discloses the use of ring-opening cross metathesis (ROCM) of 8-
oxabicyclo[3.2.1]octene derivatives for the preparation of substituted pyrans, using
Grubbs’ ruthenium-based metathesis catalyst. The oxabicyclic systems were synthesized
using Fohlish conditions, which involve the [4+3] cycloaddition between furan and an
oxallyl cation. An unusual influence in the reactivity and selectivity of the ROCM
reactions was discovered upon substituent variation at the C3 position of the oxabicyclo.
These results led to further investigations that involved the synthesis of a series of 8-
oxabicyclo[3.2.1 Joctene derivatives with different substituents at C3. Kinetic
experiments were conducted with the substrates, using NMR to monitor the reactions.
These experiments provided relative rates of ring-opening metathesis polymerization for
IX

the series of oxabicyclic derivatives when compared with 4,10-dioxa-tricyclo[5.2.1.0
26]dec-8-ene-3,5-dione (adduct of furan and maleic anhydride). The relative rate trend
observed among the substrates showed that their reactivity is affected by the combination
of electronic and steric effects. The knowledge obtained can be used to accelerate
sluggish ROCM reactions in the synthesis of pyrans from these types of substrates.
Substitution at the bridgehead position of the oxabicycle decreases the reactivity of the
system and brings into focus the problem of regioisomers. However, the careful
consideration of the substituent at the C3 position gave good yields of the pyrans, and
excellent regioselectivity was obtained having an e/iifo-alcohol as a substituent at that
position. In addition, the intramolecular ROCM of oxabicyclic system having a tethered
alkene at the C2 position was studied and led to linear-fused pyrans.
Furthermore, preliminary work was done towards the synthesis of latrunculin B
using the ROCM approach.
x

CHAPTER 1
INTRODUCTION
Polycyclic systems can be seen as a method to achieve stereoselectivity in organic
synthesis. The ring strain contained in some polycyclic compounds fixes them in a
conformation that accesses contiguous stereocenters as well as helps in the control of
stereocenters from successive reactions. Oxabicyclic compounds are polycyclic systems
that possess an oxygen atom as part of the cyclic framework. The developments of ring
cleavage reactions of oxabicyclic compounds have made them attractive starting
materials in organic synthesis. Ring-opening of oxabicyclic derivatives can lead to a
wide variety of compounds by selective cleavage of specific bonds. These compounds
are frequently highly substituted ethers, particularly tetrahydrofurans and
tetrahydropyrans.1 A large number of natural products and sugars have been synthesized
from oxabicyclic compounds.1
A particular substrate is 8-oxabicyclo[3.2.1]oct-6-en-3-one 1, which allows the
construction of different oxygen-containing compounds by specific bond disconnections.
Cleavage between the bridged-carbon, C1, and the oxygen (path a) generates a
cycloheptenol, whereas cleavage between the carbonyl, C3, and the adjacent a carbon,
C2, (path b) gives a 2,4 dihydro fiaran moiety, and cleavage of the unsaturated double
bond, C6-C7, (path c) produces a pyrone derivative (Schemel-1).

2
Scheme 1-1. Different oxygen-containing compounds by specific bond disconnections of
8-oxabicyclo[3.2.1 ]oct-6-en-3-one
The availability of this oxabicyclo, which can be synthesized by a [4+3]
cycloaddition with protocols amenable to large scale preparations,2 and the availability of
alternative ring-opening reactions make this compound an interesting starting unit in
organic synthesis.1
Our research focused on the cleavage of the double bond (path c) of 1 and its
derivatives using ruthenium-based olefin metathesis to generate a pyran moiety. To
prove the efficiency of the method, it was also applied in an approach to latrunculin B.
The precursors were readily obtained by a [4+3] cycloaddition, employing Fohlish’s
conditions, which involves the [4+3] cycloaddition of furan and trichloroacetone in the
presence of sodium trifluorethoxide, and subsequent reduction using zinc/copper couple
in methanol saturated with ammonium chloride.3 The presence of the pyran moiety in
many natural products (Figure 1-1) sparked our interest in developing this methodology.

3
Forskolin
Milbemycin
SCH351448
Figure 1-1. Natural products displaying the pyran moiety
This dissertation will present the studies on the ring opening cross metathesis of 8-
oxabicyclo[3.2.1]octene derivatives and its application in an approach to latrunculin B.
Relevant to this dissertation is to mention different types of ring-opening of 8-
oxabicyclo[3.2.1]octene derivatives and their application to the synthesis of a variety of
natural products, as well as a background on the olefin metathesis reaction. In addition, a
brief history of the latrunculins is included.
Ring-Opening of 8-Oxabicyclo[3.2.1|Octene Derivatives and its Application in
Synthesis
This section is devoted to demonstrating the versatility of 8-
oxabicyclo[3.2.1]octene derivatives in the synthesis of natural products via different ring
openings. 8-oxabicyclo[3.2.1 ]octene derivatives present some advantages that make

4
them excellent precursors in organic synthesis. Among these, specific bond
disconnections in the system allow for the construction of different oxygen-containing
moieties that are commonly seen in natural products. Moreover, the system is readily
accessible in large scale from a [4+3] cycloaddition.4 The defined conformation and
rigidity of the system allows access to multiple stereocenters in one step from the
cycloaddition reaction. Furthermore, methods have been developed towards asymmetric
[4+3] cycloadditions.4'5 In addition, chiral derivatives can be accessed from
desymmetrization of meso 8-oxabicyclo[3.2.1]octene compounds.6
Cleavage of the Unsaturated Double Bond, C6-C7, of the Oxabicyclo[3.2.1] System
Tetrahydropyrans are common features in many natural products and sugars. They
can be accessed by cleavage of the unsaturated bond of the oxabicyclo[3.2.1 ] system.
Yadav and coworkers elaborated a strategy of asymmetric hydroboration for the
desymmetrization and subsequent opening of 8-oxabicyclo[3.2.1]octene 2 in the
asymmetric synthesis of the C(19)-C(25) polypropionate unit of Rifamycin.7 Cleavage of
the double bond, C6-C7, of bicyclic ketone 2 was performed in several steps. The
sequence involves reduction and protection of 2, asymmetric hydroboration of ether 3
with (+)-Ipc2BH (Bis (isopinocampheyl) borane), PCC oxidation of the resulting alcohol
4, and Baeyer-Villiger oxidation of ketone 5. After a diastereoselective a-methylation,
the system was opened by an exhaustive reduction that lead to the resolved acyclic
compound 8, which is relevant to 9, the C(19)-C(25) segment of Rifamycin (Scheme 1-
2). The sequence elaborated by Yadav et al. was exploited by Hoffmann et al., who
proved the efficacy of the methodology in the enantioselective synthesis of various 8-
o
valerolactones and polyacetate segments of natural products (Scheme 1-3).

5
Scheme 1-2. Yadav’s asymmetric synthesis of the C(19)-C(25) unit of Rifamycin. a)
D1BAL-H, CH2C12, -10°C b) NaH, BnBr, THF, 65°C c) (+)-Ipc2BH, -20°C,
24h, 96% (>99% ee) d) PCC, CH2C12, rt, 95% e) H202, Se02, /BuOH, reflux,
40% f) LDA, Mel, THF, -78°C g) LiAlH4, THF, 0°C, h) 2,2-
dimethoxypropane, P-TsOH, acetone, r.t.
OBn
rac-10
rac-11
i. (-)-Icp2BH, Et20, PCC[OJ
ii. (+)-Icp2BH, Et20, PCC[0]
OBn
O 19
C(3)-C(9) segment
Bryostatins
C(10)-C(17) segment
Pederin; C(l2)-C(l9)
segment disorazoles
C(l)-C(7) segment
epothi Iones
C( 1 )-C(9) segment
aurisides
Scheme 1-3. Structural and stereochemical diversity from racemic oxabicyclo 10

6
Hoffmann and coworkers demonstrated the utility of 8-oxabicyclo[3.2.1]octene
derivatives as versatile scaffolds in the approach to numerous natural products containing
the tetrahydropyran unit. These include Bryostatins,9 Phorboxazoles,10 Discodermolide,11
Lasonolide A,12 Spongistatin l,13 and mevinic acids14 among others. They approached
the tetrahydropyran unit by oxidative cleavage of the unsaturated double bond, C6-C7, of
the system. In the approach to the Bryostatins, two strategies that involved the cleavage
of the unsaturated double bond were employed. The C(l)-C(16) segment of the molecule
was synthesized starting from 8-oxabicyclo[3.2.1]oct-6-en-3-one 1 and racemic 2,2-
dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one 10.9b
To synthesize the C(l)-C(9) unit, Hoffmann et al. started with racemic 2,2-
dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one 10. The synthesis of that segment involves
the preparation of lactone 16 using the strategy developed by Yadav et al. (Scheme 1-3).7
This protocol prepared the system for cleavage under standard basic conditions that
resulted in the asymmetric tetrahydropyran 20. Further manipulations including ring¬
opening with borontrifluoride and Claisen condensation afforded 23, the C(l)-C(9)
segment of the Bryostatins (Scheme 1 -4).
OBn
>98% ee
. C
OBn OH O
v
OBn O' O
O Bu
OTPS
1 C(1)-C(9)
22 23
Scheme 1 -4. Synthesis the C( 1 )-C(9) segment of the Bryostatins. a) K2CO3, MeOH, rt,
99% b) 2 equiv HS(CH2)3SH, 3 equiv BF3Et20, MeN02, -20 to -15°C, 95%
c) 5 equiv CH3C02But, LDA, -78 to 0°C, 94%

7
For the synthesis of the C(10)-C(16) fragment, ring-opening of the meso
oxabicyclic ketone 1 was performed by ozonolytic olefin cleavage. Tetrahydropyran 25,
the key intermediate in Hoffinann’s synthesis of the C(10)-C(16) unit, was obtained in 5
steps in 35% overall yield from 1 (Scheme 1-5). The enantioselectivity of 25 was
achieved by enzymatic desymmetrization of ketal 24.
Scheme 1 -5. Synthesis of the C( 10)-C( 16) unit of the Bryostatin. a) 2,2,5,5-tetramethyl-
1,3-dioxane, cat. p-TsOH, 35-45 mm Hg, 50% b) i. O3, MeOH/CFhCb, -78°C
ii. NaBH4, -20°C, 98% c) Ac20, cat 4-DMAP, py, r.t. 91% d) lipase PS,
toluene/phosphate buffer (1:4) pH 7, r.t. 88% e) Acetone, cat. Pd(CH3CN)2Cl2
r.t. 89% f) Trityl chloride, Et3N, cat. 4-DMAP, CH2CI2, r.t. g) K2CO3 5% H20
in MeOH (79% two steps) h) ethyl diisopropoxyphosphonoacetate, NaH,
toluene, -50 to -35 °C then -25°C (72%)
After various transformations including protection, deprotection and Homer-
Wadsworth-Emmons olefination, tetrahydropyrone 25 was converted to 27, the C(10)-
C(16) fragment of the Bryostatins, (Scheme 1-5). Finally, coupling of the C(l)-C(9)
segment 23 and the C(10)-C(16) unit 27 achieved the northern hemisphere of the
Bryostatins 28 (Scheme 1-6).

8
Scheme 1-6. Synthesis of the C(l)-C(16) segment of the Bryostatins
Cleavage of the Carbonyl and the a-Carbon, C3-C4, of the Oxabicyclo[3.2.1] System
Tetrahydrofurans can also be derived from oxabicyclo[3.2.1] systems.
Tetrahydrofuran 33, a key intermediate in the synthesis of the C-nucleoside
showdomycin,15 was synthesized by Simpkins and coworkers by cleavage of the C2-C3
bond of the bicyclic ketone 1 (Scheme 1-7).16
Scheme 1-7. Cleavage of C2-C3 of an oxabicyclo[3.2.1] from a chiral silyl enol ether, a)
0s04, fBuOH, Et20, H202, acetone b) PhIO, BF3OEt2, H20, 67% c)
Pb(OAc)4, MeOH; then NaCNBH3, 93%

9
The protocol involves the preparation of a chiral enol silane 31 with homochiral
lithium amide 30. Enol silane 31 was oxidized with PhIO (iodosobenzene) producing a-
hydroxyketone 32 with the hydroxyl group in an equatorial position. Oxidative cleavage
of recrystallized a-hydroxyketone 32 was effected by treatment with lead tetraacetate in
methanol, followed by reduction with NaCNBHi, in the same pot, yielding the C-
nucleoside 33 with high enantiomeric excess (>98% ee).
Cleavage of the Carbon-Oxygen Bridgehead Bond, C1-C2, of the Oxabicyclo[3.2.1|
System
Cleavage of the carbon-oxygen ether bond allows the access to functionalized
seven-membered rings, avoiding entropically disfavored cyclization approaches to it. In
addition, further cleavage of the seven-membered ring provides an efficient route to
polysubstituted acyclic chains.
Also involving enolate formation, Grieco and Hunt performed opening at the
bridgehead of an oxabicyclo[3.2.1] system.17 Thus, enol ether 34, generated from
treatment of bicyclic ketone 2 with LDA, THF, HMPA and TBSC1, was mixed with 2.0
equiv. of l-methoxy-l-(tert-buthyldimethylsiloxy)-ethylene 35 in a 4.0 M solution of
lithium perchlorate in diethyl ether (LPDE) at room temperature affording
cycloheptadienes 36 and 37 in a ratio of 4:1 in quantitative yields (Scheme 1-8).
Scheme 1-8. Ring opening of oxabicyclo[3.2.1] system with a silyl ketene acetal

10
Cycloheptadiene 36 was transformed into the C(19)-C(27) fragment 41 of
Rifamycin S (Scheme 1-9). Grieco and Hunt also applied the protocol in the synthesis of
the chiral C(19)-C(26) and C(27)-C(32) fragments of Scytophycin.18
TBSO
e.f.g.h.i
â–º
OH O. O
/\
41 C(19)-C(27)
segement
Scheme 1-9. Synthesis of C(19)-C(27) fragment of Rifamycin. a)TBAF,THF,HOAc b)
LiAl(OtBu)3H, THF, -20°C c ) i. NaOH, THF, MeOH, H20 ii. C02 iii. KI/I2,
0°C d) Bu3SnH, THF, AIBN, 60°C e) TESC1, 2,4,6-collidine, CH2C12, -78°C
í) TPAP, NMO, CH2C12, 4h g) TBAF, HOAc, THF h) MCPBA, absolute
EtOH i) K2C03, MeOH, 0°C, lh
Lautens and Cha et al. ' have also proven the utility of cleaving the carbon-
oxygen bridgehead bond, C1-C2, of the oxabicyclo[3.2.1 ] system in the synthesis of
natural products. Lautens and co-workers explored the reactivity of oxabicyclo[3.2.1 ]
compounds toward nucleophilic addition, demonstrating that they can be opened with

reagents such as aluminum hydrides,211 high order cuprates,21 and organolithium22 type-
nucleophiles by an Sn2’ mechanism. Examples are illustrated in Scheme 1-10.
OBn
OBn
O
DIBAL-H>
Hexanes’
OBn reflux
3
O
3
45
1
46
<1
Scheme 1-10. Ring opening of oxabicyclo[3.2.1 ] compounds by nucleophilic additions.
Minor products derived from anti Sn2, such as 45 were also obtained when
organocuprates were used as the nucleophile. Subsequent manipulations of
cycloheptanol 42, including ozonolytic cleavage, afforded the C(17)-C(23) unit of
ionomycin (Scheme 1-11).

12
OBn
1. Swern [O]
2. DIBAL-H, -78°C
OH 3. NaH, PMBBr"
72%
OBn
1. 03, MeOH, -78°C
2. NaBH4
"'OPMB 3. DDQ, 0°C
49 72%
Scheme 1-11. Synthesis of the C( 17)-C(27) segment of ionomycin
Cha et al. took advantage of the [4+3] cycloaddition to synthesize phorboF and
tropone-containing natural products, such as imerubrine23, colchicine24, and hinokitiol"5
from complex oxabicyclo[3.2.1] systems. Cha et al. employed Fohlish" and Mann
methods to cleave the carbon-oxygen ether bond of the oxabicyclic compounds. In his
synthesis of the tropolone, hinokitiol, Moriarty’s oxidation of cycloadduct 51 produced
alcohol 52, which was subjected to double elimination according to the procedures of
Fohlish et al.27 and Mann et al.28 (Scheme 1-12).
O
Scheme 1-12. Cha’s synthesis of hinokitiol

13
The value of oxabicyclo[3.2.1] compounds in organic synthesis has been
demonstrated by the examples presented above. This dissertation focuses on the use of
olefin metathesis to cleave the unsaturated bond, C6-C7, of the 8-oxabicyclo[3.2.1]octene
derivatives to generate a c¿s-2,6-disubstituted pyran moiety with two differentiated ends
that can be useful to synthesize pyran-containing natural products.
Olefin Metathesis
Olefin metathesis24 is a method that allows a redistribution of olefins. During the
reaction two olefin partners are exchanged to give a new unsaturated carbon-carbon bond
in the presence of a metal carbene complex. Since the discovery of the olefin metathesis
in the mid 1950’s, a large number of catalyst systems have been reported to initiate this
reaction. However, it was not until the accepted metal carbene mechanism proposed by
Chauvin that scientists were provided with a basis for the design and development of
well-defined catalysts. Chauvin and Herisson3" proposed a [2+2] cycloaddition between
an olefin 53 and a metal alkylidine catalyst 54 to generate a metallocyclobutane
intermediate 55. The metallocyclobutane intermediate 55 undergoes cycloreversion
resulting in a new olefin 56 and a new metal alkylidine 57. A second [2+2] cycloaddition
between 57 and 58, followed by cycloreversion yields the metathesis product 60 and the
turnover of the catalyst 61 (Scheme 1-13).
The development of well-defined catalysts promoted the steady increase of the
olefin metathesis usage in organic and polymer chemistry. Some well-defined catalysts
are presented in Figure 1-2.

14
Figure 1-2. Selected olefin metathesis catalysts
Molybdenum and tungsten catalysts 62, 63, and 64 were proven to be very
effective for this reaction. Basset and coworkers’s catalyst 64 was tolerant to various
functional groups such as silicon, phosphorous and tin; however, its efficiency varied
according to the steric demand of the substrate.31 Tungsten 62 and molybdenum 63
(Schrock’s catalysts) presented high reactivity toward a broad range of substrates.32
Catalyst 62 is a very useful catalyst for olefin metathesis; however, despite its high
reactivity, 62 presents some drawbacks. These are extremely high sensitivity to air, and

15
moderate to poor functional group tolerance. Ruthenium catalysts 65-67 developed by
11 if
Grubbs and coworkers ' and co-workers overcame those problems. They were more
tolerant to functional groups, reacting mainly with olefins in the presence of alcohols,
aldehydes, amides and carboxylic acids. Metal alkylidine 65 was the first ruthenium
catalyst developed by Grubbs et al.33 Besides its stability and tolerance toward many
functional groups, it was not as reactive as Schrock’s molybdenum catalyst. Shortly after
catalyst 65, ruthenium catalyst 66 was reported to present a higher reactivity.34 In the
aim of finding a better catalyst, Grubbs et al. reported another ruthenium catalyst 67 in
1999.35 Catalyst 67 exhibited higher reactivity, thermal stability and a lower rate of
decomposition compared to metal alkylidine 66. For this reason, 67 is commonly
referred as “Super Grubbs” catalyst.36 Today, metal alkylidines 62, 66 and 67 are the
most widely used catalysts for the olefin metathesis reaction. Our research involves
mainly the usage of Grubbs catalyst 67. Its mechanism of activity has been demonstrated
to proceed by a “dissociative” pathway as depicted in scheme 1-14.37
CI/> __/h -PCy, C\/} ^Ph + Olefin
+PCy3 crRu_ - Olefin
POy3
CI//¿ -
cr^u
.Ph
Cl/, '
crRu
Ph
68 69 70 71
Scheme 1-14. Dissociative olefin metathesis mechanism
The 16-electron specie 68 generates a 14-electron complex 69 by the loss of a
phosphine. This complex then associates with an olefin as in intermediate 70 that
promotes the metallocyclobutane formation of 71 that will eventually generate the
metathesis product and the catalyst turnover. One of the most fascinating aspects of the
olefin metathesis is that several types of chemistry can be performed with the same
catalyst depending on the reaction conditions and the nature of the substrate.

16
Types of Olefin Metathesis Reactions
There are five main variants on the olefin metathesis reaction. These are: a) ring¬
opening metathesis polymerization (ROMP) b) acyclic diene metathesis (ADMET) c)
cross metathesis (CM) d) ring-closing metathesis (RCM) e) ring-opening cross metathesis
(ROCM) (Scheme 1-15).
a) 0 + ^
Scheme 1-15. Different types of olefin metathesis reactions
Ring-opening metathesis polymerization
Ring-opening metathesis polymerization (ROMP) marked the beginning of olefin
metathesis, since olefin metathesis was discovered while examining the polymerization
of olefins. In this reaction, driven by the release of ring strain, a monomer is opened by a
metal alkylidine and the resulting intermediate reacts with another monomer initiating the
propagation for polymerization. The success of this reaction has been described in
several reviews. '* The main advantage in the polymer chemistry is that well-defined
catalysts allow for the realization of living polymerization. Thus, control of the

17
architecture and length of the polymer can be obtained.39"40 This has many applications
for the development of new materials.41'42
An area of research that has been growing in the last decade is the use of
functionalized polymers as scaffolds for the delivery of drugs. ROMP provides a viable
route to prepare polymeric scaffolds for the delivery of drugs by attaching the drug to a
substrate that can undergo polymerization, such as norbomene. The anti-inflammatory
and cancer preventive indomethacin 72 was attached to exo-5-norbomeol 73 to form
monomer 74 which can undergo polymerization (Scheme 1-16).43
Cl
Scheme 1-16. Monomer preparation toward a functionalized polymeric scaffold for drug
delivery
Acyclic diene metathesis
Acyclic diene metathesis (ADMET) is the acyclic cross metathesis of dienes or
the acyclic version of ROMP. In this reaction the elimination of gaseous ethylene from
the polymerization is believed to be the driving force of the reaction. In an example,
biopolymers were created by Wagner and coworkers using ADMET in dienes that
incorporated amino acid units in the backbone (Scheme 1-17).44
OR OR
Scheme 1-17. Biopolymers from ADMET

18
Cross metathesis
Another type of olefin metathesis is the cross metathesis reaction (CM). In this
reaction, the rearrangement of two olefins results in a new carbon-carbon double bond
incorporating one carbon from each partner. The CM reaction is advantageous since it
allows the synthesis of highly substituted olefins. One disadvantage, however, is the
formation of unwanted self metathesis products. Another challenge is the control of
geometry of the newly formed olefin (Scheme 1-18).
+ R2^- [Catalystl r^R2 + r/^r2 + r2/^r2
desired self-metathesis product
product undesired
Scheme 1-18. Possible cross metathesis products
To overcome these problems it is necessary to determine a way to minimize self¬
metathesis, thus maximizing cross-coupling as well as improve the stereoselectivity of
the reaction. Over the years researchers have worked on these problems. With the
development of well-defined catalysts, cross metathesis has gained more attention as a
viable tool in organic chemistry. In 1995, Crowe and coworkers showed the viability of
acrylonitrile to undergo cross metathesis with a molybdenum based catalyst.45 Although,
the cross metathesis product was obtained in moderate yield, high cis selectivity was
obtained and no self-metathesis product was observed (Scheme 1-19, entry 1). Crowe
also showed that addition of steric bulk at the allylic position of the olefin promoted trans
selectivity. This was demonstrated with a series of allyl silanes (Scheme 1-19, entries 2,
3).46 Blechert et al. observed the same with substituted allylic amines, reporting the first
example of exclusively trans selective CM (Scheme 1-19, entries 4, 5).47 The
homodimerization was controlled by the electronic and steric parameters of one of the

19
alkene partners in the CM reaction. Furthermore, the high reactivity and tolerance to
functional groups allowed catalyst 67 to give CM products of disubstituted olefins
(Scheme 1-19, entry 6)48 and a,J3-unsaturated carbonyls49 or acrylic amides50 (Scheme 1-
19, entries 7, 8). One important application of the CM reaction is that it allows for the
preparation of reagents by providing different highly functionalize olefins. Products
derived from CM of allyl silanes (Scheme 1-19, entries 2, 3) are useful for silane addition
to carbonyl compounds (Sakurai reaction). Also, products from the CM reaction of vinyl
boronates51 with alkenes are useful for Suzuki couplings (Scheme 1-20, entries 1, 2),
while CM of allyl boronates^2 with alkenes are analogous to allyl silane compounds, and
can be added to aldehydes and ketones (Scheme 1-20, entries 3, 4).
Ring-closing metathesis
A well-recognized type of metathesis reaction is the ring-closing metathesis
(RCM). RCM has found the widest application in synthesis, being a key step in various
total syntheses. The release of volatile ethylene is believed to drive this reaction. Its
value consists in being a reliable method for the formation of small, medium and large
membered-rings. Examples of RCM abound in literature. RCM have been employed in
the synthesis of carbohydrates,53 numerous heterocycles, and peptides.54 Perhaps, the
major utility of this application has been found in the synthesis of natural products. RCM
was used at the early stage of the synthesis of a marine natural product dysinosin A
(Scheme 1 -21 ).55 Meyers and co-workers reported the first successful synthesis of (-)-
griseoviridin using RCM strategy in a macrocyclization that led to the 20-membered ring
antibiotic (Scheme 1-22).56

20
Entry
1
Crowe:
OBn 62 5 mol%
NC"^ 2 eqi
PhO
62 5 mol%
^SiMe3
2 equiv
trans.cis 2.6: 1
72%
PhO
Blechert:
O
OTr
CI3C N
H
Cbz
C02Me
H H
62 5 mol% PhO^
2 equiv trans.cis 7.6: 1
77%
Si(i-Pr)3
62 10 mol%
^^^3 Ci3c^n
1.5 equiv h
OTr
SiMe-3
Grubbs:
BzO
O
All trans, 98%
C02Me
62 CtaV'^^SiMe3
H H
All trans, 92%
1.5 equiv
67 5 moP/o
^H^Hac
2 equiv
67 5 mol%
TBSO
BzO
OAc
trans.cis 4: 1
81%
TBSO
C02CH3
trans.cis 20: 1
62%
HoN
67 5 mol%
AcO
H2N v ,3
OAc
All trans, 89%
Scheme 1-19. Examples of intermolecular Cross Metathesis

21
Entry
1 BzO +
67 (5 mol%)
40°C,12h
66%, 8:1 E/Z
2 AcO'^HrJ^ +
67 (5 mol%)
40°C,12h ’
AcO'^Hr3^
65%, 13: 1 E/Z
3
1.67 (2.5 mol%)
40°C, 12h
2. PhCHO (1.5 equiv)
79%, 3.6: 1 anti/syn
4
+
1.67 (2.5 mol%)
40°C,12h
2. PhCHO (2 equiv)
88%, 99: 1 anti/syn
Scheme 1 -20. Cross metathesis of vinyl and allyl boronates
Scheme 1-21. Application of RCM in the synthesis of Dysinosin A

22
Scheme 1-22. Application of RCM in the synthesis of (-)-Griseoviridin
In addition, RCM involving alkynes has been reported. One example is presented
in scheme 1-23. Pyroglutamic acid 81 was converted to the enyne 82, which underwent
RCM with ruthenium carbene 66. Compound 83 was further elaborated to yield the
alkaloid (-)-Stemoamide.57
Me
O
(-)-Stemoamide
Scheme 1-23. RCM with an alkyne at the early stage of the synthesis of (-)-stemoamide

23
Ring-opening cross metathesis
Ring-opening cross metathesis (ROCM) is a variant of cross metathesis where one
of the olefin partners is a cyclic olefin. In this type of metathesis, the release of ring
strain drives the reaction. ROMP is avoided by performing the reaction under diluted
conditions with excess of the acyclic olefin partner. This olefin metathesis variant has
not received as much attention as the RCM. This is because it is necessary to have
efficient control of the regio- and stereoselectivity in order to make this strategy
synthetically useful. Therefore, ROCM has been limited to unsubstituted or symmetric
cyclic olefins. Regiochemical issues arise when the starting cyclic olefin is not
symmetrically substituted. For example, whereas ROCM of symmetric bicyclic alkene
84a with a terminal alkene can produce only one product (85 = 85’, X = H), an
unsymmetrical bicyclic alkene such as 84b can produce two regioisomers 86 and 87 (X i
H) (Scheme 1-24).
Scheme 1 -24. Possible regioisomers from unsymmetrical bicyclic alkenes
Early successful examples using well-defined olefin metathesis catalyst were
disclosed by Snapper et al. in 1995. He reported the ROCM of various cyclobutenes with
a series of terminal alkenes, using vinylidene catalyst 65 (scheme 1 -25).r's His studies
included the first examples of regioselectivity in the ROCM of unsymmetrical bicylic
systems. Whereas symmetric cyclobutenes gave a ratio of stereoisomers favoring the Z-
alkene, asymmetric cyclobutenes gave two regioisomers, where the more hindered alkene

24
was preferred (scheme 1-25, entry 2 and 3). Snapper explained that the products
distribution was consistent with an alternating alkylidene mechanism, where the
alkylidene A, generated from the reaction of the terminal olefin and the catalyst, was
preferred over the methylidene B as the active catalyst in the reaction (path I was favored
over Path II, scheme 1-26). In addition, Blechert et al.59 and Aijona et al.60 reported
regioselective ROCM examples of bicyclic alkenes (Scheme 1-25, entries 4-6). In their
studies, the less hindered alkenes were obtained. Furthermore, Szeimies and Feng
disclosed a highly regioselective ROCM of various 1-arylcyclobutenes with
allyltrimethylsilane and 1 -octene. In this case, the less hindered regioisomer was
obtained as the only product (Scheme 1-25, entries 7-8).61
Scheme 1-26: A selective ROCM process based on the identity of the propagating
alkylidene

25
Entry
1 O;
Snapper
<â– 
1 -octene
65
Et
EL
2 HO"
OMe
1 -decene
65
1 -octene
65
HO"
o:
Hex
Oct
EL
HO"
63%
2.3:1 Z/E
v= 56%
88:89
rOct
1.3:1
88 2.3:1 Z/E
OMe_
89 1.7:1 Z/E
^HeX V
90 1:8.8 Z/E
OMe
|"=
81%
J., Hex
90:91
'''=s
4.1:1
91 2.1:1 Z/E
Blechert
Et
OTBDMS 65
OTBS
,SiMe^
N
66
""\^CH2Si(CH3)3
N -I
Boc
Boc^ o
85%
2:1 E/Z
83%
2:1 E/Z
Plumet
O
,OAc ^''^,^CH2OAc
OAc 66
t)Ac
92
AcO
93
Szeimies
75%
92:93
19:81
,SiMe-3
OoN
66
81%
CH2SiMe3 1.3:1 E/Z
1-octene
66
Hex
54%
1.9:1 E/Z
Scheme 1-25. Examples of ROCM reaction on symmetric and unsymmetrical bicyclic
systems

26
Although regiochemical issues have limited the use of ROCM to symmetrical
cyclic systems in organic synthesis, examples have demonstrated the possibility of
obtaining good regioselectivity in the ROCM reactions. However, additional efforts are
required to evaluate the steric and electronic influence of this issue.
Tandem Metathesis
Tandem or domino metathesis reactions involve more than one transformation in a
sequential order in one pot. They are desired because they can provide complex
structures in fewer steps. Tandem metathesis can be defined as the combination of two or
more consecutive metathesis operations. The driving force for these consecutive
operations is attributed to either the loss of ethylene or ring-strain release. These
reactions need to be carried out at high dilution to promote intramolecular rearrangement
over olygomer formation.
Grubbs et al. reported double ring-closing metathesis of dienynes, catalyzed by
ruthenium metal complex 65, producing fused bicyclic [n.m.O] rings.62 In an example,
reaction of compound 94 with catalyst 65 produces the metal alkylidine 95, which
undergoes RCM, forming a new metal alkylidine 96 which is able to undergo a second
RCM yielding the fused ring 97 (Scheme 1-27). Bulky substituents at the triple bond can
significantly slow down the reaction or cause no reaction to occur.

27
Scheme 1-27. Tandem metathesis with a dienyne
Blechert et al. reported the first total synthesis of (-)-halosaline using domino
metathesis with ruthenium catalysts 66.63 Employing the combination of
RCM/ROM/RCM operations, compound 101 was built in a single operation from 100
(Scheme 1-28).
Scheme 1-28. Total synthesis of (-)-halosaline
In another example, Aijona and Plumet et al. reported the combination of
ROM/RCM/CM with 2-azanorbomenones 103 toward the synthesis of 1-azabicyclic y-
lactam compounds 104 in modest yields 55-65% (Scheme 1-29).64 The domino
metathesis was catalyzed by ruthenium complex 66.

28
N
H
102
k2co3, koh
TEBA, CH3CN
N
66 (5mol%)t
H R'
")nN-
,.«R
n=1, 2, 3,4
103
H H
R' = H, CH2OAc
104
Scheme 1-29. Tandem ROM/RCM/CM of 2-azanorbomenones
Cyclized product 104 was observed with n = 2 or 3. With n = 1, 4 ROM/CM took
place affording 110. The distribution of the products is explained based on the
mechanisms depicted in scheme 1 -30.
There are two different pathways (A and B) that lead to either product 104 or 110.
If the initial metathesis occurs at the terminal olefin (path A), the formed metal alkylidine
105 undergoes intramolecular RCM followed by CM yielding the desired lactam 104.
On the other hand, if initial metathesis occurrs at the internal olefin, two regioisomers can
be formed giving rise to alkylidines 109a and 109b. Alkylidine 109a can not undergo
RCM, but instead undergoes CM with a terminal alkene yielding 110, whereas alkylidine
109b can give rise to the lactam 104. Nonetheless, compound 110 can be converted to
104 by a separate RCM reaction.

29
RCM
ROM
RCM
ROM
105
M
N
M
O
N
CH2=CHR'
CM
)n
N
A
109a
109b
CH2=CHR'
\
CM/
\RCM
v“"\
...»R
")nN
Ms
CH2=CHR'
CM o>.
110 104 107
R = CH=CH2, CH=CHCH2OAc; R' = H, CH2OAc
Scheme 1 -30. Regioselctivity of ROM/CM of 2-substituted 2-azanorbomenones
Catalytic Asymmetric Olefin Metathesis
The latest achievement in olefin metathesis is the possibility of getting chiral
molecules from racemic substrates with the development of chiral metathesis catalysts.
The first chiral catalysts were derived from Schrock molybdenum alkylidene 62 (Figure
1-3).65'67

30
Figure 1-3. Some Asymmetric Olefin Metathesis Catalysts
In 1993, Schrock et al. reported the first asymmetric olefin metathesis catalyst 111a
for the synthesis of chiral polymers by ROMP.65 In addition to that publication, reports
on the use of asymmetric olefin metathesis catalysts concentrated on the asymmetric ring¬
closing metathesis (ARCM) reaction. The first report on ARCM was disclosed by
Grubbs and Fujimura on the kinetic resolution of various dienes using asymmetric
ruthenium catalyst 112.66 Poor enantioselectivity was observed by these workers; an
example is presented in scheme 1-31, entry 1. Starting with the pioneer work presented
by Grubbs, Hoveyda and Schrock studied a series of asymmetric molybdenum-based
catalysts, 111 and 113, in the kinetic resolution of dienes (Scheme 1-31, entries 2-5).67

31
Entry
1
2
3
4
5
Grubbs
OTES
(S)-114;Krei = 2.2; catalyst 112
Hoveyda and Schrock
OTES
(R)-115; R = H; Krei=23; catalyst 111a
(R)-116; R = CH3; Kre, >25; catalyst 111a
(R)-117; R = n-pentyl; Kre|=10; catalyst 111a
(R)-118; R = sec-butyl; Krei=23; catalyst 111a
(R)-119; R = cyclohexyl; Kre!=17; catalyst 111a
OTES
(R)-120; Krei < 5; catalyst 111a
Kre| = 24; catalyst 113a
Kre| < 5; catalyst 113b
OTBS
(R)-121; Krei < 5; catalyst 111a
Kre| >25; catalyst 113a
Kre| < 5; catalyst 113b
Scheme 1-31. Kinetic resolution of dienes with chiral Mo-based catalyst
Regardless of the good enantiocontrol observed with the chiral catalyst 111a, they
concluded that it was not possible to generalize which catalyst provide the best
enantiocontrol. For compounds 120 and 121, catalyst 113a provided the highest
enantioselection. Thus, they highlighted the importance of testing a set of chiral catalysts
per substrate to decide which one gives the best enantiocontrol. The impact of ARCM in
organic synthesis was observed in the desymmetrization of achiral molecules. Two
examples are illustrated in scheme 1-32.

32
122
Me
Me
124
111a 2 mol%
no solvent
22°C 5 min
(R)-123
99% ee, 93%
113a 2 mol%
no solvent
60°C 4h
(R)-125
>98% ee, 98%
Scheme 1-32. Desymmetrization of achiral trienes
Thus, substrates 122 and 124 were transformed to optically enriched compounds
123 and 125 respectively without the need of solvent. The absence of homodimers when
these reactions were performed neat indicates the high degree of catalyst-substrate
specificity in these reactions.68 The ARCM strategy was utilized in the enantioselective
total synthesis of e« employing chiral catalyst 111a (Scheme 1-33).66
O
'XI
Me Cr'v;
111a (10 mol%)
C6H6, 22°C O
H2, Pd/C
87%
-Me
126 127 (+)-endo-brevicomicin
Scheme l-33. Application of Mo-catalyzed ARCM to the synthesis of endo-brevicomin
In addition to the ARCM, several examples on the tandem AROM/CM were
reported. Chiral catalyst 111a gave excellent enantioselection (92-99% ee) in the tandem
AROM/CM of various substrates. Two examples are illustrated in scheme 1-34.

33
O
111a (5 mol%)
C6H6, 22°C *
92% ee, 68%
128
129
H
Me
111a (5 mol%)
pentane
92% ee, 85%
131
130
O
10 mol%
132
Scheme 1-34. Mo-catalyzed tandem AROM/RCM
The reaction of 128 with catalyst Illa generates the heterocycle triene 129 in 92%
ee and 68% yield.70 To generate compound 132 from bicycle 130, diallyl ether 131 was
necessary.71 Based on earlier mechanisms, Schrock explained that reaction of 131 with
11 la led to the formation of the chiral Mo-methylidene complex (vs Mo-neophylidene),
which reacted with the sterically hindered norbomyl system 130 to initiate the catalytic
cycle.
Tandem AROM/CM has also been explored with a series of norbomyl substrates.
As depicted in scheme 1-35, chiral catalyst 111a catalyzed the tandem AROM/CM
reaction of norbomene systems with allyl silane or styrene. Although the yields were
moderate, the enantioselectivity was high.
To address the issue of a more practical and accessible chiral catalyst, in 2001
Hoveyda and Schrock et al. reported a new chiral molybdenum type catalyst 139 (scheme

34
nTBS
133
111a 5 mol%
C6H6. 22°C
134, >98% ee, >98% trans,
57%
Scheme
OMOM
135
111a 5 mol%
(MeO)3Si'
C6H6. 22°C
(MeO)3Si
OMOM
136, >98% ee, >98%
1-35. Mo-catalyzed tandem AROM/CM toward enatioselective
cyclopentanes
trans,
functionalized
88% ee, 80%
93% ee, 86% using 111a
tV
Scheme 1-36. In situ preparation and utility of chiral catalyst 139
This catalyst exhibited the properties of a biphenolate-based complex such as 111
and binaphtholate system such as 113, which were proven to be efficient earlier, thus
leading to the expection that catalyst 139 would be more suitable for a wide range of
substrates. The advantage of this catalyst relies on its easy preparation from
commercially available reagents. The catalyst can be used in-situ without the need of

35
purification, and is air stable. They also reported a supported chiral Mo-catalyst for
olefin metathesis that did not exhibit much activity.74
Chiral ruthenium-based olefin metathesis catalysts were also developed. Grubbs et
al. reported the first chiral Ru-based catalyst 144.75 As in the previous reports, the
enantioselection depended on the substrates. The highest ee reported in the study was
90% ee (scheme 1-37). They reported that the enantioselection was increased by the
addition of Nal.
142a R = H 143a 39% ee, 22%
142b R = Me 143b 90% ee, 82%
Scheme 1-37. ARCM with Grubbs’s Ru-based chiral catalyst
More recently, Hoveyda and coworkers developed a new ruthenium chiral catalyst
145.76 This new catalyst was reported to be air stable and recyclable besides promoting
high enantioselectivity, up to 98% ee, (Scheme 1-38).
There is no doubt that the olefin metathesis will remain as an area of continuing
interest with the development of more olefin metathesis catalysts.

36
/u , r /u, "
71% recov cat. #
Scheme 1-38: Air stable Ru-based catalyst in tandem AROM/CM
Since latrunculin B was the target chosen to apply our methodology of ring¬
opening metathesis of 8-oxabicyclo[3.2.1] systems to generate pyrans, the next segment
presents a brief history of the Latrunculins.
The Latrunculins
Two toxins, namely Latrunculin A and Latrunculin B, were isolated from the Red
Sea sponge Latrunculia Magnifica (keller) by Kashman et al. in 1980.77 The Latmnculia
Magnifica is sponge that enjoys freedom from predation because it secrets a reddish fluid
that causes fish to flee. Furthermore, squeezing this sponge in an aquarium is lethal to
fish. The fluid causes them agitation, followed by hemorrhage, loss of balance and the
death within 4 to 6 min.78 The interesting biological activities of this sponge lead to the
isolation, purification and characterization of the above mentioned toxins.

37
The structures of Latrunculin A and B were determined by spectroscopic methods
and X-ray difraction.77'79 The Latrunculins were the first marine macrolide known to
possess 14 and 16 membered-rings and the first natural products found to contain a 2-
thiazolidinone moiety. The biological interest of these molecules arises from the
reversible changes in the cell morphology, disruption of the microfilament organization
and inhibition of the cytoskeletal protein actin polymerization.783
In 1985, Kashman et al. reported the first synthetic approach towards the synthesis of the
Latrunculin synthon by the preparation of the bicyclic 2-thiazolidinone-tetrahydropyran
90 (Scheme 1-50), as well as isolation of two new toxins from the same sponge,
Latrunculin C and Latrunculin D.79 In 1989, he reported the isolation of another
congener, Latrunculin M, and the preparation of Latrunculin C and M from Latrunculin
B. To date, two total syntheses of Latrunculin B as well as Latrunculin A have been
reported. The first total synthesis of Latrunculin B was reported by Smith and coworkers
in 1986. The other total synthesis was elaborated by Fiirstner and coworkers in 2003.
Latrunculin A total syntheses were independently completed by Smith83 and White84 in
1990.
Total Syntheses of Latrunculin B
Smith’s total synthesis
Smith’s synthesis was achieved in a convergent and stereocontrolled route of 14
steps in 2% overall yield.81 Smith’s retrosynthetic analysis is depicted in Scheme 1-39.
Early in the synthesis, Smith connects the thiazolidinone moiety 152 to ortho ester 151 by
an aldol reaction that generates 150. An interesting structural reorganization occurs upon
exposure of the new ortho ester 150, to tosic acid which leads to the pyran 148.
According to Smith, the skeletal rearrangement involves hydrolysis of the ortho ester 150

38
to give a hydroxy ester intermediate 153, which in the presence of methanol forms the
mixed methyl ketal 154 (Scheme 1-40). Completion of the synthesis is accomplished by
reduction of ester 154 with DIBAL, a Wittig reaction that connects the advance
intermediate 148 with the northern hemisphere of the molecule 149, and an inverted
Mitsunobu macrolactonization. The northern hemisphere of the molecule, the Wittig
reagent 149, was prepared in 5 steps in 54% overall yield (Scheme 1-41).
O
Scheme 1-39. Smith’s retrosynthetic analysis of Latrunculin B
Scheme 1-40. Acid catalyzed formation of the pyran moiety in Smith’s synthesis of
Latrunculin B

39
Scheme 1-41: Synthesis of the northen hemisphere of the Latrunculin B molecule.7
Fiirstner’s total synthesis
Fürstner assembled the molecule using aldol chemistry, esterification, ring-closing
• 82
alkyne metathesis and Lindlar reduction as the key reactions.
RCAM / Lindlar
158
T
RN^ 160
cr s
Scheme 1-42. Fiirstner’s retrosynthetic analysis of Latrunculin B
Reaction of building blocks 158 and 160 produces aldol product 161, which under
acid-catalyzed conditions rearranged to form pyran 162. Compound 162 was then
reacted with 159 to produce 163, which upon alkyne metathesis, Lindlar reduction, and
deprotection gave the target molecule, Latrunculin B (Scheme 1-43). The total synthesis
which comprised 16 steps as the longest sequence was performed in 6% overall yield.

40
Scheme 1-43. Fürstner’s synthesis of Latrunculin B
Total Syntheses of Latrunculin A
Smith’s total synthesis
Smith’s total synthesis of Latrunculin A involves the same common intermediate
150 previously used in his synthesis of Latrunculin B (Scheme 1-44).83 However, the
nitrogen atom had to be protected as a PMB (para-methoxybenzyl) rather than a benzyl
group due to interference of the sensitive diene moiety not present in Latrunculin B at the
time of its deprotection. Latrunculin A was then completed in an analogous manner to
the synthesis of Latrunculin B by a Wittig reaction that connects the common
intermediate 150 with the northern hemisphere of the molecule following the inverted
Mitsonubu macrolactonization. The northern hemisphere of Latrunculin A and B is the
differing point in these molecules. The preparation of the northern hemisphere of
Latrunculin A (164) took 10 steps and was obtained in 34% overall yield (scheme 1-45).

41
Scheme 1-44: Smith’s retro synthetic analysis of Latrunculin A
1. Swern Oxidation ^
2. (EtO)2POCH2CC>2Et
1. DIBAL, -78°C
2. DHP, PPTS *
3. nBuLi, CIC02Me
PHDO
CO2M6
167
1. Me2CuLi, -78°C
2. Amberlyst
3. LiOH
168
1. NBS, Me?S ,
2. PPh3, MeCN
Scheme 1-45: Synthesis of the northern hemisphere of Latrunculin A molecule
White’s total synthesis
White’s total synthesis of Latrunculin A was designated to exemplify his
methodology towards (E,Z)-1,3-dienes that involves tandem addition of an enolate

42
dianion to a dienylphosphonium salt following a Wittig reaction of its derivative with an
aldehyde.84 The target was sectioned in three principal subunits presented in scheme 1-
o>-‘
172
Scheme 1-46. Principal subunits in White’s total synthesis of Latrunculin A
Fragment 170 was derived from the union of epoxide 173 and sulfone 174
(scheme 1-47). Aldehyde 176 was employed in his novel methodology to form 183 in
scheme 1-48.
Y-^X/OTBDMS
d 173
BnO" ''S02Ph
174
nBuLi
Ph02S OH
THF-HMPA BnO^^-'^x/"~'X//^OTBDMS
175
OSEM
OTBDMS
176
Scheme l-47. Construction of segment 170 in White’s total synthesis of Latrunculin A

43
LDA (1 equiv)
THF, -50°C
LDA (2 equiv)
© ©
Br Ph3P
dienylphosphonium
salt 178
OLi OLi
enolate dianion 180
Scheme l-48. Construction of segment 171 in White’s total synthesis of Latrunculin A
Condensation of intermediate 183 with the (R)-4-acetyl-2-oxothiazolidine 172
proceeded without the need to protect the nitrogen atom. This condensation produced an
epimeric mixture of the alcohols 184. Selective deprotection of the SEM ether and
exposure of the resulting diol to acidic methanol produced separable ketals 185 and 186
(Scheme 1-49). Cleavage of the ester of compound 185 followed by a Mitsonubu
reaction, and hydrolysis afforded the natural compound Latrunculin A in 26 steps as the
longer linear sequence in 0.9 % overall yield. In a parallel sequence, ketal 186 was
converted to 15-epilatrunculin A.

44
*• Latrunculin A + 15-epilatrunculin A
Scheme 1-49. Completion of White’s total synthesis of Latrunculin A
Kashman’s Approach to the Latrunculin Synthon7 ’
Kashman’s approach to the Latrunculin synthon started with L-cysteine 189, which
by reaction with phosgene afforded a thiazolidinone moiety. After protection of the
thiazolidinone nitrogen atom by benzylation, the ester moiety was converted to an acid
chloride with thionyl chloride affording 188. Stille coupling of the acid chloride with the
siloxy stannane yielded 189, which produced the bicyclic 2-thiazolidinone-
tetrahydropyran 190 after removal of the TBS protecting group and partial hydrogenation
over Lindlar’s catalyst (Scheme 1-50).

45
COCI
C02Et
h2n
SH
187
1.COCL
2.BnBr, NaH
3.H+, SOCl2
188
TBSO(H2C)2C=CSnBu3
Pd(PPh3)4
190
Scheme 1-50. Kashman’s synthetic approach towards the Latrunculin synthon
Kashman's Synthesis of Latrunculin M and C79'80
From the same sponge from which Latrunculin A and B were isolated, three
additional marine toxins were obtained by Kashman. These toxins are Latrunculin C, D
and M, which are presented in Figure 1 -4.
Latrunculin C5’6 Latrunculin D5 Latrunculin M6
Figure 1 -4. Latrunculin C, D and M
Kashman et al. converted Latrunculin B to Latrunculin C and its 15-epilatrunculin
C by reduction with sodium borohydride.79 He also prepared Latrunculin M, a minor
component of the L. Magnifica sponge, from Latrunculin B in a four step sequence
(Scheme 1-51).

46
Scheme 1-51 Kashman’s synthesis of Latrunculin M from Latrunculin B

CHAPTER 2
RESULTS/DISCUSSION
Intermolecular Ring-Opening Cross Metathesis (ROCM)
Our research focused on the synthesis of the tetrahydropyran moiety using
ruthenium-based olefin metathesis on oxabicyclo[3.2.1 Joctene derivatives. Initial
investigations centered on the study of the parent compound 8-oxabicyclo[3.2.1]oct-6-en-
3-one3 (1). The intermolecular ring-opening metathesis of 1 was explored with a series
85 87
of electronically different terminal alkenes (Scheme 2-1).
67 L = Mes-N^N Mes
66 L= PCy3
Scheme 2-1. ROCM of 8-oxabyciclo[3.2.1]oct-6-en-3-one 1 with terminal alkenes
Table 2-1. ROCM of 8-oxabyciclo[3.2.1]oct-6-en-3-one 1 with terminal alkenes85,86
Pyran
Alkene
-R
Catalyst
Yields (%)
192a
Styrene
-Ph
67
83
192b
2-bromostyrene
-o-BrPh
67
65
192c
1 -hexene
-(CH2)3CH3
66
89
192d
allyl bromide
-CH2Br
67
71
192e
4-bromo-1 -butene
-CHCH2Br
67
72
192f
methylacrilate
-C02Me
67
33
192g
acrylonitrile
-CN
67
10
The reaction was highly selective for the formation of the E-alkene and
demonstrated the correlation between the alkene used and the reaction yields. The yields
were better when electron rich alkenes were used rather than electron poor alkenes.
47

48
Literature reports support the limited reactivity of electron poor alkenes in cross
metathesis.46'88 Thus, electron rich alkenes afforded the highest yields.
Another observation was the increment of reactivity of the system when the
hybridization of the carbonyl group was changed from sp2 to sp3.85-86 This was revealed in
attempts to improve the yield of the reaction. Though the yields were good (up to 83%
with styrene as the donor alkene), the reactions were not reaching completion. Studies
demonstrated that the reaction reached equilibrium after a certain amount of starting
material was consumed. To drive the reaction to completion, the addition of a set of 1,3-
diaxial interactions in the reaction intermediate (194) was proposed. This was done by
placing a bulky group at C3 in the endo position (Scheme 2-2).85-86 The idea consisted
of creating unfavorable steric interactions between the bulky group and the two
appendices of the opened intermediate, thereby driving the reaction to product, and
avoiding reversibility.
1 = X = Y = O 194a =X =
192 = X = OTBS, Y = H 194b = X =
193 = X = H, Y = OTBS 194c = X =
Y = O
OTBS, Y = H
H, Y = OTBS
X
Scheme 2-2. Reversibility of the ROCM reaction
As predicted, the consumption of the starting material was complete; however, the
yields decreased dramatically (Table 2-2).85-86 A competitive reaction was occurring,
namely the ring-opening metathesis polymerization.

49
L
CI",Ru=\
CIPCy3Ph
^ R (5eq.)
CHCI3 (0.3M)
192 = X = OTBS, Y = H r~\
193 = X = H, Y = OTBS 67 L - Mes-N^N Mes
66 L= PCy3
Scheme 2-3. ROCM of the reduced derivatives85’86
Table 2-2. ROCM of the reduced derivatives85’86
Pyran
Alkene
-R
Catalyst
Yields (%)
196a
Styrene
-Ph
67
60
196b
2-bromostyrene
-o-BrPh
67
18
196c
1 -hexene
-(CH2)3CH3
66
63
196d
allyl bromide
-CH2Br
67
62
196e
4-bromo-1 -butene
-CHCH2Br
67
56
196f
methylacrilate
-C02Me
67
0
197a
Styrene
-Ph
67
67
197b
1 -hexene
-(CH2)3CH3
66
75
196a-f= X = OTBS, Y = H
197a-b= X = H, Y = OTBS
Exo-silyl ether 193 showed that despite the absence of the large group in the axial
position, the reactivity was enhanced. Thus, the exo-silyl ether gave results comparable to
the endo-silyl ether using styrene and 1 -hexene as the donor alkene in the metathesis
reaction (Table 2-2, last two entries).
Based on these observations it was understood that a change in hybridization at C3,
and not the position of the bulky silyl ether, was responsible for the change in reactivity.
In an attempt to provide a rationale for whether the hybridization, steric hindrance or
electronic effects were affecting the reactivity of the system, further studies were
undertaken.
Kinetic Studies
Kinetic experiments were conducted with a series of 8-oxabicyclo[3.2.1]octene
derivatives differing by the functional group placed at C3. The substituent placed at C3
varied according to three categories: oxygen in the endo position (ether 192, alcohols 201

50
and 202, and ketal 203), hydrogen in the endo position (ether 193, methylene 204 and
alcohol 205), and sp2 hybridization (ketone 1, oxime 199 and exo-methylene 200). The
plan was to generate a relative trend of the reaction rate among the bicycle derivatives to
have a general idea of the effects of the remote substituents in the reactivity of the
system.
sp hybridized:
1 199 200
sp3 hybridized with electron rich oxygen in the endo position:
192 201 202 203
sp3 hybridized with hydrogen in the endo position:
193 204 205
Figure 2-l. Substrates considered for the kinetics studies.
The substrates were derived from ketone 1 (Scheme 2-4). Substrates l,3192,89
202,89 203,90 and 19389 were known compounds and were prepared according to reported
procedures in the literature. Oxime 199 was made in 81% yield by condensation of 1
with methoxylamine hydrochloride in the presence of molecular sieves. The exo¬
methylene 200 was prepared following a Peterson olefination protocol91 of 1, since
Wittig conditions produced low yields. Wolf-Kishner92 reaction of 1 afforded compound
204 in 68% yield. Grignard addition to ketone 1 in the presence of cerium chloride

51
yielded alcohol 201 in 74% yield; if cerium chloride was not present, aldol product was
isolated. Epoxidation of 200 with /n-CPBA produced epoxides 207-210, and the opening
of epoxide 208 with lithium aluminum hydride gave alcohol 205.
Py, MeONH2.HCI
CH2CI2, MS 3A°r
81%
TMSMgCI, THF
CeCI3.7H20, 76%
MeMgCI, THF|
CeCI3.7H20, 74%
KH, 4Q°C
ether, 80%
200
200
208
h2nnh2.h2o,
KOH 195°C
204
MCPBA, 0°C
CH2CI2
LAH, THF, 80%
207 208 209
8% 13% 32%
O
205
210
14%
(Scheme 2-4). Synthesis of the some substrates employed in the kinetic studies
The substrates were compared with 4,10-dioxa-tricyclo[5.2.1.0 2-6]dec-8-ene-3,5-
dione (198), namely the standard, in a ring-opening metathesis polymerization reaction
(Scheme 2-5). The relative rate of the ring opening polymerization of the substrate
versus the standard was determined using a Varían inova 500 MHz NMR. This particular
standard was chosen because: (i) its alkene proton does not overlap with the alkene

52
proton of the substrates studied; (ii) the resulting polymer precipitates out of solution
most of the time and when it does not, the signals of the resulting polymer do not
interfere with the signals monitored; (iii) its reactivity in the ROMP reaction is
comparable with the substrate’s reactivity; (iv) it is easily obtained by a Diels-Alder
reaction of furan and maleic anhydride. Thus, the standard (198) and each substrate were
mixed at different relative concentration with an internal standard to normalize their
integral area. These concentrations varied from 0.25 to 16 [standard/substrate] ratios.
The variation in concentration was done to observe how the rate was affected by
concentration. To the mixture, Grubbs’ second generation catalyst (67) was added, and
the consumption of the compounds versus time was monitored by proton NMR. Thus,
spectra were acquired on automation (ca. 100 points for the course of the reaction), which
varied from 10 minutes to 1.5 h, and the integrals of the alkene protons of the substrate
and of the standard were normalized against the integral of a comparable amount of
internal standard, benzene or residual TMS from the deuterated solvent. The normalized
proton integral area was the concentration measurement during the course of the
reactions. The plot of concentration versus time does not follow first order kinetics,
displaying an induction period at the beginning of the reaction (Figure 2-2). Therefore
individual rates for the reactions of the substrate and the standard could not be obtained.
Thus, the data was obtained by plotting the natural logarithm of the substrate
concentration against the natural logarithm of the standard (In [substrate] vs. In
[standard]), which showed linearity. Figure 2-3 is a representative example of the
linearity obtained and the generation of the data by the lineal regression equation.

53
Concentration vs Time
0.2
Time (sec)
Figure 2-2. The evolution of the normalized concentrations of the substrate [A] and the
standard [B]
Relative ksub/kstd Rate
In [Std]
Figure 2-3. Representative example of the generation of the data with the linear
regression equation of the ln[sub] vs ln[std]
This is consistent with the alkenes being consumed in a first order reaction, where
the concentration of the catalyst is included in the rate constant as established by the
following equations: d[sub]/dt = ksub[cat][sub], d[std]/dt = kstd [cat][ std], which leads to
ln[sub] = pln[std] + const., where p = ksub / kstcj and const. = ln[sub]¡n¡t - pln[std]¡nit. In the

54
induction period, the active catalyst is formed, but by using the slope of ln[sub] vs.
ln[std], the relative rates can be measured without considering the catalyst concentration.
Relative rates measured at different ratios [std]/[sub] are given in Table 2-3.
Scheme 2-5. Possible polymers from the ROMP of substrates and standard
Table 2-3. Relatives’ rates ksub/kstd of ring-opening metathesis polymerization of 8-
oxabicyclic[3.2.1] octene derivatives
Substrate
X
Y
Ratio [Std/Sub]; nm=not meassured
0.25
1
4
8
16
1
X
II
X
II
o
nm
0.21
0.29
0.34
0.42
192
OTBS
H
5.2
6.34
6.34
nm
nm
193
H
OTBS
1.46
1.38
1.55
nm
nm
199
X = Y = N-OCH3
nm
0.34
0.49
0.56
0.55
200
CM
X
0
II
>-
II
X
1.56
1.05
1.15
1.29
nm
201
OH
ch3
4.12
4.25
4.55
nm
nm
202
OH
H
6.03
6.17
5.39
nm
nm
203
X = Y = 0CH2C(CH3)2CH20
3.18
3.83
4.21
4.66
4.62
204
X
ii
>
ii
X
2.38
2.22
1.91
nm
nm
205
ch3
OH
3.92
4.28
3.38
nm
nm
The concern for the influence of the reagents ratio on the relative rates comes from
the fact that there are four reactions by which the polymers grows:
(1) sub + std-poly—*- sub-std-poly (Kl)
(2) std + std-poly —* std-std-poly (K2)
(3) sub+sub-poly —- sub-sub-poly (K3)
(4) std + sub-poly—- std-sub-poly (K4)
where: sub = substrate
std = standard
poly = the growing polymer
std-poly -
0^°y0
Scheme 2-6. Possible pathways for the reagents consumption in the ring-opening
metathesis polymerization

55
The substrate as a monomer can react with the living-growing polymer of the
standard, path (1), or with its living-growing polymer, path (3). In the same way, the
standard could react with its living-growing polymer, path (2), or via path (4), reacting
with the living-growing polymer of the substrate.
The measured relative rate is p = ksub / kstd = (kl + k3) / (k2 + k4). By eliminating
the last two reactions, the rates in the reaction with the same polymer could be compared,
meaning p¡deai = p = kl / k2. This could be achieved by making k3 and k4 closer to 0 at
high [std] / [sub] ratio. High [std] / [sub] ratio would make the substrate and the standard
compete for the same living-growing polymer, thus k3 and k4 will approach to 0.
However, ratios [std] / [sub] higher than 16 are impractical, because of the errors arising
from a small ratio substrate / internal standard. The same errors can be observed towards
the end of the reaction monitored period. Measurements become less precise as the
concentrations of substrate or standard become too small compared to the internal
standard, benzene or residual TMS, and a contiguous number of points at the end of the
reaction were discarded in order to improve the precision. Comparisons can be seen in
Figure 2-4.
Figure 2-4. Comparison of selected data points: (a) left total of 76 points (b) right total of
50 points

56
Since the data obtained (Table 2-3) showed no correlation with the concentration,
additional p values were taken for compounds 192,199, 202-204 at a ratio of [std]/[sub]
= 1. Table 2-4 presents all the values measured, the average of these values and the 95%
confidence interval.
Table 2-4. Relative rates ksub/kstd and confidence interval (95%) from the ROMP of 8-
oxabicyclic[3.2.1] octene derivatives
Substrate
X
Y
P
Mean
P
Interval for
95%
confidence
1
X
II
-<
II
o
0.21
0.29
0.34
0.42
0.32
0.18
0.45
192
OTBS
H
5.20
6.34
6.34
6.81
7.11
6.6
7.09
7.09
6.5
5.96
7.03
193
H
OTBS
1.46
1.38
1.55
1.43
1.28
1.59
199
X = Y = N-OCH3
0.34
0.49
0.56
0.55
0.78
0.40
0.75
0.76
0.58
0.44
0.72
200
X = Y = CH2
1.56
1.05
1.15
1.29
1.26
0.90
1.61
201
OH
ch3
4.12
4.25
4.55
4.31
3.76
4.86
202
OH
H
6.03
6.17
5.39
6.03
5.49
5.24
5.60
5.53
5.56
5.25
5.87
203
X = Y=
0CH2C(CH3)2CH20
3.18
3.83
4.21
4.66
4.62
3.83
3.77
3.69
3.97
3.54
4.39
204
X
II
-<
II
I
2.38
2.22
1.91
2.29
1.91
1.98
1.95
2.04
2.07
1.94
2.21
205
ch3
OH
3.92
4.28
3.38
3.85
2.79
4.92
All p values given in Table 2-3 and Table 2-4 correspond to an R2 greater than
0.98. For certain ratios, [std] / [sub], a R2 values greater than 0.98 could not be achieved.
This is because of an overlap between signals from polymer and signals from the
substrate or because the difference between the signals compared was too large. Those
cases were marked as nm (not measured) in table 2-3. Figure 2-5 presents a plot of the
average relative rates ksub / kstd and the 95% confidence interval for the substrates studied
in a decreasing order of reactivity.

57
Substrates
Figure 2-5. Plot of the average relative rates ksub / kstd and the 95% confidence interval
for the substrates studied in order of reactivity
Based on the results, the order of reactivity is depicted in Figure 2-6.
Surprisingly, the results obtained do not show a large difference in the relative rate values
among the substrates. The major difference was observed between ketone 1 and ether
192. Nonetheless, whereas the exo silyl ether 193 demonstrated the same reactivity in the
intermolecular reaction with styrene (Table 2-2), the results showed that it is less reactive
than the corresponding endo silyl ether 192. This is in agreement with the hypothesis that
a bulky group in the endo position would make the oxabicyclic system more reactive
toward ring-opening metathesis.

58
192 202 201 203
6.50 +/- 0.5 5.56 +/- 0.3 4.31 +/- 0.5 3.97 +/- 0.4
205 204 193
3.85+/-1.0 2.07+/-0.1 1.43+/-0.2
200
1.26+/-0.4 0.58+/-0.1
0.32 +/-0.1
Figure 2-6. Substrates arranged based on their order of reactivity from average relative
rates ksub / kstci and the 95% confidence interval
Though it was considered that oxygen in the endo position of the bicyclic substrates
would make the system more reactive from electrondensity donation to the double bond,
other factor such as steric hindrance play an important role in the reactivity of the
oxabicyclic compounds studied. This was exemplified by comparison of alcohols 201
and 205. Because 201 has an oxygen in the endo position, it was expected to be more
reactive than bicycle 205. Nonetheless, the alcohols displayed similar reactivity pattern,
indicating that sterics play a more important role than electronic, when the system is sp3
hybridized. Thus, a bulky group in the endo position would make the system more
reactive. On the other hand, the sp2 hybridized substrates showed a correlation between
electronegativity and reactivity. As a result, ketone 1 exhibited the lowest reactivity
when compared with the other sp2 hybridized derivatives 199 and 200. Although the
values obtained did not show a drastic difference among them, the knowledge obtained
can help improve sluggish reactions by tuning the reactivity of the system as well as

59
manipulating the system to avoid polymerization and provide the ROCM product.
Hence, the ROCM proceeds better (higher yield) with ketone 1 than with ether 192, but if
the interest is rather to obtain a polymer, ether 192 will be the preferred substrate for the
reaction.
As an expansion of the methodology to the construction of more substituted pyrans,
bridgehead substituted systems were studied. Though the olefin metathesis reaction has
been studied for a long time, little is known about the regioselectivity of this reaction.
Herein, our findings are reported on the intermolecular ROCM reactions of bridgehead
substituted oxabicyclic systems.
Bridgehead Substituted 8-Oxabicyclo[3.2.1]Octene Derivatives
Having reported the success of the ring-opening cross metathesis of 8-
or o/
oxabicyclo[3.2.1 Joctene derivatives to generate the pyran moiety, ’ it was decided to
explore bridgehead substituted systems. As shown in scheme 2-7, two regioisomers are
expected from this reaction. This outcome makes the reaction unpractical from a
synthetic perspective. However, considering the impact of the olefin metathesis reaction
in organic synthesis, this issue needed additional investigations.
Scheme 2-7: Attempted ring opening cross metathesis of substituted systems

60
In addition, interesting targets possess a substituent adjacent to the oxygen of the
pyran moiety. For example, Forskolin possesses two neighboring methyl groups, and
Latrunculin contains an adjacent alcohol (Figure 1-1).
The reaction was first explored with 1-methyl-8- oxabicyclo[3.2.1]oct-6-en-3-one,
206a. After subjecting 206a to the reaction conditions that have proven favorable in the
unsubstituted cases, no reaction was observed. Various reaction conditions were tried
such as high catalyst loading (up to 10 mol %), elevated temperatures, and higher
concentrations; however, only trace amounts of product were obtained. The system did
not polymerize even at 110°C in 1M toluene. Ketones 206b and 206c also failed to react.
Considering the enhanced reactivity previously obtained by reduction/silylation of
ketone 1 towards ring opening, ketone 206a was reduced and converted to the
corresponding ether 207a. This dramatically increased the reactivity of the system under
the reaction conditions, producing the expected regioisomers in 83% yield using 1.5
mol% of 67 and 4 equivalents of styrene. The regioisomers were obtained in a ratio of
6:1, where the major isomer placed the cross metathesized olefin on the more hindered
side (Table 2-5). Initial attempt of this reaction using 5 mol % of 67 showed a decrease
in regioselectivity to 3:1. Additional trials with unprotected alcohol 207c gave surprising
results. Though the yield of the reaction was similar to the yield obtained with the endo
ether 207a, the regioselectivity increased significantly from 6:1 (208a: 209a) to 20:1
(208c: 209c).
Additional substituted substrates, 207b and 207d, were prepared and studied in
order to increase the regioselectivity by coordination of the oxygen with the catalyst;
however, the regioselectivity did not improve, and the yields decreased.

61
r~a
MesN NMes
c|/'Ru=\ 67
cr ,u^ph
PCy3 ,
R CH2C12,0.03M
^\ph4equiv.
Scheme 2-8: Intermolecular cross-metathesis of reduced derivatives
Table 2-5: Intermolecular cross-metathesis of reduced derivatives
Alkene
R
X
Y
Yield [%]
Ratio (208:209)
207a
Me
OTBS
H
83
6:1
207b
CH2OMe
OTBS
H
65
1.6:1
207c
Me
OH
H
85
20:1
207d
CH2OMe
OH
H
66
20:1
207e
Me
H
OH
15
6:1
Efforts made to optimize the reaction yield with 207d by increasing the
temperature, lowered the regioselectivity to 3:1. To study the effect of the remote
substituent stereochemistry, the exo alcohol 207e was prepared by reduction of the
corresponding ketone 206a with samarium diiodide. The exo alcohol gave poor yield.
Moreover, the regioselectivity decreased compared with the endo alcohol 207c to equal
the selectivity obtained with the ethers (6:1), again favoring the more hindered
regioisomer. This regioselectivity preference for the more hindered alkene is in
accordance with results obtained by Snapper58 on ROCM reactions. Thus, the
regioselectivity could be attributed to a high preference for the alkylidene formed with
styrene over the methylidene as the active catalyst as Snapper findings (Scheme 1-26).
Hence, the mechanism of the reaction could be as depicted in Scheme 2-9, where the
styryl unit is placed first, forming the alkylidene 211, which upon reaction with the

62
terminal alkene (styrene) produced the more substituted product. These reactions
represent one of the few successes with regioselective ROCM of unsymmetrical bicyclic
systems.58'61
Scheme 2-9. Proposed mechanism for the high regioselective ROCM of 8-
oxabicyclo[3.2. ljoctene derivatives with styrene
In addition, two other systems were investigated: see scheme 2-10. A 1:1 mixture
of trans and cis isomers of l-methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-one-0-methyl-oxime
(213a, 213b) was obtained by condensation of 206a in refluxing dichloromethane with
methoxylamine hydrochloride salt. This example was made to have an additional case of
bridgehead substituted 8-oxabicyclo[3.2.ljoctene derivative with sp2 hybridization to
study the system. The system has similar electronic properties to the ketone but differs in
reactivity. When the mixture of isomers was subjected to the reaction conditions, no
reaction was observed. Increased temperatures did not help promote the reaction.

63
Scheme 2-10: Additional examples of ROCM of Cl substituted oxabicyclo derivatives
Ketal 214, prepared from transketalization with tetramethyl dioxane and p-toluene
sulfonic acid,90 mimics the ketone functionality, possessing the same electronic properties
of the parent ketone, but remaining sp3 hybridized at C3. The ROCM of 214 produces a
mixture of regioisomers in a 3:1 ratio and 67% yield. However, further investigation of
this case demonstrated that the regioselectivity of the reaction is dependant on the
reaction time; thus, at the early stage of the reaction, higher regioselectivity is observed
(Table 2-7). This is attributed to the reversibility of the reaction. In fact, when the
reaction was allowed to react for 1.5 hour one isomer was isolated in high yield, 90%
(Scheme 2-11). Though, ketal 214 was the only case monitored carefully by GCMS, it is
predictable that the substrates presented in Table 2-5, 207a-e, could exhibit the same
behavior and thus, high regioselectivity could be achieved if the reaction is allowed to
react for a specific amount of time, though the starting material never will be consumed
completely.

'O
214
~ PCy3 r“
^phCH2Cl2
4 equiv. 0.3M
1.5 hr
>< yu7
O
215
Ph
Scheme 2-11. The regioselectivity ratio is dependent on time
Table 2-7.
The regioselectivity
ratio is dependent on time
Time (hrs)
Regioselectivity Ratio (215:216)
1
>99:1
2
>99:1
3.5
16:1
24
3:1
Envisioning the synthesis of targets like Forskolin, a disubstituted bridgehead
substrate 217 was also explored (Scheme 2-12). The substrate was prepared in the same
fashion as the unsubstituted cases, using Fdhlish’s method.3 No reaction was observed
upon exposure of the substrate to the reaction conditions.
r~\
Mes-N N-Mes
c|/'Ru=\ 67
———•- No Reaction
CH2C12 ^Ph
217
Scheme 2-12. Attempted ring opening cross metathesis of l,5-dimethyl-8-
oxabicyclo[3.2.1] oct-6-en-3-one.
Various sets of conditions were explored to make the reaction work. These
conditions varied from increasing the amount of catalyst to using high temperatures.
Despite our efforts, no reaction was observed. The reaction was also tried using the
molybdenum-based catalyst (Schrock catalyst), which has been reported to be more
reactive than Grubbs’ catalyst; however the substrate still resisted reaction.
Considering the increment in the reactivity previously obtained converting the carbonyl

65
to the ether, the endo ether 218 was prepared from 217 and exposed to the same reaction
conditions (Scheme 2-13). However, our expectation was not met as no reaction was
observed. The disubstituted ether 218 did not undergo reaction or polymerization, even
at elevated temperatures and high concentrations.
Mes —N N -Mes
c|/'Ru=\ 67
Cr pc>
ch2ci2
Ph
No Reaction
Scheme 2-13. Attempted ring-opening cross metathesis of the disubstituted ether 218
As an expansion of the methodology to the construction of highly substituted
pyrans an intramolecular process was attempted by tethering an alkene as a substituent in
the bicycle.
Intramolecular Ring-Opening Cross Metathesis (ROCM)
In principle, there are three types of fused pyrans that can be synthesized from 8-
oxabicyclo[3.2.1]octene derivatives by varying the place of a tethered alkene in the
bicycle ( Scheme 2-14).93 A spiro-fused pyran is produced when it is placed at the
bridgehead position, C1, of the oxabicyclic system. If the tethered alkene is located at
C2, a linear-fused pyran is produced, while if the substituent is positioned at C3, a bridge-
fused pyran is generated. Previous work in our group has demonstrated the viability of
this domino metathesis toward fused pyrans.86,93 In that area, spiro-fused pyrans were
obtained in good yields and with high selectivity for the spiro-fused compound over
oligomers or dimers.86,93

66
O
Cl tether
LnRu=CHPh
C2 tether
LnRu=CHPh
C3 tether
LnRu=CHPh
Scheme 2-14. Fused-pyrans from intramolecular ROCM reaction
The fact that the intermolecular reaction of 206c with styrene did not generate
product raised interesting mechanistic questions involving the intramolecular cross
metathesis reaction in which the alkene is tethered at the Cl bridgehead position (type a,
Scheme 2-14).91 The unreactive 206c is the saturated analog of 219, an example of an
oxabicyclic system with a tethered alkene at the bridgehead position that yielded a spiro-
fused pyran 220 (Scheme 2-15).93
One plausible mechanism involves an initial reaction with the terminal alkene
followed by cyclization (path A, scheme 2-16). An alternative path would involve a
regioselective opening of the bridged olefin followed by cyclization (path B, scheme 2-
16). The high regioselectivity and yields obtained for the spiro-fused pyrans support the
former pathway.93

67
O
219
Mes .. Mes
Cl/, N
Ru=s._..
i Ph
PCy3 .
2 mol %, 0.01 M
CH2CI2, rt
80%
Scheme 2-15. Formation of a spiro-fused pyran from an oxabicyclic system with a
tethered alkene at the bridgehead position
0
Scheme 2-16. Possible mechanism for an intramolecular ROCM reaction
This section presents our efforts toward the linear-fused pyrans by placement of a
tethered alkene at the C2 position of the bicyclic system (type b, scheme 2-14). Two
examples of C2 alkylated system were studied; they were prepared by Mann’s alkylation
protocol94 (Scheme 2-17). The reaction produced the C2-carbon tethered substituted

68
intermediates in poor yield and as an epimeric mixture of the alkyl group at the C2
position. The ratios of epimers for 222 ranged from 100:1 to 70: 30, and the ratios of
epimers for 223 ranged from 65: 35 to 50: 50 favoring the axial isomer in all cases.
Nonetheless yields were reproducible and not higher than 38% and 20% for 222 and 223
respectively. Unfortunately, the epimeric mixture could not be separated after many
trials. Consequently the intramolecular ROCM of compounds 222 and 223 to yield
linear-fused pyrans was attempted with the mixture. However, no reaction occurred and
the starting material was recovered unchanged for both cases.
Scheme 2-17. Synthesis of the C2-carbon tethered substituted intermediates
To improve the reactivity of the system, as achieved earlier, and in an effort to
separate the epimeric mixtures, ketones 222 and 223 were reduced with L-Selectride, to
obtain their respective diasteromeric endo alcohols. The reduction proved to be more
complicated because the placement of the alkyl group in the axial position afforded exo
alcohol and endo alcohol from the reduction, thus making the mixture more difficult to
separate (Scheme 2-18).

69
224
225a
225a:225b
55:45
ratios determined by NMR
Scheme 2-18. Reduction of the C2-alkylated oxabicyclo[3.2.1]octene derivatives
When ketone 224, obtained as a single isomer from the alkylation, was reduced
with L-selectride alcohols 225a and 225b were produced. When a mixture of 48: 52 of
the C2 epimeric ketones 226 were submitted to the reaction conditions (L-Selectride,
THF, -78°C) afforded a mixture of alcohols 227a-c was obtained. The exo alcohols 225b
and 227b derived from ketones 224 and 226b respectively were obtained from an endo
attack of the hydride rather than the usual exo attack that provides the endo alcohols.
This is due to steric hindrance provided by the tethered alkene in the axial position. The
separation of alcohols 225a and 225b was possible. However, from the mixture
generated from ketone 226a-b, compound 227a was isolated, while alcohols 227b-c
remained as a mixture. Nevertheless with the alcohols in hand, the intramolecular
ROCM was attempted (Scheme 2-19).

70
225a
LnRu=\ 67
2 mol% F^h
CH2CI2
0.01M
13%
LnRu=\ 67
2 mol% Ph
CH2CI2
0.01 M
8%
OH
227a
LnRu=\ 67
2 mol% f^h
CH2CI2
0.01M
26%
OTBS
r
LnRu=\ 67
i%°
2 mol% fj>h
CH2CI2 r c
OTBS^
0.01M
12%
231
232
Scheme 2-19. Intramolecular ROCM of the reduced C2-tethered systems
The yields for the linear-fused pyran products were low. During the first minutes
of reaction, the mixture becomes cloudy and all the starting material is consumed. After
evaporation of the solvent, a white precipitate is left, presumably some polymer. In an
attempt to improve the yield, the bulky silyl ether 231 was prepared from alcohol 227a.
Nonetheless, the system became more reactive toward polymerization and the yield
dropped compared to the results obtained with the respective alcohol 227a. Though the
intramolecular ROCM of the reduced C2-tethered systems was not successful, the

71
hypothesis of being able to form linear-fused pyrans from that type of system was
confirmed.
To prove the efficiency of the ROCM strategy of 8-oxabicyclo[3.2.1]octene
derivatives in natural products synthesis, an approach to Latrunculin B was attempted.
Approaches Towards Latrunculin B from Ring-Opening Metathesis of 8-
Oxabicyclo[3.2.1 JOctene Derivatives
• 78
The marine macrolide Latrunculin B possesses interesting biological activity
and a pyran-skeleton that is amenable using a ROCM approach. It was foreseen that
ROCM of an oxabicycle derivative would provide the differentiated cis-2,6-substituted
pyran. The rest of the target was envisaged to be completed by chiral alkylation, Wittig
olefination, where the formation of the cis olefin would be critical for the success of the
synthesis, a macrolactonization, oxidative decarboxylation or allylic oxidation, depending
on the substituent adjacent to the oxygen, and at the last stage of the synthesis,
construction of the thiazolidinone moiety. This approach differs from previous syntheses
in the initial formation of the pyran moiety from ROCM, and the last stage placement of
the thiazolidinone moiety, allowing for the preparation of analogs at that center. A
proposed fragmentation for a retrosynthetic analysis is presented in scheme 2-20.
Lactonization
Wittig Reaction / Jl. O ' O
Alkylation <= „J ,5j>PH
Olefin Metathesis < — u
i^HN Js
Oxidative
Decarboxylation
Construction
of the thiazolidinone q
from an aldehyde
Scheme 2-20. Possible fragmentation for a retrosynthetic analysis of Latrunculin B

72
Although various methods were formulated to choose which oxabicycle system
would lead to the desired pyran, two routes were tried to approach the target and thus will
be presented in this section. All the approaches were done with racemic mixture to study
the strategy.
Initial attempts to the target were based on the ROCM of methoxy bridgehead
substituted oxabicyclo 237 (Scheme 2-21). This route permits easy access to the pyran
moiety with the contiguous oxygen, protected as a methoxy acetal. This strategy presents
interesting possibilities for other natural products possessing this acetal type pyran such
as phorboxazole, callipeltosides and the bryostatins. However, this sequence presented
some drawbacks, such as the low yields obtained for the starting material, methoxyketone
235, and the poor efficiency of the intermolecular ROCM reaction. The low yield
obtained for methoxyketone 235 (30% over two steps, cycloaddition and reduction)
represents a problem due to the price of the 2-methoxyfuran, even though the reaction
could be performed on large scales. Nonetheless, with the bridgehead substituted
oxabicyclo 235 in hand, the ROCM with styrene was attempted. Surprisingly, the ketone
yielded 20% of the trisubstituted pyran 236 as a single regioisomer. This gave us some
basis to assume that the ROCM of the reduced derivative would provide a higher yield
and high regioselectivity. However the ROCM of the reduced derivative 237 was not as
successful as expected. The reaction was monitored by NMR to determine the time of
completion with the highest regioselectivity. The regioselectivity was high, one isomer
was observed by NMR, but the reaction proved to be highly reversible, favoring the
starting material. Product was formed up to a maximum of 65% (9 hours of reaction)
based on NMR. Prolonged reactions times favored the equilibrium to the starting

73
material, thus after 24 hours only traces of products were present along with the starting
material. At that point, there was less amount of stylbene (reaction byproduct) present,
probably taking part in the reversibility of the reaction.
233
Na+'OCH2CF3
cí¡hccocíhT
&
OMe
Zn/Cu. MeOH ,
30% over two steps
OMe
234
235
Scheme 2-21. Approach to the acetal type pyrans from the ROCM strategy
Consequently, another strategy was explored simultaneously. The new method
started with the ROCM of alcohol 242 (Scheme 2-22). Ketone 241 can be obtained on
large scale in good yield from the relatively cheap fiirfuryl alcohol 239. Ketone 241
failed to undergo ROCM with styrene. On the other hand, exo alcohol 242, which
provides the desired stereochemistry at the Cl3 of latrunculin B, underwent ROCM;
however the alcohol gave low yields and poor regioselectivity. Further, ROCM of the
endo alcohol 245 gave a 79% yield of the more hindered alkene 246 as a single
regioisomer. None of the other regioisomer was observed by NMR or GCMS.
Nonetheless, high loads of styrene can provide the diphenyl cross metathesized product.

74
239
2,6-Lutidine,
TBDMS-OTf
95%
1.Na+'OCH2CF3
CI2HCCOCCIH2
2. Zn/Cu MeOH
75-85 %
over 2 steps
241
OH
Sml? THF
OTBS Reflux, 40%
LnRu=\ 67
Ph
â–º
4 eq.
CH2CI2 0.3M
13%
243; R, = H, R2 = CH2OTBS
244; Ri = CH2OTBS, R2 = H
Scheme 2-22. Initial approach to latrunculin B: generation of the pyran.
With the pyran 246 in hand, functionalization of the skeleton started with
protection of the free alcohol and hydroboration of the protected material; the two step
sequence gave a 74% yield of alcohol 247, which was then protected as a tert-butyl
dimethyl silyl ether 249 (Scheme 2-23). The hydroboration selectively oxidized the less
hindered alkene. The alcohol side chain was foreseen to be protected as a triflate to
undergo alkylation with an Evan’s oxazolidinone enolate to set the center at C8.
Nonetheless, silyl ether 240 was used as a model compound to functionalize the pyran by
studying the oxidative decarboxylation to generate the C15 alcohol, whose
stereochemistry was supposed to be set by the anomeric effect.95 After ozonolysis of
styryl compound 249 and oxidation to acid 251 with sodium chlorite, attempts were done
toward the oxidative decarboxylation of 251 (Scheme 2-23). It is interesting to mention

75
that acid 251 did not exhibit the characteristic OH stretch in the IR. Hence, an ester
derivative (263) was made by treatment of di azomethane for further confirmation.
9-BBN-H,
THF 0°C-R.T.
74% over 2
steps
Scheme 2-23. Functionalization of the pyran intermediate to approach Latrunculin B
Various conditions were attempted in an effort to promote the oxidative
decarboxylation of 251 as a strategy to install the Cl 5 alcohol of the target (Scheme 2-
24). The first thing tried was the use of lead tetraacetate (Pb(OAc)4). Lead tetraacetate is
commonly used for this type of transformation.96 Exposure of 251 to Pb(OAc)4 in
refluxing benzene gave an undefined mixture of compounds, though the starting material
was totally consumed. Presumably, the acetic acid present in the Pb(OAc)4 may have
deprotected the alcohols promoting further reactions with them that lead to a mixture of
compounds. Another possibility is that the starting material 251 decomposed under those
conditions. Another protocol, developed by Suarez et al. that was the simple oxidative
decarboxylation using the hypervalent iodine, diacetate iodobenzene (DIB), which has
been reported to react via a radical mechanism.97 Based on the proposed mechanism

76
reported in the literature, compound 251 was expected to undergo oxidative
decarboxylation as depicted in scheme 2-25.
251
251
251
Pb(OAc)4 _
PhH, reflux
DIB, l2, MeOH
DIB, l2, CH3CN
undefined
No Reaction
No Reaction
Scheme 2-24. Attempts of oxidative decarboxylation of the acid intermediate
The reaction of 251 with DIB was attempted in various solvents as reported in
successful examples from the literature. The product from oxidative decarboxylation
reaction was not observed in any of the cases. Interestingly, when dichloromethane was
used as solvent, lactone 253 was isolated as the only product. Although the yield was
moderate (49% yield), the reaction was clean: crude NMR showed only the new
compound 253 and excess of the DIB reagent. A proposed mechanism for the lactone
formation based on previous reported mechanism of this reagent with carboxylic acids is
presented in scheme 2-26.

77
OAc
OBn OBn
Scheme 2-25. Proposed mechanism based on literature reports
OBn
OBn
TBSO
TBSO
OAc
Scheme 2-26. Proposed mechanism for the lactone formation
It is proposed that compound 258 is a plausible intermediate for the lactone
formation. Compound 258 is predicted to be formed based on the mechanism depicted in

78
scheme 2-25. Thus, reaction of the carboxylic acid with DIB generates intermediate 254,
which fragments to the radical intermediate 256 by loss of CO2, then radical oxidation by
the iodine gives carbocation 257, which eventually is quenched by an acetate group to
give 258. It is supposed that deprotection of the silyl ether of 258 generates the alcohol
259 which could form radical 260 by reaction with DIB, then loss of formaldehyde could
give rise to the new radical 261, that gave lactone 253.
Based on the results and the proposed mechanism for formation of lactone 253, it
was presumed that if compound 258 was formed, the reagent was performing the
oxidative decarboxylation. Hence, compound 265, would be able to form an oxygen
radical and loss CO (Scheme 2-26), and form a carbocation intermediate 262 stabilized
by an styryl unit that can lead to the C15 alcohol. However, compound 266 appears to be
formed based on extensive NMR studies; this was not confirmed by mass spectrometry.
This may imply that the proposed mechanism is not taking place or that addition of the
iodine to the double bond, followed by cyclization is faster than the reaction of 265 with
DIB.
OBn
AcO
TBAF, THF
R.T., 73%
OBn
Scheme 2-27. An alternative attempt to form the acetal type pyran

79
Some future work that may provide the desired oxygen at C15 could be the use of
the Hunsdiecker reaction, with subsequent quench of with methanol in the presence of
catalytic acid. Nonetheless, preliminary results failed to give the desired alkyl halide.
Furthermore, Pb(OAc)4 could be tried with different protecting groups not as sensitive to
acid as the silyl ether case studied, and electrochemical oxidation, another common
procedure for the oxidative decarboxylation, should be also studied. In addition, if the
lactone could be obtained in higher yields, careful Grignard addition to the lactone could
provide the desired alcohol. Another route would be exploring the ROCM of other
oxabicycle systems, for example, ROCM of 1 and further allylic oxidation. Nevertheless,
ROCM has proven to be a useful strategy that may be employed in natural product
synthesis.

CHAPTER 3
CONCLUSIONS AND FUTURE WORK
The studies performed have proven that ring-opening cross metathesis reactions of
oxabicyclo[3.2.1]octene derivatives is a viable pathway toward the formation of highly-
substituted pyrans. The presence of a bridgehead substituent decreased the reactivity of
the system in the intermolecular ROCM. These findings disclosed mechanistic details in
the intramolecular ROCM reaction, implying that the intramolecular ROCM reaction
proceeds via initial reaction with the tethered vinyl group followed by cyclization rather
than initial regioselective opening of the bridged olefin.
The lack of reactivity in bridgehead substituted systems can be manipulated by
changes in remote substituents. The changes on remotes substituents can also affect the
regioselectivity of these reactions. However, it was observed that the regioselectivity
may depend on the reaction time. Thus, at the early stages of the reaction the
regioselectivity is higher.
Unfortunately, di substitution at the bridgehead position of the oxabicyclo leads to
no reaction. Neither reduction/silylation had an effect on the reactivity of the system.
The kinetics studies performed on the unsubstituted oxabicyclic compounds lead
to a new hypothesis of how remote substituents affect the reactivity of the system. Based
on the results, it is suggested that the enhancement in reactivity is caused by the ability of
the substituent at C3 to donate electron density to the double bond through space rather
than by changes in hybridization as initially proposed.85 In addition, steric factor plays a
major role on the reactivity of the system. Although a small difference in the relative
80

81
rates was observed for the ROMP of the 8-oxabicyclo[3.2.1]octene derivatives, the
differences manifest themselves in significant effects such as yield of ROOM products
versus polymers.
Our investigations have contributed to the expansion of the methodology towards
unsymmetrical cyclic compounds, as well as provided new insight into the factors that
can affect the valuable metathesis reaction.
The Intramolecular ROOM of the C2-tethered alkene oxabicyclic substrates was
sluggish, and rendering the direction of the reaction more to the production of polymer
rather than the linear-fused pyran.
The ROCM of of 8-oxabicyclo[3.2.1 ]octene derivatives proved to be an effective
way for the fast construction of the pyran moiety in Latrunculin B. Additional work
needs to be done to further functionalization of the pyran skeleton and obtain the acetal
type pyran.
In order for the ROCM 8-oxabicyclo[3.2.1]octene derivatives to be useful and
appealing in synthesis, asymmetric intermediates need to be obtained. Thus it is
important to study the ROCM of chiral oxabicycles, and observe the effect on the
regioselectivity of asymmetric substituted bicycles. Another alternative is the
asymmetric ROCM with a chiral catalyst.98 Of interest could be the screening of various
chiral catalysts with a series of oxabicycle to determine a trend on which chiral catalyst is
better for specific functional groups and substitution of the system.

CHAPTER 4
EXPERIMENTAL PROCEDURES
General Methods. All the solvents used in the reactions were distilled prior to
use, unless reported. Thin-layer chromatography was performed using silica gel 60 F24
precoated plates (250 pm thickness). Column chromatography was performed using 230-
400 mesh silica gel 60. Melting points were obtained on a Thomas-Hoover Capillary
Melting point apparatus, and reported uncorrected. IR spectra were obtained on a FT-IR
spectrometer. NMR spectra were obtained on a Varían 300 MHz spectrometer; chemical
shifts are reported in 5 units relative to the tetramethylsilane (TMS) signal at 0.00 ppm.
Coupling constants are reported in Hz. High-resolution mass spectroscopy was provided
by the University of Florida Mass Spectroscopy Services.
Kinetic Studies. A 0.65 ml solution of acetone containing 4,10-dioxa-tricyclo[5.2.1.0
2 6
’ ]dec-8-ene-3,5-dione (standard, 198), the substrate to be analyzed,
oxabicyclo[3.2.1]octene derivatives (1,192, 193,199-200), in different ratios (1: 1, 1:4,
4:1, and 8:1, 16:1 in some cases) and a drop of benzene as the internal standard was
prepared. To the mixture, 0.1 ml of a solution of 1.0 mg of Grubbs catalyst 67 in 1 ml of
CDCI3 was added. The reactions were monitored by 'H NMR at 500 MHz on a Varían
Inova spectrometer. The spectra were acquired on automation, ca. 100 points for the
course of the reaction, which varied from 10 minutes to 1.5 h, and the integrals of the
alkene protons of the substrate and of the standard were normalized against the integral of
a comparable amount of benzene. The plot of ln[substrate] vs ln[standard] afforded a
line, whose slope corresponded to the relative rate of the substrate versus the standard
82

83
(kSub/kstd) with a typical R of 0.98-0.99. In accordance with the following equations:
ln(Ao/A) = kt, where k=[cat]*kA, the ratio of kA/kstd is the slope of ln[A]/ln[Std], where
[A] = [substrate] and [Std] = standard.
Figure 4-1. 8-Oxa-bicyclo[3.2.1 ]oct-6-en-3-one O-methyl-oxime (199)
8-oxa-bicyclo[3.2.1]oct-6-en-3-one 1 (0.100 g, 0.806 mmol) was dissolved in 2
ml of dry CH2CI2 and mixed with methoxylamine hydrochloride (0.101 g, 1.210 mmol)
and 3 A0 molecular sieves. Then 0.10 ml of pyridine was added, a condenser was fixed
and the reaction mixture was allowed to reflux for 5 hours. Upon completion of the
reaction by TLC, the reaction was diluted in CH2CI2, the resulting powdering molecular
sieves were filtered. The filtered liquid was washed with brine and dried over MgSO-t,
filtered trough a small plug of silica gel, eluting with 85:15 hexanes: ether and
concentrated to achieved a white solid (0.1003 g, 81 %) of 199. R/= 0.33 (85: 15 hexane:
ethyl acetate). Melting Point 55-56°C. 'H NMR (300 MHz, CDCL3): 5 6.23-6.18 (2H,
m), 4.90(1 H, dt, ./ = 4.7Hz, 1.2Hz), 4.85 (1H, dt, J= 4.7Hz, 1.2Hz), 3.78 (3H, s), 2.93
(1H, dd, J = 16.1 Hz, 0.9Hz), 2.66 (1H, ddt, J= 15.2 Hz, 4.4Hz, 1.5 Hz), 2.36(1 H, ddt, J
= 16.1Hz, 4.4Hz, 1,5Hz), 2.26 (1 H,dd, J = 15.2Hz, 0.9Hz). ,3C NMR ( CDC13): 8 153.4,
133.4, 132.4, 78.0, 76.8, 61.4, 34.5, 30.4. HRMS (El) caled for CgHnNOj [M]+ 153.0790,
found 153.07889. IR (film): 2956, 2925, 2853, 2360, 1464, 1259, 1048, 994, 843 cm'1.
CH caled for C8H, ,N02: C, 62.73; H, 7.24; found: C,62.74; H, 7.27.

84
Figure 4-2. 3-Methylene-8-oxa-bicyclo[3.2.1 ]oct-6-ene (200)
A flame dry 2-neck 25 ml flask was charged with 0.70 g of CeCh heptahydrate
and stir bar. The solid was dried by heating at 140°C under vacuum for 3 hours. Then it
was allowed to cool to room temperature and a suspension was made by the addition of
THF (3 ml). The suspension was allowed to stir at room temperature for 2 hours, then it
was cooled to -78°C and 1M trimethylsilylmethyl magnesium chloride was added (0.97
ml, 97 mmol). The yellow suspension stirred for 30 min and oxabicyclic ketone 1 (0.10
g, 0.81 mmol) was added. The mixture was allowed to stir overnight and reach room
temperature slowly. The reaction was worked up by quenching with ice and adding a
solution of ammonium chloride for the emulsion formed. The layers were separated and
the aqueus layers were extracted with ether. The organic layers were dried with MgSCU,
filtered and concentrated to yield the crude alcohol in 84% yield as an orange oil. The
crude was added to a suspension of 35% wt. KH (1.1 g) in 6 ml of THF at 0°C. The
mixture was allowed to stir at room temperature for 3 hours and then it was quenched
carefully with a saturated solution of ammonium chloride at -10°C. The aqueous layers
were extracted with ether, dried with MgS04 and concentrated in a rotary evaporator.
The oil was purified by column chromatography eluting with 95: 5 (hexanes: ether)
affording 60% overall yield of the volatile, colorless oil 200. R/= 0.71 (35: 65 ethyl
acetate: hexane). 1H NMR (300 MHz, CDCL3): 5 6.10 (2H, s), 4.79 (2H, d, J= 4.1 Hz),
4.74 (2H, t, J= 2.2Hz), 2.61-2.54 (2H, m), 2.05 (2H, d, /= 14.6 Hz). 13C NMR (CDC13):
5 141.3, 131.7, 113.7,78.7,37.2. HRMS (El) caled for C8H10O [M]+ 122.0732, found

85
122.0733. IR (film): 3072, 2951, 2897, 2820, 1645, 1418, 1342, 1045, 990, 890, 871cm'
i
Figure 4-3. em/o-3-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol (201)
In a 2 neck flask 3.84g of CeCl3.7H20 were dried with stirring under vacuum at
140°C for 3 hours. The powdery white solid was cooled down under argon to room
temperature. Then 8 ml of dry freshly distilled THF were added and stirring was
maintained for two additional hours. The cloudy white suspension was cooled to -78°C
and 2.8 ml, 3.84 mmol of 1.0 M solution of MgBrCH3 were added, where upon addition
the color of the suspension turned from white to a pale yellow color. After being kept at
the same temperature for 30 min, a solution of 8-oxa-bicyclo[3.2.1]oct-6-en-3-one 1
(0.400 g, 3.2 mmol) in 4 ml of THF was added. The reaction mixture was allowed to
reach room temperature and stir under argon for 24 hours. Upon completion of the
reaction, it was quenched with ice and filtered through a pad of celite. The filtrated was
extracted with ethyl acetate, dried with Na2SC>4, filtered and the solvent was evaporated
under reduced pressure. The dark orange residue was purified by silica gel
chromatography eluting with 85:15 hexane:ethyl acetate (residue previously adsorbed on
silica) producing 201 as a pale yellow oil (0.2500g, 56%) of 21. R/= 0.14 (65: 35
hexane: ethyl acetate). 'H NMR (300 MHz, CDCL3): 5 6.48 (2H, s), 4.80 (2H, d, J =
4.3Hz), 3.44 (1H, bs), 2.07 (2H, dd, J=14.9Hz, 4.0Hz), 1.74 (2H, d, J= 14.5 Hz), 1.15
(3H, s). 13CNMR (CDCI3): 5 135.5, 77.8, 69.4, 41.6, 32.7. HRMS (El) caled for C8H,202
[M]+ 140.0837, found 140.0836. IR(film): 3429, 2947,1647, 1348, 1165, 1101, 857 cm'1.

86
Figure 4-4. 8-Oxa-bicyclo[3.2.1 ]oct-6-ene (204)
In a sealed tube KOH (1.3g, 22mmol) was dissolved at 55°C in diethylene glycol
(9 ml). To the yellow orange viscous solution (0.9025 g, 7.25 mmol) of 1 were added
followed by the addition of hydrazine monohydrate (0.9 ml, 18 mmol). Then the
mixtured was sealed and allowed to reflux to 195°C. Upon completion by TLC the
reaction was worked up by adding water and a little amount of 2% HC1 solution. The
aqueous layer was extracted 4 times with small portions of ether. The ether layers were
dried with Na2SC>4 and filtered. The solvent was removed by distillation. The residue was
purity by chromatography eluding with a mixture of 95:5 petroleum ethenether. The
compound containing fractions were collected, and the solvent was removed by
distillation to afford 204 as a volatile pale yellow oil (0.5475g, 69% yield) of pungent
smell. R/= 0.29 (95:5 hexane:ether). ’H NMR (300 MHz, CDCL3): 8 6.14 (2H, s)
4.67-4.71 (2H, m), 1.01-1.81 (6H,m). 13C NMR (CDC13): 8 130.6, 79.5.8, 41.6, 25.2.
HRMS (El) caled for C7H,0O [M]+ 110.0732, found 110.0732. IR (film): 2930, 2854,
1029, 806, 701 cm'1.
Figure 4-5. exo-3-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol (205)
To a suspension of LiAlH4(83mg, 2.18mmol) in THF (3 mL) was added epoxide
208 (40 mg, 0.29 mmol) as a solution in 2 ml of dry THF at 0°C. After the addition, the
mixture was refluxed at 66°C for 3hrs. The mixture was allowed to reach room
temperature and then was cooled to -10°C and quenched with 0.25 ml of water follow by

87
0.25 ml of 2 M NaOH. Additional 0.5 ml of water was added and the mixture was
filtered. The aqueous layer was extracted with ethyl acetate, dried with MgS04, and
concentrated in a rotary evaporator. The residue was purified by silica gel
chromatography and gave a colorless oil 205 (27 mg, 68%). R/= 0.18 (40:60 hexane:
ethyl acetate). 'H NMR (300 MHz, CDCL3): 5 6.18 (1H, s), 4.82 (1H, d, ./ = 5.4 Hz),
2.05 (2H, d, ./= 13.7 Hz), 1.69 (2H, d, 13.1 Hz), 1.27 (2H,s). I3C NMR (CDC13):
5 133.2, 77.6, 69.4,41.7, 33.6. IR (film): 3406, 2924,2850, 1258, 1096, 1047, 711 cm'
Figure 4-6. 3-endo-spiro epoxide bicycle[3.2.1 ]oct-6-ene (208)
To a solution of 3-Methylene-8-oxa-bicyclo[3.2.1]oct-6-ene (200) (0.4000g, 3.27
mmol) in methylene chloride (5 ml) was added NaHC03 (0.35g, 3.89 mmol) of and m-
CPBA 77% (1,70g, 7.78 mmol) at 0°C by portions. The reaction was allowed to stir for
6hrs at OoC then was allowed to reach room temperature and stir for additional 9hrs.
Upon completion of the reaction based on TLC the reaction was worked up by diluting
the mixture with water and washing it with 20% NaOH extracting with CH2CI2. The
organic layer was dried with MgS04, filtered and concentrated in a rotary evaporator.
The residue was then purify by silica gel chromatography using gradient elution (50g
silica gel: residue adsorbed on silica; 95:5 - 65:35 hexane: ethyl acetate) gave a white
semisolid 208 (58 mg, 13%). R/= 0.34 (65:35 hexane: ethyl acetate). 'H NMR (300
MHz, CDCL3): 5 6.21 (1H, s), 4.87 (1H, d, J= 3.5 Hz), 2.5 (2H, s), 2.32 (2H, dd, J=
13.2, 3.8 Hz), 1.35 (2H, dt,J= 13.2, 1.2 Hz). I3C NMR (CDC13): 5 132.4, 78.3, 58.5,
54.8, 36.4. IR (film): 2958, 2924, 1394, 1245, 1048, 993 cmT.

88
Other epoxides were isolated:
Figure 4-7. 3-exo-spiro epoxide bicycle[3.2.1]oct-6-ene (207)
R/= 0.25 (65:35 hexane : ethyl acetate). ‘H NMR (300 MHz, CDCL3): 5 6.37
(2H, s), 4.84 (2H,d, J= 3.33Hz), 2.54 (1H, d,J= 3.8 Hz), 2.49 (1H, d, J= 3.8 Hz), 2.38
(2H, s), 1.24 (2H, d,J= 14.1 Hz). 13C NMR (CDC13): 5 133.7, 78.3, 54.0, 48.1, 37.3.
Pale yellow oil (35 mg, 8%).
Figure 4-8. diepoxides (209)
R/= 0.13 (65:35 hexane: ethyl acetate). 'H NMR (300 MHz, CDCL3) major: 8
4.33 (2H, d,J= 4.09 Hz), 3.76 (1H, s), 2.57 (2H, s), 2.44 (2H, dd, J= 15.2, 4.4 Hz), 1.22
(2H, d, J= 15.2 Hz), minor: 8 4.38 (2H, d, J = 4.4 Hz), 3.62 (2H, s), 2.61 (2H, s), 2.30
(2H, dd, J= 14.0, 4.09 Hz), 1.38(2H,d,7= 14.3 Hz). I3C NMR (CDC13) both: 8 71.9,
71.5, 57.3, 53.6, 53.2, 53.1, 50.5, 34.5. HRMS (El) caled for C8Hi0O3 [M]+ 138.0630,
found 154.0629. A yellow oil (0.16g, 32%).
Figure 4-9. 7-Methylene-3,9-dioxa-triciclo[3.3.102,4]nonane (210)
R/= 0.52 (65:35 hexane : ethyl acetate). 'H NMR (300 MHz, CDCL3): 8 4.79
(2H, t, J= 2.3 Hz), 4.26 (1H, d, J= 4.7 Hz), 3.5 (2H, s), 2.63-2.56 (2H, m), 2.23 (2H, d, J
= 15.5 Hz). I3C NMR (CDC13): 8 132.4, 78.3, 58.5, 54.8, 36.4. HRMS (El) caled for

89
C8H,o02 [M]+ 138.0696, found 138.0696. IR (film): 2960, 2902, 1650, 1054, 854, 695
cm'l. Pale yellow oil (62 mg, 14%).
0
Figure 4-10. l-methoxymethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-one (206b)
2-Methoxymethyl-furan prepared from furfuryl alcohol, sodium hydride and
methyl iodide in THF (4.90g, 44 mmol) was placed in a 500 ml round bottom flask
without purification and cooled to 0°C. Via two separate syringes, trichloroacetone (6.0
ml, 9.2 lg, 57 mmol) was added, followed by the slow addition of trifluoroethoxide (2M,
33 ml). Upon completion of the addition, the solution was allowed to warm to room
temperature. The reaction was monitored by TLC using p-anisaldehyde as stain. After
12 hours, zinc/copper couple (8.8 g, 0.132 mmol) and a solution of methanol saturated
with ammonium chloride (75 mol) were added, and the mixture was allowed to reflux for
two days. Upon reaction completion, the mixture was filtered through celite washing
with ethyl acetate to remove the zinc/copper couple. The filtrate was then evaporated,
and the residue partitioned between dichloromethane and a saturated solution of EDTA.
The aqueous layers were extracted with dichloromethane. The organic layers were
combined and dried on MgS04, filtered, and the solvent removed in vacuo. The brown
oil residue was then purified by chromatography using gradient elution (60: 1 silica gel:
residue adsorbed on silica; (95: 5- 60: 40 hexanes: ethyl acetate) to give 206b as a yellow
oil (3.0g, 40 % over 3 steps). R/= 0.27 (70: 30 hexanes: ethyl acetate). 'H NMR (300
MHz, CDC13) 5 6.27 (1H, d,J= 5.9), 6.10 (1H, d, J= 5.9), 5.11 (1H, d,J= 4.5), 3.62
(2H, s), 3.45 (3H, s), 2.77-2.68 (2H, m), 2.36 (1H, d, J= 6.9 Hz), 2.30 (1H, d, J= 6.9

90
Hz). 13C NMR (300 MHz, CDC13): 5 205.7, 134.2, 133.5, 86.0, 77.8, 74.6, 59.7, 47.8,
45.4. HRMS (El) m/z caled for C9H1203 [M+H]+ 169.0865, found 169.0888. IR (film):
2923, 1716, 1455, 1406, 1343, 1183, 1108, 1020, 917, 854, 734 cm'1.
Figure 4-11. l-Propoxymethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-one (206c)
2-Propoxymethyl-furan (1.005 g, 7.1 mmol) was placed in a dry 100 ml round
bottom flask and cooled to 0°C. Via two separate syringes, solutions of trifluoroethoxide
(2M, 15mL) and trichloroacetone (14.3 mmol, 1.5ml) in trifluoroethanol (7.5 ml) were
added drop wise simultaneously, and the solution was allowed to warm to room
temperature. The reaction was monitored by TLC using p-anisaldehyde as stain. Upon
completion of the reaction an equal volume of water and dichloromethane was added, and
the aqueous layers extracted 2 times with dichloromethane. The organic layers were
combined and dried on MgS04, filtered, and the solvent removed in vacuo. The crude
dark orange/brown oil (7.39g) was placed in a 200 ml round bottom flask without
purification. To the crude, zinc/copper couple (10.23 g) and a solution of methanol
saturated with ammonium chloride (80 ml) were added, and the mixture was allowed to
reflux for two days. The mixture was then filtered through celite, washing with ethyl
acetate, to remove the zinc/copper couple. The filtrate was then evaporated, and the
residue partitioned between dichloromethane and a saturated solution of EDTA. The
aqueous layers were extracted with dichloromethane. The organic layers were combined
and dried on MgS04, filtered, and the solvent removed in vacuo. The brown residue was
then purified by silica gel chromatography using gradient elution (60: 1 silica gel: residue

91
adsorbed on silica; (95: 5-3:1 hexanes: ethyl acetate) to give 206c as a dark yellow oil
(1.271 g, 81 % over 2 steps). R/= 0.13 (85: 15 hexanes : ethyl acetate). 'H NMR (300
MHz, CDC13): 5 6.26 (1 H,d, J= 5.8), 6.11 (1H, d,J = 5.8), 5.10 (1 H,d, J= 4.4), 3.65
(2H, s), 3.52-3.46 (2H, m), 2.78-2.69 (2H,m), 2.33 (2H, t,J = 16.9 Hz), 1.62 (2H sextet,/
= 7.0 Hz), 0.95 - 0.90 (3H,m ).13C NMR (300 MHz, CDC13): 8 205.8, 134.0, 133.7, 86.0,
77.8, 73.6, 72.7, 47.9, 45.3, 22.6, 10.5. HRMS (El) m/z caled for C,,H,703 [M+H]+
197.1178, found 197.1183. IR (film): 2963, 2876, 1716, 1341, 1113, 917, 854, 733 cm'1.
H OTB S
\ ° 7^
Figure 4-12. ter/-Butyl-dimethyl-( 1 -methyl-8-oxa-bicyclo[3.2.1 ]oct-6-en-3-yloxy)silane
(207a)
l-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol 207c (0.6044 g, 4.28 mmol) was
dissolved in dichloromethane (4.3 ml). The solution was then cooled to 0°C and 2,6-
lutidine (0.99 ml, 8.56 mmol) was added slowly, followed by the drop wise addition of
tert-butyldimethylsilyltrifluoromethanesulfonate (1.5 ml, 6.422 mmol). The reaction was
monitored by TLC. Upon completion of the reaction, the solvent was evaporated under
reduced pressure and the residue was triturated with hexane. The hexane layers were
combined and concentrated under reduced pressure. The residue was purified by silica
gel chromatography, using gradient elution (60:1 silica gel: residue; 100:0 - 98: 2 hexane:
ethyl acetate) giving 207a as a colorless oil (0.9838 g, 90%). Rf= 0.43 (90: 10 hexane:
ethyl acetate). ‘H NMR (300 MHz, CDC13): 8 6.10 (1H, dd, J = 5.8 Hz, 1.2Hz), 5.92
( 1H, d, J= 5.8), 4.72 ( 1H, s), 4.08-4.04 (lH,m), 2.10-2.02 ( 1H, m), 1.92 ( 1H, dd,J=
14.0 Hz, 5.3 Hz), 1.58 ( lH,d,/= 14.0), 1.46(lH,d,/= 14.0), 1.32 (3H,s), 0.84 (6H,

92
s), -0.04 ( 9H, s). I3C NMR (300 MHz, CDC13): 5 136.9, 133.8, 82.8, 79.1, 65.2,42.7,
35.5, 25.9, 24.5, 17.9, -4.7. HRMS (El) caled for Q^C^Si [M]+ 254.1702, found
254.1695. 1R (film): 3440, 2953, 2930, 2857, 1721, 1472, 1377, 1256, 1132, 1083,
1056, 859, 836, 774, 720, 682 cm'1.
H OTBS
Figure 4-13. fórt-Butyl-( 1 -methoxymethyl-8-oxa-bicyclo[3.2.1 ]oct-6-en-3-yloxy)-
dimethyl-silane (207b)
l-Methoxymethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol 207d (0.1335 g, 0.78 mmol)
was dissolved in dichloromethane (0.79 ml). The solution was cooled to 0°C and 2,6-
lutidine (0.18 ml, 1.58 mmol) was added slowly followed by the drop wise addition of
tert-butyldimethylsilyltrifluoromethanesulfonate (0.27 ml, 1.18 mmol). The reaction was
monitored by TLC. Upon completion of the reaction, the solvent was evaporated under
reduced pressure and the residue was triturated with hexane. The hexane layers were
combined and concentrated under reduced pressure. The residue was purified by silica
gel chromatography using gradient elution (60:1 silica gel: residue; 100: 1 - 95: 5
hexane: ethyl acetate) gave 207b as a colorless oil (0.1952 g, 88%). R/= 0.13 (95: 5
hexane: ethyl acetate). 'H NMR (300 MHz, CDC13): 5 6.22 (1H, dd, ./ = 5.7, 0.9 Hz),
6.01 (1H, d, J= 5.7Hz), 4.819 ( 1H, s), 4.16-4.12 (1H, m), 3.50 (2H, AB quartet, J =
10.2 Hz), 3.44 (3H,s), 2.19-2.05 ( 2H, m), 1.56-1.50 (2H,m), 0.88 (9H, s), 0.00 (6H, s).
13C NMR (300 MHz, CDC13): 5 134.7, 133.7, 85.3, 79.1, 76.4, 64.8, 59.7, 37.4, 35.6,
25.8, 17.9, -4.8. HRMS (El) caled for C^gC^Si [M]+284.1823, found 284.1823. 1R

93
(film): 2953, 2929, 1472, 1463, 1255, 1116, 1044, 836, 774, 727 cm1. Teoric CH caled
for C|5H2803Si: C, 63.33; H, 9.92, found: C, 63.56, H, 10.05.
H OH
Lo--!
Figure 4-14. ew/o-l-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3ol (207c)
A solution of oxabicyclic ketone 206a (0.5150g, 3.7 mmol) in THF (4 ml) was
cooled to -78°C. L-selectride (1 M in THF, 5.5 ml) was added drop wise. After 1 hour
the reaction was allowed to reach room temperature. After 3 hours the reaction was
cooled to 0°C and a solution of 2: 1, 20% NaOH and 30% H2O2 was added slowly. After
1 hour, the solution was neutralized with 2 M H2SO4. The aqueous layers were saturated
with NaCl and extracted several times with ethyl acetate. The organic layers were
combined, dried on MgS04, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography using gradient elution (50: 1 silica gel;
residue; 75:25 to 60: 40 hexane: ethyl acetate) gave 207c as a colorless oil (0.4362 g,
83%). Rf= 0.13 (65: 35 hexanes: ethyl acetate.'H NMR (300 MHz, CDCL3): 5 6.42
(lH,dd, J= 5.85Hz, 1.76Hz), 6.22 (1H, d, J= 5.84Hz), 4.81-4.80 (1H, m), 4.02-3.99 (1H,
m), 2.30 (1H, bs), 1.37(3H,s). I3C NMR (CDC13): 5 138.8, 135.8, 82.8, 78.8, 65.7, 42.4,
35.3, 24.0. HRMS (El) caled for C8H,202 [M-H]+ 139.0759, found 139.0765. IR (film):
3426, 2934, 1718, 1650, 1345, 1041, 917, 872, 815 cmT.

94
H OH
Figure 4-15. 1 -Methoxymethyl-8-oxa-bicyclo[3.2.1 ]oct-6-en-3-ol (207d)
A solution of oxabicyclic ketone 206b (0.4000 g, 2.4 mmol) in THF (2.4 ml) was
cooled to -78°C. L-selectride (1M in THF, 3.1ml) was added drop wise. After 1 hour
the reaction was allowed to reach room temperature. After 12 hours the reaction was
cooled to 0°C and a solution of 2:1, 20% NaOH and 30% H2O2 was added slowly. After
1 hour, the solution was neutralized with 2M H2SO4. The aqueous layers were saturated
with NaCl and extracted several times with ethyl acetate. The organic layers were
combined, dried on MgSC>4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography using gradient elution (50:1 silica gel;
residue; 90:10 to 50: 50 ethyl hexane: ethyl acetate) gave 207d as a pale yellow oil
(0.3763 g, 93%). R/= 0.13 (60: 40 ethyl acetate: hexane). 'H NMR (300 MHz,
CDC13): 5 6.44 (1H, d, J= 5.9), 6.25 (1H, d, J= 5.9), 4.82 (lH,d, J= 1.9), 4.04-4.01
(1H, m), 3.51-3.43 (2H, ABquartet, J= 10.22 Hz), 3.38 (3H, d, J= 0.5), 2.40-2.08 (3H,
m), 1.74-1.65 (2H, m). ,3C NMR (CDC13): 5 136.1, 135.4, 85.1, 78.6, 75.6, 64.9, 59.5,
37.1,35.1. HRMS (El) caled for C9H,403 [M+H]+ 171.1055, found 170.1054. IR (film):
3437, 2923, 1651, 1455, 1348, 1193, 1107, 1035,975, 870, 736, 696 cm-1.
Figure 4-16. exo-l-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3ol (207e)
In a flame dry 3neck flask 206a (0.3153g, 2.28mmol) were mixed with 0.2 ml
(2.28 mmol) of isopropanol. A condenser was fitted and the mixture was degassed. Then

95
46 ml (4.56 mmol) of 0.1 M solution of SmÍ2 in THF was added under an argon
atmosphere. The deep blue solution was allowed to reflux for 5 hours. Upon completion
the reaction turned yellow color. The reaction was worked up by adding a small amount
of water, and then the solvent was evaporated under reduced pressure to almost
completion. To the residue ethyl acetate and brine solution was added. The mixture was
then filtered trough celite. The filtered was extracted with ethyl acetate, dried with
magnesium sulfate, filtered and concentrated under reduced pressure to give a dark
yellow oil that was purify by silica gel chromatography using gradient elution (75: 25-
60:40 hexane: ethyl acetate; residue adsorbed on silica) gave 11 e as a pale yellow color
(0.1659g, 57%). Rf - 0.20 (65:35 hexane: ethyl acetate). 'H NMR (300 MHz, CDCI3): 8
6.04 (1H, dd, J= 5.84Hz, 1.75Hz), 5.88 (1H, d,J= 6.14Hz), 4.82-4.81 (1H, m), 3.87-
3.76 (1H, m), 2.99(1H, s), 1.99-1.87 (2H, m), 1.58-1.37(2H, m), 1.40 (3H,s). 13C NMR
(CDC13): 8 134.8, 131.1, 83.6, 78.7, 65.3, 42.0, 34.8, 23.9. HRMS (El) caled for
C8HI202 [M]+ 140.0837, found 140.0837. 1R (film): 3393, 2969, 2847, 1650, 1453, 1378,
1063, 869, 820 cmT.
Figure 4-17. fórí-Butyl-dimethyl-(2-methyl-2-styryl-6-vinyl-tetrahydro-pyran-4-yloxy)-
silane (208a)
A solution of tert-Butyl-dimethyl- (l-methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-
yloxy)-silane 207a (0.403 lg, 1.57 mmol) in dichloromethane (5 ml) was prepared.
Styrene (0.72 ml, 6.29 mmol) was added followed by the addition of a solution of Grubbs
catalyst 67 (18 mg, 0.021 mmol) in dichloromethane (0.2 ml). The reaction was

96
monitored by TLC, after 2 hours, the reaction reached equilibrium. After 12 hours, the
solvent was evaporated under reduced pressure and the residue purified by silica gel
chromatography using gradient elution (100: 1 silica gel: residue adsorbed on silica; 100:
0 - 98: 2 hexane: ethyl acetate) gave an inseparable mixture of 208a and 208a in a ratio
of 6:1 as determined by GC/MS as a bright yellow oil (0.4690 g, 83%). R/= 0.25 (95: 5
hexane: ethyl acetate). 'H NMR (300 MHz, CDCL3): 5 7.175-7.395 (5H, m), 6.58 (1H,
d16.2), 6.29 (1H, d, J= 16.2), 5.91 (1H, ddd, J= 17.2 Hz, 10.5 Hz, 5.9 Hz), 5.30
(1H, d, J= 17.2 Hz), 5.13 (1H, d, J= 10.5 Hz), 4.20-4.00 (2H, m), 1.93-1.84 (2H,m),
1.59-1.26 (2H,m), 1.40 (3H,s), 0.90 (9H, s), 0.09 (6 H, s). 13C NMR (CDC13): 5 139.6,
137.6, 130.8, 128.9, 127.7, 126.8. HRMS (El) caled for C22H24SÍO2 [M]+358.2328,
found 358.2335. IR (film): 2952, 2929, 2857, 1601, 1495, 1472, 1463, 1449, 1377, 1255,
1082, 967, 862, 837, 776, 747, 693 cm1.
Figure 4-18. 2-Methyl-2-styryl-6-vinyl-tetrahydro-pyran-4-ol (208c)
In a 5 ml round bottom flask a solution of l-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-
3-ol 207c (0.1135 g, 0.809 mmol) in dichloromethane (2.2 ml) was prepared. To that
solution styrene (0.24 ml, 2.14 mmol) was added, followed by the addition of a solution
of Grubbs catalyst 67 (10 mg, 0.011 mmol) in dichloromethane (0.2 ml). The resulted
solution was allowed to stir under argon at room temperature. The reaction was
monitored by TLC, after 5 hours an extra volume of styrene (0.07 ml, 0.610 mmol) was
added. The reaction was monitored by TLC. After 8 hours no further reaction occurred.

97
After 12 hours, the solvent was evaporated under reduced pressure and the residue
purified by silica gel chromatography using gradient elution (100: 1 silica gel; residue
adsorbed on silica; 95:5 - 85: 15 hexane: ethyl acetate) gave an inseparable mixture of
208c and 209c in a ratio of 20:1 as determined by GC/MS as a white solid (0.1677 g,
85%). Major: R/= 0.43 (6: 4 Hexane: ethyl acetate), m.p. = (98-101) °C. 'H NMR (300
MHz, CDCL3): 5 7.40-7.19 (5H, m), 6.60 (1H, d, J= 16.2), 6.31 (1H, d,J= 16.2), 5.93
(1H, ddd, J = 17.4 Hz, 10.5 Hz, 5.7 Hz), 5.32 (1H, dd, J- 17.4 Hz, 1.2Hz), 5.16 (1H, dd,
J= 10.5 Hz, 1.2 Hz), 4.22-4.04 (2H, m), 2.09-2.00 (2H, m), 1.58(lH,bs), 1.40 (3H,s),
1.49-1.21 (2H, m), 13C NMR (CDC13): 5 139.0, 137.26, 137.0, 128.7, 127.6, 126.9, 126.7,
115.4, 75.2, 70.7, 65.7, 44.5, 41.6, 22.3. HRMS (El) m/z caled for Ci6H2o02 [M]+
244.1463, found 244.1459. IR (film): 3373, 2944, 1448, 1373, 1062, 1026, 968, 922,
748, 694 cm"1. Theoretical CH caled for C|6H2o02: C, 78.65; H, 8.25; found: C 78.32; H
8.32.
Figure 4-19. 2-Methoxymethyl-2-styryl-6-vinyl-tetrahydro-pyran-4-ol (208d)
A solution of l-Methoxymethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol 207d (0.0925g,
0.543 mmol) in dichloromethane (1.4 ml) was prepared. Styrene (0.19 mL, 1.629 mmol)
was added, followed by the addition of a solution of Grubbs catalyst 67 (6.9mg,
0.008 lmmol) in dichloromethane (0.2 ml). After 5 hours an extra volume of styrene
(0.08mL, 0.698 mmol) was added. The reaction was monitored by TLC and it reached
equilibrium after 8 hours. After 12 hours, the solvent was evaporated under reduced

98
pressure and the residue purified by silica gel chromatography using gradient elution
(100: 1 silica gel: residue adsorbed on silica; gradient, 98: 2 - 3: 1 hexane: ethyl acetate)
gave an inseparable mixture of 208d and 209d in a ratio of 20:1 as determined by GC/MS
as a semi-solid (0.0985 g, 66%). Unreacted starting material 207d (21 mg) was
recovered. R/= 0.33 (60:40 hexane: ethyl acetate). 'H NMR (300 MHz, CDCL3):
5 7.40-7.17 (5H, m), 6.67 (1H, d,J= 16.1), 6.32 (1H, d, J= 16.1), 5.91 (1H, ddd, J=
17.23 Hz, 10.52 Hz, 5.55 Hz), 5.31 (1H, d,J= 17.23 Hz), 5.14 (1H, d, 7= 10.52 Hz),
4.27 (lH,dd, J= 10.8 Hz, 4.7 Hz), 4.14-4.07 (1H, m), 3.52 (2H, s), 3.34 (3H, s), 2.30-
2.24(1 H, m), 2.07-2.01 (lH,m), 1.807 (lH,bs), 1.43-1.21 (2 H, m). ,3C NMR (CDC13):
5 138.8, 137.1, 133.6, 128.5, 128.0, 127.5, 126.6, 115.3, 76.8, 75.2, 71.7, 65.1, 59.6, 41.0,
40.7. HRMS (El) caled for C17H22O3 [M]+274.1569, found 274.1524. IR (film): 3391,
2924, 1496, 1449, 1368, 1106, 1063, 1026, 969, 923, 750, 695.
Figure 4-20. 2-Methyl-2-styryl-6-vinyl-tetrahydro-pyran-4-ol (208e)
exo-l-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol 207e (0.070 g,0.499 mmol) in
dichloromethane (0.62 ml) was prepared. Styrene (0.17 ml, 1.50 mmol) was added
followed by the addition of a solution of Grubbs catalyst 67 (6.4 mg, 0.008 mmol) in
dichloromethane (0.3 ml). The reaction was monitored by TLC, after 5 hours an extra
volume of styrene (0.05 ml, 0.436 mmol) was added. After 12 hours, the reaction did not
reach completion. The reaction solvent was evaporated under reduced pressure and the
residue purified by silica gel chromatography using gradient elution (150: 1 silica gel:

99
residue adsorbed on silica; 100: 0 - 3: 1 hexane: ethyl acetate) gave an inseparable
mixture of 208e and 209e in a ratio of 6:1 as determined by GC/MS as a semi-solid
(0.0182 g, 15%). Unreacted starting material 207e (50 mg) was recovered. R/= 0.11 (2:
8 ethyl acetate: hexane). 'H NMR (300 MHz, CDCL3): 5 7.40-7.18 (5H, m), 6.55 (1H, d,
J= 16.2), 6.28 (1H, d,J= 16.2), 5.95 (1H, ddd,/= 17.2 Hz, 10.5 Hz, 5.9 Hz), 5.33 (1H,
ddd, J = 17.2 Hz, 3.1 Hz, 1.1 Hz), 5.14 (1H, ddd,/= 10.5 Hz, 2.82 Hz, 1.28Hz), 4.63-
4.57 (1H, m), 4.34-4.31 (1H, m), 1.83-1.65 (7 H, m), 13C NMR (CDC13): 6 139.8, 138.2,
137.5, 128.7, 127.4, 126.6, 126.4, 115.2, 73.6, 67.0, 65.1,41.1, 38.4, 24.8. HRMS (El)
caled for [M]+244.1463, found 244.1459. 1R (film): 3433, 2923, 1722, 1494,
1448, 1277, 1050, 988, 968, 923, 747, 693 cm'1.
MeCU MeCU
N N
Figure 4-21. cis and trans 1 -Methyl-8-oxa-bicyclo[3.2.1 ]oct-6-en-3-one O-methyl-oxime
(213a, 213b)
l-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-one 206a (0.5120, 3.70 mmol) was
dissolved in 12mL of dry CH2CI2 and, mixed with methoxylamine hydrochloride (0.6301,
7.5 mmol) and 3A° molecular sieves. Then 0.62 ml of pyridine was added, a condenser
was fixed and the reaction mixture was allowed to reflux for two days. Upon completion
of the reaction by TLC, the reaction was diluted in CH2CI2; the resulting powdering
molecular sieves were filtered. The filtered liquid was washed with brine and dried over
MgS04, filtered trough a small plug of silica gel and concentrated to achieve pale yellow
oil (0.4530g, 73%) of 1:1 ratio of 213a and 213b. The isomers were separated by
chromatography using gradient elution of (98:2 - 95:5 ether: hexanes).

100
fra«s-l-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-one O-methyl-oxime (213a)
R/= 0.61 (65: 35 hexane: ethyl acetate). 'H NMR (300 MHz, CDCL3): 5 6.11 (1H, dd, J
= 5.9Hz, 1.7Hz), 5.98 (1H, d, J= 5.9Hz), 5 4.88 (1H, dt,/= 4.8Hz, 1.2Hz), 3.78 (3H, s),
. 2.89 (1H, d,J= 16.2 Hz), 2.41 (1H, d,J= 15.2 Hz), 2.32(lH,d,7= 15.0Hz),2.29
(lH,ddt, J=16.2Hz, 4,8Hz, 1.2Hz), 1.45 (3H,s). I3C NMR (CDC13): 5 154.6, 135.7,
133.3, 83.8, 77.7, 61.4, 40.5, 29.4, 23.4. HRMS (El) caled for C9H13N02 [M]+ 167.0946,
found 167.0949. IR (film): 2919, 2850, 2360, 2359, 1463, 1264, 1050, 745 cm1.
c/s-l-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-one O-methyl-oxime (213b)
R/= 0.55 (65: 35 hexane: ethyl acetate). ‘H NMR (300 MHz, CDCL3): 5 6.13 (1H, dd, J
= 6.0Hz, 1,4Hz), 5.98 (1H, d, J= 6.0Hz), 4.92 (1H, d, J = 4.3Hz), 3.78 (3H, s), 3.02 (1H,
d,J= 16.2 Hz), 2.60(lH,dd,7= 15.5 Hz, 4.5 Hz), 2.22 (1H, d,J= 15.5 Hz), 2.11 (1H,
d, J= 16.2 Hz). I3C NMR (CDC13): 5 154.6, 136.5, 132.4, 82.6, 78.7, 61.3, 36.2, 33.5,
23.2. HRMS (El) caled for C9H,3N02 [M]+ 167.0946, found 167.0942. IR (film): 2964,
2908, 2820, 1379, 1073, 1054, 1024, 951, 942, 865 cm'1.
Figure 4-22. 1 -Methyl-8-oxa-bicyclo[3.2.1 ]oct-6-en-3-(2,2-dimethyldioxane) ketal (214)
In a 2-neck flask, 206a (0.8085g, 5.86mmol) was dissolved in 6ml of 2,2,5,5-
tetramethyl-l,3-dioxane. /7-TSOH H2O (0.0444g, 0.234mmol, 0.04 equiv.) was added.
The flask was connected to a reduced pressure vacuum regulated to 28mmHg to remove
the liberated acetone. The colorless solution started to turn pale pink-orange color to a
dark pink-orange color. The reaction was allowed to stir under reduced pressure

101
overnight. After no further reaction was observed it was quenched with Et3N (36pl,
0.0237 g, 0.234 mmol). Then the solvent was evaporated under reduced pressure and the
residue was purify by silica gel chromatography using gradient elution (100:1 silica gel;
residue; 98: 2 to 70: 30 hexane: ethyl acetate) gave 214 as a colorless oil (0.4365g, 33%).
Some starting material was recovered, the rest decomposed. R/= 0.243 (60: 40 hexanes:
ether). 'H NMR (300 MHz, CDCL3): 5 6.06 (1H, dd, 7 = 5.8Hz, 1.8Hz), 5.91 (1H, d, 7 =
5.8Hz), 4.82-4.81 (1H, m), 3.43 (4H, d, 7- 3.2Hz), 2.24 (1H, d, 7- 14.2 Hz), 2.19 (1H,
d, 7= 13.2 Hz), 1.91(1 H, dd,7= 13.9Hz, 4.7Hz), 1.77 (1H, d,7 =
14.0Hz), 1.39 (3H, s), 0.93 (6H, d, 7 = 9.6Hz). 13C NMR (CDC13): 5 135.8, 132.5,97.2,
82.5, 78.0, 69.8, 69.7, 43.2, 35.5, 29.9, 24.0, 22.82, 22.76. HRMS (El) caled for
C13H20O3 [M]+224.1412, found 224.1430. IR (film): 3078, 2953, 2930, 2868, 1602,
1471, 1344, 1099 cm1. Theoretical CH caled for C13H20O3: C, 69.61; H, 8.99, found: C,
69.19; H, 9.02.
Figure 4-23. 3,3,8-Trimethyl-8-styryl-10-vinyl-l,5,9-trioxa-spiro[5.5]undecane (215)
A solution of l-methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-(2,2-dimethyldioxane)
ketal 214 (0.049 g, 0.22 mmol) in dichloromethane (0.53 ml) was prepared. Styrene (0.1
ml, 0.88 mmol) was added followed by the addition of a solution of Grubbs catalyst 67 (3
mg, 0.003 mmol) in dichloromethane (0.1 ml). The reaction was monitored by TLC,
using p-anisaldehyde as stain. After 50 min, the solvent was evaporated under reduced

102
pressure and the residue purified by silica gel chromatography using gradient elution
(100: 1 silica gel: residue adsorbed on silica; 100:0 - 95:5 hexane: ethyl acetate) gave a
white semisolid (66 mg, 90%). R/= 0.68 (65:35 hexane : ethyl acetate). 'H NMR (300
MHz, CDCL3): 5 7.18-7.40 (5H, m), 6.58 (1H, d, J= 16.1), 6.27 (1H, d,J= 16.1), 5.93
(1H, ddd, J = 17.2 Hz, 10.5 Hz, 5.8 Hz), 5.34 (1H, dt, J= 17.2, 1.5 Hz), 5.16 (1H, dt,J =
10.5, 1.5 Hz), 4.35-4.41 (1H, m), 3.65-3.43 (4H, m), 2.46 (1H, dd, J=14.0, 2.6 Hz), 2.13
(1H, dt, J= 13.4, 2.3 Hz), 1.58-1.43 (2H, m), 1.50 (3H,s), 1.08 (3H, s), 0.91 (3H,s). 13C
NMR (CDCI3): 5 139.0, 137.7, 137.3, 128.7, 127.4, 126.6, 126.6, 115.5, 96.7, 74.6, 70.5,
70.1, 69.2, 40.5, 39.0, 30.4, 23.2, 22.7, 22.2. HRMS (El) caled for C2iH2803 [M]+
328.2038, found 328.2033. IR (film): 2960, 2934, 2865, 1090, 913, 745, 694 cnfl.
O
Figure 4-24. l-Methoxy-8-oxa-bicyclo[3.2.1]oct-6-en-3-one (235)
2-Methoxyfuran 233 (1.25 g, 12.7 mmol) was placed in a 3-neck round bottom
flask and cooled to 0°C. Via two separate addition funnels, solutions of trifluoroethoxide
(2M, 12.7 ml) and trichloroacetone (19.1 mmol, 2.0 ml) in trifluoroethanol were added
dropwise simultaneously. After the addition was completed, the solution was allowed to
warm to room temperature. The reaction was monitored by TLC using p-anisaldehyde as
stain. Upon completion of the reaction, an equal volume of water and dichloromethane
was added, and the aqueous layers extracted twice with dichloromethane. The organic
layers were combined and dried on MgSC>4, filtered, and the solvent removed in vacuo.
The crude dark orange/brown oil is filtered through a bed of silica gel, eluding with 70:
30 hexanes: ethyl acetate. The filtered was concentrated under reduced pressure in a

103
rotary evaporator. The pale yellow solid was diluted with methanol, and zinc/copper
couple (2.51 g) was added. The mixture was allowed to reflux for 4 hours. The mixture
was then filtered through celite, eluding with ethyl acetate, to remove the zinc/copper
couple. The filtrate was then evaporated to almost completion. Then the residue is
adsorbed on silica and purified by silica gel chromatography using gradient elution (40: 1
silica gel; 90: 10 - 80: 25 hexanes: ethyl acetate) to give pale yellow oil (0.74 g, 37 %
over 2 steps). Rf= 0.57 (40: 60 hexanes: diethyl ether). 'H NMR (300 MHz, CDC13): 5
6.35 (1H, dd, J= 6.0, 2.5 Hz), 6.12 (1H, dd, J= 5.8, 0.6 Hz), 5.08-5.06 (1H, m), 3.43
(3H, s), 2.75-2.59 (3H,m), 2.28 (lH,dt,J= 16.4, 1.5 Hz). I3C NMR (300 MHz,
CDC13): 5 205.4, 136.7, 132.6, 109.9,74.8,51.9,51.8,44.2. HRMS (El) m/z caled for
C8H10O3 [M]+ 154.0630, found 154.0623. IR (film): 2976, 2913, 2838, 1718, 1338, 1172,
1043,851,728 cm'1.
O
Figure 4-25. endo-1 -Methyl-8-oxa-bicyclo[3.2.1 ]oct-6-en-3ol (236)
In an NMR tube, a solution of oxabicycle ketone 235 (33 mg, 0.21 mmol) and
styrene (0.1 ml, 0.84 mmol) in deuterated chloroform (0.5 ml) was prepared. To the
solution, grubbs catalyst 67 (3 mg, 0.0031 mmol) in deuterated chloroform (0.1 ml) was
added. The resulted solution was allowed to stir under argon at room temperature for 5
days. The solvent was evaporated under reduced pressure and the residue purified by
silica gel chromatography using gradient elution of ethyl acetate and hexane mixture,

104
affording 236 as a colorless oil (11 mg, 20 %). Starting material 235 was also recovered.
'H NMR (300 MHz, CDCL3): 5 7.45-7.26 (5H, m), 6.87 (1H, d, J= 16.2 Hz), 6.13 (1H,
d,J= 16.2 Hz), 6.02 (1H, ddd, J= 17.0, 10.5,5.9 Hz), 5.42 (1H, dt, J= 17.2, 1.3 Hz),
5.28 (1H, dt, J= 10.5, 1.3 Hz), 4.49-4.43 (1H, m), 3.19 (3H, s), 2.70-2.37 (4H, m). I3C
NMR (CDC13): 6 204.5, 137.1, 135.9, 132.8, 128.9, 128.5, 127.8, 127.0, 116.7, 101.5,
70.9, 51.8, 49.6, 46.6. HRMS (El) m/z caled for Cl6H,803 [M]+258.1256, found
258.1250.
H OH
OCH,
Figure 4-26. e«i/o-l-Methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3ol (237)
A solution of oxabicyclic ketone 235 (0.30 g, 1.95 mmol) in THF (2 ml) was
cooled to -78°C. L-selectride (1M in THF, 2.35 ml) was added drop wise. After 1 hour
the reaction was allowed to reach room temperature. After 3 hours the reaction was
cooled to 0°C and a solution of 2: 1, 20% NaOH and 30% H2O2 was added slowly. After
1 hour, the solution was neutralized with 2M H2SO4. The aqueous layers were saturated
with NaCl and extracted several times with ethyl acetate. The organic layers were
combined, dried on MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography using gradient elution (30: 1 silica gel;
residue; 90:10 to 70: 30 hexane: ethyl acetate) gave 237 as a pale yellow oil (0.26 g,
86%). R/= 0.18 (40: 60 hexanes: ethyl acetate. 'H NMR (300 MHz, CDCL3): 5 6.54
(1H, dd, J= 5.9 Hz, 2.04 Hz), 6.25 (1H, d, J= 5.9 Hz), 4.90-4.87 (1H, m), 4.17-4.13 (1H,
m), 3.37 (3H, s), 2.35-2.15 (1H, m), 2.15 (1H, d, .7=6.1 Hz), 1.98 (1H, d,J= 14.1 Hz),
1.65 (1H, dd, J= 14.6 Hz, 1.2 Hz). ,3C NMR (CDC13): 5 138.9, 134.6, 109.4,78.1,66.1,

105
50.9, 41.1, 35.4. HRMS (El) caled for C8H|303 [M+H]+ 157.0864, found 157.0869. IR
(film): 3432, 2929, 1667, 1342, 1174, 1108, 1018, 816 cm'1.
0
OTBS
Figure 4-27. 1 -(/er/-Butyl-dimethyl-silanyloxymethyl)-8-oxa-bicyclo[3.2.1 ]oct-6-en-3-
one (241)
/erí-Butyl-(furan-2-ylmethoxy)-dimethyl-silane 240 (7.8243g, 36.9mmol) was
placed in a 3-neck round bottom flask and cooled to 0°C. Via two separate addition
funnels, solutions of trifluoroethoxide (2 M, 221.4 ml) and trichloroacetone (442.8 mmol,
23.42 ml) in trifluoroethanol (190.0 ml) were added dropwise simultaneously. After the
addition was completed, the solution was allowed to warm to room temperature. The
reaction was monitored by TLC using p-anisaldehyde as stain. Upon completion of the
reaction an equal volume of water and dichloromethane was added, and the aqueous
layers extracted 2 times with dichloromethane. The organic layers were combined and
dried on MgSC>4, filtered, and the solvent removed in vacuo. The crude dark
orange/brown oil was placed in a 500 ml round bottom flask without purification. To the
crude, zinc/copper couple (58 g) and a solution of methanol saturated with ammonium
chloride (250 ml) were added, and the mixture was allowed to reflux for two days. The
mixture was then filtered through celite, eluding with ethyl acetate, to remove the
zinc/copper couple. The filtrate was then evaporated to almost completion. Then the
residue is adsorbed on silica and purified by silica gel chromatography using gradient
elution (40: 1 silica gel; 90: 10 - 75: 25 hexanes: ethyl acetate) to give yellow oil (9.0 g,
90 % over 2 steps). R/= 0.21 (85: 15 hexanes: diethyl ether). 'H NMR (300 MHz,
CDC13): 5 6.23 (lH,dd,/= 5.9, 1.5 Hz), 6.11 (1H, d,7= 5.9 Hz), 5.08 (1H, d,J- 5.1

106
Hz), 3.81 (2H,d,7 = 1.8 Hz), 2.72 (1H, dd, 7 = 16.4,5.1 Hz), 2.68 (1H, d, 7= 15.9 Hz),
2.41 (1H, d, 7= 16.4 Hz), 2.30 (1H, d,7 = 16.4 Hz), 0.90 (9H, s), 0.08 (6H, s). I3C NMR
(300 MHz, CDC13): 5 206.5, 134.0, 133.9, 86.9, 77.9, 66.1, 48.2, 45.6, 26.0, 18.5, -5.2.
HRMS (El) m/z caled for C,oH,503 [M-C4H9]+211.0790, found 211.0781. IR (film):
2955, 2929, 2857, 1717, 1103, 839, 778 cm'1.
H OH
f0J /OTBS
Figure 4-28. exo-l-(terr-Butyl-dimethyl-silanyloxymethyl)-8-oxa-bicyclo[3.2.1]oct-6-
en-3-ol (242)
In a flame dry 2neck flask 241 (0.5000 g, 1.86 mmol) were mixed with 0.3 ml
(3.73 mmol) of isopropanol. A condenser was fitted and the mixture was degassed. Then
40 ml (4.0 mmol) of 0.1 M solution of Sml2 in THF was added under an argon
atmosphere. The deep blue solution was allowed to reflux overnight. The reaction was
worked up by adding a small amount of water, and then the solvent was evaporated under
reduced pressure to almost completion. To the residue, ethyl acetate and brine solution
were added. The mixture was then filtered trough celite. The filtered was extracted with
ethyl acetate, dried with magnesium sulfate, filtered and concentrated under reduced
pressure to give a dark yellow oil that was purify by silica gel chromatography, yielding
242 as a pale yellow color (0.20g, 40%). R/= 0.10 (70:30 hexane: ethyl acetate). 'H
NMR (300 MHz, CDCL3): 5 6.06 (1H, dd, 7 = 5.9Hz, 1.7Hz), 5.98 (1H, d, 7 = 5.9Hz),
4.83-4.82 (1H, m), 3. 88-3.77 (1H, m), 3.69 (2H, s), 2.30 ( 1H, bs), 2.04 (1H, dd, 7=12.7,
6.1 Hz), 1.89 (1H, dd, 7 = 12.8, 6.4 Hz), 1.61-1.52 (1H, m), 1.41 (1H, dd, 7= 12.7, 9.8
Hz), 0.91 (9H, s), 0.07 (6H, s). I3C NMR ( CDC13): 5 132.2, 131.2, 86.9, 78.9, 67.0,
65.0, 37.1, 35.0, 26.0, 18.5, -5.3. HRMS (FAB) caled for C,4H2603Si [M]+271.1729,

107
found 271.1723. IR (film): 3388, 2952, 2928, 2857, 1471, 1462, 1253, 1103, 1052, 838,
779, 725 cm'1.
HQ H
0_/OTBS
Figure 4-29. 1 -(férr-Butyl-dimethyl-silanyloxymethyl)-8-oxabicyclo[3.2.1 ]oct-6-en-3-ol
(245)
To a solution of 241 (1.0 g, 3.7 mmol) in THF (5.0 ml) at-78°C, L-selectride (1M
in THF, 4.8 ml) was added drop wise. After 1 hour the reaction was allowed to reach
room temperature. After 3 hours the reaction was cooled to 0°C and a solution of 2:1,
20% NaOH and 30% H2O2 was added slowly. After 0.5 hour, the solution was
neutralized with 2M H2SO4. The aqueous layers were saturated with NaCl and extracted
several times with ethyl acetate. The organic layers were combined, dried on MgS04,
filtered, and concentrated under reduced pressure. The residue was purified by silica gel
chromatography using gradient elution (40:1 silica gel; residue; 90:10 to 85: 15 ethyl
hexane: ethyl acetate) gave 245 as a pasty colorless oil (0.9194 g, 90%). R/= 0.42 (60:
40 ethyl acetate: hexane). 'H NMR (300 MHz, CDC13): 8 6.45 (1H, dd, J- 6.6, 1.8
Hz), 6.33 (1H, d, J= 5.9), 4.84-4.81 (1H, m), 4.09-4.02 (1H, m), 3.67 (2H, s), 2.22 (1H,
dd, J- 14.8, 1.5 Hz ), 2.22 (1H, dd, J= 14.9, 9.9 Hz), 1.87 (1H, d,/=14.6 Hz), 1.71 (1H,
dd, J = 14.6, 1.17 Hz). ,3C NMR (300 MHz, CDC13): 5 136.7, 136.3,86.3,79.0,67.2,
65.9, 38.1, 26.1, 18.6, -5.1. HRMS (El) caled for C,4H2603Si [M-C4H9]+213.0947, found
213.0930. IR (film): 3436,2956,2938, 2864, 1478, 1282, 1260, 1170, 1096,846,778,
696 cm'1.

108
Figure 4-30. 2-(tert-Butyl-dimethyl-silanyloxymethyl)-2-styryl-6-vinyl-tetrahydro-
pyran-4-ol (246)
In a 25 ml round bottom flask, a solution of e«7o-l-(tert-Butyl-dimethyl-
silanyloxymethyl)-8-oxabicyclo[3.2.1]oct-6-en-3-ol 245, (1.04 g, 3.85 mmol) and styrene
(0.24 ml, 2.14 mmol) in dichloromethane (11.0 ml) was prepared. To the solution,
Grubbs catalyst 67 (65 mg, 0.08 mmol) in dichloromethane (1.0 ml) was added. The
resulted solution was allowed to stir under argon at room temperature for 10 hours. The
solvent was evaporated under reduced pressure and the residue purified by silica gel
chromatography using gradient elution (40: 1 silica gel; residue adsorbed on silica; 100:0
-85: 15 hexane: ethyl acetate) gave 246 as a viscous colorless oil (1.13 g, 78%) and 81
mg of starting material 245 were recovered. R/= 0.19 (80: 20 Hexane: ethyl acetate). 'H
NMR (300 MHz, CDCL3): 5 7.30-7.18 (5H, m), 6.65 (1H, d, 7= 16.4 Hz), 6.33 (1H, d, 7
= 16.4 Hz), 5.91 (1H, ddd, 7= 17.2, 10.5,5.8 Hz), 5.32 (1H, dt, 7= 17.2, 1.5 Hz), 5.15
(1H, dt, 7= 10.5, 1.5 Hz), 4.35-4.30 (1H, m), 4.23-4.12 (1H, m), 3.86 (1H, d,7= 10.2
Hz), 3.59 (1H, d, 7 = 9.6 Hz), 2.43 (1H, ddd, 7- 12.6, 4.7, 2.0 Hz), 2.04 (1H, dq, J =
12.3,2.3 Hz), 1.57 (1H, bs), 1.37-1.26 (2H,m), 0.90 (9H,s), 0.46 (6H, d, J = 3.6 Hz). ,3C
NMR (CDC13): 5 139.2, 137.4, 134.0, 128.7, 128.6, 128.0, 127.4, 126.6, 115.3, 104.8,
72.0, 66.1, 65.4, 41.3, 40.0, 26.1, 18.4, -5.2. HRMS (El) m/z caled for C22H34O3SÍ [M]+
374.2277, found 374.2290. IR (film): 3362, 2952, 2928, 2856, 1495, 1471, 1463, 1449,
1389, 1302, 1254, 1098, 1027, 838, 777, 747, 693 cm'1.

109
Figure 4-31. (4-Benzyloxy-2-styryl-6-vinyl-tetrahydro-pyran-2-ylmethoxy)-tert-butyl-
dimethyl-silane (247)
In a flame dry 10 ml round bottom flask, 32mg of NaH, 60% dispersion in
mineral oil, were washed twice with 0.6ml of pentane. A suspension of NaH in THF was
prepared by adding 0.3mL of dry THF. A solution of compound 246 (0.072 g, 0.19
mmol) in 0.6 ml THF was added slowly to the white suspension at room temperature.
After 10 min of the alcohol addition, benzene bromide was added (50mg, 0.29mmol).
Then the mixture was allowed to reflux for 1.5 hours. The reaction was worked up by
quenching with water and extracting with ethyl acetate. The solvent was evaporated
under reduced pressure and the residue purified by silica gel chromatography producing
247 as a colorless oil (0.13 g, 68%). R/= 0.59 (80: 20 hexane: ethyl acetate). 'H NMR
(300 MHz, CDCL3): 5 7.42-7.17 (5H, m), 6.65 (1H, d,7 = 16.4 Hz), 6.33 (1H, d, 7 =
16.0), 5.91 (1H, ddd, 7= 17.2, 10.5,5.8 Hz), 5.31 (lH,dt,7= 17.2, 1.5Hz), 5.14 (1H, dt,
7= 10.5, 1.5 Hz), 4.60 (2H, d,7= 0.87 Hz), 4.35-4.30 (1H, m), 3.99-3.89(1 H, m), 3.84
(1H, d, 7= 9.9 Hz), 3.55 (1H, d,7= 9.6 Hz), 2.54 (1H, ddd,7= , 12.8, 4.4, 2.0 Hz), 2.12
(1H, dq, J- 12.6,2.3 Hz), 1.43 (1H, d, 7= 11.4 Hz), 1.35 (lH,d, 7= 11.4 Hz), 0.89
(9H,s), 0.02 (6H, d, 7= 3.2 Hz). I3C NMR (CDC13): 5 157.4, 139.3, 137.5, 134.1, 128.6,
128.0, 127.7, 127.4, 126.6, 115.2, 77.7, 72.2, 71.9, 69.8, 66.2, 38.3, 36.9, 26.1, 18.4, -5.3,
-5.2. HRMS (El) m/z caled for C29H40O3Si [M-C4H9f 407.2042, found 407.2041. IR

110
(film): 3090, 3061, 3030, 2956, 2930, 2856, 1498, 1470, 1448, 1361, 1253, 1096, 1072,
838, 777, 746, 694 cm'1.
Figure 4-32. 2-[4-Benzyloxy-6-(tert-butyl-dimethyl-silanyloxymethyl)-6-styryl-
tetrahydro-pyran-2-yl]-ethanol (248)
To a solution of ether 247 in 0.3 ml THF, 0.22 ml of 0.5 M soln of 9-BBN-H were
added at 0°C. After the addition the mixture was allowed to reach room temperature
slowly. The reaction was allowed to stir for 12 hours. Then it was quenched with 0.6ml
of 2:1, 30 % H2O2: 6 M NaOH and refluxed for 1 hour. The aqueous layers were
saturated with K2CO3 and extracted with ether. The ether layers were dried with MgS04,
filtered and concentrated under reduced pressure. The residue was purified by silica gel
chromatography using gradient elution (90: 5-80:10 Hexanes: Ether) yielding 248 as a
colorless oil (39mg, 74%). R/- = 0.27 (80: 20 Hexane: ethyl acetate). 'H NMR (300
MHz, CDCL3): 5 7.37-7.19 (10H, m), 6.59 (1H, d, J= 16.0 Hz), 6.24 (1H, d, J= 16.0
Hz), 4.58 (2H, s), 4.03-3,74 (5H, m), 3.64 (1H, d, J= 10.2 Hz), 2.34 (1H, dd, J= 12.3,
4.3 Hz), 2.09-2.03 (1H, m), 1.92-1.70 (2H, m), 1.50 (1H, d, J= 11.7 Hz), 1.37 (1H, d, J=
11.7 Hz), 0.88 (9H, s), 0.02 (6H, s). 13C NMR (CDC13): 8 138.7, 137.2, 133.8, 128.7,
128.6, 128.3, 127.8, 127.7, 127.6, 126.6, 77.7, 72.0, 70.4, 69.9, 65.0, 61.4, 38.3, 38.2,
37.2, 26.0, 18.5, -5.3, -5.2. HRMS (El) m/z caled for C25H33O3SÍ [M-C4H9]+425.21482,
found 425.2100. IR (film): 3464, 3060, 2951,2927, 2857, 1495, 1470, 1453, 1360, 1254,
1089, 1027, 969, 838, 746, cm1.

OTBS
Figure 4-33. 4-Benzyloxy-6-[2-tert-butyl-dimethyl-silanyloxy)-ethyl]-2-(tert-butyl-
dimethyl-silanyloxymethyl)-2-styryl-tetrahydro-pyran (249)
Alcohol 248 (0.25 g, 0.52 mmol) was dissolved in dichloromethane (1.0 ml) and
added to an heterogeneous solution of tert-butyldimethylsilyl chloride (0.200 g, 0.73
mmol) and imidazole (53 mg, 0.78 mmol in methylene chloride (1ml). The mixture was
allowed to stir at room temperature for two hours then the solvent was evaporated under
reduce pressure. The residue was triturated with n-pentane and the solid formed was
removed by filtration. The filtered solution was concentrated and purified by silica gel
chromatography eluding with 5 % Et2Ü / Hexanes that produced 249 as a viscous
colorless oil (0.1560 g, 84 %). R/= 0.44 (85: 15 hexane: ethyl acetate). 'H NMR (300
MHz, CDCL3): 8 7.38-7.17 (1 OH, m), 6.61 (1H, d, J= 16.2 Hz), 6.32 (1H, d, J= 16.2),
4.62 (1H, d,y = 11.8 Hz), 4.57 (1H, d, J= 12.0 Hz), 3.94-3.72 (5H, m), 3.47 (1H, d, J=
9.8 Hz), 2.54 (1H, ddd,J= 12.5, 4.5, 1.8 Hz), 2.06 (1H, dt,J= 12.3,2.3 Hz), 1.86-1.66
(2H, m), 1.38-1.18 (1H, m), 0.91 (9H, s), 0.89 (9H,s), 0.07 (6H, s), 0.00 (6H, s). I3C
NMR (CDCI3): 5 138.9, 137.6, 134.5, 128.6, 127.8, 127.5, 127.3, 126.6, 77.2, 72.2, 69.8,
67.4, 65.2, 59.8, 40.1, 38.5, 36.6, 26.2, 26.1, 18.5, 18.4, -5.05, -5.02, -5.3, -5.2. HRMS
(FAB) m/z caled for C35H57O4SÍ2 [M-H]+ 597.3795, found 597.3742. IR (film): 3064,
3027, 2956, 2934, 2860, 1498, 1474, 1360, 1258, 1096, 840, 778, 745, 692 cm'1.

112
Figure 4-34. 4-Benxyloxy-6-[2-(terí-butyl-dimethyl-silanyloxy)-ethyl]-2-(fórt-butyl-
dimethyl-silanyloxymethyl)-tetrahydro-pyran-2-carbaldehyde (250)
A solution of compound 249 (0.22 g 0.35 mmol) in methylene chloride (1.2 ml) at
-78°C underwent ozonolysis with Welsbach Ozonator T-408 for 8 min, until colorless
solution turned light blue. Then excess of CH3SCH3 were added. The mixture was
allowed to reach room temperature and water was added. Then the layers were separated
and aqueous layers were extracted with small portions of methylene chloride. The
organic layers were dried with MgS04, filtered and concentrated. The residue was
purified by silica gel chromatography using gradient elution of (100 hexanes - 90:10
hexanes/ethyl acetate) yielding 250 as a colorless oil (0.174 g, 94 %). R/= 0.44 (85: 15
hexane: ethyl acetate). ‘H NMR (300 MHz, CDCL3): 5 9.50 (1H, s), 7.37-7.26 (5H, m),
4.57 (1H, d, J = 11.8 Hz), 4.51 (1H, d, J = 11.8 Hz), 3.89-3.68 (6H, m), 2.16 (1H, dd, J =
13.5,4.5 Hz), 2.07 (1H, dt, J = 12.0, 2.1 Hz), 1.91-1.65 (2H, m), 1.39-1.21 (2H, m), 0.90
(9H, s), 0.86 (9H,s), 0.05 (6H, s), 0.016 (6H, d, J= 2.1 Hz). 13C NMR (CDC13):
5 202.9, 138.5, 130.3, 128.7, 128.6, 127.8, 127.8, 127.7,82.0,71.6,69.9,68.1,63.0,
59.9, 39.7, 38.2, 32.2, 26.2, 26.0, 18.5, 18.3, -5.06, -5.07, -5.4, -5.5. HRMS (FAB) m/z
caled for C28H51O5SÍ2 [M+H]+ 523.3275, found 523.3266. IR (film):2958, 2934, 2890,
2857, 1714, 1471, 1255, 1093,837, 777cm'1.

113
Figure 4-35. 4-Benxyloxy-6-[2-(fór/-butyl-dimethyl-silanyloxy)-ethyl]-2-(fór?-butyl-
dimethyl-silanyloxymethyl)-tetrahydro-pyran-2-carboxylic acid (251)
To a solution of aldehyde 250 (80 mg, 0.15 mmol) in 2-methyl-2-butene (0.6 ml)
was added a mixture of 1:1 f-BuOH: H2O (1.4 ml), NaFhP&t and sodium chlorite at 0°C.
The mixture was allowed to stir at 0°C for 3 hours then allowed to warm to room
temperature and stir for another 20 hours. The mixture was partitioned between ethyl
acetate and water (4 ml). Then the aqueous layers were extracted with ethyl acetate. The
ethyl acetate layers were dried with MgSC>4 and concentrated. The residue was purified
by silica gel chromatography using gradient elution (90: 10-65: 35 hexanes: ether)
yielding (60 mg, 74 %). Some starting material, aldehyde 250, was recovered. 'H NMR
(300 MHz, CDCL3): 5 7.37-7.26 (5H, m), 4.58 (1H, d, J= 11.8 Hz), 4.50 (1H, d, J= 11.8
Hz), 3.94-3.70 (6H, m), 2.34 (1H, dd, J= 13.3, 3.2 Hz), 2.09 (1H, dt, J= 9.3, 1.8 Hz),
1.95-1.71 (2H, m), 1.32 (1H, d, J= 11.4 Hz), 0.89 (9H, s), 0.86 (9H,s), 0.05 (6H, s), 0.03
(6H, s). 13C NMR (CDCI3): 5 173.3, 138.3, 128.6, 127.8, 127.7, 80.7, 71.3, 70.1, 69.3,
63.3, 59.9, 39.4, 37.6, 34.3, 26.2, 25.9, 18.5, 18.3, -5.07, -5.1, -5.3, -5.5. HRMS (FAB)
m/z caled for C28H5,06SÍ2 [M+H]+ 539.3224, found 539.3250. IR (film):2956, 2930,
2888, 2857, 1780, 1734, 1100, 837, 780 cm’1.

114
Figure 4-36. 4-Benxyloxy-6-[2-(terí-butyl-dimethyl-silanyloxy)-ethyl]-2-(fórt-butyl-
dimethyl-silanyloxymethyl)-tetrahydro-pyran-2-carboxylic acid methyl ester
(263) '
Acid 251 (29 mg, 0.05 mmol) was reacted with excess of freshly prepared
diazomethane at 10°C. The mixture was allowed to stir for 6 hours then the solvent was
removed under reduced pressure yielding a quantitative amount of ester 263. 1H NMR
(300 MHz, CDCL3): 5 7.36-7.28 (5H, m), 4.60 (1H, d, J= 11.7 Hz), 4.55 (1H, d,J= 11.7
Hz), 3.98-3.67 (6H, m), 3.73 (3H, s), 2.46 (1H, ddd, J= 13.1,4.8, 2.1 Hz), 2.06 (1H, dt,
J= 12.6, 2.1 Hz), 1.94-1.81 (1H, m), 1.73-1.23 (3H, m), 0.90 (9H, s), 0.86 (9H,s), 0.05
(6H, s), 0.01 (6H, s). 13C NMR (CDC13): 5 172.6, 138.6, 128.6, 127.8, 127.7, 80.7, 71.7,
69.8, 68.3, 63.5, 59.7, 57.3, 52.4, 39.5, 37.9, 34.0, 26.2, 25.9, 18.5, 18.3, -5.08, -5.1, -5.3,
-5.4. HRMS (FAB) m/z caled for C29H53O6SÍ2 [M+H]+ 553.3380, found 553.3357. IR
(film): 2952, 2856, 1747, 1452, 1256, 1106, 837, 777 cm'1.
Figure 4-37. 4-Benxyloxy-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-tetrahydro-pyran-
2-one (253)
To a solution of acid 251 (35 mg, 0.065 mmol) in CH2CI2 (2.6 ml) was added
diacetoxyiodo benzene (DIB) (55 mg, 0.16 mmol) and iodine (10 mg, 0.039 mmol) as
solids. After 3 hours the reaction was worked up by adding a saturated aqueous solution
of sodium thiosulfate and extracting the aqueous layers with methylene chloride. After

115
silica gel chromatography, lOmg of 253 were recovered yielding 48%. Rf- 0.41 (70: 30
Hexane: ethyl acetate). 'H NMR (300 MHz, CDCL3): 5 7.39-7.28 (5H, m), 4.56 (2H, s),
4.43-4.33 (lH,m), 3.96 (1H, ddt, J= 8.9, 7.1, 5.8 Hz), 3.86-3.70 (2H, m), 2.88 (1H, ddd,
J= 17.2,5.9, 1.0 Hz), 2.60 (1H, dd, J= 17.2, 7.2 Hz), 2.35 (1H, dddd,7 = 13.9,5.6,3.0,
1.1 Hz), 1.93 (1H, ddt, J = 14.1,8.2, 4.9 Hz), 1.81 (1H, dddd,J= 13.9,8.4, 5.4, 4.5 Hz),
1.66 (1H, ddd, J = 13.9, 11.9, 9.0 Hz), 0.89 (9H, s), 0.05 (6H, s). 13C NMR (CDC13):
5170.5, 137.9, 128.7, 128.1, 127.8, 74.2, 70.5, 58.8, 38.8, 37.0, 35.7, 29.2, 26.1, 18.5, -
5.2. HRMS (Cl) m/z caled for C20H33O4SÍ [M+H]+ 365.2148, found 365.2164. IR (film):
2954, 2928, 2856, 1744, 1253, 1093, 836, 777 cm'1.
Figure 4-38. Acetic acid 2-[4-benzyloxy-6-[tert-butyl-dimethyl-silanyloxymethyl)-6-
styryl-tetrahydro-pyran-2-yl]ethyl ester (264)
Alcohol 248 (0.1 OOg, 0.025 mmol) was diluted in 0.4 ml of CH2CI2 with 4-
dimethylamino pyridine (DMAP) (<1 mg) and pyridine (25mg, 0.31 mmol). After 10
min, acetic anhydride (30 pi, 0.029 mmol) and the mixture was refluxed for 2 hours. The
solvent was removed under reduced pressure and the residue was purified by silica gel
chromatograpy using gradient elution (98: 2- 85: 15 hexanes: ether). The reaction gave
264 (95 mg, 87%). R/= 0.59 (70: 30 hexane: ethyl acetate). 'H NMR (300 MHz,
CDCL3): 5 7.34-7.16(1 OH, m), 6.59 (1H, d,J= 16.2 Hz), 6.26 (1H, d,7= 16.2 Hz), 4.59
(1H, d,J= 13.3), 4.55 (1H, d, J= 13.3), 4.26-4.21 (1H, m), 3.93-3.85 (2H, m), 3.74 (1H,
d, 9.7Hz), 3.52 (1H, d,J= 9.7 Hz), 2.51-2.44 (1H, m), 2.03 (3H, s), 1.96-1.78 (3H,

116
m), 1.42-1.20 (2H, m), 0.87 (9H,s), 0.00 (6H, s). I3C NMR (CDC13): 5 171.3, 138.9,
36.0, 26.0, 21.2, 18.3, -5.3, -5.4. HRMS (FAB) m/z caled for C3iH450sSi [M+H]+
525.3036, found 525.2991. 1R (film): 2953, 2856, 1738, 1249, 1090, 838 cm1.
H OBn
Figure 4-39. Acetic acid 2-(4-benzyloxy-6-hydroxymethyl-6-styryl-tetrahydro-pyran-2-
yl)-ethyl ester (265)
To a solution of ether 264 (90 mg, 0.17 mmol) in THF (0.5 ml) was added
tetrabuthyl ammonium fluoride (Bu4NF) (0.7 ml of 1 M solution, 0.7 mmol) at room
temperature. The solution was allowed to stir for 3 hours. The mixture was worked up
by adding a saturated solution of sodium bicarbonate. The aqueous layers were extracted
with ether, and the ether layers were dried over MgS04 and concentrated under reduced
pressure. The residue was purified by silica gel chromatography using gradient elution
(90: 10 - 75: 25 hexanes: ethyl acetate) affording 265 (50 mg, 71%). R/= 0.17 (70: 30
Hexane: ethyl acetate). 'H NMR (300 MHz, CDCL3): 8 7.40-7.20 (1 OH, m), 6.67 (1H, d,
J= 16.2 Hz), 6.22 (1H, d, J= 16.2 Hz), 4.57 (2H, s), 4.45-4.37 (1H, m), 4.29-4.22 (1H,
m), 3.95 (1H, d, J= 11.7 Hz), 3.81-3.70 (2H, m), 3.48-3.42 (1H, m), 2.18-2.05 (3H, m),
2.06 (3H,s), 1.97-1.86 (2H, m), 1.558 (1H, t,J= 12.2 Hz). I3C NMR (CDC13):
5 171.6, 138.5, 136.9, 132.9, 128.7, 128.6, 127.9, 127.8, 127.7, 126.7, 77.8, 71.9, 70.0,
66.6, 63.0, 61.2, 38.3, 37.8, 35.8, 21.2. HRMS (Cl) m/z caled for C25H3,05 [M+H]+

117
411.2171, found 411.2150. IR (film): 3480, 3064, 3030, 2948, 2924, 2878, 1738, 1495,
1364, 1244, 1067, 969, 749, 696 cm'1.

APPENDIX A
SELECTED SPECTRA

A
199
B
i
i L
130 120 110 100 90 80 70 60 50 40 30
PPm
Figure A-l. Spectroscopy data for 199. A) Structure B) 'H spectrum C) l3C spectrum
119

120
A
200
B
180
160 140 lZlT 100
40 20 0 ppm
Figure A-2. Spectroscopy data for 200. A) Structure B) 'H spectrum C) l3C spectrum

121
A
h3c, OH
201
B
C
Figure A-3. Spectroscopy data for 201. A) Structure B) 'H spectrum C) l3C spectrum

122
205
Figure A-4. Spectroscopy data for 205. A) Structure B) *H spectrum C) l3C spectrum

123
Figure A-5. Spectroscopy data for 206b. A) Structure B) 'H spectrum C) l3C spectrum

124
A
206c
B
Figure A-6. Spectroscopy data for 206c. A) Structure B) 'H spectrum C) l3C spectrum

125
A
207a
B
C
dL
j /
Jl L
// /
jolJWl
I
J
I
i
Figure A-7. Spectroscopy data for 207a. A) Structure B) ‘H spectrum C) l3C spectrum

126
A
H OH
Figure A-8. Spectroscopy data for 207d. A) Structure B) 'H spectrum C) l3C spectrum

127
A
207e
B
C
Figure A-9. Spectroscopy data for 207e. A) Structure B) 'H spectrum C) l3C spectrum

128
A
OH
B
150 140 130 120 110 100 90 80 70 60 50 40 30 ppn
Figure A-10. Spectroscopy data for 208c. A) Structure B) 'H spectrum C) l3C spectrum

129
C
Figure A-l 1. Spectroscopy data for 208e. A) Structure B) 'H spectrum C) l3C spectrum

130
A
OH
B
Figure A-12. Spectroscopy data for 208d. A) Structure B) ’H spectrum C) l3C spectrum

131
Figure A-13. Spectroscopy data for 213a. A) Structure B) 'H spectrum C) l3C spectrum

132
A
N-OMe
213b
B
C
_lL «A llll
Ij
Figure A-14. Spectroscopy data for 213b. A) Structure B) 'H spectrum C) l3C spectrum

133
A
Figure A-15. Spectroscopy data for 214. A) Structure B) 'H spectrum C) l3C spectrum

134
A
C
Figure A-16. Spectroscopy data for 215. A) Structure B) 'H spectrum C) l3C spectrum

135
A
O
235
B
Figure A-17. Spectroscopy data for 235. A) Structure B) 'H spectrum C) l3C spectrum

136
A
O
B
J
M lU f\ 1 . 1
i, L,
8 7 6 5 4 3 2 I Ó ppm
. oo * “ i «i" »•** 4.*7
C
l_lt«tonyK* 3_Pui «ve IlowSpot.C
= 55
wiwuNNwü
2 s
"¿S
200 180 160 140 120 100
60 40
Figure A-18. Spectroscopy data for 236. A) Structure B) 'H spectrum C) 13C spectrum

137
A
237
B
wJV »J
L
—i—,—' ■'—i—i—•—-—’ «-
3 2
JL_
pp*
mmmmrn
mum
mm
mm
HO 130
120
110
100
1—j—1—I—i—1—|—I I ¡—I—¡ I—1 I—]—I—I—I—I—|—I
80 70 60 50 40
Figure A-19. Spectroscopy data for 237. A) Structure B) 'H spectrum C) l3C spectrum

138
A
OTBS
B
I
M
»
_ .. .L
ai JLjUUl_
L
R
! J
1
7
6
5
4
3
2
1
ppm
C
Figure A-20. Spectroscopy data for 241. A) Structure B) 'H spectrum C) l3C spectrum

139
A
Figure A-21. Spectroscopy data for 242. A) Structure B) 'H spectrum C) IJ!C spectrum

140
A
HO
OTBS
245
B
JuUük
¿ |J
I ,1
«5
*0
MM*
130 120 110 100 90 80 70 60 50 40 30 20 10
• 1 1 o
Figure A-22. Spectroscopy data for 245. A) Structure B) H spectrum C) C spectrum

141
A
OH
B
C
= !:
525
J
I
L Í 8
\i I
| |
1-jJ,
s
Si
i
t
J 1
140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
Figure A-23. Spectroscopy data for 246. A) Structure B) 1H spectrum C) 13C spectrum

142
A
OBn
B
3 " 2 1 ppm
C
Figure A-24. Spectroscopy data for 247. A) Structure B) 'H spectrum C) l3C spectrum

143
A
OBn
B
l jL.L
c
Figure A-25. Spectroscopy data for 248. A) Structure B) 'H spectrum C) 13C spectrum

144
A
OBn
TBSO
B
C
Figure A-26. Spectroscopy data for 249. A) Structure B) *H spectrum C) l3C spectrum

145
A
Figure A-27. Spectroscopy data for 250. A) Structure B) 1H spectrum C) 13C spectrum

146
A
OBn
. JL J»A__
6 5 4
c
Figure A-28. Spectroscopy data for 251. A) Structure B) ‘H spectrum C) l3C spectrum

147
A
C
J A
I
Figure A-29. Spectroscopy data for 263. A) Structure B) !H spectrum C) l3C spectrum

148
A
C
P
Figure A-30. Spectroscopy data for 253. A) Structure B) 'H spectrum C) l3C spectrum

149
A
OBn
B
AM uAiAj
JL
12 11 10 9 B 7 6
5 4 3 2 1
j- !
iwm—
T
I
1
-I
9
160 140 120 100 80 60 40
Figure A-31. Spectroscopy data for 264. A) Structure B) 'H spectrum C) l3C spectrum

150
C
Q- 3 j*
S • K .
r1
Ik
a
ÚJ
> j * ; ~ m •
- "• I* * w
VJp
i
mm
rnmm
220 200
180 160 140 120 100 80 60 40 20 0 ppn
Figure A-32. Spectroscopy data for 265. A) Structure B) ]H spectrum C) l3C spectrum

APPENDIX B
LIST OF TABLES FOR KINETIC STUDIES

The tables presented in this appendix are representative examples of the data generated
by proton NMR used to calculated the relative rates of the ring opening metathesis
polymerization of 8-Oxabicyclo[3.2.1 ]octene derivatives. The first column, time, refers
to the second intervals at which each spectrum was collected. The second column, CéHé,
is the integral area of benzene collected per second interval during the reaction. Benzene
was used as an internal standard to normalize the integral area. The third column,
standard, refers to the integral area of standard collected per second interval during the
reaction. The forth column represents the measurement of the integral area used as a
concentration measure of the substrate during the reaction. The fifth and sixth column
represents the integral area normalized for standard and substrate respectively by dividing
the individual respective integral area over the benzene integral area. The last two
columns, shadow areas, are the natural logarithm of column fifth and sixth respectively,
where the first one is placed in the x axe and the second one is placed in the y axe of the
graphs presented in appendix C. The tables presented here corresponds to graphs 5, 4,
13, 24 and 32 respectively.
Time (s)
Benzene
standard
alkene
std/C6H6
sub/C6H6
ln[std/C6H6)
ln[sub/C6H6]
45
0.318
0.1121
0.342
0.35252
1.07547
-1.04266
0.07276
54
0.3205
0.1119
0.3384
0.34914
1.05585
-1.05228
0.05435
63
0.3224
0.1115
0.3352
0.34584
1.03970
-1.06177
0.03893
72
0.3253
0.111
0.331
0.34122
1.01752
-1.07522
0.01737
81
0.3273
0.1106
0.3275
0.33792
1.00061
-1.08496
0.00061
90
0.3297
0.1102
0.3239
0.33424
0.98241
-1.09589
-0.01775
99
0.3325
0.1094
0.3201
0.32902
0.96271
-1.11163
-0.03801
108
0.3352
0.1091
0.3158
0.32548
0.94212
-1.12246
-0.05962
117
0.3373
0.1086
0.3124
0.32197
0.92618
-1.13330
-0.07669
126
0.3399
0.1081
0.3086
0.31803
0.90791
-1.14559
-0.09661
135
0.3424
0.1075
0.3049
0.31396
0.89048
-1.15849
-0.11600
144
0.345
0.1071
0.3008
0.31043
0.87188
-1.16978
-0.13710
153
0.347
0.1065
0.2974
0.30692
0.85706
-1.18118
-0.15425
162
0.3498
0.1059
0.2935
0.30274
0.83905
-1.19487
-0.17548
171
0.352
0.1051
0.2902
0.29858
0.82443
-1.20872
-0.19306
180
0.3549
0.1046
0.2861
0.29473
0.80614
-1.22169
-0.21549
189
0.3575
0.104
0.2825
0.29091
0.79021
-1.23474
-0.23546
198
0.3598
0.1035
0.2787
0.28766
0.77460
-1.24598
-0.25541
207
0.3621
0.1027
0.2753
0.28362
0.76029
-1.26011
-0.27406
216
0.3643
0.1023
0.2717
0.28081
0.74581
-1.27007
-0.29328
225
0.3669
0.1015
0.2679
0.27664
0.73017
-1.28503
-0.31448
234
0.3689
0.1008
0.2652
0.27324
0.71889
-1.29739
-0.33004
243
0.3715
0.1005
0.2615
0.27052
0.70390
-1.30739
-0.35111
252
0.3738
0.0995
0.2581
0.26619
0.69048
-1.32356
-0.37037
261
0.3765
0.099
0.2546
0.26295
0.67623
-1.33580
-0.39122
270
0.3785
0.0982
0.2515
0.25945
0.66446
-1.34921
-0.40877
279
0.3806
0.0976
0.2483
0.25644
0.65239
-1.36087
-0.42711
288
0.3828
0.097
0.2451
0.25340
0.64028
-1.37280
-0.44585
152

153
Table B-2(4). Data generated measuring integral area vs. time at [std/exo-OTBS 193] =
0.25
Time (s)
Benzene
[Standard]
[exo-OTBS]
[std/C6H6]
[sub/CgH6]
ln[std/C6H6]
In[sub/CSH6]
45
0.1104
0.0834
0.2377
0.75543
2.15308
-0.28046
0.76690
54
0.1114
0.0817
0.23
0.73339
2.06463
-0.31007
0.72495
63
0.1127
0.0807
0.2225
0.71606
1.97427
-0.33399
0.68020
72
0.1142
0.0792
0.2152
0.69352
1.88441
-0.36597
0.63362
81
0.1156
0.078
0.2073
0.67474
1.79325
-0.39343
0.58403
90
0.1173
0.0765
0.1994
0.65217
1.69991
-0.42744
0.53058
99
0.1187
0.0746
0.1918
0.62848
1.61584
-0.46446
0.47985
108
0.1203
0.0728
0.1855
0.60515
1.54198
-0.50227
0.43307
117
0.1216
0.0715
0.1781
0.58799
1.46464
-0.53104
0.38161
126
0.1226
0.0697
0.1709
0.56852
1.39396
-0.56473
0.33215
135
0.124
0.0683
0.1649
0.55081
1.32984
-0.59637
0.28506
144
0.1256
0.0672
0.1576
0.53503
1.25478
-0.62543
0.22696
153
0.1265
0.0647
0.1515
0.51146
1.19763
-0.67048
0.18034
162
0.1278
0.0634
0.1456
0.49609
1.13928
-0.70100
0.13040
171
0.1301
0.0623
0.1395
0.47886
1.07225
-0.73634
0.06976
180
0.1303
0.0614
0.134
0.47122
1.02840
-0.75243
0.02800
189
0.1314
0.0595
0.1284
0.45282
0.97717
-0.79227
-0.02310
198
0.1326
0.0574
0.1235
0.43288
0.93137
-0.83729
-0.07110
207
0.1334
0.0564
0.1182
0.42279
0.88606
-0.86088
-0.12097
216
0.1356
0.0532
0.1134
0.39233
0.83628
-0.93565
-0.17879
225
0.1362
0.0525
0.1091
0.38546
0.80103
-0.95331
-0.22186
234
0.137
0.0516
0.1037
0.37664
0.75693
-0.97646
-0.27848
243
0.1375
0.0502
0.1006
0.36509
0.73164
-1.00761
-0.31247
252
0.1385
0.0478
0.0965
0.34513
0.69675
-1.06384
-0.36133
261
0.1394
0.0487
0.0918
0.34935
0.65854
-1.05167
-0.41774
270
0.1403
0.0467
0.0889
0.33286
0.63364
-1.10004
-0.45627
279
0.1412
0.0457
0.0852
0.32365
0.60340
-1.12808
-0.50518
288
0.142
0.0436
0.0811
0.30704
0.57113
-1.18077
-0.56014
297
0.1432
0.0437
0.0776
0.30517
0.54190
-1.18689
-0.61267
306
0.1432
0.0424
0.0757
0.29609
0.52863
-1.21709
-0.63746
315
0.1438
0.0412
0.0726
0.28651
0.50487
-1.24999
-0.68346
324
0.1433
0.0393
0.0701
0.27425
0.48918
-1.29372
-0.71502
333
0.145
0.0373
0.068
0.25724
0.46897
-1.35774
-0.75723
342
0.1455
0.0377
0.0657
0.25911
0.45155
-1.35052
-0.79508

154
Table B-3( 13). Data generated measuring integral area vs. time at [std/eni/o-OTBS 192]
= 1
Time (s)
benzene
standard
end-OTBS
std/C6H6
sub/C6H6
ln[std/C6H6]
ln[sub/C6H6]
125
0.542
0.2526
0.2053
0.4661
0.3788
-0.7635
-0.9708
150
0.553
0.2543
0.1926
0.4599
0.3483
-0.7768
-1.0547
175
0.5627
0.2552
0.1821
0.4535
0.3236
-0.7907
-1.1282
200
0.5708
0.2564
0.1727
0.4492
0.3026
-0.8003
-1.1955
225
0.5786
0.2571
0.1643
0.4443
0.2840
-0.8111
-1.2589
250
0.5853
0.2579
0.1567
0.4406
0.2677
-0.8196
-1.3178
275
0.5918
0.2584
0.1498
0.4366
0.2531
-0.8287
-1.3739
300
0.5974
0.2592
0.1435
0.4339
0.2402
-0.8350
-1.4263
325
0.602
0.2597
0.1383
0.4314
0.2297
-0.8407
-1.4708
350
0.6076
0.26
0.1324
0.4279
0.2179
-0.8488
-1.5237
375
0.6133
0.2602
0.1264
0.4243
0.2061
-0.8574
-1.5794
400
0.6169
0.2603
0.1227
0.4219
0.1989
-0.8629
-1.6150
425
0.6213
0.2608
0.1179
0.4198
0.1898
-0.8681
-1.6620
450
0.6252
0.2612
0.1136
0.4178
0.1817
-0.8728
-1.7054
475
0.6294
0.2608
0.1098
0.4144
0.1745
-0.8810
-1.7461
500
0.6343
0.2607
0.1049
0.4110
0.1654
-0.8892
-1.7995
525
0.6377
0.2606
0.1017
0.4087
0.1595
-0.8949
-1.8358
550
0.6398
0.2612
0.0989
0.4083
0.1546
-0.8959
-1.8670
575
0.6442
0.2613
0.0946
0.4056
0.1468
-0.9023
-1.9184
600
0.6477
0.2612
0.0912
0.4033
0.1408
-0.9081
-1.9604
625
0.6497
0.2611
0.0892
0.4019
0.1373
-0.9116
-1.9856
650
0.6533
0.2611
0.0856
0.3997
0.1310
-0.9171
-2.0324
675
0.6562
0.2611
0.0827
0.3979
0.1260
-0.9216
-2.0712
700
0.6596
0.2605
0.0799
0.3949
0.1211
-0.9290
-2.1109
725
0.6615
0.2603
0.0782
0.3935
0.1182
-0.9327
-2.1352
750
0.6659
0.2599
0.0742
0.3903
0.1114
-0.9408
-2.1944
775
0.6679
0.2595
0.0725
0.3885
0.1085
-0.9454
-2.2206
800
0.6705
0.2596
0.07
0.3872
0.1044
-0.9489
-2.2595
825
0.674
0.2592
0.0668
0.3846
0.0991
-0.9556
-2.3115

155
Table B-4(24). Data generated measuring integra
Time (s)
standard
ketone
TMS
std/TMS
sub/TMS
In [std/TMS]
ln[sub/TMS]
45
0.5219
0.1332
0.3291
1.5858
0.4047
0.4611
-0.9045
54
0.5199
0.1338
0.3297
1.5769
0.4058
0.4555
-0.9018
63
0.5181
0.1341
0.3313
1.5638
0.4048
0.4471
-0.9044
72
0.5154
0.1351
0.3343
1.5417
0.4041
0.4329
-0.9060
81
0.5118
0.1352
0.337
1.5187
0.4012
0.4179
-0.9133
90
0.5097
0.135
0.3385
1.5058
0.3988
0.4093
-0.9192
99
0.5062
0.1354
0.3416
1.4819
0.3964
0.3933
-0.9254
108
0.504
0.1361
0.3425
1.4715
0.3974
0.3863
-0.9229
117
0.5018
0.1367
0.3456
1.4520
0.3955
0.3729
-0.9275
126
0.4993
0.1382
0.3467
1.4401
0.3986
0.3647
-0.9198
135
0.4967
0.1379
0.3483
1.4261
0.3959
0.3549
-0.9265
144
0.4943
0.1375
0.3513
1.4071
0.3914
0.3415
-0.9380
153
0.4911
0.1383
0.354
1.3873
0.3907
0.3274
-0.9399
162
0.49
0.1385
0.3542
1.3834
0.3910
0.3245
-0.9390
171
0.4872
0.1392
0.3563
1.3674
0.3907
0.3129
-0.9399
180
0.4835
0.1385
0.3597
1.3442
0.3850
0.2958
-0.9544
189
0.4817
0.1393
0.3605
1.3362
0.3864
0.2898
-0.9509
198
0.4784
0.14
0.3644
1.3128
0.3842
0.2722
-0.9566
207
0.4755
0.1395
0.3669
1.2960
0.3802
0.2593
-0.9670
216
0.4739
0.14
0.3682
1.2871
0.3802
0.2524
-0.9670
225
0.4701
0.1411
0.3714
1.2658
0.3799
0.2357
-0.9678
234
0.4672
0.1407
0.3736
1.2505
0.3766
0.2236
-0.9766
243
0.4643
0.1412
0.3761
1.2345
0.3754
0.2107
-0.9797
252
0.4626
0.1414
0.3774
1.2258
0.3747
0.2036
-0.9817
261
0.4597
0.142
0.3795
1.2113
0.3742
0.1917
-0.9830
270
0.4561
0.143
0.3817
1.1949
0.3746
0.1781
-0.9818
279
0.4538
0.1429
0.3843
1.1808
0.3718
0.1662
-0.9893
288
0.4505
0.1429
0.3882
1.1605
0.3681
0.1488
-0.9994
297
0.4477
0.1439
0.3896
1.1491
0.3694
0.1390
-0.9960
306
0.4457
0.1434
0.391
1.1399
0.3668
0.1309
-1.0031
315
0.4428
0.144
0.3939
1.1241
0.3656
0.1170
-1.0063
324
0.4401
0.1445
0.3963
1.1105
0.3646
0.1048
-1.0089
333
0.4364
0.1454
0.3986
1.0948
0.3648
0.0906
-1.0085
342
0.4335
0.1458
0.4008
1.0816
0.3638
0.0784
-1.0112
351
0.4314
0.1466
0.4012
1.0753
0.3654
0.0726
-1.0068
360
0.4285
0.1467
0.4058
1.0559
0.3615
0.0544
-1.0175
369
0.4251
0.1466
0.408
1.0419
0.3593
0.0411
-1.0236
378
0.4214
0.1473
0.4114
1.0243
0.3580
0.0240
-1.0271
387
0.4187
0.1473
0.4143
1.0106
0.3555
0.0106
-1.0341
396
0.4174
0.1478
0.4139
1.0085
0.3571
0.0084
-1.0298
area vs. time at [std/ketone 1] = 4

156
Table B-5(32). Data generated measuring integral area vs. time at [std/Methylene 204]
1
Time
C6H6
Standard
Methylene
std/C6H6
sub/C6H6
ln[std/C6H6]
ln[sub/C6H6]
144
0.3588
0.3316
0.3096
0.9242
0.8629
-0.0788
-0.1475
168
0.3752
0.3306
0.2942
0.8811
0.7841
-0.1266
-0.2432
192
0.3919
0.3293
0.2789
0.8403
0.7117
-0.1740
-0.3402
216
0.409
0.3268
0.2643
0.7990
0.6462
-0.2244
-0.4366
240
0.4246
0.3247
0.2507
0.7647
0.5904
-0.2682
-0.5269
264
0.4403
0.3225
0.2372
0.7325
0.5387
-0.3114
-0.6186
288
0.4552
0.3194
0.2254
0.7017
0.4952
-0.3543
-0.7029
312
0.4688
0.3158
0.2154
0.6736
0.4595
-0.3951
-0.7777
336
0.4839
0.3129
0.2032
0.6466
0.4199
-0.4360
-0.8677
360
0.4976
0.309
0.1934
0.6210
0.3887
-0.4765
-0.9450
384
0.511
0.3052
0.1838
0.5973
0.3597
-0.5154
-1.0225
408
0.5236
0.3014
0.175
0.5756
0.3342
-0.5523
-1.0959
432
0.5366
0.2971
0.1663
0.5537
0.3099
-0.5912
-1.1715
456
0.5463
0.2942
0.1595
0.5385
0.2920
-0.6189
-1.2311
480
0.5589
0.2895
0.1516
0.5180
0.2712
-0.6578
-1.3047
504
0.5706
0.284
0.1454
0.4977
0.2548
-0.6977
-1.3672
528
0.5796
0.2812
0.1392
0.4852
0.2402
-0.7233
-1.4264
552
0.5915
0.2767
0.1318
0.4678
0.2228
-0.7597
-1.5014
576
0.6003
0.2725
0.1272
0.4539
0.2119
-0.7898
-1.5517
600
0.6109
0.2674
0.1217
0.4377
0.1992
-0.8262
-1.6134
624
0.6195
0.2642
0.1163
0.4265
0.1877
-0.8522
-1.6727
648
0.6296
0.2596
0.1108
0.4123
0.1760
-0.8859
-1.7374
672
0.6385
0.2554
0.1061
0.4000
0.1662
-0.9163
-1.7947
696
0.6479
0.2502
0.1019
0.3862
0.1573
-0.9515
-1.8497
720
0.6545
0.2466
0.0989
0.3768
0.1511
-0.9761
-1.8898

APPENDIX C
LIST OF GRAPHS FOR KINETIC STUDIES

Graph C-l. Data generated measuring integral are vs. time for [std/substrate 193] = 1
Relative ksub193/kstd Rate
-3.50 -3.40 -3.30 -3.20 -3.10 -3.00 -2.90 -2.80 -2.70
Graph C-2. Data generated measuring integral are vs. time for [std/substrate 193] = 1
158

In [substrate 193] ^ In [substrate 193]
159
Relative ksub193/kstd Rate
-3.50 -3.00 -2.50 -2.00 -1.50 -1.00 -0.50
0.00
-0.50
-1.00
-1.50
-2.00
-2.50
-3.00
-3.50
Data generated measuring integral are vs. time for [std/substrate 193] = 0.25
Relative ksubWkstd Rate
-1.5 -1.25 -1 -0.75 -0.5 -0.25 0
1.2
0.8
0.4
0
-0.4
-0.8
-1.2
In [standard]
i i r
In [standard]
Graph C-4. Data generated measuring integral are vs. time for [std/substrate 193] = 0.25

160
Relative ksub200/kstd Rate
-1.4 -1.35 -1.3 -1.25 -1.2 -1.15 -1.1 -1.05
-1
0.1
0
-0.1
-0.2
-0.3
-0.4
-0.5
Graph C-5. Data generated measuring integral are vs. time for [std/substrate 200] = 0.25
Relative ksub200/kstd Rate
In [standard]
Graph C-6. Data generated measuring integral area vs. time for [std/substrate 200] = 1

161
Relative ksub2oo/kstd Rate
-1.45 -1.35 -1.25 -1.15 -1.05 -0.95
Graph C-7. Data generated measuring integral area vs. time for [std/substrate 200] = 4
Relative ksub20(Astd Rate
-1.35 -1.3 -1.25 -1.2 -1.15 -1.1 -1.05 -1
In [standard]
Graph C-8. Data generated measuring integral area vs. time for [std/substrate 200] = 8

In [substrate 192]
162
Relative ksub192/kstd Rate
-2.06 -2.01 -1.96 -1.91 -1.86 -1.81 -1.76 -1.71
In [standard]
Graph C-9. Data generated measuring integral area vs. time for [std/substrate 192] = 1
Relative ksub192/kstd Rate
-0.95 -0.9 -0.85 -0.8 -0.75
-1
-1.2
-1.4
-1.6
-1.8
-2
-2.2
-2.4
Graph C-10. Data generated measuring integral area vs. time for [std/substrate 192] = 1

In [substrate 192] = In [substrate 192]
163
Reative ksub192/kstd Rate
In [standard]
Data generated measuring integral area vs. time for [std/substrate 192] - 1
Relative ksub192/kstd Rate
â– 0.35 -0.3 -0.25 -0.2 -0.15 -0.1 -0.05
0
-0.5
-1
-1.5
-2
-2.5
In [standard]
Graph C-12. Data generated measuring integral area vs. time for [std/substrate 192] = 1

164
Relative ksub192/kstd rate
-1 -0.95 -0.9 -0.85 -0.8 -0.75 -0.7
In [standard]
Graph C-13. Data generated measuring integral area vs. time for [std/substrate 192] = 1
Relative ksub192/kstd Rate
-0.6 -0.55 -0.5 -0.45 -0.4 -0.35 -0.3 -0.25
-1
-1.4
-1.8
-2.2
-2.6
-3
In [standard]
Graph C-14. Data generated measuring integral area vs. time for [std/substrate 192] = 1

165
Relative ksub192/kstd Rate
-0.45 -0.4 -0.35 -0.3 -0.25 -0.2
Graph C-15. Data generated measuring integral area vs. time for [std/substrate 192] = 4
Relative ksub192/kstd Rate
-0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0
In [standard]
Graph C-16. Data generated measuring integral area vs. time for [std/substrate 192] =
0.25

166
Relative ksub201/kstd Rate
In [standard]
Graph C-17. Data generated measuring integral area vs. time for [std/substrate 201] =
0.25
Relative ksub201/kstd Rate
-1 -0.9 -0.8 -0.7 -0.6 -0.5
Graph C-18. Data generated measuring integral area vs. time for [std/substrate 201] =1

167
Relative ksub2oi/kstd Ratio
-0.75 -0.65 -0.55 -0.45 -0.35
In [standard]
Graph C-19. Data generated measuring integral area vs. time for [std/substrate 201] = 4
Relative ksub2o5/kstd Rate
-2.2 -2.0 -1.8 -1.6 -1.4 -1.2 -1.0
In [standard]
Graph C-20. Data generated measuring integral area vs. time for [std/substrate 205] =
0.25

168
Relative ksub205/kstd Rate
-2 -1.9 -1.8 -1.7 -1.6 -1.5
-2.4
-2.6
-2.8
-3
-3.2
-3.4
-3.6
-3.8
-4
-4.2
-4.4
Graph C-21. Data generated measuring integral area vs. time for [std/substrate 205] = 1
Relative ksub205/kstd Rate
-1.55 -1.5 -1.45 -1.4 -1.35 -1.3 -1.25
Graph C-22. Data generated measuring integral area vs. time for [std/substrate 205] = 4

169
Relative ksub1/kstd Ratio
In [standard]
Graph C-23. Data generated measuring integral area vs. time for [std/substrate 1] = 1
Relative ksub1/kstd Rate
-0.10 0.00 0.10 0.20 0.30 0.40 0.50
-0.85
-0.90
-0.95
-1.00
-1.05
Graph C-24. Data generated measuring integral area vs. time for [std/substrate 1] = 4

170
Relative ksub1/kstd Rate
1.12 1.14 1.16 1.18 1.20 1.22 1.24 1.26 1.28
-0.68
-0.70
-0.72
-0.74
-0.76
Graph C-25. Data generated measuring integral area vs. time for [std/substrate 1] = 8
Relative ksub1/kstd Rate
-1.50 -1.40 -1.30 -1.20 -1.10 -1.00 -0.90 -0.80
-3.55
-3.60
-3.65
-3.70
-3.75
-3.80
-3.85
In [standard]
Graph C-26. Data generated measuring integral area vs. time for [std/substrate 1] = 16

171
Relative ksub204/kstd Ratio
In [standard]
Graph C-27. Data generated measuring integral area vs. time for [std/substrate 204] =
0.25
Relative ksub204/kstd Rate
-0.5 -0.45 -0.4 -0.35 -0.3 -0.25
In [standard]
Graph C28. Data generated measuring integral area vs. time for [std/substrate 204] = 1

172
Relative ksub204/kstd Rate
-0.25 -0.2 -0.15 -0.1 -0.05 0 0.05 0.1
In [standard]
Graph C-29. Data generated measuring integral area vs. time for [std/substrate 204] = 1
Relative ksub204/kstd Rate
-0.6 -0.4 -0.2 0 0.2
In [standard]
Graph C-30. Data generated measuring integral area vs. time for [std/substrate 204] = 1

173
Relative ksub204/kstd Rate
-0.8
-0.6
-0.4
-0.2
0.2
In [standard]
Graph C-31. Data generated measuring integral area vs. time for [std/substrate 204] = 1
Relative ksub204/kstd Rate
-1.1 -0.9 -0.7 -0.5 -0.3 -0.1 0.1
In [standard]
Graph C-32. Data generated measuring integral area vs. time for [std/substrate 204] = 1

174
Relative ksub204/kstd Rate
-0.8 -0.6 -0.4 -0.2 0 0.2
In [standard]
Graph C-33. Data generated measuring integral area vs. time for [std/substrate 204] = 1
Relative ksub204/kstd Rate
-0.41 -0.39 -0.37 -0.35 -0.33 -0.31 -0.29 -0.27 -0.25
In [standard]
Graph C-34. Data generated measuring integral area vs. time for [std/substrate 204] = 4

175
Relative ksub2o4/kstd Rate
-0.4 -0.3 -0.2 -0.1 0 0.1
Graph C-35 Data generated measuring integral area vs. time for [std/substrate 204] = 4
Relative ksub199/kstd Rate
-0.4
In [standard]
Graph C-36. Data generated measuring integral area vs. time for [std/substrate 199] = 1

176
Relative ksub199/kstd Rate
Graph C-37. Data generated measuring integral area vs. time for [std/substrate 199] = 4
Relative ksub199/kstd Rate
-1.15 -0.95 -0.75 -0.55 -0.35
In [standard]
Graph C-38. Data generated measuring integral area vs. time for [std/substrate 199] = 8

177
Relative k^^g/k^d Rate
In [standard]
Graph C-39. Data generated measuring integral area vs. time for [std/substrate 199] = 8
Relative ksub199/kstd Rate
0.97 0.99 1.01 1.03 1.05 1.07 1.09 1.11
Graph C-40. Data generated measuring integral area vs. time for [std/substrate 199] = 8

178
Relative ksub199/kstd rate
1.08 1.1 1.12 1.14 1.16 1.18 1.2 1.22
In [Standard]
Graph C-41. Data generated measuring integral area vs. time for [std/substrate 199] = 8
Relative ksub199/kstd rate
1.1 1.12 1.14 1.16 1.18 1.2
Graph C-42. Data generated measuring integral area vs. time for [std/substrate 199] = 8

In [substrate 199]
179
Relative ksub199/kstd Rate
-0.6 -0.55 -0.5 -0.45 -0.4 -0.35 -0.3 -0.25
-2.7
-2.75
-2.8
-2.85
-2.9
-2.95
Graph C-43. Data generated measuring integral area vs. time for [std/substrate 199] = 16
In [standard]
Relative ksub203/kstd Rate
-2.4 -1.9 -1.4 -0.9 -0.4
In [standard]
Graph C-44. Data generated measuring integral area vs. time for [std/substrate 203] =
0.25

180
Relative ksub203/kstd Rate
-1.40 -1.30 -1.20 -1.10 -1.00 -0.90
In [standard]
Graph C-45. Data generated measuring integral area vs. time for [std/substrate 203] = 1
Relative ksub203/kstd Rate
-0.25 -0.2 -0.15 -0.1 -0.05 0
-0.7
-0.8
-0.9
-1
-1.1
-1.2
-1.3
-1.4
-1.5
Graph C-46. Data generated measuring integral area vs. time for [std/substrate 203] = 1

181
Relative ksub203/kstd Rate
-0.35 -0.3 -0.25 -0.2 -0.15 -0.1 -0.05 0
-0.6
-0.8
-1
-1.2
-1.4
-1.6
-1.8
Graph C-47. Data generated measuring integral area vs. time for [std/substrate 203] = 1
In [standard]
-0.14
Relative ksub203/kstd Rate
-0.12 -0.1 -0.08 -0.06
-0.04
In [standard]
Graph C-48. Data generated measuring integral area vs. time for [std/substrate 203]

182
Relative lWoa/kstd Rate
0.50 0.60 0.70 0.80 0.90 1.00
Graph C-49. Data generated measuring integral area vs. time for [std/substrate 203] = 4
Relative ksub203/kstd Rate
1.50 1.55 1.60 1.65 1.70 1.75 1.80
Graph C-50. Data generated measuring integral area vs. time for [std/substrate 203] = 8

In [substrate 202]
183
Relative ksub2o3/kstd Rate
1.55 1.65 1.75 1.85 1.95 2.05
Graph C-51. Data generated measuring integral area vs. time for [std/substrate 203] = 16
Relative kSUb202/kstd Rate
0.9 1 1.1 1.2 1.3 1.4
Graph C-52. Data generated measuring integral area vs. time for [std/substrate 202] = 1

In [substrate 202]
184
Relative ksub2o2/kstd Rate
0.9 1 1.1 1.2 1.3 1.4
Graph C-53. Data generated measuring integral area vs. time for [std/substrate 202] - 1
Relative ksub202/kstd Rate
0.98 1.08 1.18 1.28 1.38
Graph C-54. Data generated measuring integral area vs. time for [std/susbtrate 202] = 1

185
Relative ksub202/kstd Rate
-0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2
Graph C-55. Data generated measuring integral area vs. time for [std/susbtrate 202] =
0.25
Relative ksub202/kstd Rate
-1.2 -1 -0.8 -0.6 -0.4
In [standardd]
Graph C-56. Data generated measuring integral area vs. time for [std/substrate 202] = 1

186
Relative ksub202/kstd Rate
0.75 0.80 0.85 0.90 0.95 1.00 1.05
Graph C-57. Data generated measuring integral area vs. time for [std/substrate 202] = 4
-1.4
Relative ksub202/kstd Rate
-1.3
-1.2
-1.1
-1.0
In [standard]
-0.9
Graph C-58. Data generated measuring integral area vs. time for [std/substrate 202]
0.25

187
Relative ksub2o2/kstd Rate
0.0 0.1 0.2 0.3 0.4 0.5
-2.0
-2.4
-2.8
-3.2
-3.6
-4.0
In [standard]
Graph C-59. Data generated measuring integral area vs. time for [std/substrate 202] = 4
Relative ksub202/kstd Rate
0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60
Graph C-60. Data generated measuring integral area vs. time for [std/substrate 202] = 4

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BIOGRAPHICAL SKETCH
María E. Estrella-Jiménez was the first bom of three, bom in New York on May 8,
1977, from Sheila Jiménez and Félix A. Estrella. After living in New York with her
mother for seven months, they moved to Puerto Rico to meet her father. She grew up in
Puerto Rico, were she attended the Colegio de la Inmaculada to obtain her high school
diploma. Then, she earned her Bachelor of Arts in chemistry from the University of
Puerto Rico, Río Piedras Campus, where she first experienced working with organic
chemistry doing undergraduate research with Professor John A. Soderquist. During her
undergraduate research, she earned the Pfizer fellowship, which gave her the opportunity
to participate in a summer internship. After she completed her B.S., she spent three
months working at Pfizer in Groton, CT. Then, she started her graduate studies in
organic chemistry on August 2000 at the University of Florida under the supervision of
Professor Dennis L. Wright. Upon completion of her Ph.D., she will move to Texas,
University of Texas Medical Branch, to be a postdoctoral fellow of Dr. Scott R.
Gilbertson. After that experience, she plans to work in industry.
194

I certify that I have read this study and that in my opinion it conforms to acceptable
standards of scholarly presentation and is fully adeqyáfei, in scope and quality, as a thesis
for the degree of Doctor of Philosophy.
Dennis L. Wright, Chairman
Associate Professor of Chemistry
I certify that 1 have read this study and that in my opinion it conforms to acceptable
standards of scholarly presentation and is fully adequate, in scope and quality, as a thesis
for the degree of Doctor of Philosophy.
Merle A. Battiste, Cochair
Professor of Chemistry
I certify that I have read this study and that in my opinion it conforms to acceptable
standards of scholarly presentation and is fully adequate, in scope and quality, as a thesis
for the degree of Doctor of Philosophy.
¿¿¿¿lit*
William R. Dolbier Jr.
Professor of Chemistry
I certify that I have read this study and that in my opinion it conforms to acceptable
standards of scholarly presentation and is fully adequate, in scope and quality, as a thesis
for the degree of Doctor of Philosophy.
Scientist of Chemistry
1 certify that I have read this study and that in my opinion it conforms to acceptable
standards of scholarly presentation and is fully adequate, in scope and quality, as a thesis
for the degree of Doctor of Philosophy.
Kenneth Sloan
Professor of Medicinal Chemistry

This thesis was submitted to the Graduate Faculty of the Department of Chemistry
in the College of Liberal Arts and Sciences and to the Graduate School and was accepted
as partial fulfillment of the requirements for the degree of Doctor of Philosophy.
May 2005
Dean, Graduate School




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