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The Development of Chiral Catalysts for Asymmetric Reactions

Permanent Link: http://ufdc.ufl.edu/UFE0043572/00001

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Title: The Development of Chiral Catalysts for Asymmetric Reactions
Physical Description: 1 online resource (151 p.)
Language: english
Creator: Rodig, Michael John
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2011

Subjects

Subjects / Keywords: catalysis -- epoxides -- nitro-aldol
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: The body of this work is focused on the development of new chiral catalysts for asymmetric reactions. Chiral catalysts can provide an atom economical route to a variety of synthetically importance chiral molecules including compounds of biological and pharmacological interest to novel materials with superior structural properties. The efficiency of a chiral catalyst can be measured in both its ability to accelerate a reaction and to promote a highly selective reaction pathway, yielding reaction products with a high degree of optical purity. In many cases, these two criteria are best met when two or more reaction partners are cooperatively activated and organized by a single catalytic species. The latter portion of this work is focused on the development of transition metal catalysts designed to self-assemble in solution to yield multimetallic catalysts capable of activating multiple reaction partners. The first portion is focused on the application of novel, chelating nitrogen donor ligands synthesized en route to N-heterocyclic carbene ligands.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Michael John Rodig.
Thesis: Thesis (Ph.D.)--University of Florida, 2011.
Local: Adviser: Hong, Sukwon.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2013-12-31

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Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2011
System ID: UFE0043572:00001

Permanent Link: http://ufdc.ufl.edu/UFE0043572/00001

Material Information

Title: The Development of Chiral Catalysts for Asymmetric Reactions
Physical Description: 1 online resource (151 p.)
Language: english
Creator: Rodig, Michael John
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2011

Subjects

Subjects / Keywords: catalysis -- epoxides -- nitro-aldol
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: The body of this work is focused on the development of new chiral catalysts for asymmetric reactions. Chiral catalysts can provide an atom economical route to a variety of synthetically importance chiral molecules including compounds of biological and pharmacological interest to novel materials with superior structural properties. The efficiency of a chiral catalyst can be measured in both its ability to accelerate a reaction and to promote a highly selective reaction pathway, yielding reaction products with a high degree of optical purity. In many cases, these two criteria are best met when two or more reaction partners are cooperatively activated and organized by a single catalytic species. The latter portion of this work is focused on the development of transition metal catalysts designed to self-assemble in solution to yield multimetallic catalysts capable of activating multiple reaction partners. The first portion is focused on the application of novel, chelating nitrogen donor ligands synthesized en route to N-heterocyclic carbene ligands.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Michael John Rodig.
Thesis: Thesis (Ph.D.)--University of Florida, 2011.
Local: Adviser: Hong, Sukwon.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2013-12-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2011
System ID: UFE0043572:00001


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1 THE DEVELOPMENT OF CHIRAL CATALYSTS FOR ASYMMETRIC REACTIONS By MICHAEL J. RODIG A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DO CTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2011

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2 2011 Michael J. Rodig

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3 To my family

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4 ACKNOWLEDGMENTS I need to thank my graduate advisor, Dr. Sukwon Hong who has provided guidance, support and patience and whose door has always been open. learned from him, the lessons on life were greatest. Thanks go to my graduate committee members, Dr. Aaron Aponick, Dr. Lisa McElwee White, Dr. Jo n Stewart and Dr. Kenneth Sloan, who have help ed shape my path through instruction, counsel and wisdom. Special thanks to my parents, who gave me the freedom to make my own choices supported my decision s and always stood in my corner T o my brother, who spent a good portion of his late adolescence looking after his little brother and providing a s healthy a ro le model as one could hope for. Thanks go to my undergraduate advisors, Dr. Miguel Mitchell and Dr. Elizabeth Papish, who provided me with the training and motivation to pursue a future in chemistry. Special thanks to my co workers, especial ly my lab partner, Jongwoo Park, who happily shared a wealth of experience and knowledge with me over the years. I wish to acknowledge my son, Ryan, whose joy and laughter instantly erase any memory of frustration and reminds me of my purpose. I especially wish to thank my wife, Jennifer. Her support and patience have been without measure She has provided love and encouragement in spite of a husband who was often absent and even more often, absent minded.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 LI ST OF SCHEMES ................................ ................................ ................................ ...... 10 ABSTRACT ................................ ................................ ................................ ................... 13 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 14 N N Ligan ds in Asymmetric Catalysis ................................ ................................ ..... 14 Diimine Based Chiral Ligands ................................ ................................ .......... 15 Salen Ligands ................................ ................................ ................................ ... 16 Asymmetric epoxidation (AE) ................................ ................................ ..... 17 Epoxide ring opening reactions ................................ ................................ .. 21 Desymmetrization of meso epoxides ................................ ......................... 21 Kinetic resolution of terminal epoxides ................................ ....................... 23 Multinuclear salen catalyst for epoxide opening ................................ ......... 26 Carbonyl addition processes ................................ ................................ ...... 36 Diels Alder and Hetero Diels Alder ................................ ............................ 40 Cyclopropanation ................................ ................................ ....................... 41 Aziridination ................................ ................................ ............................... 42 Oxidation of sulfides ................................ ................................ ................... 43 Oxidation of enol derivatives ................................ ................................ ...... 44 Asymmetric Baeyer Villiger oxidations ................................ ...................... 45 Kinetic resolution of racemic allenes ................................ .......................... 46 Asymmetric hydroxylation of C H bonds ................................ ................... 47 Heterocyclic Nitrogen Donor Ligands ................................ ............................... 47 2,2 Bipyridine based ligands ................................ ................................ ...... 47 Oxazoline ligands ................................ ................................ ....................... 49 Pyridyloxazoline based ligands ................................ ................................ .. 49 Self Assembling Ligands in Asymmetric Catalysis ................................ ................. 50 Self assembling Catalysts Based on Secondary Metal Coordination ............... 51 Self Assembling Catalysts Based on Hydrogen Bonding ................................ 62 2 NEW N N LIGANDS FOR ASYMMETRIC CATALYSIS ................................ ......... 73 Asymmetric Nitro Aldol Reaction ................................ ................................ ............ 73 Background ................................ ................................ ................................ ...... 73 Results and Discussion ................................ ................................ .................... 74

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6 1,2 Boronic Acid Addition ................................ ................................ ........................ 78 Background ................................ ................................ ................................ ...... 78 Results and Discussion ................................ ................................ .................... 79 Summary ................................ ................................ ................................ ................ 80 Experimental ................................ ................................ ................................ ........... 80 Synthesis and Characterization of Reported MIQ and BIQ Ligands ................. 81 General Procedure for Enantioselective Henry Reaction ................................ 86 Characterization of Nitroaldol Adducts ................................ ............................. 86 Crystal Structure Analysis of 2.1a Pd Cl 2 ................................ .......................... 92 General Procedure for Enantioselective 1,2 Addtion of Phenylboronic Acid .... 93 3 NEW SELF ASSEMBLING LIGANDS FOR ASYMMETRIC CATALYSIS .............. 96 Meso epoxide opening ................................ ................................ ............................ 96 Background ................................ ................................ ................................ ...... 96 Results and D iscussion ................................ ................................ .................... 98 Meso Aziridine Opening ................................ ................................ ........................ 112 Background ................................ ................................ ................................ .... 112 Results a nd Discussion ................................ ................................ .................. 113 Summary ................................ ................................ ................................ .............. 116 Experimental ................................ ................................ ................................ ......... 117 Synthesis and Cha racterization of Bis Urea Bis Salen Ligands ..................... 118 General Procedure for the Asymmetric Hydrolysis of Meso Epoxides ........... 128 General Pro cedure for the Asymmetric Addition of TMSN3 to Meso Epoxides ................................ ................................ ................................ ..... 131 Synthesis and Characterization of Bis Urea Tridentate Ligands and Meso Aziridines ................................ ................................ ................................ ..... 132 General Procedure for Enantioselective Aziridine Opening ............................ 134 Characterization of Ring Opened Products ................................ .................... 135 4 CONCLUSION ................................ ................................ ................................ ...... 136 LIST OF REFERENCES ................................ ................................ ............................. 138 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 151

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7 LIST OF TABLES Table page 1 1 Enantioselective opening of meso epoxides with Cr(III)Cl salen. ....................... 22 2 1 Nitro aldol ligand survey ................................ ................................ ..................... 75 2 2 Optimization of reaction conditions ................................ ................................ ..... 76 2 3 Nitroaldol substrate scope ................................ ................................ .................. 77 2 4 1 ,2 Addition of aryl boronic acids to aryl aldehydes ................................ ............ 79 2 5 Crystal data and structure refinement for 1a PdCl 2 ................................ ........... 92 3 1 Survey of spacing unit on bis urea(bis salens) for epoxide hydrolysis. ............ 101 3 2 Solvent screening with bis urea(bis salen). ................................ ...................... 104 3 3 Substra te scope with bis urea(bis salen). ................................ ......................... 108 3 4 Survey of spacing unit on bis urea(bis salens)for azide addition to epoxide. ... 110 3 5 Survey of spacing unit on bis urea(bis salens) for azide addition to epoxide. .. 111 3 6 Substrate scope for epoxide desymmetrization by TMSN 3 .............................. 1 12 3 7 Preliminary screening of asymmetric aziridine ring opening. ............................ 115

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8 LIST OF FIGURES Figure page 1 1 Quadrant analogy as applied to C 2 symmetric ligands. ................................ ...... 15 1 2 A selection of C 2 symmetric diimine ligands. ................................ ...................... 16 1 3 Some examples of metal salen complexes. ................................ ....................... 17 1 4 Examples of structural variations of the salen ligand framework. ....................... 18 1 5 Models for olefin epoxidation and epoxide activation by chiral metal salen complexes. ................................ ................................ ................................ ......... 21 1 6 Molecules of biological interest synthesized using kinetic resolution. ................. 24 1 7 Proposed bim etallic mechanism for the asymmetric ring opening of epoxides with Cr(III) salen catalyst. ................................ ................................ ................... 26 1 8 Backbone linked dimeric Cr(III)Cl salen and its monomeric analogue. ............... 27 1 9 Limiting geometries for the transition state of the ARO. ................................ ..... 27 1 10 Aryl linked dimeric Cr(III)Cl salen and their monomeric analogue. ..................... 28 1 11 Structures of dendrimeric, dimeric and monomeric Co(III)salen. ........................ 29 1 12 Cyclic oligomeric Co(salen) catalysts developed by Jacobsen. .......................... 30 1 13 Amphiphilic ( R R ) macrosalen ligand (w=41, x=4.5, y=2.8, z=2.3) ..................... 33 1 14 Macrocyclic Co(II)salen complexes developed by Weck. ................................ ... 34 1 15 bipyridine ligands. ................................ ........... 48 1 16 Bis oxazoline and related ligands. ................................ ................................ ...... 49 1 17 Typical pyridylimine type ligand. ................................ ................................ ......... 49 1 18 Three component supramolecular bidentate ligands involving a template. ........ 52 1 19 Self assembling heterobidentate ligand on bis zinc(II) salphen template. ......... 54 1 20 Macrocyclic allosteric salen catalyst. ................................ ................................ .. 57 1 21 Hinged allosteric salen catalyst. ................................ ................................ ......... 58 1 22 Tetrahedral coordination cage. ................................ ................................ ........... 60

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9 1 23 Aza Cope rearrangement within a supramolecular cage. ................................ ... 61 1 24 Self assembling pyridine based ligands for the Rh catalyzed hydrogenation of olefins. ................................ ................................ ................................ ............ 63 1 25 Regioselective hydroformylation of 1 octene using heterocombinations. ........... 65 1 26 X ray crystal structure of Ni(II)salen showing dimeric structure. ......................... 67 1 27 PhthalaPhos ligands: structure of the pre catalytic complex [Rh(L)2(cod)]+ ...... 70 1 28 Proposed mechanism of self assembly to enforce bimetallic coop eration. ......... 72 2 1 Isoquinoline based chiral carbene ligands. ................................ ......................... 74 2 2 X ray structure of 2.1a PdCl 2 ................................ ................................ ............. 78 3 1 side urea (bis salen) catalyst. ................................ 99 3 2 Prosposed equilibrium of EHUT described by Bouteiller. ................................ 102 3 3 The effect of catalyst concentration on yield and selectivity. ............................ 105 3 4 Screening of sulfonate counter ions for Co(III) bis salen. ................................ 106

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10 LIST OF SCHEMES Scheme page 1 1 Conditions for asymmetric epoxidation (AE) of conjugated olefins catalyzed by Mn(III)Cl salen complex. ................................ ................................ ................ 19 1 2 Stepwise mechanism of oxygen transfer from Mn to olefin leads to diastereomeric mixtures of epoxides. ................................ ................................ 20 1 3 HKR of terminal epoxid es with water using Co(III)OAc salen. ............................ 23 1 4 HKR of terminal epoxides with TMSN 3 using Cr(III)Cl salen. .............................. 24 1 6 Examples of ARO u sing oligomeric Co(III)salen catalysts. ................................ 31 1 7 Example of (HKR) of terminal epoxides in water in the presence of polymeric catalyst. ................................ ................................ ................................ .............. 33 1 8 HKR of epichlorohydrin by macrocyclic Co(III)OAc salen. ................................ .. 34 1 9 Bimetallic salen catalyst for enantioselective epoxide polymerization. ............... 35 1 10 Asymmetric Strecker reaction catalyzed by Al(II)Cl salen complex. ................... 37 1 11 Asymmetric addition of NH 3 salen. ................................ ................................ ................................ .................. 37 1 12 Asymmetric addition 5 alkoxyoxazoles to aldehydes catalyzed by Al(III)SBF 6 salen. ................................ ................................ ................................ .................. 37 1 13 Asymmetric addition of TMSCN to benzaldehydes catalyzed by Ti(IV)salen. .... 38 1 14 Asymmetric aldol Tischenko reaction catalyzed by Y(III)salen ........................... 39 1 15 Asymmetric addition of Et 2 Zn to aldehydes catalyzed by bifunctional Zn(II)salen. ................................ ................................ ................................ ......... 39 1 16 Asymmetric hetero Diels Alder reaction catalyzed by Cr( III)SbF 6 Salen. ........... 40 1 17 Asymmetric Diels Alder reaction catalyzed by Cr(III)SbF 6 salen. ....................... 40 1 18 Cyclopropanation of styrene deri vitives with Co and Ru salen complexes. ........ 41 1 19 First report of aziridination of styrene using Mn(salen) complexes. .................... 42 1 20 Asym metric aziridination of styrene with Mn(salen) complexes. ......................... 42 1 21 Asymmetric oxidation of methyl phenyl sulfide with V(IV) oxo salen. ................. 43

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11 1 22 Asymmetric oxidation of methyl phenyl sulfide with cationic Mn(V)PF 6 salen. .... 44 1 23 Asymmetric oxidation of cyclic enol ethers with cationic Mn(V)PF 6 salen. .......... 45 1 24 Baeyer Villiger oxidation. ................................ ................................ ................... 45 1 25 Asymmetric Baeyer Villiger oxidation catalyzed by cationic Co(salen). ............. 46 1 26 Kinetic resolution of racemic 1 phenylbuta 1,2 diene. ................................ ........ 46 1 27 Asymmetric benzylic hydroxylation with cationic Mn(salen)s. ............................. 48 1 29 Asymmetric hydrosilylation of acetophenone. ................................ ..................... 50 1 30 Heterobidentate ligand on dimeric zinc(II) porphyrin. ................................ ......... 53 1 31 Supramolecular complex for Pd catalyzed allylic amination and Rh catalyzed olefin hydroboration. ................................ ................................ ........................... 55 1 32 Asymmetric addition of Et 2 Zn to aryl aldehydes. ................................ ................ 59 1 33 Asymmetric aza Cope rearrangement. ................................ ............................... 61 1 34 Tautomer system of 2 pyridone/2 hydroxypyridine. ................................ ............ 62 1 35 Heterocomplexes formed by aminopyridine/isoquinolone interaction. ................ 64 1 36 Rhodium catalyzed hydrogenation of acetamidoacrylate. ................................ .. 65 1 37 Catalytic epoxidation by self assembling heterobimetallic system. ..................... 66 1 38 Asymmetric nitro aldol (Henry) reaction catalyzed by self assembling Co(II)salen ................................ ................................ ................................ ......... 67 1 39 Structure and application of selected UREAphos ligands. ................................ .. 68 1 40 Hydrogen bonded phosphoramidite ligands applied in the [Rh] catalyzed asymmetric hydrogenation. ................................ ................................ ................ 69 1 41 Example of a PhthalaPhos ligand and the application to the asymmetric hydrogenation of olefins. ................................ ................................ .................... 70 1 42 Selected example of HKR reactions using self assembling catalyst. .................. 71 2 1 Synthesis of isoquinoline containing chiral imine ligands. ................................ 75 3 1 Synthesis of bis urea functionalized bis salen catalyst ................................ ..... 100 3 2 Comparison vs monomeric salen for epoxide hydrolysis. ................................ 102

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12 3 3 Asymmetric hydrolysis of cyclopentene oxide by Kim and co workers. ............ 107 3 4 Cr(III)Cl and Co(III)OTs complex mixtures for the ARO with TMSN 3 ............... 109 3 6 Synthesis of bis urea bis tridentate Schiff base ligands. ................................ .. 114 3 7 Example of asymmetric addition of TMSN 3 to N alkyl meso aziridine. ............. 114

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13 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 THE DEVELOPMENT OF CHIRAL CATALY STS FOR ASYMMETRIC REACTIONS By Michael J. Rodig December 2011 Chair: Sukwon Hong Major: Chemistry The body of this work is focused on the development of new chiral catalysts for asymmetric reactions. C hiral catalysts can provide an atom economical ro ute to a variety of synthetically important chiral molecules including compounds of biological and pharmacological interest to novel materials with superior structural properties. The efficiency of a chiral catalyst can be measured in both its ability to a ccelerate a reaction and to promote a highly selective reaction pathway, yielding reaction products with a high degree of optical purity. In many cases, these two criteria are best met when two or more reaction partners are cooperatively activated and orga nized by a single catalytic species. The latter portion of this work is focused on the development of transition metal catalysts designed to self asse mble in solution to yield multimetallic catalysts capable of activating multiple reaction partners. The fi rst portion is focused on the application of novel, chelating nitrogen donor ligands synthesized en route to N heterocyclic carbene ligands.

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14 CHAPTER 1 INTRODUCTION N N L igands in Asymmetric Catalysis Nitrogen containing ligands have earned a position of s ignificant importance in asymmetric catalysis due in part to their relative ease of synthesis from a readily available, enantiopure chiral pool and their ability to coordinate a variety of metals. A great number of highly enantioselective transform ations are possible using Lewis acids supported by chiral ligands based on amine, imine, pyridin e, oxazoline, py r role and many other nitrogen donor groups. The use of chiral catalysts for asymmetric transformations is a highly attractive process for increasing a substrate s structural complexity with relatively low expenditures in terms of materials, labor and cost. Synthetic routes for a given target can be greatly shortened by using chiral catalysts, avoiding direct use of enantiopure starting materials. Atom e conomy can also be improved by avoiding the attachment and subsequent removal of stoichiometric chiral auxiliaries Additionally, reaction conditions are often more mild yielding less by products and easing purification The development of successful cat alysts is highly dependent on the generation of new ligands that will support the central metal. The approach to the development of new ligands is often a mixture of car e ful observations, rational design and luck. There are however several principles tha t lend themselves to the development of successful ligands: (1) the synthesis should be modular, preferably at more than one point along the synthesis. The ability to quickly and easily tune the ligand in terms of electronics and sterics is highly desirabl e (2) the synthesis should be short and relatively straight forward with as many high yielding steps as possible (3) t he basic ligand framework

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15 can be created. The variety of nitr ogen donor ligands is vast and in an effort to focus this disc ussion, those that most closely resemble the structural framework of the ligand s developed in the course of this research will be reviewed here. These sec tions will describe the d esign and application of these ligand types. Diimine Based Chiral L igands Developed nearly 70 year ago, diimine ligands are easily synthesized via Schiff base condensation of carbonyl compounds and primary amines. 1 One of the first examples of chiral imin e ligands was reported by Uhlemann 2 who investigated the metal selectivity with Schiff bases synthesized from ortho substituted ketones and (1 R ,2 R ) trans diaminocyclohexane. The C 2 symmetry created by these ligands is a common and popular approach, found in both nitrogen based and chelating phosphine ligands In this way the number of diastereomeric pathways an asymmetric reaction can take are limited. The incorporation of C 2 sy m metry has been pillar of ligand design since the introduction of DIOP ligands by Kagan 3 40 years ago A quadrant analogy is often used to simplify and predict the interactions between catalyst and substrate. Figure 1 1. Quadrant analogy as applied to C 2 sym m etric ligands.

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16 Figure 1 2. A selection of C 2 symmetric diimine ligands One of the attractive features of di imine ligands are their simple synthesis, either by condensation of achiral carbonyl compounds with chiral trans diamines (types 1 .1 1.3 ) or by condensat ion of dialdehydes with chiral monoamines (type 1. 4 ) Steric bulk and electronics can be easily modified and a variety of chiral amines are readily available. The successful application of C 2 symmetric diimine ligands varies. While yield and selectivity su ffers in some cases exceptions are the Cu(II) catalyzed aziridination of olefins by types 1.2 4 and 1.3 5 and the reduction of ketones with polymeric silanes and diethyl zinc with ligand type 1 1 6 Salen Ligands Modifications to the C 2 symmetric diimine lig ands include the tetradentate salen ligands formed through the condensation of chiral diamines and salicylaldehyde derivatives. The commercial synthesis of the most universal salen ligand ( 1.5a ) starts

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17 from inexpensive raw materials and is available on a l aboratory or bulk scale. The fi r st salen ligand and its copper complex were discovered by Combes in 1889. 7 Figure 1 3. Some e xamples of metal salen complexes Salen ligands are capable of coordinating a variety of first a nd second row transition metals as well as main group elements including Mn, Co, Cr, Al, Ti V and Ru and have been employed in many asymmetric reactions including aziridinations 17 oxidations, 16 8 epoxide ring opening 9 hetero Diels Alder, 10 hydroxylation s, cyclopropanations 11 and many, many others. A great number of variations to the basic framework utilizing tertiary 1,2 diamines, 1,3 or 1,4 diamines and chiral sal i cylaldehydes have been reported (Figure 1 4) but the basic structure of 1.5a shows impressive versatility due to some key features. The steric bulk of the tertiary butyl groups at the 3 the approaching substrate over the chir al diamine. The trans diaxial hydrogen atoms effectively (and quite remarkably) communicate t heir stereochemical information with high fidelity. Due in part to the central position of salen ligands in this research, this section will be further reviewed in terms of the reactions sa len ligands have been applied Asymmetric e poxidation (AE) Asymmetric olefin epoxidation was reported as early as 1985 by Kochi using Cr(V)oxo salen complexes whose structures were confirmed by X ray analysis. 12 It was

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18 later discov ered that cationic Mn(V)salen was superior to the Cr(V) spec ies and the Mn(V)oxo salen was i nvoked as the active catalyst. Figure 1 4. Examples of structural variations of the salen ligand framework Arguably the most infl uential seminal work on the application of salen ligands to asymmetric epoxidation has been contributed by Jacobsen 13 14 and co workers and independently in the same year by Katsuki, 15 and co workers, with their investigation of Mn(I II)Cl salen complex 1.5b f or the asymmetric epoxidation of olefins. Other early contributions from Thornton 16 and Burrows 17 should be noted as well. This practical approach uses a Mn(III)Cl salen as a pre catalyst and a stoichiometric oxidant such as bleach or an organic peracid to g enerate the active Mn(V) oxo species.

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19 Scheme 1 1. Conditions for asymmetric epoxidation (AE) of conjugated olefins catalyzed by Mn(III)Cl salen complex. The addition of organic N oxide s such as 4 phenylpyridine N oxide or N methylmorpholine N oxide have been shown to dramatically improve efficiency 18 N oxides are believed to act as axial ligands that inhibit formation of the inactive oxo Mn(IV)dimer. Jacobsen and co workers demonstrated the importance of these additives by developing salen complexes in which the additive was covalently tethered to the catalyst. 19 Better reactivity is generally observed with e lectron rich alkenes that lie in conjugation with some other group. High enantiomeric excess can be achieved for cis 1,2 di substituted tri and even tetrasubstituted alkenes 20 21 while lower temperatures are generally need for terminal olefins. 22 Interestingly, epoxidation of trans o lefins generally suffers from low enantioselectivity using Mn(V)oxo salen catalysts while the correspo nding Cr(V)oxo salen catalyst are capable of achieving higher % ee. 23 Trans methylstyrene undergoes epoxidation in 71% ee (vs 24% ee for the corresponding Mn (V) oxo salen complex) 24 but reported reactivity is sluggish and the less convenient iodosylbenzene is employed as oxidant. While the Mn(V)oxo salen complex has been proven t o be involved in the epoxidation reaction by electrospray mass spectrometric analysis 25 the active catalyst is to o unstable to be isolated, however the Cr(V)oxo salen catalyst is isolable 26 and can be used directly.

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20 Scheme 1 2. Stepwise mechanism of oxygen transfer from Mn to olefin leads to diastereomeric mixtures of epoxides. In the case of isomerically pure cis 1,2 di substituted olefins, primary reaction products of catalytic epoxidation include both cis and trans epoxide s, suggesting a n on concerted reaction mechanism Several pathways have been proposed including stepwise via a carbocation [2 + 2] cycloaddition leading to a metallaoxetane and stepwise via radical currently earning the greatest support. 27 In summary, the epoxidation of non terminal olefins by Mn(V)oxo salen complexes has proven a highly efficient and practical process for the asymmetric synthesis of enantioenriched epoxides. As one of the first reactions studied using this ligand system, a wealth of import ant data has been collected in terms of mechanism, scope and limitations. One of those limitations is the enantioselective epoxidation of terminal olefins to give secondary epoxides, an exceedingly valuable intermediate for the synthesis of chiral alcohols In response to this deficiency, an alternate method has been developed using salen ligands to obtain those products.

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21 Epoxide ring opening r eactions Many asymmetric reactions generate new stereogenic sp 3 carbon atoms by the transformation of prochiral sp 2 centers in the form of C=C, C=O or C=N bonds. In contrast much less attention has been paid to the generation of new stereogenic sp 3 centers from pre existing sp 3 centers by asymmetric substitution reactions. This approach can be best applied in the desy mmetrization of meso compounds or by kinetic resolution of racemic mixtures Jacobsen and co work ers previously reported work of the catalytic asymmetric epoxidation of olefins led them to question an extension of the simplified model of enantiofacial disc rimination of the olefin approaching the oxo metal center in a side on manner (Figure 1 5) While the exact mechanism of oxygen transfer is still under debate as previously mentioned this transition state model originally proposed by Groves 28 is generally accepted It was proposed that if the transition state of oxygen transfer to olefins was able to discri mi nate between the prochiral faces of the olefin, than the ground state of coordinated epoxide may provide a chiral environment to direct incoming nucle ophiles. Fi gure 1 5. Models for olefin epoxidation and epoxide activation by chiral metal salen complexes Desymmetrization of meso e poxides The first asymmetric ring opening (ARO) of meso epoxides catalyzed by metal salen complexes was reported by Jacobsen and co workers using trimethylsilylazide

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22 (TMSN 3 ) and Cr(III) Cl salen complex 1.5f 29 Complex 1.5g was later revealed as the active catalyst from observation that stoichiometric azide transfer could be accomplished using 1.5g 41 Cyclic epoxides provided higher enantioselectivities than acyclic epoxides and selectivity generally decreased with increasing ring size (Table 1 1) Epoxides derived from cycli c olefins containing hete roatom s were well tolerated in terms of selectivity with furan derived epoxide 1.17 giving lower yield, presumably from competing coordination to the metal center with the epoxide oxygen. The synthetic utility in this reaction results from the rapid access to differentially protected 1,2 amino alcohols, a common element in several classes of pharmacologically important compounds such as prostaglandins, 30 chitinase inhibitors, 31 protein kinase inhibitors 32 and antitumor antibiotics. 33 Table 1 1. Enantioselectiv e opening of meso epoxides with Cr(III)Cl salen a Isolated yield of the cor responding azidioalcohol after hydrolysis. Other nucleophiles have been employed in the desymmetrization reaction including thiols, 34 halides including fluoride 35 36 and even scattered reports of enolate 37 and aryllithium 38 carbon nucleophiles. While oxygen nu cleophiles are to be given 1.15 1.16 1.17 1.18 1.19 1.20 1.21 Time (h) 18 28 18 36 16 46 30 Yield (%) a 80 80 80 80 90 80 65 ee (%) 88 94 98 95 95 81 82

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23 special consideration due to the central role played in the hydrokinetic resolution (HKR) of terminal epoxides, reports of their addition of meso epoxides are limited. Shortly after the report on the addition of azide to meso ep oxides, Jacobsen and co workers also demonstrated the desymmetrization reaction with Co(III)OAc salen catalyst ( 1.5d ) using benzoic acid as a nucleophile. Enantioselectivities are best in the case of aryl substituted epoxides but the depressed selectivity in the case of cyclohexene oxide can be improved from 77% ee to 98% ee through a single recrystallization. Kinetic resolution of terminal epoxides While not the first asymmetric epoxide opening reaction catalyzed by salen metal complexes reported, the hyd rolytic kinetic resolution (HKR) of terminal racemic epoxides might certainly be classified as the most important. The p revious limitations of Mn(V)oxo salen complexes to access enantioenriched ter minal epoxides where overcome in the initial report in 1997 39 by Jacobsen and co workers and expanded upon the following year. 40 Scheme 1 3 HKR of terminal epoxides with water using Co(III)OAc salen. In that report several terminal epoxides derived from allyl halides and ethers undergo resolution with Co(III)OAc salen ( 1.5d ) with remarkable selectivity and efficiency (Scheme 1 3) While resolutions can theoretically only achieve a 50% maximum yield, the HKR process is still highly attractive for several practical reasons. When al lowed to reach full resolution (50% yield) both the epoxide and the diol can be

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24 obtained in high enantiomeric excess generally with very low catalyst loadings The reaction products can be easily isolated by vacuum distillation or extraction. Using water as a nucleophile is safe, convenient and has a low molecular weight. After the reaction products are removed the catalyst residue has been found to retain its activity many times over. The introduction of nitrogen nucleophiles in the kinetic resolution o f terminal epoxides using salen catalysts was reported shortly after Jacobsen and co workers seminal publication on the asymmetric ring opening of meso epoxides 29 using trimethylsilylazide (TMSN 3 ) and Cr(III)Cl salen complex 1.5f (Scheme 1 4). Scheme 1 4. HKR of terminal epoxides with TMSN 3 using Cr(III)Cl salen. The synthetic utility of this reaction was rapidly demonstrated in the short synthesis of ( S ) propranolol, a widely used anti hypertensive agent, and ( R ) 9 [2 (phosphonomethoxy) propyl]adenine (PMPA), a compound displaying prophylactic activity against simian immunodeficiency virus Figure 1 6. Molecules of biological interest synthesi zed using kinetic resolution.

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25 It was near this time that Jacobsen and co workers discovered one of the most interesting mechanistic features of this reaction and other ring opening reactions. It was found that a linear correlation existed between k obs and [catalyst] 2 reflecting a second order dependence on catalyst concentration. 41 This provided strong evidence for a bimetallic reaction pathway in which one meta l center coordinates and activates the epoxide for attack while another metal center coordinates a nd delivers the incoming nucleophile. This pathway is also supported by a non linear relationship between enantiopurity of the catalyst and of the resulting product, further suggesting that two equivalents of catalyst are involved in the stereodifferentiat ing step. While this bimetallic mechanism is highly intriguing, it creates some significant limitations on how low the catalyst loading can be and on the overall catalyst concentration in solution. Since high enantiomeric excess of epoxide can only be achi eved at high conversion (near 50%) in the case of kinetic resolution, the ability to completely turn over substrate becomes very crucial. Excess nucleophile or higher catalyst loadings are often used to overcome these issues but another useful and fascinat ing method in the case of the HKR reaction, is in the selection of counter ion to the penta coordinate Co(III) center. It was observed early on that trace amounts of chlorohydrins could be isolated as by products that resulted from nucleophilic addition of the chloride counter ion from the metal center. If this addition is rapid, Co(III) can be reduced to Co(II) and considerably slow the reaction. It was found that weakly nucleophilic anions from electron deficient benzoic and arylsulfonic acids could incre ase the rate of reaction by slowing this unwanted addition. Furthermore, it was found in an elegant study by Jacobsen and co workers 42 that in the case of the HKR reaction, the choice of oxidizing acid was extremely crucial

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26 in providing the correct proporti on of Co(III)OH and Co(III)X with bound epoxide. The problem of local catalyst concentration would soon be overcome as well. Figure 1 7. Proposed bimetallic mechanism for the asymmetric ring opening of epoxides with Cr(III ) salen catalyst. Multinuclear salen catalyst for e poxide opening In an effort to combat the entropic problem created by the necessity of two discrete catalysts being involved in the transition state for asymmetric ring opening reactions considerable effo rts have been made to construct bi or multimetallic catalysts. Jacobsen and co workers reported that while at lower concentrations, dimeric Cr(III)Cl salen catalysts linked through their diamine backbone displayed rate acceleration in the delivery of azid e to cyclopentene oxide versus their analogous monomeric counterparts (Figure 1 8) although the observed enantiomeric excess was less than 10%. 43

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27 Figure 1 8. Backbone linked dimeric Cr(III)Cl salen and its monomeric analog ue. It was rationalized that two limiting geometries existed for the approach of the two to to (Figure 1 9) The results from the previously described reaction suggest that wh ile the bimetallic mechanism was in operation using 1.22 to dramatically eroded stereoselectivity. In response to these results, dimeric salen complexes were developed that were joined through ester linkages of various lengths on the aryl rings. These dimeric catalyst s were tested in the ARO reaction of cyclopenteneoxide with H N 3 versus their monomeric analogue. Kinetic studies were carried out measuring initial reaction rates and indicated that dimeric catalysts 1.24a g displayed both inter and intramolecular catalytic behavior where as 1.25 only displayed intermolecular behavior (Figure 1 10) Figure 1 9. Limiting geometries for the transition state of the ARO

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28 Figure 1 10. Aryl linked dimeric Cr(III)Cl salen and their monomeric analogue. Other multimeric systems were soon to follow including a dendrimeric system developed by Jacobsen and co workers. 44 In the preceding years, increasing interest had been devoted to the synthesis and characterization of compounds that displayed unique behavior as a direct consequence of the dendrite architecture. 45 This series of catalysts were based on the commercially available NH 2 terminated polyamidoamine (PAMAM) precursors (Fi gure 1 11) For comparison, analogous monomeric and dimeric catalysts were also prepared and initially evaluated in the HKR of (rac.) vinylcyclohexene oxide. As expected, at 0.0025 mol% Co(III), the native, unfunctionalized Co(III)I salen ( 1.5h ) was eff ectively unreactive after 40 hours while the dendrimeric catalyst 1.26b completely resolved (rac.) vinylcyclohexene oxide in only 20 hours giving the resolved epoxide in 98% ee. Rate plots also revealed that dendrimeric catalysts of various orders of branc hing not only exhibit rate acceleration versus the monomeric catalyst analogue 1.28 but the dimeric catalyst 1.27 as well. While reaction rates on a per molecule basis of catalyst were linear with respect to the order of branching, on a per mole of Co(III) it

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29 was found that catalyst 1.26a with four Co(III)salen units provided the greatest rate acceleration. These findings represent an interesting example of cooperative inter action between salen units and also revealed that limitations may exist in terms of the creating Figure 1 11. Structures of dendrimeric, dimeric and monomeric Co(III)salen.

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30 In 2001 Jacobsen and co workers 46 developed cyclic oligomeric sa len catalysts (Figure 1 12) that were later improved upon in 2002. 47 These oligomeric catalysts were highly reactive in the HKR of terminal epoxides, desymmetrization of meso cyclohexene oxide by hydrolysis and the addition of other oxygen nucleophiles to t erminal epoxides including phenols, benz y lic and aliphatic alcohols (Scheme1 6) One of the more striking examples is the desymmetrization cyclohexene oxide via hydrolysis. Disubstituted epoxides are a considerably more challenging substrate and had not b een illu strated since the earlier report of azide addition in 1995. 29 Catalysts 1.3 1 and 1.3 2 not only show vastly improved reactivity and selectivity over their monomeric counter part they also show improved r eactivity and selectivity over their previous generation oligomer 1. 29 In the initial report 46 the installation of the chlorine substituent was a result of improvement of monomeric salen adorned in a similar f ashion. Figure 1 12. Cyclic oligomeric Co(salen) catalysts developed by Jacobsen. The resulting oligomeric catalyst 1. 29 was difficult to synthesize, displayed poor stability under the ring opening reaction conditions and when used as a mixture where n

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31 = 1 5 resulted in more than 10 000 different possibl e compounds due to the additional stereocenters involved. Removing this group allowed for a much easier synthesis and allowed for isolation of discrete oligomers as a means to gain a better understanding the influence of oligomer size. Scheme 1 6. Examples of ARO using oligomeric Co(III)salen catalysts.

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32 As an alternate method of electr onic tuning, the counter ion was modified and show n to h ave a positive impact on reactivity and, surprisingly, selectivity when camphorsulfonic acid ( 1.31 CSA=10 camphorsulfonate) and 3 nitrobenzenesulfonic acid ( 1.32 NBS=3 nitrobenzenesulfonate) are used. While the catalysts can effectively be used as mixtures of oligomers where n=1 3, evaluation of discrete oligomers revealed that the best results occurred with the trimer when n=2. It was proposed that the trimer processed the right balance of structural rigidity to minimize nonselective pathways while mainta ining enough flexibility to access the optimal transition state. The above contributions from the labs of E. Jacobsen constitute a successful development of covalently linked catalysts based on data that strongly suggested a bimetallic mechanism in epoxide ring opening reactions. While these tethered catalyst show dramatic improvements versus their monomeric counterparts, the development of novel catalysts based on a similar approach is far from over. In 2006 Weberskirch and co workers 48 reported a polymeri c Co(III)OAc salen catalyst These polymeric catalysts were synthesized by covalently linking hydroxyl substituted salen ligands to block co polymer containing pendant carboxylic acid groups. These block co polymers were comprise d of a hydrophobic and a hy drophilic block with the pendent salen ligands located in the hydrophilic region. These catalysts were designed with the observation that in the HKR reaction the addition of water generally needs to be carefully controlled and at lowered temperatures since the process is exothermic. The equivalents of water must also be controlled to provide high enantiomeric excesses. These salen containing block co polymers were designed to create a micell ar

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33 environment in which the hydrophilic shell of the micelle provi des water solubility while the hydrophobic core creates a higher, local concentration of salen catalyst. Figure 1 13 Amphiphil ic ( R R ) macrosalen ligand (w=41, x=4.5, y=2.8, z=2.3) This polymeric catalyst was show n to r esolve several aromatic substituted terminal epoxides with exceptionally high % ee at very low catalyst loadings. Furthermore, these reactions can be conducted in water as solvent and the catalyst can be subsequently removed and recycled without appreciabl e loss of efficiency, for up to 4 cycles. These results demonstrate the first HKR of terminal epoxides catalyzed by Co(III)OAc salen incorporated into amphiphllic block co polymer carried out in water as a solvent. S cheme 1 7. Example of (HKR) of terminal epoxides in water in the presence of polymeric catalyst

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34 In 2007 Weck and co workers 49 developed a highly efficient variation of macrocyclic oligomeric Co(II)salen catalyst s for the HKR of terminal epoxides (Figure 1 14) These oligomers were constructed using a ring expanding olefin metathesis approach using Grubbs 3rd generation catalyst. These catalysts showed impressive rate enhancements versus their monomeric analogues and in comparison to any previously developed sys tems for the HKR of terminal epoxides. Resolution of ra cemic epichlorohydrin could be e ffected in only 2.5h with greater than 99% ee with only 0.01 mol% catalyst (Scheme 1 8) While no kinetic evidence was provided in order to better understand these new c atalysts, they show impressive rate acceleration over previously reported systems over a broad range of substituted terminal epoxides. Figure 1 14 Macrocyclic Co(II)salen complexes developed by Weck. S cheme 1 8. HKR of epichlorohydrin by macrocyclic Co(III)OAc salen.

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35 In 2007 Coates 50 and co workers developed a bis salen dimer based on a chiral BINOL backbone for the polymerization of terminal epoxides. These dimeric catalysts show exc eptionally high selectivity factors (s) and near perfect isotacticity for a series of substituted terminal epoxides (Scheme 1 9). While the polymer enantioselectivities are generally over 99% the conversions are somewhat low leading to lower enantiopurity in the remaining epoxide. Interestingly, neither the Co(II )salen species 1.52 nor its oxidized form Co(III)Cl 1. 52 showed any catalytic activity alone. The reaction requires bis(triphenylphosphine)iminium acetate (PPN)OAc salt as a co catalyst. This depen dency was also observed in the co polymerization with epoxides and CO 2 with similar catalysts. 51 While the mechanism is still currently unclear for polymerizations and co polymerizations of this type, it is believed that the exogenous anion may facilitate the initial ring opening to begin polymerization. 52 53 Scheme 1 9. Bimetallic salen c atalyst for enantioselective e poxide polymerization

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36 These findings represent the first example of a polymerization catalyst for the ki netic resolution of terminal epoxides. The racemic form of the catalyst polymerizes racemic epoxides to highly isotactic polyethers in quantitative yield and provides a highly int eresting application of epoxide opening chemistry by metallosalen catalysts. Carbonyl addition p rocesses The asymmetric addition of nucleophiles to carbonyl groups is of considerable interest due not only to the variety of newly formed C Nu bonds that can be generated but in the high synthetic value placed on the chiral alcohol s or amines generated from ketones and aldehydes or imines, respectively. Since the construction of ster e ogenic C C bonds is central to asymmetric synthesis, the addition of carbon nucleophiles such as HCN to carbonyl groups is of particular interest. The addi tion of HCN to imines ( the Stre c ker reaction) provides access to optically active amino acids and metallosalen catalysts have played a considerable role in this reaction. Jacobsen and co workers 54 screened a series of metal salen complexes for catalysis in the reaction of N allyl benzaldimine with trimethylsilylcyanide. Several (salen)metal complexes were found to catalyze the reaction with varying degrees of conversion and enantioselectivity, and the best results were observed with the Al (III)Cl salen co mplex 1.5k (Scheme 1 10) Kinetic analysis demonstrated that this reaction was not second order in the Al(III)Cl catalyst, indicating a bimetallic mechanism was not operating. Jacobsen and co workers 55 also described the asymmetric addition of HN 3 to unsaturated imides catalyzed by Al(III)Cl salen 1.5k giving products easily converted into amino acids (Scheme 1 11) Evans and co workers 56 also employed an Al(III)SbF 6 in the asymmetric addition of 5 alkoxyoxazoles to aldehydes.

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37 Scheme 1 10 Asymmetric Strecker reaction catalyzed by Al(II)Cl salen complex Scheme 1 11 Asymmetric addition of NH 3 atalyzed by Al(III)Cl salen This salen catalyst incorporate d diamino binaphthyl (BINAM) as the chiral backbone (Scheme 1 12) The reaction products were obtained in high yield, diastereo and enantiomeric excess hydroxy amino acid derivatives. Scheme 1 12 Asymmetric addition 5 alkoxyoxazoles to aldehydes catalyzed by Al(III)SBF 6 salen. While the reaction products were obtained as the cis isomer, they could be equilibrated to the trans isomer under basic conditio ns providing ready access to both diastereomers. Asymmetric addition of TMSCN to aldehydes has been demonstrated by

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38 Belkon 57 and North using a Ti(IV)Cl 2 complex of salen 1.5a in quantitative yield and high enantioselectivity. Interestingly, mechanistic anal ysis of the Ti(IV)Cl 2 salen complex revealed a non first order dependency on catalyst concentration and is believed to proceed through a cis di oxo species that allows for the intermolecular transfer of cyanide to the carbonyl substrate. 58 Scheme 1 13 Asymmetric addition of TMSCN to benzaldehydes catalyzed by Ti(IV)salen Che and co workers also found the reaction to be catalyzed in the presence of Ti(O i Pr) 4 and salen ligand 1. 64 diamino binaphthyl (BINAM) backbone. 59 Other examples include the asymmetric aldol Tischenko reaction catalyzed by Y(III)salen 1.67 Scheme 1 14 Asymmetric addition of TMSCN to benzaldehydes catalyzed by Ti(IV)BINAM salen.

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39 Ko zlowski and co workers 60 developed Zn(II) salen catalysts for the asymmetric addition of Et 2 Zn to aryl and aliphatic aldehydes. These catalysts were designed to operate via a bimetallic mechanism but not in the traditional manner seen in epoxide opening rea ctions. Scheme 1 14 Asymmetric aldol Tischenko reaction catalyzed by Y(III)salen of the aryl rings to aid in the delivery of nucleophile t o the electrophile coordinated to the central Lewis acid (Scheme 1 15) It was shown that the pKa of the corresponding conjugate acid of the basic pendant group correlated to observed enantioselectivity. A pKa near 6 was found to be optimal while others of higher or lower value displayed lower selectivity. Scheme 1 15 Asymmetric addition of Et 2 Zn to aldehydes catalyzed by bifunctional Zn(II)salen

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40 Diels Alder and Hetero Diels Alder Salen ligands have also been successfu lly employed in a variety of cy cloaddition reactions Jacobsen and co workers 61 found that Cr(III)SbF 6 salen catalyst 1.5i was effective in catalyzing the asymmetric hetero Diels Alder reaction between [(2 chlorobenzoyl)oxy] acetaldehyde and 1 methoxy 3 [(t rimethylsilyl)oxy]buta 1,3 diene (Scheme 1 16) Scheme 1 16 Asymmetric hetero Diels Alder reaction cat alyzed by Cr(III)SbF 6 Salen Rawal and co workers 62 also demonstrated the efficiency of these Cr(III)salen catalysts i n the highly endo selective Diels Alder reaction between 1 amino 1,3 butadiene derivatives and substituted acroleins (Scheme 1 17). In these cases enantioselectivity was generally greater than 90%. Reactivity is dramatically improved when cationic Co(III) SbF 6 salen catalysts are used allowing catalyst loadings as low as are replaced with trialkylsilyl groups both selectivity and reactivity is improved. Scheme 1 17 Asymmetric Diels Alder reaction catalyzed by Cr(III)SbF 6 salen

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41 Cyclopropanation While considerable efforts have been devoted to the advancement of new methods of cyclopropanation, arguably the most versatile and useful are the reac tions between terminal olefins and diazo compounds leading to cis and trans diastereomeric products. Th e d iazo compounds are convenient metal carbenoid precursors in the presence of a suitable metal with loss of molecular nitrogen. Metallosalen catalyzed a symmetric cyclopropanation was first reported by Otsuka and Nakamura 63 using a Co(II)salen complex as catalyst, though enantioselectivity was rather poor (> 10% ee ) Katsuki and co workers have demonstrated high trans and enantioselectivity with Co(III)sal en complex 1. 76 that has positions of the salen ligand (Scheme 1 18) It was reasoned that olefins may approach the carbenoid species along the Co O bond axis with an orientation perpendicular to the Co carbenoid bond. The prese nce of substituents blocks incoming substrate approach and rotation. 64 Katsuki also demonstrated high cis selectivity with Ru(III)salen 65 ( 1. 77 ) and Co(II)salen 66 complexes ( 1.78 ) utilizing second generation salen ligands bearing axially chiral salicyla ldehyde derivatives. Scheme 1 18 Cyclopropanation of styrene derivitives with Co and Ru salen complexes.

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4 2 Aziridination Aziridinatio n through the reaction of olefins with metal nitrenes can be thought of as analogous to e poxidation via oxene transfer. I n the same manner that enantioenriched epoxides are of high synthetic value, so are their nitrogen analogues. As such, catalytic methods to access such compounds are of considerable interest. Burrows and co workers 67 first in vestigated chiral Mn(III)Cl salen complex 1. 79 as a catalyst in the aziridination of styrene using tosyliminoiodobenzene as nitrene transfer reagent. The observed yield was low and no asymmetric induction was observed. S cheme 1 19 First report of aziridination of styrene using Mn(salen) complexes Katsuki and co worker s early examination of aziridination of styrene with Mn(salen) complex 1.80 a was shown to give poor yield and only modest % ee. 68 Scheme 1 20 Asymmetric aziridination of styrene with Mn(salen) complexes.

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43 Unlike metal oxo complexes the metal bound nitrene contained an additional substituent and less ste ric demand from the ligand may be required for improved efficiency. I ndeed, replacement of the aryl groups for methyl ( 1.80b ) along the backbone significantly improved enantioselectivity but conversion was still sluggish. When second generation salen ligand 1.81 was used, a dramatic increase in reactivity was observed. 69 It CH facilitate the nitrene transfer. These interactions have been observed in X ray crystal structures of Mn(salen) complexes. 70 Oxidation of sulfides Chiral sulfoxides are useful chiral auxiliaries for asymmetric synthesis and catalytic asymmetric sulfoxidation is a straightforward and efficient method for their preparation. Fujita 71 reported the first example of asymmetric sulfide oxidation using V(IV)oxo salen complex 1. 84 This catalyst afforded the enantioselec tive oxidation of methyl phenyl sulfide with cumene hydroperoxide (CHP) in methylene chloride in high yield albeit modest enantioselectivity. Scheme 1 21 Asymmetric oxidation of methyl phenyl sulfide with V(IV) oxo salen

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44 Jacobsen and co workers 72 reported similar results using Mn(III)Cl salen 1.5b to catalyze the oxidation of sulfides using unbuffered hydrogen peroxide as the oxidant. Katsuki and co workers showed that cationic Mn(III)PF6 second generations salen complex 1.89 were found to serve as efficient catalysts for asymmetric sulfoxidation. These reactions did require however, the less atom efficient iodosylbenzene as the terminal oxidant. Scheme 1 22 Asymmetric oxidation of methy l phenyl sulfide wi th cat ionic Mn(V)PF 6 salen Oxidation of enol derivatives Thornon and co workers 73 reported that Mn(III)Cl salen complex type 1.14 catalyzed the oxidation of silyl enol ethers to give hydroxyketones using iodosylbenzene as oxidant and p roceed with good to excellent yield (70 94%) and moderate asymmetric induction (14 62%) although good substrates are limited to conjugated enol ethers or esters.

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45 However, Katsuki and co workers 74 demonstrated that cationic Mn(III)PF 6 salen complex 1. 90 can be successfully applied to the oxidation of simple enol ethers. Reactions of cyclic enol ethers in ethanol proceeded with high enantioselectivity, giving hydroxy acetals. Scheme 1 23 Asymmetric oxidation of cyclic enol ethers wi th cat ionic Mn(V)PF 6 salen Asymmetric Baeyer Villiger o xidations The conversion of carbonyl c ompounds to esters by the Baeyer Villiger reaction is widely used in organic synthesis. 75 This transformation can be performed in an enantioselective manner when the carbonyl compounds are racemic or prochiral. The first step of this reaction is nucleophili c addition of a peroxy compound to a carbonyl compound giving a Criegee intermediate followed by migration of the carbon to the peroxy oxygen atom This step is rate determining and migration c an occur only when the carbon C O bond and peroxy O O bond are anti periplanar to one an other. Scheme 1 24 Baeyer Villiger oxidation

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46 Scheme 1 25 Asymmetric Baeyer Villiger oxidation catalyzed by c ationic Co(salen) The ability to control this migration would lead to enantioenriched products. While traditional trans Co(salen) complexes like 1.95 bearing the cyclohexanediamine backbone gave racemic product, Katsuki and co workers demonstrated that Co(salen) complexes of cis structure ( 1.94 ) resulting from the strained binaphthyl backbone resulted in good selectivity in several cases. 76 Kinetic resolution of racemic allenes As discussed above, Mn(salen) complexes are efficient catalyst s for the enantioselective epoxidation of racemic cis olefins. Katsuki and co workers had reasoned that these catalysts would also be efficient in the kinetic resolution of racemic olefins under similar conditions. Epoxidation of racemic 1 alkylindenes were examined but only mod est enantiomer d ifferentiation was observed Interestingly, better enantiomer differentiation was observed in the oxidation of racemic aryl substituted allenes with Mn(salen)OAc 1. 90 Scheme 1 26 Kinetic resolution of racemic 1 phenylbu ta 1,2 diene

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47 Asymmetric hydroxylation of C H b onds In an early report, Kochi and co workers 77 reported that Mn(salen) complexes are capable of catalyzing C H hydroxylation. Two years later, Nishinaga and co workers 78 reported the hydroxylation of styrene us ing chiral Co(salen) complex to produce 1 phenylethanol in modest yield (30% isolated) and enantiomeric excess (38% ee). In 1994, Jacob sen and co workers reported a fascinating kinetic resolution of racemic dihydronaphthalene oxide and related epoxides wi th Mn(salen) complex 79 This resolution was discovered a fter observing an increasing % ee with decreasing yield toward the end of an asymmetric epoxidation reaction. In the initial findings, the minor epoxide enantiomer was selectively oxidized at the benzy lic position to give the syn epoxy alcohol. Katsuki and co workers 80 examined enantioselective benzylic oxidation with second generation Mn(salen) complexes. The ligands 1.104a + b were designed with the intent of inhibiting radical decay by slowing the rate of dissociating radical intermediate away from the metal center through the incorporation of sterically encumbered silyl groups that hover over the metal center (Scheme 1 27). Heterocyclic Nitrogen Donor Ligands 2,2 Bipyridine based ligands Ligands based on 2,2 bipyridine (BIPY) have been shown to chelate a variety of different metals from across the periodic table. These ligands are generally synthesized via Ni catalyzed coupling halosubstituted pyridines with pre installed chiral pendant groups. Bolm a nd co workers reported one of the first synthesis of chiral 2,2 bipyridyl ligands using chiral boranes to obtain the desired alcohols for type 1.105 81

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48 Scheme 1 27 Asymmetric benzylic hydroxylation with cationic Mn(sale n)s Other interesting examples are those who se chirality is based on atropisomers 82 ( 1. 10 6 ), on planar chirality ( 1. 10 7 ) or those relying on a secondary functionalization ( 1. 10 8 ). These ligands are often employed in reactions such as Cu catalyzed cycloprop anation, 82 allylic oxidations, 83 Rh catalyzed hydrosilylations, 84 and alkylations with R 2 Z n 83 C 1 symmetric BIPY ligands have also been developed using similar condit ions and for similar applications. Figure 1 15 bipyridine ligands

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49 Oxazoline ligands Oxazoline rings have been the basis of C 2 ( 1.10 9 ) and C 1 ( 1.1 10 ) symmetric ligands developed largely b y Pfaltz and have been thoroughly reviewed 85 Aza bis ( oxazolines ) ( 1.1 11 ) are an interesting variant that allows for further functionalization at the bridging nitrogen. Most often, functionalization at the central nitrogen is in the form of solid supports s uch as methoxypoly(ethylene glycol) (MeOPEG 5000) 86 or dendritic structures 87 in an effort to access recoverable catalysts. Figure 1 16 Bis oxazoline and related ligands. Pyridylox azoline based l igands Bridging the gap bet ween bipyridine and diimine ligands are pyridylimine based ligands. These ligands are easily synthesized via Schiff base condensation of chiral amines and either pyridyl aldehydes or ketones and were independently developed in the labs of Camus, 88 van Kote n 89 and Brunner. 90 Figure 1 17 Typical pyridylimine type ligand Brunner and co workers 90 achieved up to 57% ee in the enantioselective hydrosilylation of acetophenone with dip henylsilane using the neutral Rh( I ) cod complexes of pyridylimine ligand 1. 11 3a (R = H) as precatalyst.

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50 Scheme 1 29 Asymmetric hydrosilylation of acetophenone. The section above reviews just some of the more important typ es of nitrogen donor ligands with a special emphasis on salen type ligands and some examples of the asymmetric reactions they can affect. The cited examples are in no way a comprehensive review which should be taken as evidence to the breadth and depth of contributions in this area. Self Assembling Ligands in Asymmetric Catalysis Catalysis lies at heart of synthetic chemistry and provides a highly atom economical method for the conversion of basic chemicals into more useful and valuable commodity chemicals. At a time when the careful management of resources has become more important than ever, the use of efficient catalysts to accelerate and control chemical transformations will become increasingly important. The field of catalysis is often segregated in to one of several categories, homogenous catalysis (including organocatalysis), heterogeneous catalysis and biocatalysis. While these fields have grown and made considerable achievements in the past few decades, the area of supramolecular chemistry has also become quite well established In contrast, the development of chemistry at the interface between catalysis and supramolecular chemistry 91 has only recently started to gain momentum. Supramolecular catalysis often focuses on either the use of non covalent interactions for the recognition of substrate molecules or for the self assembly of more complex

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51 ligand architectures from simple pre cursors containing functional groups programmed for recognition in solution. This approach to catalysis is not without i ts challenges. The prediction of how these interactions occur (and to what extent) is difficult and often highly dependent on intrinsic factors associate d with reaction conditions such as solvent polarity, concentration and the reactants or products themse lves. However, if these factors can be successfully controlled, highly efficient catalysts that exhibit superior levels of selectivity are possible. In this section, catalysts that use self assembly in the construction of their ligand architecture will be reviewed. Self assembling Catalysts Based on Secondary Metal C oordination With respect to biocatalysis, enzymes are capable of incredible rate accelerations ed in a synthetic system. For example, carbonic anhydrase, a metalloprotein whose active site contains a Zn(II) cation, rapidly reacts CO 2 with water to form bicarbonate as a means to regulate physiological pH and to help transport CO 2 out of the body This transformation i s carried out at a rate of 10 6 reactions/ min! 92 In light of these impressive systems, considerable effort has been placed on mimicking the catalytic environment provided by enzymes. While the exact nature of rate acceleration provided by enzymes is under de bate, it is believed that electronic and structural features within the active site stabilize the transition state to an extent that facilitates rapid conversion of the substrate molecules. As a result, much of the efforts focused on supramolecular catalys is are centered on encapsulating reaction partners or the active site itself to increase the local concentration of reactants and/or confer some structural constraints that selectively

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52 favor one reaction product over another. The application of secondary m etal coordination as a structural feature of these catalysts has seen considerable use. Ligands that possess two different metal binding motifs have been widely employed for forming supramolecular bidentate ligands. The major limitation for this approach i s the compatibility between the two different ligating groups, which have to coordinate two different metals in the presence of one and other. One metal has to play an exclusively structural role while the other remains catalytically active for the reactio n of choice In many examples, the catalytic metal is played by soft transition metals such as rhodium or palladium, while harder metals such as zinc or titanium play a structural role. P N ligands are often employed for their respective affinities for sof t and hard metals respectively. A common feature of self assembled ligands based on this coordinative bonding are three component systems containing two heterobidentate ligands non covalently linked to a metal template (Figure 1 18 ). Figure 1 18 Three component supramolecular bidentate ligands involving a template. Reek and co workers reported one of first supramolecular bidentate ligands based on this template approach in 2003. 93 Pyridyl phosphite bidentate ligands cont aining a BINOL chiral backbone were used to support the catalytically active Rh(I) center while the pyridine nitrogen coordinated to the zinc porphyrin template. This catalyst ( 1. 11 6 )

PAGE 53

53 gave only modest enantioselectivity but was highly selective for the br anched product in the hydroformylation of styrene. Scheme 1 30 H eterobiden tate ligand on dimeric zinc( II ) porphyrin Reek and co workers later reported a template induced supramolecular ligand involving a bis zinc( II ) s alphen template and P N heterobidentate ligands ( 1.1 20 ) similar to those above. This catalyst was reported to give up to 78% ee in the hydroformylation of styrene. 94 Reek and co workers also used a combinatorial approach to develop supramolecular bidentate ligands in the absence of a template. Instead, these catalysts relied on the interaction between a free pyridyl phosphine and a chiral phosphite covalently tethered to a zinc porphyrin ( 1. 120 ). A library of the new bidentate ligands were screened in a vari ety of reactions, including the Rh catalyz ed hydrogenation of

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54 enamide 1.1 21 which gave the unsaturated amide 1.12 2 with 100% conversion and 94% ee. 95 Figure 1 19 Self assembling heterobiden tate ligand on bis zinc( II ) s alphen template. In 2004, Takacs and co workers reported an alternative approach to chiral supramolecular bidentate ligands where the structural metal is chelated by modular bis(oxazoline) ligands to form stable tetrahedral zinc( II ) complexes ( 1.12 6 ) 96 The differentiating bifunctional ligands contain chiral TADDOL phosphites for binding the second catalytically active metal. The modularity of these supramolecular catalysts allowed for the screening of 50 ligands for various asymmetric reactions. Screening th e ligands for the palladium catalyz ed asymmetric allylic amination gave enantioselectivities between 20% and 97% ee.

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55 Scheme 1 31 Rh catalyz ed hydrogenation of enamide Scheme 1 31 Supr amolecular complex for Pd catalyz ed allylic amination and Rh catalyz ed olefin hydroboration. The same library was also screened in the Rh catalyzed asymmetric hydroboration of olefins. 97 These catalysts showed good to excellent regioselectivity for the bra nched product and high enantioselectivity (up to 96% ee).

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56 In 2003 Mirki n and co workers 98 reported the development of functionalized salen structures capable of binding a secondary metal center through P S ligation. Unlike previous metal here is used as the structural element while the The development of these catalysts was born from the observation of enzymes whose activity is altered by an allosteric effector. These effectors bind to locat io ns other than the active site causing a conformational change that alters the enzymes activity. 99 It was reported th 1.131 a displayed a 20 fold rate increase over the analogous monomeric Cr(III)Cl salen ( 1.5f ) in the asymmetric addition of TMSN 3 to cyclohexene oxide. After treatment with bis(triphenylphosphine)iminium chloride (PPNCl) and CO (1 1.131 b ) it gave a 40 fold rate increase over monomer 1.5f While enantioselectivity was impro ved over the monomer (68% vs. 12% ee) at the given concentration, it was lower than what has been previously In the following year, Mirkin 100 previously report ed macrocyclic salen catalyst, did not contain a site for additional metal chelation on one side ( 1.133 and 1.134 ). Instead, they were replaced with simple tertiary butyl groups, increasing the complexes solubility to a range of solvents known to yield rin g opened products in higher % ee. As predicted, asymmetric ring opening of cyclohexene oxide with TMSN 3 with the Cr(III)Cl salen 1.133a

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57 Figure 1 20 Macrocyclic alloste ric salen catalyst. Interestingly, while both outperform the monomeric catalyst 1.5f the selectivity 1.133a 1.133b ) is not as dramatic as one might expect. What is dramatic, however, is the differenc e in reaction rate in situ catalysts controlled by allosteric effectors.

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58 Figure 1 21 Hinged allosteric salen catalyst. The previously descri bed examples generally rely on two equivalents of a bifunctional ligand, capable of coordinating to both a templating metal as a structural element and a second catalyticall y active metal. Lin and co workers 101 developed an interesti ng variation that incorporates three equivalents of bi functional ligand to create the sides of a triangular supramolecular catalyst creating a chiral, catalytic pocket in the center In this case, the structure while Ti(O i Pr) 4 acts as the harder Lewis acid supported by the BINOL oxygen s. Trimer 1. 13 5 in the presence of Ti(O i Pr) 4 catalyzes the asymmetric addition of Et 2 Zn to se veral aromatic aldehydes with high conversion and high levels of selectivity.

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59 Scheme 1 32 Asymmetric addition of Et 2 Zn to aryl aldehydes. While the previously discussed examples were focused on the phenomena of ligand te mplating and/or insulating or encapsulating a catalytic active site, there are still other approaches in which self assembly is used to create reversible, encapsulating Raymond and co workers 102 have developed the chiral tetr ahedral [M 4 L 6 ] 12 coordination cage consisting of four metal ions and six bis bidentate catechol amide ligands. Four metal ions are situated at the corners of the tetrahedron and the ligands create the edges of the tetrahedron. The chelation by three biden tate ligands renders the metal atoms chiral ( ), and the coupling between the metals through those ligands results in exclusive formation of the homochiral assemblies and A guest template molecule (such as NR 4 + where R = Me, Et, Pr) is needed during the assembly process to achie ve the desired stoichiometry with a tetrahedral shaped cage. The negatively charged tetrahedral cage is soluble in water and other polar solvents. The anionic character of the cage allows for the encapsulation of

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60 monocationic guests such as alkylammonium i ons and cationic organometallic complexes. Figure 1 22 Tetrahedral coordination cage. Many self assembled, cage type capsules have been developed to create either concentrated local environments and/or impart some struct ural constraints on encapsulated substrate molecules for enhanced selectivity. One of the more common challenges in these systems is product inhibition. In these cases, the product molecule is better stabilized within the capsule than the substrate molecul es themselves. This problem often requires stoichiometric amounts of these structures. While still able to impart selectivity to certain reactions, these cannot truly be defined as catalysts. In 2009 Raymond and co workers 103 reported the use of their deve loped supramolecular cage i n the catalytic asymmetric aza C ope rearrangement of enammonium substrates. In this remarkable example, the chiral but racemic mixture of 1. 13 9 and 1. 13 9 was first separated using ion exchange chromatography. Due to its anionic nature, en a mmonium cations are suitable molecules for encapsulation and once inside the capsule, a reactive conformation is enfor ced. The

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61 cavity itself bears no other sites for coordination or reactive functional groups. As it may be expected, this encapsulation approach is highly substrate specific, giving low to modest yield and enantioselectivity in several cases A t reduced temperatures and elongated reaction times en ammonium 1. 13 7 was rearranged then hydrolyzed to aldehyde 1. 13 8 in moderat e yield and good enantioselectivity. Scheme 1 33 Asymmetric aza C ope rearrangement. Figure 1 23 A za Cope rearrangement within a supramolecular cage The examples described in this se ction are only a few of the more important developments in coordination driven self assembly as applied to asymmetric catalysis.

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62 Equally important are those developments in ligand self assembly driven by hydrogen bonding. Self Assembling Catalysts Based on H ydrog en B onding The use of hydrogen bonds for the construction of supramolecular ligands is a highly practical approach. The functional groups capable of hydrogen bonding such as amides, ureas and guanidines are attractive since they tend to be stable an d easy t o install. The hydrogen bonds themselves are self repairing, controllable and/or reversible in the reaction medium and can often co exist with other interactions. The first example of ligands designed specifically for self assembly through hydrogen bonds to form bidentate ligands was reported by Breit and Seiche in 2003. 104 The 2 pyridone ( 1.141 a )/2 hydroxypyridine ( 1.141 b ) tautomer system was employed as a dynamic scaffold (Scheme 1 3 4 ). The parent system (where D = H) is known to dimeriz e in aprotic solvents to form predominantly the symmetrical pyridone dimer 1 1 40 However, is a donor atom capa ble of binding to a metal center such as phosphine, the equilibrium can be shifted towards the mixed hydroxypyridine/pyridone dimer 1. 1 42 Scheme 1 34 T automer system of 2 pyridone/2 hydroxypyridine B rner, Breit and co workers later reported the synthesis of several derivatives of these tautomeric pyridones bea ring a chiral phosphine (Figure 1 24 ) 105 106 107 The self

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63 as sembled rhodium complexes were employed for catalyzing the enantioselective hydrogenation of several prochiral olefins with high enantioselectivity (up to 99% ee). All of the ligands capable of self assembly were found to be superior to O alkylated analogu es, demonstrating the benefit of self assembly. R 1 R 2 ee(%) H NHAc up to 91% Ph NHAc up to 94% H CH 2 CO 2 Me up to 99% Figure 1 24 Self assembling pyridine based ligands for the Rh catalyz ed hydrogenation of olefins. U sing 2 pyridone as a scaffold has its limitations. The complexes gener ated can only be homodimers as a result from the equilibrium between 1.141 a and 1.141 b If two different ligating functionalities were to be introduced to the 2 pyridone unit, a mixture of homo and heterodimers would be formed. Reminiscent of the hydrogen bonding network of nucleobase pairs in DNA, Breit and co workers selected an A T base pair model, relying on the aminopyridine 1. 14 7 and i soquinolone 1. 14 8 to create the heterodimeric ligand assembly seen in Scheme 1 35. 108 When phosphine ligands based on this platform were mixed in the presence of a Pt( II ) salt, the cis heterodimeric platinum complex 1. 14 9 was formed exclusively. The X

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64 ray structure of 1. 14 9 showed the expected Watson Cr ick type two point binding interactions of A and T in DNA. Scheme 1 35 H eterocomplexes formed by a minopyr idine/isoquinolone interaction. The major advantage of these heterodimeric complexes is the ability to structurally modify both the 2 amino pyridine and the 2 pyridone subunits to generate large combinatorial libraries for the rapid screening and identification of optimal pairs for a selected reaction. For example, a Rh(I) complex was found supported by 2 aminopyridine 1.153 c and 2 pyridone 1.154 c that catalyzed the hydroformylation of terminal alkenes (Figure 1 25) with outstanding activity (TOF = 8643 h 1 ) and regio selectivity (linear:branched= 96: 4). Later, Breit and co workers 109 reported that the self assembly strat egy relying on aminopyridine/isoquinolone interactions was also effective for the enantioselective Rh catalyz ed hydrogenation of prochiral olefins. Several chiral P ligands bearing either the aminopyridine or the isoquinolone moiety were synthesized and co mbined to form Rh heterocomplexes that gave high enantioselectivity in the hydrogenation of acetamidoacrylate with a remarkable catalyst loading of only 0.01 mol% (Scheme 1 36).

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65 Figure 1 25 Regioselective hydroformylatio n of 1 octene using heterocombinations. Scheme 1 36 Rhodium catalyzed hydrogenation of acetamidoacrylate. W rnmark and co workers 110 reported a unique heterobimetallic supramolecular catalyst containing a manganese salen subunit paired with a zinc porphyrin subunit hydrogen bonded by complementary 2 pyridone/isoquinolone groups. This system was designed with the intent to selectively recognize nitrogen containing olefins by the zinc porphyrin subunit for catalytic epoxida tion. While the difference in selectivity was not great, it was still noticeable in competition experiments.

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66 Scheme 1 37. Catalytic epoxidation by self assembling heterobimetallic system. Exploiting the 2 aminopyridine/2 pyridone type interactions, Hong and co workers 111 developed Co(II)salen catalysts functionalized with nucleobase mimics also designed to self assemble in solution. Yamada 112 and the Skarzewski 113 had previously reported the use of simple salen ligands for the a symmetric Henry reaction in the presence of base. It was reasoned that this reaction may provide a good model system for these new self assembling catalysts. The newly developed catalysts were in fact found to catalyze the asymmetric nitro aldol (Henry) re action between substituted benzaldehydes and nitromethane in excellent yield and enantioselectivity. Evidence for self assembly was also provided by similar 1 H NMR experiments that allowed for the calculation of a dimerization constant estimated as 53 21 M 1 by using nonlinear curve fitting methods. Single crystals suitable for X ray diffraction were grown from the Ni(II) complex of 1.16 5 and clearly show a well organized dimer formed from the two point hydrogen bonding between the amino pyridine and pyrid one functional groups.

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67 Scheme 1 38 Asymmetric nitro aldol (Henry) reaction catalyzed by s elf assembling Co(II)salen Figure 1 26 X ray crysta l structure of Ni(II)salen showing dimeric structure. Reek and co workers developed a new class of chiral urea functionalized phosphite 114 ( 1. 16 8 ) and phosphoramidite 115 ligands ( 1.1 71 ) called UREAphos, capable of self assembly in the presence of a rhodium precursor to give the supramolecular homocomplexes. These catalysts relied o n the self complementary hydrogen bonding between urea functional groups. Rhodium complexes of UREAphos ligands were screened in the enantioselective hydrogenation of traditional substrates giving high

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68 conversion and % ee while other, more challenging, in dustrially relevant olefins such as 1. 16 6 and 1. 16 9 gave lower conversions but in good % ee (Scheme 1 39) Sc heme 1 39 Structure and application of selected UREAphos ligands. In 2006, Ding and co workers 116 reported a new class of phosphoramidite ligands (DpenPhos, 1. 17 4 ) for the enantioselective hydrogenation of several unsaturated esters (Scheme 1 40 ). Interestingly, when the phosphoramidite nitrogen is tertiary and thus lacking a hydrogen bond donor group, it become s totally inactive. This observation emphasizes the role that hydrogen bonding plays for these systems. DFT calculations carried out on the Rh complex of a simplified structural mimic of 1. 17 4 allowed some insight to the structure of the pre catalytic comp lex featuring two hydrogen bonds between the adjacent phosphoramidite ligands.

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69 Gennari, Piarulli and co workers 117 reported a new class of ligands capable of self assembling by means of self complementary amide hydrogen bonds. These ligands (PhthalaPhos) owe their chirality to a BINOL derived phosphite backbone possessing a phthalic acid bis amide moiety which can act as both hydrogen bond donor and acceptor. Scheme 1 40 Hydrogen bonded phosphoramidite ligands applied in th e [Rh] catalyzed asymmetric hydrogenation. A library of ligands were prepared whose rhodium complexes showed good enantioselectivity and high conversion in the asymmetric hydrogenation of commonly employed olefins such and N (1 phe nylvinyl)acetamide 1. 17 5 (up to 99% ee ). Outstanding levels of enantioselectivity and conversion were also observed in the hydrogenation of challenging substrates (Scheme 1 41) such as the cyclic enamide 1. 17 7 (up to 96% ee). S pectroscopic (NMR, IR and HRMS) studies were carried o ut on a representative PhthalaPhos ligand and on its Rh complex. Interestingly, w hile no intramolecular hydrogen bonds were detected in the free ligand, the NH A group is intramolecularly hydrogen bonded in the metal complex. C omputational studies

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70 including conformational analysis followed by DFT optimization of the most stable structures, gave insight into the nature of the pre catalytic complex [Rh(L) 2 (cod)] + and was found to be consistent with the spectroscopic data (Figure 1 27 ) Scheme 1 41 Example of a PhthalaPhos ligand and the application to the asymmetric hydrogenation of olefins. Figure 1 27 PhthalaPhos ligands: structure of the pre catalytic complex [Rh(L) 2 (cod)] + Hong and c o workers 118 recently developed bis urea functionalized salen catalysts that are capable of self assembly in solution to form multimetallic systems from simple monomeric species. Various substituti ons to the terminal aryl group o f the urea function

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71 were synt hesized in an attempt to find a catalyst with superior rate acceleration. Salen catalyst 1. 181 was shown to be highly efficient in the HKR reaction with terminal epoxides with a reaction rate more than 13 times faster relative to the parent monomeric Co(II I)OTs salen catalyst. This self assembling catalyst showed an impressive substrate scope (11 examples) showing greater than 98% ee and good conversions with catalyst loadings as low as 0.03 mol%. Scheme 1 42 Selected ex ample of HKR reactions usi ng self assembling catalyst Evidence of self assembly was provided in a variety of forms. Changes in the stretching frequencies of urea protons involved in H bonding were measured with IR. Stretching frequencies associate d with H bonds disappeared with increasing catalyst concentration; while frequencies associate d with hydrogen bonded N H groups appeared. A similar effect could be observed with increasing catalyst concentration using 1 H NMR and X ray crystal packing al so clearly showed the interaction of urea functional groups. Indirect methods were also used to support the concept of self assembly, such as determination of the reaction order in terms of catalyst and observed rate deceleration

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72 when the urea nitrogens are methylated, thus removing the ability to self assemble. The development and success of these catalysts demonstrate the utility of self assembly as a viable alternative to covalently tethered multimetallic systems. Figu re 1 28 Proposed mechanism of self assembly to enforce bimetallic cooperation. This section highlights some of the more important developments in ligand ligand interactions driven by hydrogen bonding for use in asymmetric catalysis. These contributions d emonstrate the utility of this strategy toward achieving better, more efficient catalysts for a variety of practical applications.

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73 CHAPTER 2 NEW N N LIGANDS FOR ASYMMETR IC CATALYSIS Asymmetric Nitro Aldol Reaction Background The nitroaldol (Henry) reactio n constitutes an important C C bond formation th at nitroalcohols produced contain at least one newly formed stereogenic center and are valuable intermediates in the construction of syntheti cally important building blocks. 119 120 121 122 The value of these reaction products has prompted the development of a number of successful asymmetric variants including organocatalysts 123 124 125 126 and numerous Lewis acid catalysts employing metals such as lanthanides, 127 128 129 130 Cr(III), 131 132 133 Co(II), 134 135 136 137 Zn(II) 138 139 140 141 Cu(I), 142 143 144 145 146 147 and Cu(II) 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 Of the Lewis acids described, copper in particular h as found considerable attention due in part to its availability, low toxicity and ease in handling. The Cu metal center is often sup ported by nitrogen based chiral ligands bearing amine, 142 146 147 148 149 150 151 152 153 154 155 156 imine (or pyridine), 145 157 158 oxazoline, 144 159 163 oxazolidine, 143 162 or imidazoline 16 0 161 moieties. Recently, we developed synthetic routes to isoquinoline based chiral diaminocarbenes via Bischler Napieralski cyclization and several chiral diimines such as compounds 2. 1 164 and 2. 3 165 were prepared as precursors to those carbenes (Figure 2 1). The literature precedence of imine containing ligands used in the asymmetric Henry reaction, as well as our experience in this reaction 134 144 led us to question whether the isoquinoline based imine ligands ( 2.1 and 2.3 ) could be effective in the

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74 enantioselective Henry reaction. Reported here are the applications of isoquinoline based chiral diimines in the Cu(II) catalyzed asymmetric Henry reaction. Figure 2 1 Isoquinoline based chiral carbene ligands Results and Discussion Scheme 2 1 summarizes a concise synthesis of various isoquinoline based diimines ( 2. 1 and 2. 3 ) from the phenethylamine precursors ( 2. 5a d ). C 2 symmetric dii mines ( 2. 1a d ) 164 as well as a C 1 symmetric diimine ( 2. 3a ) 165 were prepared by the procedures previously reported by our group. The isoquinoline based diimine ligands were evaluated in the copper catalyzed Henry reaction of nitromethane and 4 nitrobenzaldehyde (Table 2 1). C 2 symmetric, i Bu substituted diimine ( 2. 1a ) gave higher enantioselectivity than structurally related C 1 symmetric diimine ( 2. 3a ) (entry 2 vs entry 1). When the R group in C 2 symmetric diimines was varied, more sterically demanding substituents resulted in lower enantioselectivity and longer reaction time ( i Bu ~ CH 2 Cy > i Pr >> t Bu, entries 2 5). Thus, the best result was obtained using the C 2 symmetric diimine with the i Bu substituent ( 2. 1a ), affording nitroaldol product 2. 10a in 89 % yield and 77% ee after 24 h. Attempts were made to further optimize the reaction conditions by changing the Lewis acidic metal and the solvent (Table 2 2).

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75 Scheme 2 1 Synthesis of isoquinoline containing chiral imine ligands. Reagents and conditions: a) oxalyl chloride, Et 3 N, THF, 0 C to rt, 12 h. b) PCl 5 Zn(OTf) 2 toluene, 85 C, 12h. c) EDC, HOBt, rt, 12 h. d) Tf 2 O, DMAP toluene, 90 C, 8 h. e) 2,6 diisopropylaniline, TiCl 4 Et 3 N, toluene, rt, 12 h. Table 2 1. Nitro aldol l igand survey entry a ligand time (h) yield(%) b ee (%) c 1 2. 3a (R = i Bu) 48 84 11 2 2. 1a (R = i Bu) 24 89 77 3 2. 1b (R = CH 2 Cy) 24 90 75 4 2. 1c (R = i Pr) 48 90 65 5 2. 1d (R = t Bu) 48 48 5 a All reactions were performed on a 0.5 mmol scale at a 0.4 M concentration. Reactions were run at room temperature in a screw capped vial for the indicated time. b V alues are isolated yields after

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76 chromatographic purification. c Enantiomeric excess was determined by HPLC using Chiralpak IB column. Replacing Cu(OAc) 2 with other divalent metal acetates such as Ni(OAc) 2 or Zn(OAc) 2 resulted in lower enantioselectivity ( entry 1 vs. entries 2 3). Pr otic solvents (EtOH or i PrOH) proved to be better than aprotic solvents (THF or CH 2 Cl 2 ), giving higher yield and % ee (entries 1 & 4 vs entries 5 6). These results led us to retain our originally selected conditions (entry 1) as optimal. W e then sought to explore the scope of the reaction (Table 2 3) In gen eral, high enantiomeric excess (75 93% ee) was observed at room temperature with various substrates. Table 2 2 Optimization of reaction conditions entry a Lewis acid solvent yield (%) b ee (%) c 1 Cu(OAc) 2 H 2 O EtOH 89 77 2 Ni(OAc) 2 4H 2 O EtOH 91 30 3 Zn(OAc) 2 2H 2 O EtOH 64 0 4 Cu(OAc) 2 H 2 O i PrOH 84 72 5 Cu(OAc) 2 H 2 O THF 59 40 6 Cu(OAc) 2 H 2 O CH 2 Cl 2 38 54 a All reactions were performed on a 0.5 mmol scale at a 0.4 M concentration. Reactions were run at room temperature in a screw capped vial. b Values are isolated yields after chromatographic purification. c Enantiomeric excess was determined by HPLC using Chiralpak IB or Whelk O 1 column s While yields were depressed in some cases, additional reaction time was not found to improve those yields. It was observed however that increasing the catalyst loading to 10 mol% could improve the yield without loss of selectivity (entry 2). Ortho, m eta and para substituted benzaldehydes gave uniformly good enantiomeric excess

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77 (77 93% ee, entries 3 11). It is interesting to note that the substrate scope is not limited to benzaldehydes, as cinnamaldehyde was an effective substrate, affording nitro aldo l product 2.10k in 75% ee (entry 12). Table 2 3. Nitroaldol s ubstrate scope entry a R product yield (%) b ee (%) c 1 Ph 2. 10b 55 91 2 d Ph 2. 10b 80 90 3 2 MeO C 6 H 4 2. 10c 57 77 4 2 Cl C 6 H 4 2. 10d 87 90 5 2 F C 6 H 4 2. 10e 52 93 6 3 F C 6 H 4 2. 10f 51 91 7 4 F C 6 H 4 2. 10g 59 90 8 4 Cl C 6 H 4 2. 10h 78 88 9 4 NO 2 C 6 H 4 2. 10a 89 77 10 4 Ph C 6 H 4 2. 10i 78 81 11 1 Naphthyl 2. 10j 68 87 12 PhCH=CH 2. 10k 50 75 a All reactions were performed on a 0.5 mmol scale at a 0.4 M concentration. Reactions were run at room temperature in a screw capped vial. b Values are isolated yields after chromatographic purification. c Enantiomeric excess was determined by HPLC using Chiralpak IB or Whelk O 1 columns. d 10.0 mol % l % of ligand 2. 1a were used The X ray structure of 2.1a PdCl 2 shed some light on unique structural features of the isoquinoline based C 2 symmetric diimines. The i Bu substituent takes the axial position on the six membered azacycle that is folded into a boat like conformation. In addition, helical (or axial) chirality seems to exist owing to the severe steric repulsion

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78 between two phenyl rings. 2.1a PdCl 2 shows P helicity (or axial chirality) as well as S stereogenic centers. Figure 2 2 X ray structure of 2.1a PdCl 2 Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (), angles ( ), and torsion angles ( ): Pd N1: 2.0095(18), N1 C1: 1.302 (3), N1 Pd N1A: 79.32(7), N1 C1 C1A: 113.9(2), Pd N1 C1 C1A: 11.1(2), C2 C1 C1A C2A: 25.1(3). 1,2 Boronic Acid Addition Background Organoboron reag ents are very attractive amongst other organometallic reagents for their low toxicity, functional group tolerance and stability towards air and moisture. 166 167 168 169 The addition of aryl organoboron reagent s to aldehydes has received considerable attention as a powerful C C bond forming reaction and provides access to diaryl alcohols, a structural motif found in compounds with reported activity as antimuscarinics, 170 an tidepressants, 171 and endothelin antagonists. 172 While examples

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79 of Rh(I) catalyzed addition of organoboron reagents to aldehydes are known, 173 174 175 176 177 178 less attention has been paid to the Pd(II) catalyzed transformation. 179 180 181 182 It has been shown that cationic Pd(II) complexes of 2,2 bipyridine (BIPY ) cata lyzed the 1,2 addition of aryl boronic acids to aryl aldehydes. 183 Seeing our li gand family as relatives to BIPY we wished to survey our BIQ ligands in this reaction Results and Discussion In general, yields are low to moderate and were poor for several differently substituted BIQ ligands. More sterically congested ligands (entry 2 vs. entry 1) resulted in significantly lower yields. Table 2 4. 1,2 Addition of aryl boronic acids to aryl a ldehydes Entry a Ligand R Product Pd(II) Yield (%) b ee (%) c 1 2.1a p NO 2 C 6 H 5 2.12a Pd(OAc) 2 76 15 2 2.1e p NO 2 C 6 H 5 2.12a Pd(OAc) 2 33 13 3 2.1b p NO 2 C 6 H 5 2.12a Pd(OAc) 2 63 10 4 2.1d p NO 2 C 6 H 5 2.12a Pd(OAc) 2 n.r. d 5 2.1a p NO 2 C 6 H 5 2.12a Pd(CF 3 CO 2 ) 2 61 15 6 2.1a p NO 2 C 6 H 5 2.12a Pd(CH 3 CN) 4 (BF 4 ) 2 52 7 7 2.1a 1 Naphthyl 2.12b Pd(OAc) 2 37 0 8 2.1a 2 Naphthyl 2.12c Pd(OAc) 2 31 0 a All reactions were performed on a 0.3 mmol scale at a 1.0 M concentration. b Values are isolated yields after chromatographic purification. c Enantiomeric excess was determined by HPLC using Chiralpak IB column d n.r. = No reaction

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80 Pd(II) sources with more weakly coordinating counter ions were used in hope of providing a more accessible palladium c enter to increase activity, however, we found the opposite to be true (entries 5 and 6). More sterically demanding naphthaldehydes (entries 7 and 8) were found to be much more sluggish and resulted in a complete erosion of stereoselectivity. Summary In su mmary, a series of chiral isoquinoline based imine ligands are conveniently prepared through Bischler Napieralski cyclization. i Bu substituted, C 2 symmetric diimine ligand 2.1a is effective in Cu(II) catalyzed enantioselective Henry reactions between nitr omethane and various aldehydes (12 examples), showing 50 89% yield and 75 93% ee. The application of these ligands in the Pd(II) catalyzed 1,2 addition of phenyl boronic acid to substituted benzaldehydes suffered from sluggish reactivity, low selectivity and a narrow range of substrates. The development of these ligands mark a significant addition to the diverse range of chelating N,N donor ligands for asymmetric catalysis. Their relative ease of synthesis, structural modularity and unique structural featu res make them a valuable addition to the tools available for a variety of important asymmetric transformations. Experimental All reactions were conducted in flame dried glassware under an inert atmosphere of dry argon unless otherwise specified. THF, CH 2 C l 2 CH 3 CN and Et 2 O were passed through two packed columns of neutral alumina under positive pressure of argon prior to use. All other chemicals used were commercially available and were used as received without further purification. NMR spectra were record ed using a n FT NMR machine, operating at 300 MHz for 1 H NMR and at 75.4 MHz for 13 C NMR. All chemical shifts for

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81 1 H and 13 C NMR spectroscopy were referenced to Me 4 1 H and 13 C or residual signals from (CDCl 3 1 13 C. High resolution mass spectra were recorded on a DIP CI MS spectrometer, an APCI TOF spectrometer, an ESI TOF spectrometer, or a TOF LC/MS spectrometer Specific o ptical rotations were obtained on a JASCO P 2000 Series Polarimeter (wavelength = 589 nm). Enantiomeric ratios were determined by chiral HPLC analysis (Shimadzu) using Chiralpak IB and (S,S) Whelk O 1 column s or by Chiral GCMS analysis (Shimad zu) using an Astec CHIRALDEX TM column (G TA) with helium as the carrier gas. Substituted benzaldehydes were purchased from Sigma Aldrich and used without further purification. Known compounds have been identified by comparison of spectral data ( 1 H NMR and 13 C NMR) with those previously reported. Synthesis and Characterization of Reported MIQ and BIQ L igands ( S ) 1 Cyclohexyl 3 phenylpropan 2 amine (2.5b) Synthesis of ( S ) N (1 cyclohexyl 3 phenylpropan 2 yl) 4 methylbenzenesulfonamide. To a suspension of Cu I (0.276 g, 1.45 mmol) in THF (5.0 mL), PhMgCl solution (2.0 M in THF, 4.8 mL, 9.6 mmol) was slowly added at 30C. After 30 min stirring at 30C, (S) 2 (Cyclohexylmethyl) 1 toluenesulfonylaziridine (1.42 g, 4.84 mmol) was added. The reaction temperature was slowly increased to room temperature for 3 h. The reaction was cautiously quenched by a saturated aqueous NH 4 Cl solution (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic mixture w as dried over anhydrous MgSO 4 filtered, and concentrated under reduced pressure. The residue was filtered through a column of silica gel with EtOAc as an eluent to afford the sulfonamide. 164

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82 ( S ) 1 Cyclohexyl 3 phenylpropan 2 amine (2.5b) To a suspension of Li (0.50 g, 72 mmol) in THF (30 mL) under argon, naphthalene (50 mg, 0.39 mmol) was added at room temperature. After 30 min, the solution turned dark blue. ( S ) N (1 cycl ohexyl 3 pheny lpropan 2 yl) 4 methylbenzenesulfonamide was added at 78C, and the reaction temperature was slowly warmed to room temperature. After 12h, the solution was transferred through a canula to another flask to remove the remaining Li. The solutio n was quench ed by a saturated aqueous NH 4 Cl solution (50 mL) and rinsed with water (100 mL). To the organic solution was added 1 M HCl aqueous solution (15 mL), and the organic layer was discarded. To the acidic aqueous solution was added 20% NaOH aqueous solution (20 mL). The aqueous layer was extracted by Et 2 O (3 x 20 mL) and was dried over anhydrous MgSO 4 filtered, and concentrated under reduced pressure to aff D 23 = 9.7 (c 0.27, CHCl 3 ); 1H NMR (300 MHz, CDCl 3 ) 7.39 7.02 (m, 5H), 3.10 (br. s, 1H), 2.78 (dd, J = 4.3, 13.3 Hz, 1H), 2.41 (dd, J = 8.8, 13.5 Hz, 1H), 1.89 0.71 (m, 13H); 13 C NMR (75 MHz, CDCl 3 ) 140.0, 129.5, 128.6, 126.3, 49.9, 45.9, 45.5, 34.7, 34.4, 33.2, 26.9, 26.6, 26.5. HRMS (ESI) calcd for C 15 H 23 N (M+H) + : 218.1903; found : 218.1906.

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83 Bis(( S S ) 1 cyclohexyl 3 phenylpropan 2 yl)oxalamide (2.6b) To a cooled, magnetically stirred solution of ( S ) 1 c yclohexyl 3 phenylpropan 2 amine ( 2. 5b ) ( 90.2 mg, 0.415 mmol) and triethylamine (65 L, 0.46 mmol) in THF (5.0 mL) under argon, oxalyl chloride (17.6 L, 0.202 mmol) was added dropwise at 0C. The reaction mixture was allowed to warm to room temperature and was then stirred for 12h. The reaction mixture was cooled to 0 C before quenching with water (10 mL). The mixture was extracted with CHCl 3 (3 x 15 mL). The combined organic extracts were dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 3:1 chloroform/hexane) to afford the oxalamide (90.1 mg, 0.184 mmol, 92% yi D 23 = 21.9 (c 0.29, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) 7.33 7.10 (m, 1 2 H), 4.32 4.11 (m, 2H), 2.78 (d, J = 6.4 Hz, 4H), 1.89 1.49 (m, 12H), 1.43 1.05 (m, 11H), 1.01 0.63 (m, 4H); 13 C NMR (75 MHz, CDCl 3 ) 159.4, 137.7, 129.6, 128.6, 126.7, 48.7, 41 .9, 41.6, 34.5, 34.0, 32.8, 26.7, 26.4, 26.3. HRMS (ESI) calcd for C 32 H 44 N 2 O 2 (M+Na) + : 511.3295; found : 511.3308. ( S, 3 'S ) 3,3' Bis(cyclohexylmethyl) 3,3',4,4' tetrahydro 1,1' biisoquinoline (2.1b) To a solution of N,N Bi s(( S ) 1 cyclohexyl 3 phenylpropan 2 yl)oxalamide ( 2. 6b ) (0.450 g, 0.921 mmol) in toluene (45 mL) under nitrogen was added Zn(OTf) 2 (1.00 g, 2.76 mmol) and PCl 5 (1.15 g, 5.52 mmol). The reaction mixture was heated at 85C for 12h and then was cooled to room temperature before quenching with a 30% aqueous

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84 NH 4 OH solution (20 mL). The mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over MgSO 4 filtered, and concentrated under reduced pressure. Purification of the crude pro duct by flash column chromatography (silica gel, 5:1 hexanes/EtOAc) afforded the biisoquinoline (0.380 g, 0.839 mmol, 91% yield) D 23 = 12.9 (c 0.37, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) 7.44 7.04 (m, 8H), 3.98 3.75 (m, 2H), 2.93 (dd, J = 5.6, 15.8 Hz, 2H), 2.64 (dd, J = 11.1, 15.8 Hz, 2H), 1.98 1.48 (m, 16H), 1.38 1.06 (m, 6H), 1.06 0.75 (m, 4H); 13 C NMR (75 MHz, CDCl 3 ) 164.0, 13 7.5, 131.1, 128.6, 128.0, 127.1, 126.9, 54.5, 43.5, 34.6, 34.1, 33.3, 31.6, 26.9, 26.6. HRMS (ESI) calcd for C 32 H 40 N 2 (M+H) + : 453.3264; found : 453.3286. ( R ) 3,3 Dimethyl 1 phenylbutan 2 amine (2.5d) 9 3 % 22 = 48.6 (c 0.88, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) 7.35 7.27 (m, 2H), 7.25 7.18 (m, 3H), 2.98 (dd, J = 2.3, 13.3 Hz, 1H), 2.69 (dd, J = 2.4, 10.9 Hz, 1H), 2.21 (dd, J = 11.0, 13.3 Hz, 1H), 1.00 (s, 9H); 13C NMR (75 MHz, CDCl 3 ) 141.3, 129.4, 128.7, 126.3, 62.3, 39. 0, 34.5, 26.6. HRMS (ESI) calcd for C12H19N (M+H) + : 178.1590; found : 178.1582. Bis(( R ) 3,3 dimethyl 1 phenylbutan 2 yl)oxalamide (2.6d) 80% 22 = 36.3 (c 0.54, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) 7.21 7.00 (m, 12H), 3.86 (td, J = 2.8, 11.0 Hz, 2H), 3.01 (dd, J = 2.8, 14.2 Hz, 2H), 2.36 (dd, J = 11.3, 14.2 Hz, 2H), 0.97 (s,

PAGE 85

85 18H); 13 C NMR (75 MHz, CDCl 3 ) 159.5, 138.8, 129.0, 128.5, 126.4, 60 .1, 36.6, 35.1, 26.7. HRMS (ESI) calcd for C 26 H 36 N 2 O 2 (M+Na) + : 431.2669; found : 431.2671 (3 R ,3' R ) 3,3' Di tert butyl 3,3',4,4' tetrahydro 1,1' biisoquinoline (2.1d) 82% 22 = 204.8 (c 0.62, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) 7.49 (d, J = 7.9 Hz, 2H), 7.35 7.27 (m, 2H), 7.24 7.11 (m, 4H), 3.23 (dd, J = 5.0, 15.1 Hz, 2H), 2.86 2.56 (m, 4H), 1.09 (s, 18 H); 13 C NMR (75 MHz, CDCl 3 ) 163.2, 139.1, 130.5, 128.9, 127.7, 127.5, 126.5, 66.4, 34.3, 27.1, 26.9. HRMS (ESI) calc d for C 26 H 32 N 2 (M+H) + : 373.2638; found : 373.2639 Dichloro [ (3 S ,3' S ) 3,3' diisobutyl 3,3',4,4' tetrahydro 1,1' biisoquinoline] palladium(II) (2.1a PdCl 2 ) To a solution of 1a (0.205 g, 0.550 mmol) in toluene (3 mL), PdCl 2 (C H 3 CN) 2 (0.130 g, 0.500 mmol) was added, and the solution was stirred at room temperature for 12 h. The precipitated product was filtered and washed with hexanes D 23 = 702.5 (c 0.43, CHCl 3 ); 1 H NMR (300 MHz ,CDCl 3 ) 7.55 (m, 2 H), 7.34 (d, J = 7.4 Hz, 2H), 7.13 (m, 2H), 6.86 (d, J = 7.6 Hz, 2H), 5.04 4.86 (m, 2H), 3.26 3.06 (m, 2H), 3.04 2.84 (m, 2H), 2.11 1.87 (m, 2H), 1.67 1.40 (m, 2H), 1.00 (d, J = 6.8 Hz, 6H), 0.91 0.80 (m, 2H), 0.78 (d, J = 6.5 Hz, 6H); 13 C NMR (75 MHz,

PAGE 86

86 CDC l 3 ) 170.9, 135.7, 134.4, 129.4, 129.2, 126.8, 126.7, 56.4, 35.1, 29.3, 25.9, 24.2. Anal. calcd for C 26 H 32 Cl 2 N 2 Pd: C, 56.79; H, 5.87; N, 5.09. found: C, 57.00; H, 6.00; N, 5.01 General Procedure for Enantioselective Henry Reaction To a 3.0 mL screw cap v ial, a magnetic stir bar and ligand (0.025 mmol) were added followed by absolute EtOH (1.25 mL). After the ligand was fully dissolved, Cu(OAc) 2 2 O (4.99 mg, 0.025 mmol) was then added and allowed to stir at room temperature for 1 h. CH 3 NO 2 was then added (0.27 mL, 5.0 mmol) followed by aldehyde (0.50 mmol) and allowed to stir for the indicated time. The reaction mixture was purified by flash column chromatography on silica gel and the enantiomeric ratios were determined by chiral HPLC analysis (Shimadzu) u sing Chiralpak IB and ( S,S ) Whelk O 1 columns. Characterization of Nitroaldol Adducts ( S ) 2 Nitro 1 (4 nitrophenyl)ethanol (2.1 0 a) 1 H NMR (300 MHz, CDCl 3 8.44 (m, 2 H), 7.62 (d, J = 8.2 Hz, 2 H), 5.53 5.76 (m, 1 H), 4.47 4.71 (m, 2 H), 3.17 3.47 (m, 1H); 13 C NMR (75 MHz, CDCl 3 Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85 : 15 hexane s : isopropanol, 1 .0 mL/min, 254 nm); t R (minor) = 12.87 min., t R (major) =14.47 min; 77% ee. Configuration assignment: a bsolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literature data 134 144

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87 ( S ) 2 Nitro 1 phenylethanol (2.1 0 b) 1 H NMR (300 MHz, CDCl 3 7.43 (m, 5H), 5.42 (dd, J = 9.3, 1.8 Hz, 1H), 4.59 (ddd, J = 13.2, 9.6, 0.9 Hz, 1 H), 4.49 (ddd, J = 13.5, 3.0, 0.9 Hz, 1 H), 2.91 (s, 1H); 13 C NMR (75 MHz, CDCl 3 126.6, 81.9, 71.6; HRMS (DART) calcd for C 8 H 13 N 2 O 3 [M+NH 4 ] + : 185.0921. Found 185.0918. Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85 : 15 hexane s : isopropanol, 0.8 mL/min, 215 nm); t R (minor) = 8.94 min, t R (major) = 9.82 min; 91% ee. Configuration assignment: a bsolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literature data 134 144 ( S ) 1 (2 Methoxyphenyl) 2 nitroethanol (2.1 0 c) 1 H NMR (300 MHz, CDCl 3 ppm 7.27 7.36 (m, 2 H), 6.86 6.96 (m, 2 H), 5.40 (d, J = 9.6 Hz, 1 H), 4.60 (dd, J = 12.7, 9.1 Hz, 1 H) 4.47 (dd, J = 13.3, 3.1 Hz, 1 H), 3.80 (s, 3 H), 2.80 (d, J = 2.3 Hz, 1 H); 13C NMR (75 MHz, CDCl 3 .3, 130.4, 127.5, 114.6, 81.5, 70.9, 55.6; HRMS (DART) calcd for C 9 H 10 NO 4 [M H] + : 196.0615. Found 196.0608. Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85 : 15 hexane s : isopropanol, 0.8 mL/min, 215 nm); t R (minor) = 8.64 min; t R (major) = 9.32 min; 77% ee. Configuration assignment: a bsolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literature data 134 144

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88 ( S ) 1 (2 Chlorophenyl) 2 nitroethanol (2.1 0 d) 1 H NMR (300 MHz, CDCl 3 (d, J = 6.8 Hz, 1 H), 7.23 7.41 (m, 3 H), 5.83 (td, J = 9.3, 2.5 Hz, 1 H), 4.66 (dd, J = 13.6, 2.5 Hz, 1 H), 4.44 (dd, J = 13.3, 9.3 Hz, 1 H), 3.24 (br s, 1 H); 13 C NMR (75 MHz, CDCl 3 CI) m/z calcd for C 8 H 8 ClNO 3 [M] + : 201.0193. Found: 201.0208.Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O 1 column (95 : 5 hexane s : isopropanol, 1 .0 mL/min, 215 nm); t R (minor) = 8.53 min; t R (major) = 9.39 min; 90% ee. Configuration assignm ent: a bsolute configuration of major isomer was determined to be (S) by comparison of the retention time with literature data. 134 144 ( S ) 1 (2 Fluorophenyl) 2 nitroethanol (2.1 0 e) 1 H NMR (300 MHz, CDCl 3 7.54 (td, J = 7.6, 1.8 Hz, 1 H), 7.28 7.42 (m, 1 H), 7.15 7.25 (m, 1 H), 7.01 7.15 (m, 1 H), 5.64 5.79 (m, 1 H), 4.50 4.68 (m, 2 H), 3.26 (br s, 1 H); 13 C NMR (75 MHz, CDCl 3 ppm 159.6 (d, J CF = 246.2 Hz), 130.7 (d, J CF = 8.3 Hz), 127.8 (d, J CF = 3.7 Hz), 125.1 (d, J CF = 3.4 Hz), 116.7 (d, J CF = 21.5 Hz), 116.0 (d, J CF = 21.2 Hz), 80.0 (d, J CF = 2.0 Hz), 65.7 (d, J CF = 2.9 Hz); HRMS (DART) m/z calcd for C 8 H 7 FNO 3 [M H] + : 184.0415. Found 184.0411. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O 1 column (95 : 5 hexane s : isopropanol, 0.8 mL/min, 215 nm); t R (major) = 10.6 min; t R (minor) = 11.5 min; 93% ee. Configuration assignment: a bsolute configuration of major isomer was determined to be ( S ) by comparison of the retention time w ith literature data 134 144

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89 ( S ) 1 (3 Fluorophenyl) 2 nitroethanol (2.1 0 f) 1 H NMR (300MHz, CDCl 3 7. 45 (m, 1H), 7.10 7.21 ( m, 2H), 7.04 (td, J = 8.4, 2.5 Hz, 1H), 5.46 (dd, J = 8.8, 3.4 Hz, 1H), 4.43 4.64 (m, 2H), 3.11 ppm (s, 1H); 13 CF = 246.0 Hz), 140.8 (d, J CF = 6.8 Hz), 130.9 (d, J CF = 8.3 Hz), 121.7 (d, JCF = 3.0 Hz), 116.1 (d, J CF = 21. 0 Hz), 113.3 (d, J CF = 22.5 Hz), 81.2, 70.5 (d, J CF = 1.5 Hz); HRMS (DART) c alcd for C 8 H 26 FN 2 O 3 [M+NH 4 ] + : 203.0826, f 22 = 26.8 (c 0.26, CH 2 Cl 2 ); Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85 : 15 hexane s : i sopropanol, 1.0 mL/min, 215 nm); t R (minor) = 6.84 min; t R (major) = 7.42 min; 91% ee; Configuration assignment: a bsolute configuration of major isomer was determined to be ( S ) by analogy of the retention time with other products ( S ) 1 (4 Fluorophenyl) 2 nitroethanol (2.1 0 g) 1 H NMR (300 MHz, CDCl 3 ) 7.49 (m, 2 H), 7.00 7.20 (m, 2 H), 5.45 (d, J = 9.1 Hz, 1 H), 4.58 (dd, J = 13.5, 9.4 Hz, 1 H), 4.49 (dd, J = 13.2, 3.5 Hz, 1 H), 2.94 (d, J = 3.8 Hz, 1 H); 13 C NMR (75 MHz, CDCl 3 ) CF = 246.8 Hz), 134.1, 128.0 (d, J CF = 8.2 Hz), 116.2 ( d, J CF = 21.8 Hz), 81.3, 70.5; HRMS (DART) calcd for C 8 H 7 FNO 3 [M H] + : 184.0415. Found 184.0413. Enantiomeric excess was determined by HPLC with a Chiralpak IB column (90 : 10 hexane s : isopropanol, 1.0 mL/min, 215 nm); t R (minor) = 9.11 min; t R (major) = 9.97 min; 90% ee. Configuration assignment: a bsolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literature data 134 144

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90 ( S ) 1 (4 Chlorophenyl) 2 nitroethanol (2.1 0 h) 1 H NMR (300MHz, CDCl 3 7.27 7.47 (m, 4 H), 5.44 (dd, J = 9.1, 3.5 Hz, 1 H), 4.42 4.67 (m, 2 H), 2.99 ppm (s, 1 H); 13 C NMR (75 MHz, CDCl 3 136.8, 135.1, 129.5, 1 27.6, 81.2, 70.5; HRMS (DART) Calcd. for C 8 H 12 ClN 2 O 3 [M+NH 4 ] + : 219.0531, Found: 219.0527; Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85 : 15 hexane s : isopropanol, 1.0 mL/min, 254 nm); t R (minor) = 7.38 min; t R (major) = 8.15 m in; 88% ee. Configuration assignment: a bsolute configuration of major isomer was determined to be ( S ) by with literature data 144 151 152 ( S ) 1 (Biphenyl 4 yl) 2 nitroethanol (2.1 0 i) 1 H NMR (500 MHz, CDCl 3 7.69 (m, 4 H), 7.44 7.55 (m, 4 H), 7.38 7.42 (m, 1 H), 5.55 (d, J = 9.5 Hz, 1 H), 4.52 4.75 (m, 2 H), 2.86 ppm (br s, 1 H); 13 C NMR (75 MHz, CDCl 3 142.3, 140.5, 137.2, 129.1, 128.0, 127.9, 127.4, 126.7, 81.4, 71.1; HRMS (DART) Calcd. For C 14 H 17 N 2 O 3 [M+NH 4 ] + : 261.1234, Found: 261.1225; Enantiomeric excess was determined by HPLC with a (S,S) Whelk O 1 column (85 : 15 hexane s : isopropanol, 1.0 mL/min, 215 nm); t R (minor) = 8.53 min; t R (major) = 10.51 min; 81% ee. Configuration assignment: a bsolute configuration of major isomer was determined to be ( S ) by comparison with literature data 144 151 152

PAGE 91

91 ( S ) 1 (Naphthalen 1 yl) 2 nitroethanol (2.10j) 1 H NMR (300 MHz, CDCl3) 8.02 (d, J = 8.5 Hz, 1 H), 7.91 (d, J = 7.6 Hz, 1 H), 7.85 (d, J = 8.2 Hz, 1 H), 7.75 (d, J = 7.3 Hz, 1 H), 7.47 7.63 (m, 3 H), 6.23 (dd, J = 7.5, 4.3 Hz, 1 H), 4.58 4.70 (m, 2 H), 2.98 (s, 1 H); 13C NMR (75 MHz, CDCl3) 133.9, 133.7, 129.7, 129.6, 129 .5, 127.3, 126.3, 125.7, 124.0, 122.0, 81.0, 68.5; HRMS (DART TOF MS) Calcd. for C 12 H 10 NO 3 [M H] + : 216.0666, Found: 216.0658; Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85 : 15 hexane s : isopropanol, 1.0 mL/min, 215 nm); t R (m inor) = 8.15 min; t R (major) = 10.7 min; 87% ee. Configuration assignment: a bsolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literature data 134 ( S,E ) 1 Nitro 4 phenylbut 3 en 2 ol (2.1 0 k) 1 H NMR (500 MHz, CDCl 3 7.47 (m, 5 H), 6.83 (d, J = 15.9 Hz, 1 H), 6.13 6.22 (m, 1 H), 5.04 5.15 (m, 1 H), 4.50 4.62 (m, 2 H), 2.65 ppm (d, J = 4.5 Hz, 1 H); 13 C NMR (126 MHz, CDCl 3 134.0, 129.0, 128.8, 127.0, 125.1, 80.1, 69.9; HRMS (DART) calcd for C 10 H 15 N 2 O 3 [M+NH 4 ] + : 211.1077. Found 211.1077. Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85 : 15 hexane s : isopropanol, 0.8 mL/min, 215 nm); t R (minor) = 18.56 min; t R (major) = 17.16 min; 75% ee. Configuration assignment: a bsolute configuration of major isomer was determined to be ( S ) by comparison with literature data 138

PAGE 92

92 Crystal Structure Analysis of 2.1a PdCl 2 Data were collected at 173 K on a Siemens SMART PLATFORM equipped with a CCD area detector a ). Cell parameters were refined using up to 8192 reflections. A full sphere of data scan method (0.3 frame width). The first 50 frames were re me asured at the end of data collection to monitor instrument and crystal stability (maximum correction on I was < 1 %). Absorption corrections by integration were applied based on measured indexed crystal faces. T he structure was solved by the Direct Method s in SHELXTL6, 184 and refined using full matrix least squares. The non H atoms were treated anisotropically, whereas the hydrogen atoms were calculated in ideal positions and were riding on their respective carbon atoms. The asymmetric unit consists of a h alf complex (located on a two fold rotation symmetry element) and a dichloromethane molecule. A total of 168 parameters were refined in the final cycle of 6.40%, respectivel y. These data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif (CCDC 812994 ). The t hermal ellipsoid drawing (Figure 2 2 ) was produced using OLEX2. 185 Table 2 5 Crystal data and structur e refinement for 1a PdCl 2 Identification code 2.1a PdCl 2 Empirical formula C 28 H 36 Cl 6 N 2 Pd Formula weight 719.69 Temperature 173(2) K Wavelength 0.71073 Crystal system Tetragonal Space group P41212

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93 Table 2 5 continued. U nit cell dimensions a = 12.8898(3) = 90 b = 12.8898(3) = 90 c = 19.4625(9) = 90 Volume 3233.63(18) 3 Z 4 Density (calculated) 1.478 Mg/m 3 Absorption coefficient 1.090 mm 1 F(000) 1464 Crystal size 0.32 x 0.32 x 0.26 mm 3 range for data collection 1.89 to 27.49 Index ranges Reflections collected 18011 Independent reflections 3722 [R(int) = 0.0591] Completeness to = 27.49 100.0 % Absorption correction Integration Max. and min. transmission 0.7995 and 0.7030 Ref inement method Full matrix least squares on F 2 Data / restraints / parameters 3722 / 0 / 168 Goodness of fit on F 2 1.078 Final R indices [I>2 (I)] R1 = 0.0248, wR2 = 0.0640 [3615] R indices (all data) R1 = 0.0259, wR2 = 0.0646 Absolute structure param eter 0.03(3) Largest diff. peak and hole 0.447 and 3 General Procedure for Enantioselective 1,2 Addtion of Phenylboronic Acid In a thick walled high pressure tube the Pd(II) precursor was dissolved in CH 3 NO 2 Diimine ligand was then added and allowed to stir at room temperature for 30 min. Phenylboronic acid was then added and the mixture was stirred for another 30 min.

PAGE 94

94 The s ubstituted benzaldehyde was then added and the mixture heated to 80C with stirring for 24 h. The reaction mixture was then cooled to room temperature and purifi ed by flash column chromatography on silica gel. The enantiomeric ratios were determined by chiral HPLC analysis (Shimadzu) using Chiralpak IB column. (4 Nitrophenyl)phenylmethanol (2.12a) 1 H NMR (300 MHz, CDCl 3 ) 1H), 5.92 (s, 1H), 7.30 7.36 (m, 5H), 7.58 (d, J=8.8Hz, 2H), 8.19 (J= 8.8 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) Enantiomeric excess was determined by HPLC with a Chiralpak IA column (90 : 10 hexane s : isopropanol, 0.5 mL/min, 254 nm); t R (major) = 11.3 min; t R (minor) = 12.3 min; 15% ee. Naphthalen 1 yl(phenyl)methanol (2.12b) 1 H NMR (300 MHz, CDCl 3 (bs, 1H), 6.35 (s, 1H), 7.17 7.42 (m, 8H), 7.53 (d, J=7.2 Hz, 1H), 7.75 (d, J=9.6 Hz,1H), 7.80 (d, J=7.2 Hz, 1H), 7.95 (d, J=9.6 Hz, 1H). 13 C NMR (75 MHz, CDCl 3 ) 124.3, 124.9, 125.7, 125.9, 126.4, 127.4, 127.9, 128.8, 128.9, 129.1, 131.0, 134.2, 139.1, 143.4.

PAGE 95

95 Naphthalen 2 yl(phenyl)methanol (2.12c) 1 H NMR (300 MHz, CDCl 3 (bs, 1H), 6.04 (s, 1H), 7.29 7.56 (m, 8H), 7.66 (m, 1H), 7.83 7.93 (m, 3H). 13 C NMR (75 MHz, CDCl 3 ) 132. 9, 133.2, 133.3, 141.1, 143.6

PAGE 96

96 CHAPTER 3 NEW SELF ASSEMBLING LIGANDS F OR ASYMMETRIC CATALY SIS Meso epoxide opening Background The asymmetric ring opening of meso epoxides is a highly valuabl e reaction that affords two new contiguous chiral centers. The wid e variety of nucleophilic species that can be employed in this ring opening include sulfur, nitrogen, carbon, halide and oxygen and offer access to a multitude of ring opened products that serve as important synthetic building blocks. 186 187 188 It has been well established that catalytic hydrolysis of terminal epoxides by Co(salen) complexes shows a second order dependence on catalyst concentration. 189 190 The desymmetrization of meso epoxides with TMSN 3 by Cr(salen) complex also shows the same dependence 191 and it i s commonly believed that this kinetic phenomenon is general to metal salen catalyzed epoxide opening. In the proposed bimetallic mechanism, it is believed that one metal center acts as a Lewis acid to activate the epoxide, while the other serves as counter ion to the nucleophile. Both metals must also orient the reaction partners in the correct spatial alignment to afford the desired product in high enantioselectivity. 192 In response to these mechanistic insights, there has been significant interest in the dev elopment of catalysts that place multiple metal centers in close proximity to one ano ther. A common design element to some previously reported and highly successful systems for the hydrolytic kinetic resolution (HKR) of terminal epoxides focus on incorpora ting chiral ligands in to macromolecular scaffolds such as dimmers, 193 194 oligomers, 195 196 197 polymers, 198 199 200 201 202 203 204 dendrites, 205 colloids 206 and capsules. 207 208 through covalent bonds. While many of these systems afford ring opened products in high yield and

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97 enan tioselectivity, we envisioned a more modular system that could bring multiple metal centers in close proximity through non covalent hydrogen bonds. In this way, simple monomeric units can be synthesized that contain sites for hydrogen bonding, that in solu tio n will self assemble to form more structurally complex aggregates in order to organize the requisite metal centers. This approach allows for the rapid structural tailoring of monomeric units in terms of sterics and electronics, to suite the reaction con ditions or the manner in which we wish self assembly to occur. We have previously reported two generations of catalyst s based on this concept. The first generation catalyst ( 1.16 5 ) relied on hydrogen bonding between an amino pyridine and 2 pyridone on the periphery of an existing chiral salen ligand. 209 The design was intended to mimic the hydrogen bonding pattern between the nucleobases adenine and thymine, to form a well defined dimeric structure. The second generation ( 1. 1 81 ) replaced the existing H bondi ng motif with urea and offered much more flexibility in terms of steric and electronic tuning. 210 The installation of the urea motif also created a much more dynamic picture in terms of self assembly due to the self complementary nature of the urea hydrogen bond. The directional hydrogen bonding pattern of the urea functional group allows for the possibility of much higher order aggregates, even infinite two dimensional and three dimensional arrays. Because of their unique hydrogen bonding, ureas have been ex tensively employed as hydrogen bond donor/acceptors in the construction of varied supramolecular structures such as enantiodifferentiating organogels, 211 hydrogels, 212 opteoelectronics, 213 artificial micelles 214 and ion channels. 215

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98 The reported bis urea salen catal yst was found to kinetically resolve a broad scope of terminal epoxides in high yield and excellent % ee at very low catalyst loadings with co nsiderable rate acceleration versus monomeric salen catalyst. As expected, kinetic data revealed a second order de pendence on catalyst concentration. Other, both direct and in direct data, strongly suggested that hydrogen bonding was responsible for the observed rate acceleration. Intrigued by both the flexibility and capability of urea as a hydrogen bonding scaffold, we wished to see what effect would be had by repositioning the urea groups toward the center of the catalyst structure, essentially side (Figure 3 1) We proposed that by centralizing the two urea groups we could i ncrease the self assembly strength and suppress the possibility of a staggered self assembly that could arise in bis urea salen 1.181 In addition to its application in the resolution of terminal epoxides, our previously reported bis urea Co(salen) also ca talyzed the asymmetric hydrolysis of cyclohexene oxide. While outperforming the monomeric salen catalyst, we felt there existed room for improvement and saw this notoriously challenging reaction as a fitting target for our newly conceived design. Herein we wish to report a novel bis urea functionalized, bis Co(salen) catalyst for the desymmetrization of meso epoxides. Results and Discussion Catalyst Preparation. Similar to our previous design, the CH 2 spacer was used to connect the peripheral Co(salen) uni ts to the N,N disubstituted bis urea core. In order to study the influence of different linking units, several bis Co(salen) complexes were prepared. These complexes can be prepared in as few as six steps from inexpensive, commercially available materials Prior to the catalytic reactions, the Co(II) pre catalysts ( 3.8a g ) were oxidized to the active Co(III) species ( 3.8a g OTs ) by using 1.0

PAGE 99

99 equivalent (per equiv. of cobalt) of p TsOH ( p Ts= p toluenesulfonyl) in the open air. Bis urea dialdehydes 3.6a g we re conveniently prepared by the reaction of azide 3.4 with the corresponding isocyanates under catalytic hydrogenation conditions. 216 The unsymmetrical salen ligands were prepared using a standard protocol 217 where the chiral diamine 3.7 is first mono protecte d as the hydrochloride salt followed by condensation with 3,5 di tert butyl 2 hydroxybenzaldehyde. Figure 3 side urea (bis salen) catalyst. After the first condensation, the free amine was l iberated under basic conditions in the presence of bis urea dialdehydes 3.6 a g and 3 MS to afford the desired bis salen ligands. Although care was taken to remove adventitious water from the reaction, some disproportionation of the monoamine intermediate was still observed, giving the simple, symmetrical salen as by product. Finally, Co(II) complexes 3.8 a g were prepared from the reaction of Co(OAc) 2 2 O with the corresponding bis salen ligands in refluxing MeOH under an argon atmosphere (Scheme 3 1)

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100 Scheme 3 1. Synthesis of bis urea functionalized bis salen c atalyst We first sought to identify the optimal spacing unit for the bis urea moiety (Table 3 1). The initial reaction conditions chosen were based on those previo usly reported in our group for the hydrolysis of cyclohexene oxide. 218 The chosen spacing units consisted of alkyl, aryl and combinations thereof. While alkyl chains of both C 6 and C 12 gave encouraging enantioselectivities the yields were somewhat disappoin ting. The same trend was also observed for more flexible aryl spacers b earing methylene groups (entries 6 and 7). Interestingly, the 1,4 disubstituted aryl spacer (entry 3) also gave a similar result while 1,3 dis ubstituted aryl spacers (entries 4 and 5) w ere considerably improved in terms of both yield and selectivity and complex 3.8e (entry 5) was selected for further optimization. It was determined early on that bis urea catalyst 3.8e was already significantly more efficient than the corresponding monome ric catalyst ( 1.5c OTs: 9% yield & 45%

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101 ee) and slightly more efficient than our second generation bis urea catalyst 1.179 (63% yield & 75% ee) (Scheme 3 2). Table 3 1. Survey of spacing uni t on b is urea(bis salens) for epoxide hydrolysis Entry a R Complex yield( % ) b e e ( % ) e 1 (CH 2 ) 6 3.8a 38 72 2 (CH 2 ) 12 3.8b 43 76 3 3.8c 45 71 4 3.8d 69 81 5 3.8e 70 84 6 3.8f 38 74 7 3.8g 31 76 a All reactions were performed on a 0.5 mmol scale at a 5.0 M concentration. Reactions were run at room temperature in a screw capped vial. b Values are isolated yiel ds after chromatographic purification. c Enantiomeric excess was determined by GCMS using a Sup e lco G TA column. We were intrigued to find that the self assembling properties of the bis urea structural core of our newly designed catalyst had been extensive ly studied by Bouteiller and co workers. 219 220 221 Bouteiller had proposed that an equilibrium exists between three self It was also demonstrated that the direction in which the equilibrium lies between these s tructures could be shifted by the variation of conditions such as temperature, concentration and solvent. Since the nature in which self assembly occurs could have a p rofound effect on the outcome of

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102 the targeted ring opening reaction, we were eager to see if any similarities could be draw n between these two related systems. Scheme 3 2.Comparison vs. monomeric salen for epoxide hydroly sis. Figure 3 2 Prosposed equilibrium of EHUT described by Bouteiller. The choice of solvent was expected to play a significant role in both catalysis and self assembly and we felt it was important to observe those effe cts for a variety of

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103 solvent types (Table 3 2). Bouteiller had determined that at ambient temperature, non polar solvents favored the thic k filament structure while chlorinated solvents favored the thin filament structure. 219 220 We reasoned that the thin filament structure would place the metal centers at the appropriate distance while the thick filament structures would elongate the metal metal distance, disfavorin g a rapid or highly se lective pathway for asymmetric r ing opening. Both the catalyst mol% and reaction concentration were increased slightly in a desire to improve the reaction yield in the given time frame while screening various solvents. Chlorinated so lvents gave significantly lower yields but maintained an acceptable level of enantioselectivity. Coordinating solvents generally ga ve good yields and selectivities with the exception of CH 3 CN, although there was a notable decrease in selectivity when using MTBE under the newly chosen conditions. Surprisingly, a liphatic hydrocarbon solvent s gave higher yields but lower ee while aromatic hydrocarbon solvents provided a balance between good yield and selectivity. We wer e intrigued by both the efficiency in n on polar solvents and the decrease in selectivity in the case of MTBE under the more concentrated reaction conditions. To determine the extent the role of concentration played, toluene and benzene were selected to further study the effect of reaction and c atalyst concentration. In the cases where toluene or benzene was used, similar trends were observed in each with respect to catalyst concentration (Figure 3 3). In both solvents, the effect of lowering catalyst concentration resulted in lower substrate tur nover while the enantioselectivities remained consistently high.

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104 Table 3 2. Solvent screening with bis urea(bis salen ) Entry a Solvent yield(%) b ee( %) c 1 CHCl 3 24 78 2 CH 2 Cl 2 24 71 3 Et 2 O 85 74 4 THF 74 65 5 CH 3 CN 41 56 6 MTBE 76 70 7 None 53 63 8 Cyclohexane 68 81 9 Hexanes 85 69 10 Heptane 81 67 11 Benzene 84 83 12 Toluene 71 87 13 Xylenes 81 83 14 Mesitylene 77 83 a All reactions were performed on a 0.5 mmol scale at a 5.0 M concentration. Reactions wer e run at room temperature in a screw capped vial. b Values are isolated yields after chromatographic purification. c Enantiomeric excess was determined by GCMS using a Supel co G TA column. It has been observed that in ring opening reactions catalyzed by m ono meric salen complexes, decreasing catalyst loading is directly proportional to decreasing enantioselectivty 47 These observations are consistent with a competition between a second order, bimetallic pathway and a less selective monometallic pathway. In contrast, if our self assembled system behaved as if it were covalently linked, we would expect product ee to be independent of catalyst concentration as the highly selectively intermolecular pathway is enforce d.

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105 Figure 3 3 The effect of catalyst concentration on yield and selectivity. This observation suggests that even at lower catalyst concentrations, our system maintains its self assembled structure to enforce the more selective bimetallic pathway. De spite the marginally higher ee when toluene is used as solvent we felt the higher yield in benzene was worth the small sacrifice in enantioselectivity and was selected as our optimized solvent. As it has been previously noted, the car e ful choice of count er ion to the Co(III) center can have a considerable effect on substrate turnover. In general, non coordinating, weakly nucleophilic ions, such as sulfonates, are known to give superior results. In some cases, the choice of counter ion can also impact the enantioselectivity,

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106 although it is currently unclear why. A small series of substituted sulfonic acids were screened in order to fine tune our catalyst and bring it to a more competitive level with state of the art technology. Figure 3 4 Screening of sulfonate counter ions for Co(III) bis salen Compared to the originally selected tosyl sulfonate, other sulfonates gave either comparable or worse results terms of yield and selectivity As a result, the original tosyl sulf onate was retained as the counter ion of choice. G iven the general lack of literature precedent, we were intrigued to finally explore the substrate scope of this hydrolytic rin g opening. In contrast to the H K R of terminal epoxides or even the desymmetrizat ion of meso epoxides by other nucleophiles with metal salen catalysts, there is only one report of asymmetric hydrolytic ring opening of meso epoxides other than cyclohexene oxide. While investigating polymer bound Co(III) salen catalysts, Kim and co worke rs 222 found that simple Co(III)OAc salen was capable of hydrolyzing cyclopentene oxide in modest yield and moderate selectivity under neat conditions (Scheme 3 2)

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107 Scheme 3 3 Asymmetric hydrolysis of cyclopentene oxide by Kim and co workers A series of meso epoxides were selected of varying ring size, substitution and saturation to determine the scope of our catalyst. We were surprised to observe that in nearly all cases the yield was co nsistently poor over the series of s ubstrate s and simply resulted in un reacted starting material The enantioselectivity varied considerably though b eing as high as 89% (entry 1) or as low 43% (entry 6) The origin of this low turnover is present ly unclear as even epoxides whose ring opene d diol products are similar to 1,2 cyclohexane diol ( 3. 22 and 3.2 4 ) also give low yield. Some measures were explored in an effort to trap the diol products with various reagents such as boronic acids, acid chlorides or anhydrides all of which gave unsatis factory results. As a result, this problem is still under current investigation. While investigating the scope of the hydrolytic ring opening reactions we were also interested in applying our new ligand system to other ring opening reactions known to be c atalyzed by metallosalen catalysts such as the asymmetric addition of TMSN 3 to meso epoxides. As previously discussed, the asymmetric addition of TMSN 3 to meso

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108 seminal work on epoxide opening and was the reaction involved in much of the early multimeric salen chemistry. Table 3 3. Substrate sco pe with bis urea(bis salen) Entry Compound Number Epoxide a Product yield(%) b ee(%) c 1 3.15 3.16 16 89 2 3.17 3.18 nr d n/a 3 3.19 3.20 13 66 4 3.21 3.22 28 85 5 3.23 3.24 13 43 6 3.25 3.26 12 64 a All reactions were performed on a 0.5 mmol scale at a 5.0 M concentration. Reactions were run at room temperature in a screw capped vial. b Values are isolated yields after chromatographic purification. c Enantiomeric excess of the bis TFA ester was determined by GCMS using a Supelco G TA column. d nr = no reaction. It was our hope that we could contribute to the current method ologies by capitalizing on the unique strength of our self assembling design to create heterobimetallic catalysts simply by mixing different prepared metal salen catalysts. In this way, we sought to employ the demonstrated ability of Cr(III) to deliver the azide nucleophile while at the same time relying on Co(III) to activate the epoxide for nucleophilic attack. Cr(III)Cl bis urea(bis salen) 3.28 was prepared in a similar manner

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109 as the corresponding Co(III) bis urea(bis salen) complexes from ligands 3.7a g and evaluated under similar conditions that were selected for epoxide hydrolysis. catalyst(mixture) 3.28 (1:1) 3.28 : 3.8c 3.8c yield(%) 81 79 74 ee(%) 48 56 61 Scheme 3 4 Cr(III)Cl and Co(III)OTs complex mixtures for the ARO with TMSN 3 We were intrigued to discover that when Cr(III)Cl complex 3. 28 was used alone as the catalyst, the asymmetric addition of TMSN 3 proceeded in high yield but with only moderate % ee. A 1:1 mixture of the Cr(III)Cl complex and origina l Co(III)OTs complex 3.8e gave slightly lower yield but improved % ee. Unexpectedly, in the final scenario when 3.8e was used exclusively, yield was depressed further but enantioselectivity was improved further still. In general, chromium salen complexes are used in the delive ry of nitrogen nucleophiles while cobalt salen complexes are used for the delivery of oxygen nucleophiles. Examples of using cobalt for the delivery o f nitrogen nucleophiles are quite rare. 223 Although, from these result alone there is no way to determine the type of aggregation that forms in solution by the mixture and may simply be an average of the two independently acting catalysts.

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110 We were curious if further similarities existed between epoxide hydrolysis and the addition of azide i n terms of catalyst structure and chosen conditions. We returned to a screening of the central spacer as our first point of comparison. Table 3 4. Survey of spacing unit on bis urea(bis salens) for azide addition to epoxide Entry a R Complex yield(%) b ee( %) e 1 (CH 2 ) 6 3. 8 a 40 45 2 (CH 2 ) 12 3. 8 b 50 51 3 3. 8 c 60 49 4 3. 8 d 70 66 5 3.8 e 74 61 6 3. 8 f 51 42 7 3. 8 g 55 56 a All reactions were performed on a 0.5 mmol scale at a 5.0 M concentration. Reactions were run at room temperature in a screw capped vial. b Values are isolated yields of the azidoa lcohol after chromatographic purification. c Enantiomeric excess was determined by GCMS using a Supelco G TA column. It was observed that variation of the spacing unit for the addition of azide gave consistent results in terms of yield and selectivity for spacers of different t ypes. The alkyl spacers (entries 1+2) performed poorly under the given conditions while m ore ridged aryl spacers (entries 3 5) gave the best results. Spacers that contained both alkyl and aryl uni ts gave yields and selectivities betw een the two extremes. The symmetric

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111 1,3 phenylene linked catalyst 3.8 d gave the best resu lts in terms of enantioselectivity and was chosen for further optimization. A brief survey of reaction solvents was carried out and revealed that solvents more common to asymmetric epoxide opening b y metal salen catalysts (entries 2 4) proved to be superior in terms of yield and enantioselectivity. Table 3 5 Survey of spacing unit on bis urea(bis salens) for azide addition to epoxide. Entry a Solvent yield(%) b ee( %) c 1 CHCl 3 48 47 2 Et 2 O 71 76 3 THF 43 82 4 MTBE 70 81 5 Benzene 70 66 a All reactions were performed on a 0.5 mmol scale at a 5.0 M concentration. Reactions were run at room temperature in a screw capped vial. b Values are isolated yields of the azidoalcohol after chromatographic purification. c Enantiomeric excess was determined by GCMS using a Supel co G TA column. Due to the rarity of Co(III)salen catalyst used for the addition of nitrogen nucleophiles we were intere sted in our catalysts efficiency versus the monomeric Co(III)salen ( 1.5c OTs). Our catalyst was indeed mo re efficient, providing the azi d o alcohol from cyclohexene oxide ( 3.17 ) in 70% yield and 81 % ee while monomeric salen 1.5c OTs yielded less that 5% of the desired product in only 9% ee. Similar results were observed for a sm all range of substrates (Table 3 6). Increasing the catalyst loading to 1.0 mol% helped to increase our chemical yield and while we are encouraged by the current level of conversion and efficiency compared to the un functionalized monomeric parent metal sa len catalyst, the

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112 enantioselectivity is not yet to a competitive level with the current technology. Efforts to further improve this selectivity and expand the substrate scope are currently underway. Table 3 6 Substrate scope for e poxide desymmetrization b y TMSN 3 Entry a Catalyst Epoxide Product yield(%) c ee(%) d 1 3.8d 3.27 88 83 2 1.5 c 3.27 5 9 3 3.8d 3.28 73 68 4 1.5 c 3.28 3 0 5 3.8d 3.29 82 67 6 1.5 c 3.29 3 0 a All reactions were performed on a 0.5 mmol scale at a 5.0 M concentration. Reactions were run at room temperature in a screw capped vial. b Determined by GCMS using an internal standard. c Values are isolated yields of the azidoalcohol after chromatographic purification. d Enantiomeric excess was determined by GCMS using a Supel co G TA column. Meso Aziridine O pening Background Analogous to the value and synthetic utility of enantioenriched epoxides and their ring opened products, a ziridines and their ring opened products are equally valuable i ntermediates in organic synthesis. 224 225 In particular, vicinal diamines are extensively used as chiral auxiliaries and ligands and can also be found in anti cancer agents, anti influenza drugs, as well as many other biologically active compounds. Similar t o the chemistry associated with epoxides, access to optically active amines by nu cleophilic

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113 ring opening of ten requires either the use of enantiomerically enriched aziridines or enantioselective method s of ring opening the meso compounds. While researchers have developed many methods for the synthesis of these diamines, 226 one of the more direct methods for their synthesis is the ring opening of aziridines with nitrogen nucleophiles. 227 228 Methods for asymmetric aziridination have been well developed 229 but not u ntil more recently have methods been developed for the desymmetrization of the meso compounds using nitrogen nucleophiles In 1999, Jacobsen and co workers reported enantioselective ring opening of meso benzyl substituted aziridines with TMSN 3 using a chir al chromium complex of tridentate Schiff bases 230 Shibasaki and co workers have reported the use of chiral yttrium complexes for the desymmetrization of meso aziridines in route to the synthesis of Tamiflu. 231 232 In 2007, Antilla and co workers rep orted the e nantioselective ring opening of benzoyl substituted aziridines with chiral phosphoric acids. 233 I chiral tridentate Schiff base chromium complexes that le d us to consider if our internal bis urea approach could be applied to d evelop self assembling metal complexes as aziridine ring opening catalysts. Results and Discussion The construction of bis urea bis tridentate Schiff base lig ands is considerably more straightforward than the corresponding tetradentate bis salen ligands. The synthesis relies only on a single imine condensation from readily available chiral amino alcohols with our existing bis urea di aldehydes 3.6a c which were chosen for our preliminary screening (Scheme 3 6) In Jacobsen and co worker s report, 230 c hiral amino indanol in combination with sterically demanding ortho substituted salicaldehydes provided Schiff base ligands that gave the fastest rates and highest levels of enantioselectivity. E lectron deficient N

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114 benzyl substituted aziridines were opened in high conversion with goo d enantioselectivity (Scheme 3 7 ). Scheme 3 6 Synthesis of bis urea bis tridentate Schiff base ligands. Scheme 3 7 Example of asymmetric addition of TMSN 3 to N alkyl meso aziridine.

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115 It was also determined that the N substituent on the aziridine played an important role in terms of both rate and selectivity. Amide and carbamate substituted aziridines gave high conver sions but suffered from low selectivity while sulfonyl substituted aziridines were co mpletely un r e active under the selected conditions. For our preliminary screening, simple N benzyl and benzoyl substituted aziridines were chosen as model substrates. Under our conditions, bis urea catalysts with both alkyl ( 3.3 1a+b ) and aryl ( 3.31 c ) spacers were sluggish compared to the monomeric catalyst 3.3 4 requiring considerably longer reaction times to reach appreciable conversion. To our surprise, N benz yl substituted aziridines gave better yields than N benzoyl substituted aziridines. The ring opened azidoamide product ( 3.3 8 ) was found to be a racemic mixture of isomers. Unfortunately, enantiomers from the ring opened azidobenzylamine product ( 3.3 7 ) could not be resol ved via chiral HPLC, despite a variety of conditions and derivatization While initial results may have warranted further exploration, the inability to confidently analyze reaction products forced us to delay further study. Table 3 7 Preliminary screenin g of asymmetric aziridine ring opening. Entry a Aziridine R Complex yield(%) b ee( %) c Product 1 3.3 5 Bn 3.3 1a 97 n.d. d 3.3 7 2 3.3 5 Bn 3.3 1b 90 n.d. 3.3 7 3 3.3 5 Bn 3.3 1c 96 n.d. 3.3 7 4 3.3 6 Bz 3.3 1a 73 rac. 3.3 8 5 3.3 6 Bz 3.3 1b 73 rac. 3.3 8 6 3.3 6 Bz 3.3 1c 75 rac. 3.3 8 a All r eactions were performed on a 0.5 mmol scale at a 1.0 M concentration. b Values are isolated yields after chromatographic purification. c Enantiomeric excess was deter mined by HPLC using Chiralpak IA column. d n.d. = not determined.

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116 Summary Described here is the development of chiral tri and tetradentate dimeric Schiff base ligands, designed to self assemble in solution through hydrogen bonding provided by a bis urea scaffold. The concept of self assembly was introduced to create multinuclear transition metal complexes withou t the need for covalently linked supramolecular structures. These ligands were designed with the intent to provide an alternative to covalently linked supramolecular catalysts known to provide accelerated rates and high levels of stereoselectivity in asymmetric ring opening reactions. Bis urea, dimeric Co(III)salen catalyst 3.8e was found to be an efficient catalyst for the asymmetric hyd rolysis of cyclohexene oxide versus the m onomeric Co(III) salen catalyst, providing the trans diol in 84% yield and 83% ee with only 0.5 mol% catalyst under the optimized conditions. Interestingly the closely related bis urea Co(III)salen 3.8d was also found to be an efficient catalyst for the as ymmetric addition of TMSN 3 to cyclohexene oxide versus the monomeric Co(III)salen catalyst, providing the trans azidoalcohol with up to 88 % yield and 83% ee with only 1.0 mol% catalyst. The use of Co(III) catalysts for the delivery of nitrogen nucleophiles is quite rare. Currently, these self assembling catalysts fall just short in terms of efficiency compared to the more traditional, covalently bonded, supramolecular catalysts for the desymmetrization of meso epoxides by hydrolysis or by the addition of TM SN 3 In respect to the advantages over the covalently linked catalysts in terms of ease of synthesis and characterization the use of self assembly through hydrogen bonding in place of covalent bonds still provides a reasonable alternative to access multin uclear catalysts.

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117 At the present time, it is difficult to make any clear conclusions about the use of this bis urea architecture to construct self assembling tridentate Schiff base catalysts for the asymmetric ring opening of meso aziridines. Further optim ization of reaction conditions as well as better methods for the resolution of reaction products are needed if this chemistry is to be developed further. Experimental All reactions were conducted in flame dried glassware under an inert atmosphere of dry ar gon unless otherwise specified. THF, CH 2 Cl 2 CH 3 CN and Et 2 O were passed through two packed columns of neutral alumina under positive pressure of argon prior to use. All other chemicals used were commercially available and were used as received without furt her purification. NMR spectra were recorded using a n FT NMR machine, operating at 300 MHz for 1 H NMR and at 75.4 MHz for 13 C NMR. All chemical shifts for 1 H and 13 C NMR spectroscopy were referenced to Me 4 1 H and 13 C or residual signals fr om (CDCl 3 1 13 C. High resolution mass spectra were recorded on a DIP CI MS spectrometer, an APCI TOF spectrometer, an ESI TOF spectrometer, or a TOF LC/MS spectrometer. Enantiomeric ratios were determined by chiral HPLC analysis (Shimadzu) using Chiralpak IA, IB or by Chiral GCMS analysis (Shimadzu) using an Astec CHIRALDEX TM column (G TA) with helium as the carrier gas. Meso epoxides were purchased from Sigma Aldrich and used without further purification. Known compoun ds have been identified by comparison of spectral data ( 1 H NMR, and 13 C NMR) with those previously reported.

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118 Synthesis and Characterization of Bis Urea Bis Salen Ligands Compounds 5 234 6 and 7 235 were prepared according to known literature method. A represent ative procedure for the synthesis of bis ureas, bis salens and respective cobalt complexes are described below. 1, (4 Methyl 1,3 phenylene)bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3.6e) To a solution of 5 (azid omethyl) 3 tert butyl 2 hydroxybenzaldehyde (0.663 g, 2.84 mmol) in THF (50 mL) was added toluene 2,4 diisocyanate as a solution in THF (4 mL). A slurry of Pd/C (10%) in THF was added (3 mL) and the reaction mixture was then exposed to a atmosphere of H 2 v ia balloon and stirred vigorously for 18h. The reaction mixture was then diluted with THF (20 mL) and vacuum filtered over a pad of Celite. The solvent was then removed under reduced pressure and the crude solid dissolved in acetone and triturated with hex anes/Et 2 O to give a white solid (0.223 g, 48%) 1 H NMR (300 MHz, DMSO d 6 ) ppm 11.75 11.79 (m, 2 H) 9.94 10.00 (m, 2 H) 7.75 7.78 (m, 1 H) 7.51 7.58 (m, 4 H) 7.11 7.16 (m, 1 H) 6.93 7.01 (m, 2 H) 6.46 6.53 (m, 1 H) 4.23 4.30 (m, 4 H) 2.09 (s, 3 H)1.36 1.47 (m, 18 H); 13 C NMR (75 MHz DMSO d 6 ) ppm 198.5, 158. 8, 155.3, 155.2, 138.4, 138.0, 137.1, 133.4, 131.5, 131.3, 130.5, 130.4, 129.9, 120.3, 119.7, 112.0, 110.6, 42.2, 34.4, 29.1, 17.2; HRMS (APCI) calcd for C 33 H 40 N 4 O 6 [M+H] + : 589.3021, found 589.30307

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119 1,1' (Hexane 1,6 diyl )bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3.6a) (48%) 1 H NMR (300 MHz, DMSO d 6 6.26 6.32 (m, 2 H) 5.90 5.96 (m, 2 H) 4.16 (d, J =6.10 Hz, 4 H) 2.98 3.03 (m, 4 H) 2.48 2.52 (m, 4 H) 1.36 (s, 18 H) 1.25 (br. s., 1 H)1.25 (m, 4 H); 13 C NMR (75 MHz DMSO d 6 ppm 198.6, 158.8, 15 8.1, 137.0, 133.4, 132.1, 130.3, 120.3, 42.3, 34.4, 30.1, 29.1, 26.1; HRMS (APCI) calcd for C 32 H 46 N 4 O 6 [M+H] + : 583.3490, found 583.3484 1,1' (Dodecane 1,12 diyl)bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3.6b) ( 62%) 1 H NMR (300 MHz, DMSO d 6 ) ppm 11.73 (s, 2 H) 9.93 9.98 (m, 2 H) 7.47 (s, 4 H) 6.30 (s, 2 H) 5.89 5.95 (m, 2 H) 4.16 (dd, J =6.12, 0.09 Hz, 4 H) 2.92 3.02 (m, 4 H) 1.36 (s, 18 H)1.22 1.29 (m, 20 H); 13 C NMR (75 MHz, DMSO d 6 ppm 198.5, 158.8, 158.1, 137.0, 133.3, 132.1, 1 30.3, 120.3, 42.3, 34.4, 30.1, 29.1, 28.9, 26.4; HRMS (APCI) calcd for C 38 H 58 N 4 O 6 [M+H] + : 667.4429, found 667.4447 1,1' (1,4 phenylene)bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3.6c) ( 44%) 1 H NMR (300 MHz, DMSO d 6 7.52 (d, J =2.9 Hz, 11 H), 7.24 (s, 11 H), 6.52 (t, J =5.9 Hz, 4 H), 4.24 (d, J =5.8 Hz, 10 H), 1.36 ppm (s, 48 H); 13 C NMR (75 MHz, DMSO d 6 ) ppm 199.3, 159.5, 156.1, 137.8,

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120 135.0, 134.2, 132.2, 131.2, 1 21.0, 119.2, 42.8, 35.1, 29.7 HRMS (APCI) calcd for C 32 H 38 N 4 O 6 [M+H] + : 575.2864, found 575.2861; calcd for C 32 H 38 N 4 O 6 [M+Na] + : 597.2684, found 597.2679 1,1' (1,3 Phenylene)bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)ur ea) (3.6d) ( 79%) 1H NMR (300 MHz, DMSO 8.56 (m, 2 H) 7.52 7.57 (m, 4 H) 7.52 (br. s., 1 H) 6.95 7.08 (m, 3 H) 6.55 (s, 2 H) 4.26 (dd, J=6.04, 0.20 Hz, 4 H)1.38 (s, 18 H); 13C NMR (75 MHz, DMSO d6) ppm 198.5, 158.8, 155.1, 140.7, 137.1, 133.4, 131.4, 130.4, 128.7, 120.3, 110.8, 107.2, 42.1, 40.3, 34.4, 29.1, 22.7; HRMS (ESI) calcd for C 32 H 38 N 4 O 6 [M+Na]+: 597.2684, found 597.2702 1,1' (1,3 Phenylenebis(methylene))bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3.6f) (53%) 1 H NMR (300 MHz, DMSO d 6 ) ppm 11.74 (s, 2 H) 9.94 (s, 2 H) 7.49 (s, 4 H) 7.20 7.25 (m, 1 H) 7.08 7.14 (m, 3 H) 6.42 6.50 (m, 4 H) 4.21 (d, J =5.99 Hz, 8 H)1.37 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) ppm 198.4, 158.7, 158.0, 140.8, 137.0, 133.3, 131.9, 130.2, 128.1, 125.8, 12 5.2, 120.3, 43.0, 42.3, 34.4, 29.1; HRMS (APCI) calcd for C 34 H 42 N 4 O 6 [M+H] + : 603.3177, found 603.3170

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121 1,1' (4,4' Methylenebis(4,1 phenylene))bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3.6g) ( 30%) 1 H NMR (300 MHz DMSO d 6 ) ppm 11.76 (s, 2 H) 9.96 (s, 2 H) 8.47 (s, 2 H) 7.53 (d, J =2.48 Hz, 4 H) 7.29 (d, J =8.62 Hz, 4 H) 7.04 (d, J =8.62 Hz, 4 H) 6.55 6.59 (m, 2 H) 4.26 (d, J =5.84 Hz, 4 H) 3.75 (s, 2 H)1.37 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) ppm 198.7, 158.9, 155.3, 138. 3, 137.1, 134.4, 133.5, 131.4, 130.5, 128.8, 120.4, 117.9, 42.1, 34.4, 29.1; HRMS (APCI) calcd for C 39 H 44 N 4 O 6 [M+H] + : 665.3334, found 665.3355 1, (4 Methyl 1,3 phenylene)bis(3 (3 tert butyl 5 (( E ) ((1 R ,2 R ) 2 (( E ) 3,5 di tert butyl 2 hydroxybenzylideneamino)cyclohexylimino)methyl) 4 hydroxybenzyl)urea) (3.7e) A solution of (1 R ,2 R ) 1,2 cyclohexanediamine (0.133 g, 1.17 mmol) in absolute ethanol (6.0 mL) was cooled to 0 C via ice bath for 10 minutes. An HCl solution (2.0 M in Et 2 O) was then added drop wise (0.58 mL, 1.17 mmol) and allowed to stir for 1 h. 3 MS were then added (98.4 mg) followed by 3,5 di tert butyl 2 hydroxybenzaldehyde (0.274 g, 1.17 mmol) as a solution in absolute ethanol (6.0 mL) and allowed to stir for 3 h. A solution of 9e was then added (0.344 g, 0.585 mmol) in a (1:1) mixture of absolute ethanol and THF (6.0 mL) followed by triethylamine (0.33 mL. 2.34 mmol). The reaction was allowed to stir for another 18 h, slowly warming to room

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122 temperature. The r eaction mixture was then vacuum filtered over a pad of celite and the solvent then removed under reduced pressure. The crude residue was then purified by column chromatography on silica to give a yellow solid (0.298 g, 42%) 1 H NMR (300 MHz, DMSO d 6 ) ppm 14.10 14.13 (m, 2 H) 13.86 13.88 (m, 2 H) 8.45 8.49 (m, 4 H) 8.32 (s, 1 H) 7.72 (s, 1 H) 7.49 (s, 1 H) 7.20 7.23 (m, 2 H) 7.15 7.18 (m, 2 H) 7.07 7.13 (m, 5 H ) 6.89 (s, 1 H) 6.75 6.79 (m, 1 H) 6.25 6.29 (m, 1 H) 4.11 (d, J =5.84 Hz, 4 H) 3.40 (br.s., 4 H) 2.03 (s, 3 H) 1.88 1.92 (m, 4 H) 1.75 1.81 (m, 4 H) 1.63 (br.s., 4 H) 1.38 1.46 (m, 4 H) 1.31 (d, J =3.94 Hz, 36 H)1.18 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) ppm 166.4, 158.8, 158.8, 15 7.4, 155.1, 139.5, 138.5, 138.1, 136.3, 135.5, 129.9, 129.3, 129.0, 128.8, 128.6, 126.1, 119.2, 117.9, 117.9, 117.5, 71.3, 40.3, 34.5, 34.4, 33.7, 32.5, 31.2, 29.2, 29.1, 23.8, 17.2 HRMS (ESI) calcd for C 75 H 104 N 8 O 6 [M+H] + :1213.8152, found 1213.8153 1, ((4 Methyl 1,3 phenylene)bis (urido salen))cobalt (3.8e) A schlenk flask was charged with a magneti c stir bar, bis salen ligand 3.7e (0.203 g, 0.168 mmol) and Co(OAc) 2 2 O (83.6 mg, 0.336 mmol). The flask was evacuated then back filled with argon. MeOH (17 mL) was added and the flask was heated to 60 C with stirring for 18h. The reaction mixture was allowed to cool to room temperature and the solid collected by vacuu m filtration, washing with MeOH. The resultant solid was then re suspended in boiling MeOH, allowed to cool to room temperature and collected by

PAGE 123

123 vacuum filtration to give a deep red microcrystalline solid (0.142 g, 64%) HRMS (ESI) calcd for C 75 H 100 N 8 O 6 Co 2 [M] + :1326.6424, found 1326.6344; calcd for C 75 H 100 N 8 O 6 Co 2 [M] +2 : 663.3209, found 663.3200 1, ((4 Methyl 1,3 phenylene)bis (urido salen))cobalt (3.8e) A schlenk flask was charged with a magnetic stir bar, bis salen ligan d 3.7e ( 0.250 g, 0.21 mmol) and CrCl 2 ( 0.123 g, 50.6 mmol). The flask was evacuated then back filled with argon. THF ( 21 mL) was added and the flask was heat ed to 60 C with stirring for 3 h. The flask was then exposed to the atmosphere and allowed to stir over night. Hexane was then added (25 mL) and the solid collected by vacuu m filtration The resultant solid was triturated with THF and hexanes and collected by vacuum filtration to give a green solid (0. 210 g, 74 %) HRMS (ESI) calcd for C 75 H 100 N 8 O 6 ClCr 2 [ M Cl] + :1347.6266, found 1347.6290; calcd for C 75 H 100 N 8 O 6 ClCr 2 [M+4H Cl] + : 1351.6580, found 1351.5935 1,1' (Hexane 1,6 diyl)bis(3 (3 tert butyl 5 (( E ) ((1 R ,2 R ) 2 (( E ) 3,5 di tert butyl 2 hydroxybenzylideneamino)cyclohexyli mino)methyl) 4 hydroxybenzyl)urea) (3.7a) 1 H NMR (300MHz, DMSO d 6 ) ppm 14.06 (br. s., 2 H), 13.87 (br. s., 2 H), 8.47 (d, J =6.0 Hz, 4 H), 6.91 7.34 (m, 8 H), 6.08 (br. s., 2 H), 5.78 (br. s., 2 H), 4.03 (br. s.,

PAGE 124

124 4 H), 3.40 (br. s., 4 H), 2.96 (br. s., 4 H), 1.89 (d, J =10.4 Hz, 4 H), 1.80 (br. s., 4 H), 1.64 (br. s., 4 H), 1.44 (br. s., 4 H), 1.32 (d, J =4.5 Hz, 40 H), 1.18 ppm (br. s., 22 H); 13 C NMR (75 MHz, DMSO d 6 ) ppm 166.3, 165.8, 158.5, 157.9, 157.3, 139.4, 136.0, 135.4, 129.8, 128.5, 126.1, 117.7, 117.5, 71.3, 70.7, 42.6, 34.5, 34.3, 33.7, 32.5, 31.2, 30.0, 29. 2, 29.1, 26.1, 23.8; HRMS (ESI) calcd for C 74 H 110 N 8 O 6 [M+H] + :1207.8621, found 1207.8601 1,1' (Hexane 1,6 diyl)bis (urido salen))cobalt (3.8a) HRMS (ESI) calcd for C 74 H 106 N 8 O 6 Co 2 [M] + :1320.6894, found 1320.6885; calcd for C 74 H 106 N 8 O 6 Co 2 [M] +2 :660.3444, found 660.3471 1,1' (Dodecane 1,12 diyl)bis(3 (3 tert butyl 5 (( E ) ((1 R ,2 R ) 2 (( E ) 3,5 di tert butyl 2 hydroxybenzylideneamino)cyclohexylimino)methyl) 4 hydroxybenzyl)urea) (3.7b) 1 H NMR ( DMSO d 6 ,300MHz) ppm 13.99 (s, 2 H), 13.81 (s, 2 H), 8.40 (d, J =8.1 Hz, 4 H), 7.18 (d, J =1.9 Hz, 2 H), 7.06 (d, J =5.4 Hz, 4 H), 6.95 (s, 2 H), 6.02 (s, 2 H), 5.71 (s, 2 H), 3.97 (d, J =5.4 Hz, 4 H), 3.31 3.38 (m, 4 H), 2.90 (d, J =6.0 Hz, 2 H), 1.81 1. 86 (m, 2 H), 1.36 1.43 (m, 4 H), 1.22 1.32 (m, 44 H), 1.07 1.21 (m, 42 H); 13 C NMR (75 MHz, DMSO d 6 ppm 166.4, 165.8, 158.5, 157.9, 157.3, 139.4, 136.0, 135.4, 129.8, 128.4, 126.1, 117.7, 117.5, 71.3, 70.8, 42.6, 40.3,

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125 34.5, 34.3, 33.7, 32.6, 31.2 30.1, 29.2, 29.1, 28.9, 26.4, 23.8, 22.7; HRMS (ESI) calcd for C 80 H 122 N 8 O 6 [M+H] + :1291.9560, found 1292.9546 1,1' (Dodecane 1,12 diyl)bis (urido salen))cobalt (3.8b) 1 HRMS (ESI) calcd for C 80 H 118 N 8 O 6 Co 2 [M+H] + :1405.791 1, found 1405.7878; calcd for C 80 H 118 N 8 O 6 Co 2 [M] + :1404.7833, found 1404.7825; calcd for C 80 H 118 N 8 O 6 Co 2 [M] +2 :702.3914 found 702.3948 1,1' (1,4 phenylene)bis(3 (3 tert butyl 5 (( E ) ((1 R ,2 R ) 2 (( E ) 3,5 di tert butyl 2 hydroxybenzylideneamino)cyclohexylimi no)methyl) 4 hydroxybenzyl)urea) (3.7c) 1,1' (1,4 phenylene)bis (urido salen))cobalt (3.8c) HRMS (APCI) calcd for C 74 H 98 N 8 O 6 Co 2 [M+] + : 1312.6268, found 1312.6226 1,1' (1,3 Phenylene)bis (3 (3 tert butyl 5 (( E ) ((1 R ,2 R ) 2 (( E ) 3,5 di tert butyl 2 hydroxybenzylideneamino)cyclohexylimino)methyl) 4 hydroxybenzyl)urea) (3.7d) (0.182 g, 57%) 1 H NMR (300 MHz, DMSO d 6 ) ppm 14.09 14.15 (m, 2 H) 13.85

PAGE 126

126 13.90 (m, 2 H) 8.48 (d, J =3.07 Hz, 4 H) 8.36 (s, 2 H) 7.44 (s, 2 H) 7.22 (d, J =2.12 Hz, 2 H) 7.17 (s, 2 H) 7.11 (d, J =2.23 Hz, 2 H) 7.08 (s, 2 H) 6.98 7.05 (m, 1 H) 6.96 (s, 2 H) 6.93 (s, 1 H) 4.12 (d, J =5.15 Hz, 4 H) 3.37 3.47 (m, 4 H) 1.89 (s, 4 H) 1.80 (d, J =7.01 Hz, 4 H) 1.66 (d, J =7.05 Hz, 4 H) 1.37 1.52 (m, 4 H) 1.32 (d, J =4.24 Hz, 36 H)1.18 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ppm 166.4, 165.9, 158.7, 157.3, 154.9, 140.7, 139.4, 136.2, 135.4, 129.1, 128.6, 126.1, 117.8, 117.5, 110.6, 106.9, 71.2, 70.7, 42.4, 34.5, 34.3, 33.7, 32.5, 31.2, 29.2, 29.1, 23.8; HRMS (ESI) calcd for C 74 H 102 N 8 O 6 [M+Na] + :1221.7815, found 1221.7816 1,1' (1,3 Phenylene)bis (urido salen))cobalt (3.8d) HRMS (ESI) calcd for C 74 H 98 N 8 O 6 Co 2 [M] + :1312.6268, found 1320.6265; calcd for C 74 H 98 N 8 O 6 Co 2 [M] +2 :656.3131, found 656.3148 1,1' (4,4' Methylenebis(4,1 phenylene))bis(3 (3 tert butyl 5 (( E ) ((1 R ,2 R ) 2 (( E ) 3,5 di tert but yl 2 hydroxybenzylideneamino)cyclohexylimino)methyl) 4 hydroxybenzyl)urea) (3.7f) 1 H NMR (DMSO d 6 ,300MHz) ppm 14.11 (s, 2 H), 13.87 (s, 2 H), 8.47 (s, 4 H), 8.33 (s, 2 H), 7.15 7.32 (m, 8 H), 6.96 7.14 (m, 8 H), 6.38 (s, 2 H), 4.12 (d, J =5.2 Hz, 4 H ), 3.74 (s, 2 H), 3.39 (br. s., 4 H), 1.91 1.87 (s, 4 H), 1.78 (br. s., 4 H), 1.63 (br. s., 4 H), 1.37 1.50 (m, 4 H), 1.24 1.36 (m, 36 H), 1.13 1.21 (m, 18

PAGE 127

127 H); 13 C NMR (DMSO d 6 ppm 166.3, 165.9, 158.7, 157.3, 155.0, 139.4, 138.3, 136.2, 1 35.4, 134.2, 129.2, 128.7, 126.1, 126.1, 117.8, 117.7, 117.5, 71.3, 70.7, 42.4, 34.5, 34.3, 33.7, 32.5, 31.2, 29.2, 29.1, 23.8; HRMS (ESI) calcd for C 81 H 108 N 8 O 6 [M+H] + :1289.8465, found 1289.8491 1,1' (4,4' Methylenebis(4, 1 phenylene))bis (urido salen))cobalt (3.8f) HRMS (ESI) calcd for C 81 H 104 N 8 O 6 Co 2 [M] + :1402.6731, found 1402.6763; calcd for C 81 H 104 N 8 O 6 Co 2 [M] +2 :701.3366, found 701.3396 1,1' (1,3 Phenylenebis(methylene))bis(3 (3 tert but yl 5 (( E ) ((1 R ,2 R ) 2 (( E ) 3,5 di tert butyl 2 hydroxybenzylideneamino)cyclohexylimino)methyl) 4 hydroxybenzyl)urea) (3.7g) 1 H NMR (DMSO d 6 ppm 14.05 (s, 2 H), 13.85 (s, 2 H), 8.45 (d, J =6.6 Hz, 4 H), 7.21 (d, J =2.2 Hz, 2 H), 7.00 7.17 (m, 10 H ), 6.22 6.32 (m, 4 H), 4.16 (d, J =5.8 Hz, 4 H), 4.06 (d, J =5.6 Hz, 4 H), 3.33 3.45 (m, 4 H), 1.87 (d, J =13.5 Hz, 4 H), 1.75 (br. s., 4 H), 1.60 (br. s., 4 H), 1.36 1.50 (m, 4 H), 1.31 (d, J =3.5 Hz, 36 H), 1.17 (s, 18 H) 13 C NMR (75 MHz, DMSO d 6 pp m 166.4, 165.9, 158.6, 157.9, 157.4, 140.9, 139.5, 136.1, 135.5, 129.8, 128.47, 128.1, 126.1, 125.8, 125.2, 117.8, 117.5, 71.4, 70.7, 56.1, 42.7, 43.0, 34.5, 34.3, 33.7, 32.6, 32.5, 31.2, 29

PAGE 128

128 HRMS (ESI) calcd for C 76 H 106 N 8 O 6 [M+H] + :1227.8308, found 1227.827 1; calcd for C 76 H 106 N 8 O 6 [M+Na] + :1249.8128, found 1249.8135 1,1' (1,3 Phenylenebis(methylene))bis (urido salen))cobalt (3.8g) HRMS (ESI) calcd for C 76 H 102 N 8 O 6 Co 2 [M] + :1340.6581, found 1340.6569; calcd for C 76 H 102 N 8 O 6 Co 2 [ M] +2 :670.3288, found 670.3309 General Procedure fo r the Asymmetric Hydrolysis of M eso Epoxides Under air, a 3.0 dram vial was charged with a magnetic stir bar and Co(II)bis salen nd allowed to stir for 1 h. The solvent was then removed under vacuum and to the residue was added epoxide (0.50 mmol), followed by solvent (0.10 ml) and water (0.60 mmol, reaction mixture was loaded onto a plug of silica gel and sequentially eluted with acetate/acetone)] to give the desired 1,2 diol. The bis TFA ester derivative was prepared by addeing 0.2 mL TFAA to 5 mg product and allow to stand for 5 min. The volatiles were then removed under vacuum and the residue dissolve d in CH 2 Cl 2 (2.0 mL). The enantiomeric excess of the bis TFA ester was then determined by chiral GC (Astec Chiraldex TM G TA) or chiral HPLC (Chiralcel OJ H).

PAGE 129

129 (1 S ,2 S ) Cyclohexane 1,2 diol (3.10 ) 1 H NMR (300 MHz, CDCl 3 d ): ppm 3.77 (s, 2 H), 3.35 (br. s., 2 H), 1.91 2.02 (m, 2 H), 1.70 (d, J =2.2 Hz, 2 H), 1.26 ppm (br. s., 4 H); 13 C NMR (75MHz, CDCl 3 d (83% yield, 85% ee) Enantiomeric excess was determine d by chiral GCMS, G TA, 80 C, isothermal, t R (minor) = 10.8 min, t R (major) = 14.1 min. (1 S ,2 S ) cyclopentane 1,2 diol (3.16 ) 1 H NMR (300 MHz, CDCl 3 d ): ppm 3.92 4.22 (m, 2 H), 3.64 (br. s., 2 H), 1.91 2.07 (m, 2 H), 1.71 (m J =7.4 Hz, 2 H), 1.25 1.60 (m, 2 H); 13 C NMR (75MHz, CDCl 3 d ): ppm 79.3, 31.3, 19.7 (16% yield, 89% ee) Enantiomeric excess was determine d by chiral GCMS, G TA, 80 C, isothermal, t R (minor) = 4.5 min, t R (major) = 5.8 min. (1 S ,2 S ) cycloheptane 1,2 di ol (3.20 ) 1 H NMR (300 MHz, CDCl 3 d ): ppm 3.39 3.47 (m, 2 H), 3.25 (s, 2 H), 1.82 1.92 (m, 2 H), 1.61 1.71 (m, 2 H), 1.42 1.57 (m, 6 H); 13 C NMR (75MHz, CDCl 3 d ): ppm 78.1, 32.6, 26.6, 22.3 (13% yield, 66% ee) Enantiomeric excess was determine d by chiral GCMS, G TA, 50 C 100 C, ramp = 1C/min, t R (minor) = 39.3 min, t R (major) = 41.1 min.

PAGE 130

130 (1 S ,2 S ) cyclohex 4 ene 1,2 diol (3.22) 1 H NMR (300 MHz, Acetone d 6 ): ppm 5.38 5.61 (m, 2 H), 3.98 (br. s., 2 H), 3.4 5 3.66 (m, 2 H), 1.85 2.16 (m, 4 H); 13 C NMR (75MHz, Acetone d 6 ): ppm 125.4, 72.2, 34.1, 30.7, 30.4, 30.2, 29.9, 29.7, 29.4, 29.1 (28% yield, 85% ee) Enantiomeric excess was determine d by chiral GCMS,G TA, 80 C, isothermal, t R (minor) = 8.3 min, t R ( major) =11.0 min. (2 S ,3 S ) 1,2,3,4 tetrahydronaphthalene 2,3 diol (3.24) 1 H NMR (300 MHz, Acetone d 6 ): ppm 7.03 7.10 (m, 4 H), 4.13 (s, 2 H), 3.74 3.84 (m, 2 H), 3.07 3.15 (m, 2 H), 2.66 2.77 (m, 2 H); 13 C NMR ( 75MHz, Acetone d 6 ): ppm 134 .7, 128.8, 125.9, 71.4, 36.4 (13% yield, 43% ee) Enantiomeric excess was determine d by chiral HPLC, Chiralcel OJ H (97.0 : 3.0 n hexane:isopropanol, 1.0 mL/min, 254 nm); t R (major) = 19.3 min, t R (minor) = 26.1 min. (2 S ,3 S ) butane 2,3 diol (3.26) (12% yield, 64% ee) Enantiomeric excess was determine d by chiral GCMS, G TA, 60 C 70 C, ramp = 0.5C/min, t R (minor) = 5.1 min, t R (major) = 7.1 min. The diol product mixture was compared to an authe ntic sample of (2 R ,3 R ) butane 2,3 diol. The corresponding signals were found to have the same Total Ion Chromatogram (TIC) as the authentic sample.

PAGE 131

131 General Procedure for the A symmetric Addition of TMSN3 to M eso Epoxides Under air, a 3.0 dram vial was charg ed with a magnetic stir bar and Co(II)bis salen allowed to stir for 1 h. The solvent was then removed under vacuum and to the residue was added epoxide (0.50 mmol), followed by solvent (0.10 mL) and mesitylene as an 2 O (0.5 mL) for GCMS analysis. TMSN 3 was then added (0.6 mmol) and the reaction was then allowed to stir for 45h. After the indicated time the reaction mixture diluted with Et 2 O (1.0 mL), loaded onto a plug of dry silica gel (1 x 3 cm) and eluted with Et 2 O (2 x 5.0 mL). The crude mixture was then analysized by GCMS to determine substrate conversion versus the internal standard and the enanti omeric excess of the azido silylether (Astec Chiraldex TM G TA). The Et 2 O was then removed under vacuum and the residue dissolved in MeOH (1.0 mL). A solution of CSA (0.05 M) was added (0.25 mL) and the mixture was allowed to stir for 30 min. The MeOH was t hen removed under vacuum and the residue purified on silica gel eluting with hexanes/ethyl acetate (1 S ,2 S ) 2 azidocyclohexanol (3.27) 1 H NMR (300 MHz, CDCl 3 d ): ppm 3.28 3.1 6 (m, 1H), 3.06 2.97 (m,1H), 1.94 1.79 (m, 3H), 1.66 1.46 (m, 2H), 1.3 0.97 (m, 4H). 13 C NMR (75MHz, CDCl 3 d ): 74.0, 67.0, 30.0, 29.5, 24.1, 23.5 (99% conversion, 83% ee) Enantiomeric excess of the azidosilylether determine by chiral GCMS, G TA, 80 C, i sothermal, t R (minor) = 24.8 min, t R (major) = 27.8 min.

PAGE 132

132 (1 S ,6 S ) 6 azidocyclohex 3 enol (3.28) 1 H NMR (300 MHz, CDCl 3 d (m, 2H), 3.70 (m, 1H), 3.51 (m, 1H), 2.67 (br s, 1H) 2.45 (m, 2H), 2.09 (m, 2H) 13 C NMR (75MHz, CDCl 3 d azidosilylether determine by chiral GCMS, G TA, 75 C, isothermal, t R (minor) = 32.7 min, t R (major) = 35.9 min. (1S,2S) 2 azidocyclopentanol (3 .29 ) 1 H NMR (300 MHz, CDCl 3 d ppm 4.04 (m, 1H), 3.66 (m,1H), 2.14 (br s, 1H), 2.10 1.96 (m, 2H), 1.84 1.55 (m, 4H). 13 C NMR (75MHz, CDCl 3 d (99% conversion, 67% ee) Enantiomeric excess of the azidosilylether determine by chiral GCMS, G TA, 55 C, isothermal, t R (minor) = 40.2 min, t R (major) = 45.9 min Synthesis and Char acterization of Bis Urea Trident ate Ligands and Meso A ziridines Compounds 3.35 and 3.36 were prepared according to known literature method s A represen tative proced ure for the synthesis of trident ate ligands, and respective chromium complexe is described below. Dialdehyde 3.6c (0.104 mg, 0.18 mmol) was suspended in a 1:1 mixture of absolute EtOH and THF (8 mL) and gently warmed at 50 C to dissolve. (1 S ,2 R ) cis 1 Amino 2 indanol( 55.5 mg, 0.37 mmol) was then added and allowed to stir for 18h. TLC in 1:1 ethyl aceate/MeOH showed total consumption of starting material. Solvent was then removed under vacuum and the residue was treated with ethyl acetate. The

PAGE 133

133 bright yellow liquid was decanted away from the dark residue then triturated with hexane to give a bright yellow solid (0.135 mg, 90%) 1,1' (1,4 phenylene)bis(3 (3 tert butyl 4 hydroxy 5 (( E ) ((1 S ,2 R ) 2 hydroxy 2,3 d ihydro 1H inden 1 ylimino)methyl)benzyl)urea) (3.30 ) 1 H NMR (300 MHz, DMSO d 6 ): ppm 14.37 (s, 2 H), 8.67 (s, 2 H), 8.32 (s, 2 H), 7.19 7.33 (m, 16 H), 5.24 (d, J =4.5 Hz, 2 H), 4.79 (d, J =5.1 Hz, 2 H), 4.56 (t, J =5.0 Hz, 2 H), 4.22 (d, J =4.4 Hz, 4 H), 3.07 3.15 (m, 2 H), 2.97 (d, J =5.7 Hz, 2 H ), 1.76 (br. s., 2 H), 1.35 (s, 18 H) ; 13 C NMR (DMSO d 6 ,75MHz): ppm 166.5, 159.9, 155.4, 142.0, 141.1, 136.6, 134.3, 128.9, 128.8, 128.1, 126.7, 125.1, 124.7, 118.5, 118.0, 73.9, 73.5, 67.0, 42.5, 34.4, 29.2, 25.1 1,1' (1,4 phenylene)bis urea tridentate S chiff base(chromium) (3.31c ) Under argon, a schlenk flask was charged with CrCl 2 (26. 3 mg, 0.21 mmol) then suspended in THF (1.0 mL). Schiff base ligand 3 30c ( 85.3 mg, 0.10 mmol) was then added as a solution in THF (1.0 mL) via syringe and allowed to s tir for 3h. The reaction was then

PAGE 134

134 exposed to air for 2h then flushed with argon and resealed. 2,6 lutidine was then added (47.5 L, 0.40 mmol) and then allowed to stir overnight. MTBE was then added (40 mL) and the green precipitate was collected by vacuum filtration, washing liberally with MTBE. The solid was then dried on high vacuum to give the title compound. (0.117 mg, 99%) 7 be nz yl 7 azabicyclo[4.1.0]heptane (3.35 ) 1 H NMR (CDCl 3 300 MHz) ppm 7.36 7.19 (m, 5H), 3.46 (s, 2H), 1.87 (m, 2H), 1.75 (m, 2H), 1.61 (m, 2H), 1.45 1.35 (m, 2H), 1.24 1.12 (m, 2H); 13 C NMR (CDCl 3 75 MHz) 140.2, 128.3, 127.5, 126.7, 64.5, 38.6, 24.6, 20.7. 7 azabicyclo[4.1.0]heptan 7 yl(phenyl)methanone (3. 36 ) 1 H NMR (400 MHz, CDCl 3 ppm 7.98 (2H, d, J = 8.0 Hz), 7.53 (1H, t, J = 7.3 Hz), 7.44 (2H, t, J = 7.6 Hz), 2.75 (2H, m ), 2.11 2.04 (2H, m), 1.94 1.88 (2H, m), 1.58 1.53 (2H, m), 1.37 1.34 (2H, m); 13 C NMR (100 MHz, CDCl 3 = 180.5, 133.9, 132.7, 129.3, 128.6, 37.3, 24.2, 20.2 General Procedure for Enantioselective Aziridine Opening To a screw cap vial was added protecte d aziridine (0.5 mmol) and bis tridentate Schiff base Cr(III)Cl complex (25.0 mol, 5 mol%). CH 2 Cl 2 was then added (0.5 mL) and the mixture allowed to stir for 5 min. TMSN 3 was then added and the mixture was allowed to stir for 20h. The reaction was then d iluted with CH 2 Cl 2 (0.5 mL) and purified

PAGE 135

135 on silica gel with a mixture of hexanes and ethyl acetate. Enantiomeric ratios were determined by chiral HPLC analysis (Shimadzu) using Chiralpak IA. Characterization of Ring Opened Products (1 S ,2 S ) 2 azido N benzylcyclohexanamine (3.37 ) 1 H NMR (CDCl 3 300 MHz) ppm 7.42 7.30 (m, 4H), 7.26 7.21 (m, 1H), 3.48 (s, 2H), 1.93 1.85 (m, 2H), 1.83 1.74 (m, 2H), 1.66 1.62 (m, 2H), 1.47 1.37 (m, 2H), 1.26 1.16 (m, 2H); 13 C NMR (100 MHz, CDCl 3 139.97, 128.12, 127.33, 126.49,64.25,38.43,24.41,20.52. N ((1 S ,2 S ) 2 azidocyclohexyl)benzamide (3.38 ) 1 H NMR (CDCl 3 300 MHz): ppm 7.79 (d, 2H), 7.48 (t, 1H), 7.39 (t, 2H), 6.50 (d, 1H), 3,96 (m, 1H), 3.30 (m, 1H), 2.10 (m, 2H), 1.80 (m, 1H), 1.71, (m, 1H), 1.44 (m, 1H), 1.32 (m, 3H) ppm 13 C NMR (100 MHz, CDCl 3

PAGE 136

136 CHAPTER 4 CONCLUSION Nitrogen containing chiral ligands have become a cornerstone in asymmetric catalysis. These ligands are prized for their ease of synthesi s from a readily available chiral pool, their modularity and their ability to coordinate to a variety of transition metals. Described in Chapter 2 is the application of a series of chiral isoq uinoline based di imine ligands conveniently prepared through Bi schler Napieralski cyclization. These ligands were originally synthesized as an intermediate to novel tricyclic NHC ligands. The i Bu substituted, C 2 symmetric diimine ligand 2.1a was found to be effective in Cu(II) catalyzed enantioselective Henry reaction s between nitromethane and various aldehydes displaying good yields and excellent enantioselectivities Single crystal X ray analysis of the Pd(II)Cl 2 complex of the same ligand show a unique helical chirality in addition to the expected planar chirality. The development of these ligands mark a significant addition to the diverse range of chelating N,N donor ligands for asymmetric catalysis. A synergistic relationship between two (or more) activating metal centers is common in many biological catalysts. The rate and selectivity of transformations mediated by these catalysts are often highly dependent on the cooperative nature of those metal centers within the active site. This observation has prompted significant interest in the development of asymmetric catalysts based on a cooperative relationship between two or more metals. The use of covalent bonds to link two or more metal complexes together has been a well studied and successful approach to cooperative asymmetric catalysis.

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137 Described in Chapter 3 is the development of chiral tri and tetradentate dimeric Schiff base ligands, designed to self assemble in solution through hydrogen bonding provided by a bis urea scaffold. The concept of self assembly was introduced to create multinuclear transition metal complexes without the need for covalently bound supramolecular structures. Bis urea, dimeric Co(III)salen catalyst 3.8e was found to be significantly more efficient in catalyzing the asymmetric hydrolysis of cyc lohexene oxide versus the unfunctionalized C o(III)salen catalyst and slightly better than our second generation monomeric, bis urea Co(III)salen From the observation that progressively decreasing catalyst concentration s eroded only the reaction yield and not the enantioselectivity suggests that a bimetallic mechanism is still in operation, even at low catalyst concentrations and supports a self assembled structure that behaves as if the monomers were covalently tethered. Interestingly, the closely related bis urea Co(III)salen 3.8d was found to be an efficient catalyst for the asymmetric addition of TMSN 3 to cy clohexene oxide versus the un functionalized Co(III)salen catalyst Thus, t he use of an internal bis urea, dimeric salen scaffold has been demonstrated to be an effective and interesting me thod to invoke self assembly in cooperative asymmetric catalysis.

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151 BIOGRAPHICAL SKETCH Michael J. Rodig was born at Sinai Hospital in Baltimore, MD. Soon after his birth his family moved farther outside the city to the rural suburb of Westminster where he spent his formative years with mother Paula, father Charles and brother Anthony and attended public primary school After high school he earned his Associates in Arts and Science at a local junior college then enrolled at Salisbury eastern shore. At Salisbury University he worked in the laboratories of Dr. Miguel Mitchell and Dr. Elizabeth Papish on the synthesis of biologically active compounds and the development of transition metal catalysts for the hydrol ysis of phosphotriesters respectively. H in 2005 At Salisbury he also met his wife Jennifer and they were marr ied a year after his graduation in 2006. Michael started graduate school at the University of Flor ida the same year working in the laboratory of Dr. Sukwon Hong developing chiral transition metal catalysts for asymmetric reactions. Michael and Jennifer w ere blessed with a son, Ryan in 2010. Michael and his family plan to move back north to begin his post doctoral study.