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Self-Assembled Dinuclear Catalysts through Hydrogen-Bonds for Asymmetric Reactions

Permanent Link: http://ufdc.ufl.edu/UFE0043184/00001

Material Information

Title: Self-Assembled Dinuclear Catalysts through Hydrogen-Bonds for Asymmetric Reactions
Physical Description: 1 online resource (213 p.)
Language: english
Creator: Park, Jongwoo
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2011

Subjects

Subjects / Keywords: catalysis -- self-assembly
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: Recently, there have been growing efforts to develop multinuclear catalysts enabling cooperative, simultaneous activation of both an electrophile and a nucleophile in asymmetric catalysis. To construct multi-metallic catalysts, the use of covalent bond linkage has been a general strategy. As an alternative way, a self-assembly approach toward bimetallic catalyst using hydrogen bonds has been devised. Based on this idea, we have developed a novel dinuclear (salen)Co(II) catalyst self-assembled through two complementary H-bonding interactions for asymmetric Henry reaction. Our catalyst design features two 2-pyridone/aminopyridine hydrogen bonding pairs to create a self-assembled dimer in solution. The self-assembled dinuclear (salen)Co(II) catalyst results in significant rate acceleration (48 times faster) as well as high enantioselectivity in the Henry reaction compared to the corresponding non-functionalized (salen)Co(II) catalyst. Rate laws were found to be second order in cobalt concentration for both self-assembled (salen)Co and monomeric complexes, suggesting a bimetallic mechanism is operating. The self-assembly through hydrogen-bonding was confirmed by the X-ray structure and by the 1H NMR experiments. Bis-urea functionalized (salen)Co catalysts have been also devised for the hydrolytic kinetic resolution of epoxides. This new design features urea hydrogen bonding as a self-assembling motif and is expected to benefit from simple catalyst synthesis and desired metal-metal distance for dual activation. Those bis-urea (salen)Co(III) catalysts showed significant rate acceleration (4.2 to 13.7 times) compared to the unfunctionalized (salen)Co(III) catalyst in the HKR of epichlorohydrin in THF. The rate acceleration was caused by self-assembly of catalytic units, which was verified by control experiments, IR and NMR experiments, X-ray analysis and MM2 calculations. As an extension of this promising strategy, we also developed novel bis-urea spacing dimeric (salen)Co catalysts. In this ligand design, two salen units are linked by a bis-urea spacer. The resulting complexes have been found to efficiently catalyze asymmetric hydrolysis reaction of meso-epoxides which is known to be very challenging with the monomeric (salen)Co catalyst. Those results demonstrate the novel self-assembled approach can provide a powerful tool for the generation of bimetallic catalysts.
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 Jongwoo Park.
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: UFE0043184:00001

Permanent Link: http://ufdc.ufl.edu/UFE0043184/00001

Material Information

Title: Self-Assembled Dinuclear Catalysts through Hydrogen-Bonds for Asymmetric Reactions
Physical Description: 1 online resource (213 p.)
Language: english
Creator: Park, Jongwoo
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2011

Subjects

Subjects / Keywords: catalysis -- self-assembly
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: Recently, there have been growing efforts to develop multinuclear catalysts enabling cooperative, simultaneous activation of both an electrophile and a nucleophile in asymmetric catalysis. To construct multi-metallic catalysts, the use of covalent bond linkage has been a general strategy. As an alternative way, a self-assembly approach toward bimetallic catalyst using hydrogen bonds has been devised. Based on this idea, we have developed a novel dinuclear (salen)Co(II) catalyst self-assembled through two complementary H-bonding interactions for asymmetric Henry reaction. Our catalyst design features two 2-pyridone/aminopyridine hydrogen bonding pairs to create a self-assembled dimer in solution. The self-assembled dinuclear (salen)Co(II) catalyst results in significant rate acceleration (48 times faster) as well as high enantioselectivity in the Henry reaction compared to the corresponding non-functionalized (salen)Co(II) catalyst. Rate laws were found to be second order in cobalt concentration for both self-assembled (salen)Co and monomeric complexes, suggesting a bimetallic mechanism is operating. The self-assembly through hydrogen-bonding was confirmed by the X-ray structure and by the 1H NMR experiments. Bis-urea functionalized (salen)Co catalysts have been also devised for the hydrolytic kinetic resolution of epoxides. This new design features urea hydrogen bonding as a self-assembling motif and is expected to benefit from simple catalyst synthesis and desired metal-metal distance for dual activation. Those bis-urea (salen)Co(III) catalysts showed significant rate acceleration (4.2 to 13.7 times) compared to the unfunctionalized (salen)Co(III) catalyst in the HKR of epichlorohydrin in THF. The rate acceleration was caused by self-assembly of catalytic units, which was verified by control experiments, IR and NMR experiments, X-ray analysis and MM2 calculations. As an extension of this promising strategy, we also developed novel bis-urea spacing dimeric (salen)Co catalysts. In this ligand design, two salen units are linked by a bis-urea spacer. The resulting complexes have been found to efficiently catalyze asymmetric hydrolysis reaction of meso-epoxides which is known to be very challenging with the monomeric (salen)Co catalyst. Those results demonstrate the novel self-assembled approach can provide a powerful tool for the generation of bimetallic catalysts.
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 Jongwoo Park.
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: UFE0043184:00001


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1 SELF ASSEMBLED DI NUCLEAR CATAL YSTS THROUGH HYDR O GEN BONDS FOR ASYMMETRIC REACTIONS By JONGWOO PARK A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2011

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2 2011 Jongwoo Park

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3 To my family

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4 ACKNOWLEDGMENTS First of all, I am especially grateful to my adviser, Dr. Sukwon Hong, for his valuable guidance encouragement, and advi ce throughout my study I also thank my committee members : Dr Lisa Mc Elwee White Dr. Jon Stewart Dr. Ronald Castellano and Dr. Raymond Booth Without their valuable suggestion, and continuous encouragement, I would not have been able to complete my stu dy I want to thank Hong group members Dr. Hwimin Seo Dimitry Hirsch Weil David Snead and Sebastien Inagaki They were all wonderful friends and nice co workers. I would like to thank especially Mike Rodig. We shared the same lab and hood during over f our years and w e spent enjoyable time I would like to thank Kai Lang for valuable discussion and his help in research I wish to thank my parents for their endless support and patience over the years All the support they have provided me over the years w as the greatest gift anyone has ever given me. I want thank my brother, his wife, and their lovely son. I also want to thank my parents in law and their family for their support and encouragement. Last and certainly not least, I want to thank my wife Sang eun for her selfless sacrifices, and for supporting me in everyway possible.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 LIST OF SCHEME S ................................ ................................ ................................ ...... 12 ABSTRACT ................................ ................................ ................................ ................... 16 CHAP TER 1 INTRODUCTION ................................ ................................ ................................ .... 18 Cooperative Activation in Asymmetric Catalysis ................................ ..................... 18 Bimetallic Catalysts in Asymmetric Synthesis ................................ ......................... 20 Enhancement of Cooperative Bimetallic Activation ................................ ................. 31 Supramolecular Catalysis ................................ ................................ ....................... 39 Coordination Driven Supramolecular Catalysts ................................ ................ 40 Hydrogen Bonding Mediated Supramolecular Catalysts ................................ .. 49 Supramolecular Bioconjugate Systems ................................ ............................ 63 2 SELF ASSEMBLED DINUCLEAR CATALYST THROUGH HYDROGEN BONDS FOR ASYMMETRIC HENRY REACTIONS ................................ .............. 68 Ligand Design and Synthesis ................................ ................................ ................. 6 8 Catalytic Enantioselective Henry (Nitro Aldol) Reaction ................................ ......... 77 Self Assembled Dinu clear (Salen)Co(II) Catalyzed Henry Reaction ....................... 80 Kinetic Study ................................ ................................ ................................ ........... 83 Self Assembly Study ................................ ................................ ............................... 85 Summary ................................ ................................ ................................ ................ 89 Experimental ................................ ................................ ................................ ........... 89 General Remarks ................................ ................................ ............................. 89 Catalyst Preparation ................................ ................................ ......................... 90 General Procedure for Asymmetric Henry Reaction ................................ ....... 101 Kinetic Experiments ................................ ................................ ........................ 105 3 SELF ASSEMBLED CATALYSTS THROUGH UREA UREA HYDROGEN BONDS FOR EPOXIDE OPENING REACTIONS ................................ ................ 106 Backgrounds ................................ ................................ ................................ ......... 106 Hydrolytic Kinetic Resolution (HKR) of Terminal Epoxides ................................ ... 112 Design and Preparation of Bis Urea (Salen)Co Catalysts ................................ ..... 123 Self Assembled Bis Urea (Salen)Co(III) Catalyzed HKR ................................ ...... 128

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6 Kinetic and Mechanistic Study ................................ ................................ .............. 136 Self Assembly Study ................................ ................................ ............................. 143 X Ray Packing Structures and MM2 Calculation ................................ .................. 146 Asymmetric Hydrolysis of Cyclohexene Oxide ................................ ...................... 151 Design of Bis Urea Spacing Dimeric (Salen)Co Complexes ................................ 151 Summary ................................ ................................ ................................ .............. 156 Experimental ................................ ................................ ................................ ......... 156 General Remarks ................................ ................................ ........................... 156 General Procedure for the Preparation of Ureidophenyl Boronic Esters ........ 157 General Procedure for the Preparation of Ureidophenyl Salicylaldehydes ..... 159 General Procedure for the Preparation of Ureidophenyl Salen Ligands ......... 163 General Procedure for the Preparation of Bis Urea (Salen)Co Complexes .... 165 General Procedure for the Preparation of Ureidomethylene salicylaldehydes 167 Synthesis of 4 (Aminomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol ............. 172 General Procedure for the Preparation of 3 41g and 3 41h ........................... 173 General Procedure for the Preparation of Bis Urea Salen Ligands (3 44) ..... 175 General Procedure for the Preparation of Bis Urea (Salen)Co Complexes (3 30) ................................ ................................ ................................ .......... 181 Synthesis of Mono Urea (Salen)Co Complex (3 51) ................................ ...... 184 Synthesis of Urea (Salen)Ni Complexes ................................ ........................ 186 Preparation of Bis ( N N Dimethyl Phenylurea) (Salen)Cobalt Complex ........ 189 Reaction Rate Determination ................................ ................................ ......... 191 General Procedure for Hydrolytic Kinetic Resolution of Epoxides .................. 192 Asymmetric Hydrolysis of Cyclohexene Oxide ................................ ............... 194 Molecular Mechanics Calculations ................................ ................................ 195 General Procedure for the Preparation of Bis Urea Salicylaldehydes ............ 195 Bis Urea Spacing Dimeric (Salen)Co Complexes ................................ .......... 198 4 CONCLUSION ................................ ................................ ................................ ...... 200 LIST OF REFERENCES ................................ ................................ ............................. 202 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 213

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7 LIST OF TABLES Table page 2 1 Henry reaction of o methoxybenzaldeh y de ................................ ........................ 81 2 2 Substrate scope of self assembled (salen)Co catalyzed Henry reaction ............ 82 2 3 Measured chemical shifts of pivalamide N H H a H b and H c using 2 5% v/v CD 3 NO 2 in CDCl 3 at 25C ................................ ................................ ................... 87 3 1 Catalyst efficiency of multinuclear salen systems ................................ ............. 118 3 2 Kinetic data for the HKR of ( rac ) epichlorohydrin ................................ ............. 132 3 3 Kinetic data for the HKR of ( rac ) epichlorohydrin ................................ ............. 133 3 4 HKR of terminal epoxides under solvent free conditions ................................ .. 136 3 5 Kinetic data for the HKR of ( rac ) epichlorohydrin ................................ ............. 143 3 6 Desymmetrization of cyclohexene oxide ................................ .......................... 155

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8 LIST OF FIGURES Figure page 1 1 Schematic illustration of bifunctional catalytic systems ................................ ....... 19 1 2 Schematic illustration of tethering strategy for bimetallic catalysts ..................... 19 1 3 Proposed transition state for the Pd catalyzed allylic alkylation .......................... 21 1 4 Crown ether substituted ferrocenylphosphine ligands ................................ ........ 21 1 5 Structure of 1 7 and the enantioselective Henry reaction ................................ ... 22 1 6 Proposed bimetallic activation for the enantioselective conjugate addition ........ 23 1 7 Proposed transition state of cyanohydrin reaction ................................ .............. 24 1 8 Proposed mechanism for Strecker reaction ................................ ........................ 27 1 9 Proposed cooperative bimetallic activation mechanism ................................ ..... 31 1 10 Bimetallic mechanism for ARO of epoxides with TMSN 3 ................................ .... 33 1 11 Dimeric (salen)Cr catalyst for ARO of epoxides ................................ ................. 33 1 12 Chiral vanadium complexes for oxidative coupling ................................ ............. 37 1 13 ................................ .......................... 41 1 14 Schematic illustrat ion of supramolecular bidentate ligands ................................ 42 1 15 6 L 4 supramolecular assembly ................................ .............................. 45 1 16 4 L 6 supramolecular asse mbly ................................ ....................... 47 1 17 Aza Cope rearrangement within a self assembled cavity ................................ ... 48 1 18 Supramolecular oxidative decarboxylation of pyruvate ................................ ....... 50 1 19 Self assembled molecular capsule for Diels Alder reaction ................................ 51 1 20 Self assembled cylindrical capsule for cycloaddition r eaction ............................ 51 1 21 Supramolecular catalyst via multiple hydrogen bonds ................................ ........ 52 1 22 Self assembled heterobidentate ligand ................................ .............................. 56 1 23 Supported hydrogen bonded catalysts ................................ ............................... 61

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9 1 24 Supramolecular anchoring of catalysts on dendrimer ................................ ......... 61 2 1 Design of self assembled dinuclear catalyst via H bonding interactions ............ 68 2 2 Homodimeric, heterodimeric, and heterobimetallic catalysts mediated by hydrogen bo nding interactions ................................ ................................ ............ 69 2 3 Self complementary dipyridone system ................................ .............................. 69 2 4 Design of pyridone/pyridone H bonding self assembled salen catalysts ............ 71 2 5 Plausible intramolecular cyclization of intermediate 2 17 ................................ ... 73 2 6 New catalyst design using a pyridone/aminopyr idine H bonding pair ................. 74 2 7 Template effect in the synthesis of 2 23 ................................ ............................. 75 2 8 ORTEP view of the crystal structure of 2 24 with the thermal ellipsoids drawn at 50% probability ................................ ................................ ............................... 77 2 9 X ray structure of self assembled dimeric (salen)Ni complex 2 24 2 24 ............ 77 2 1 0 Metal complex/ligand self assembly ................................ ................................ ... 82 2 11 Initial rates of the asymmetric Henry reaction with 2 19 ................................ ..... 83 2 12 Initial rates of t he asymmetric Henry reaction with 2 26 ................................ ..... 84 2 13 Rate dependence on catalyst concentration ................................ ....................... 84 2 14 Stacked 1 H NMR (300 MHz) spectr a of aromatic region of salen ligand 2 23 at the concentration of 0.15, 1.5, and 10 mM in CDCl 3 at 25 C .......................... 85 2 15 Stacked 1 H NMR (300 MHz) spectra of aromatic region of diluted samples (0.14 19. 1 mM) of 2 23 in 25% v/v CD 3 NO 2 in CDCl 3 at 25 C ............................ 86 2 16 Complexation induced chemical shift changes of proton signals in metal free salen ligand 2 23 in 25% v/v CD 3 NO 2 in CDCl 3 at 25 C ................................ ..... 88 2 17 Self assembled (salen)CrCl catalyst for epoxide opening reactions ................... 88 3 1 Urea self assembly ................................ ................................ ........................... 106 3 2 Dimeric self assembly of tetra urea calix[4]arene ................................ ............. 107 3 3 Dimeric self assembly of tris urea compounds ................................ ................. 108 3 4 X ray packing structures of macrocy c lic bis and tetra urea compounds .......... 109

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10 3 5 Some examples of bis urea gelators ................................ ................................ 110 3 6 Bis urea monomers for supramolecular polymer ................................ .............. 110 3 7 Urea monomers for the self assembly in polar media ................................ ...... 111 3 8 (P orphyrin)Cu based tetra urea gelator ................................ ............................ 112 3 9 Two limiting geometries in HKR of epoxides ................................ .................... 1 14 3 10 Counterion effect in HKR ................................ ................................ .................. 114 3 11 Dendrimeric multinuclear (salen)Co complex 3 17 ................................ ........... 116 3 12 Macrocyclic oligomeric (salen)Co complexes ................................ ................... 117 3 13 ................................ ...... 117 3 14 Polymer supported (salen)Co complexes ................................ ......................... 119 3 15 Polymer supported (salen)Co complexes by Weck ................................ .......... 120 3 16 Gold immobilized colloidal salen ................................ ................................ ...... 121 3 17 HKR o n (salen)Co catalysts confined in nanocages ................................ ......... 122 3 18 ................................ ............................ 123 3 19 Self assembly of bis urea incorporated (salen)Co complexes .......................... 124 3 20 Design of bis urea (salen)Co complexes ................................ .......................... 124 3 21 Induction period of HKR of allyl glyci dyl ether ................................ ................... 130 3 22 Rate plots of the HKR of ( rac ) epichlorohydrin in THF ................................ ..... 132 3 23 Rate plots of the HKR of epichlorohydrin ( 3 30 (a f) and 2 26 ) ......................... 134 3 24 Rate plots of the HKR of epichlorohydrin ( 3 30(g k) and 2 26 ) ........................ 134 3 25 HKR of ( rac ) epichlorohydrin wit h 0.05 mol% 3 30k(OTs) and 2 26(OTs) in THF and under solvent free conditions ................................ ............................. 135 3 26 Rate plots of the HKR of epichlorohydrin (5.0 mmol) using the bis urea (salen)Co 3 30f(OTs) (0.02, 0.03, 0.04, and 0.05 mol%) in THF ...................... 137 3 27 Kinetic dependence on catalyst concentration ................................ ................. 137 3 28 Relative rates of H bonds blocked cat alysts ................................ ..................... 140

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11 3 29 Relative rate of mono urea (salen)Co complex ................................ ................ 141 3 30 Possible urea/metal dual activation scenario ................................ .................... 142 3 31 The NH stretching region of the FTIR spectra of 3 26k in THF ........................ 144 3 32 Bis urea (salen)Ni complex and mono urea (salen)Ni complex. ....................... 144 3 33 Concentration dependent 1 H NMR shifts of two urea protons .......................... 145 3 34 ORTEP view of the crystal structure of 3 56 The H ato ms of the framework are omitted for clarity ................................ ................................ ........................ 146 3 35 X ray packing structures of 3 56 showing interstack arrangement between two hydrogen bond networks ................................ ................................ ............ 147 3 36 H bonded network in the packing structure of 3 56 ................................ .......... 147 3 37 Two plausible structures of bis urea (salen)Ni dimer: antiparallel (A) and parallel (P) ................................ ................................ ................................ ........ 148 3 38 X ray crystal structure of bis urea (salen)Ni complex 3 57 ............................... 149 3 39 Self assembled dimeric structure of 3 57 (side view) ................................ ....... 149 3 40 Self assembled dimeric structure of 3 57 (top view) ................................ ......... 149 3 41 Hydrogen bond packing structure of bis urea (salen)Ni complex ..................... 150 3 42 Conceptual design of the bis urea dimeric (salen)Co complex ......................... 152

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12 LIST OF SCHEME S Scheme page 1 1 Enantioselective allylic alkylation ................................ ................................ ........ 20 1 2 Enantioselective conjugate addition ................................ ................................ ... 22 1 3 Conjugat e addition of malonate to cyclic enone ................................ ................. 23 1 4 Asymmetric trimethylsilylcyanation of aldehydes ................................ ................ 24 1 5 Conjugate addition of TMSCN to unsaturated imides catalyzed by (salen)AlCl complex ................................ ................................ ................................ .............. 25 1 6 Conjugate addition of TMSCN to unsaturated imides ................................ ......... 26 1 7 Catalyti c enantioselective Strecker reaction of ketimines ................................ ... 26 1 8 Enantioselective Strecker reaction of ketimines catalyzed by 1 27 .................... 28 1 9 Chiral dinuclear zinc catalyst for asymmetric aldol reactions .............................. 28 1 10 Sm Schiff base system ................................ .............................. 29 1 11 Diastereose lective nitro Mannich reaction catalyzed by 1 36 ............................. 30 1 12 Heterogeneous bimetallic system for anti selective nitroaldol reactions ............. 30 1 13 Bispalldacycle catalyzed asymmetric Michael addition ................................ ...... 31 1 14 Asymmetric ring opening of meso epoxide with TMSN 3 ................................ ..... 32 1 15 Covalently tethered dinuclear (salen)Al catalyst for conjugate addition .............. 34 1 16 Enantioselective polymerization of epoxides ................................ ...................... 35 1 17 Bridged bimetallic titanium complex for enantioselective cyanohydrin synthesis ................................ ................................ ................................ ............ 36 1 18 Dinuclear Cu catalyst for the enantioselective oxidative coupling ....................... 37 1 19 Dinuclear vanadium catalyzed oxidative coupling of 2 naphthols ....................... 38 1 20 Asymmetric dialkylzinc addition to aldehyde ................................ ...................... 40 1 21 Asymmetric hydroformylation using supramolecular rhodium catalyst ............... 43 1 22 Asymmetric hydrogenation using supramolecular rhodium catalyst ................... 44

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13 1 23 Self assembled chiral diphosphite palladium catalyzed asymmetric allylic aminations ................................ ................................ ................................ .......... 44 1 24 [2+2] Photocycloaddition within encapsulated catal yst ................................ ....... 46 1 25 Asymmetric [2+2] photocycloaddition within a cage ................................ ........... 46 1 26 Enantioselective aza Cope rearrangement by a chiral supram olecular assembly ................................ ................................ ................................ ............ 48 1 27 Self assembled organocatalyst for asymmetric conjugate addition .................... 53 1 28 Chiral ion pair catalyst for t he conjugate addition ................................ ............... 54 1 29 Multicomponent catalyst for the asymmetric conjugate addition ......................... 54 1 30 Main chain ionic polymer cat alyst ................................ ................................ ....... 55 1 31 Supramolecular bidentate catalyst for hydroformylation ................................ ..... 56 1 32 Self assembled heterobidentate catalyst for asymmet ric hydrogenation ............ 57 1 33 Asymmetric hydrogenation catalyzed by 1 121 ................................ .................. 58 1 34 Supramolecular bidentate ligand for asymmetric hyd rogenation ........................ 58 1 35 Supramolecular Rh catalyst for asymmetric hydrogenation ................................ 59 1 36 Adaptive supramolecular catalyst for asymmetr ic hydrogenation ....................... 59 1 37 Asymmetric hydrogenation catalyzed by PhthalaPhos Rh complex ................... 60 1 38 Self supported Rh complex through hydrogen bonds ................................ ......... 62 1 39 Catalytic epoxidation by supramolecular catalytic system ................................ .. 63 1 40 Enantioselective hydrogenation catalyzed by biotin/avidin hybrid Rh complex .. 64 1 41 Ruthenium complex/streptavidin hybrid catalyzed asymmetric reduction ........... 65 1 42 Albumin conjugated copper complex for Diels Alder reactions ........................... 65 1 43 DNA based hybrid catalysts for the stereoselective Diels Alder cyclization ....... 66 2 1 Synthesis of symmetrical (salen)Co complex 2 3 ................................ ............... 72 2 2 Synthesis of intermediate 2 17 ................................ ................................ ........... 73 2 3 Synthesis of symmetri cal (salen)Co complex 2 18 ................................ ............. 75

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14 2 4 Synthesis of unsymmetrical (salen)Co complex 2 19 ................................ ......... 75 2 5 Synthesis of (salen)Ni and (salen)Zn complexes ................................ ................ 76 2 6 (Salen)metal catalyzed asymmetric Henry reaction ................................ ............ 78 2 7 Sterically modified (salen)Cr complex for asymmetric He nry reactions .............. 79 2 8 The anti selective catalytic asymmetric nitroaldol reactions promoted by a Pd/La heterobimetallic catalyst ................................ ................................ ........... 79 2 9 (Salen)Co catalyzed asymmetric Henry reaction ................................ ................ 81 2 10 Self assembled (salen)Co catalyzed asymmetric Henry reaction ....................... 82 3 1 Hydrolytic kinetic resolution using a (salen)Co catalyst ................................ .... 113 3 2 Hydrolytic kinetic resolution catalyzed by 3 22 ................................ ................. 119 3 3 Polyst yrene based dimeric salen developed by Jones ................................ ..... 121 3 4 Synthesis of bis urea (salen)Co complexes containing the p phenylene linker 125 3 5 Synthesis of bis urea (salen)Co complexes containing the m phenylene linker ................................ ................................ ................................ ................. 126 3 6 Synthesis of urea functionalized salicylaldehyde ................................ .............. 127 3 7 Synthesis of bis urea (salen)Co complexes containing the methylene linker ... 128 3 8 HKR of ( rac ) allyl glycidyl ether catalyzed by bis urea (salen)Co complexes ... 129 3 9 HKR of ( rac ) epichlorohydrin catalyzed by (salen)Co(OTs) complexes ............ 132 3 10 HKR of ( rac ) epichlorohydrin catalyzed by (salen)Co(OTs) complexes ............ 133 3 11 HKR of ( rac ) epoxides catalyzed by (salen)Co(OTs) complexes ...................... 136 3 12 Synthesis of 2,6 diisopropylphenylurea (salen)Co complex ............................. 139 3 13 Synthesis of N N dimethylated urea (salen)Co complex ................................ .. 140 3 14 Synthesis of mono urea (salen)Co compl ex 3 51 ................................ ............. 141 3 15 Epoxide opening reaction catalyzed by thiourea ................................ .............. 141 3 16 Kinetic data for the HKR of ( rac ) epichlorohydrin catal yzed by 2 26(OTs) and urea additives ................................ ................................ ................................ ... 143

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15 3 17 Asymmetric hydrolysis of cyclohexene oxide ................................ .................... 1 51 3 18 Synthesis of bis urea spacing salicylaldehyde intermediates ........................... 152 3 19 Synthesis of bis urea spacing dimeric (salen)Co complexes ............................ 153 3 20 Synthesis of mono urea spacing dimeric (salen)Co complex 3 64 ................... 154 3 21 Desymmetrization of cyclohexene oxide catalyzed by (salen)Co complexes ... 155

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16 Abstract of Dissertation Presente d to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy S EL F A SSEMBLED DI NUCLEAR CATALYSTS THROUGH HYDROGEN B ONDS FOR ASYMMETRIC REACTIONS By Jongwoo Park Dec ember 2011 Chair: Sukwon Hong Major: Chemistry Recently, there have been growing efforts to develop multinuclear catalysts enabling cooperative, simultaneous activation of both an electrophile and a nucleophile in asymmetric catalysis. To construct multi metallic catalysts, the use of covalent bond linkage has been a general strategy. As an alternative way a self assembly approach toward bimetallic catalyst using hydro gen bonds has been devised B ased on this idea, we have developed a novel dinuclear (sa len) Co(II) catalyst self assembled through two compl e mentary H bonding interactions for asym metric Henry reaction Our catalyst design features two 2 pyridone/aminopyridine hydrogen bonding pairs to create a self assembled di mer in solution. The self assem bled dinuclear (salen) Co(II) catalyst results in significant rate acceleration (48 times faster) as well as high enantioselectivity in the Henry reaction compared to the corresponding non functionalized (salen) Co(II) catalyst. Rate laws were found to be se cond order in cobalt concentration fo r both self assembled (salen)Co and monomeric complexes, suggesting a bimetallic mechanism is operating. The self assembly through hydrogen bonding was confirmed by the X ray structure and by the 1 H NMR experiments.

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17 Bis urea functionalized (salen)Co catalysts have been also devised for the hydrolytic kinetic resolution of epoxide s This new design features urea hydrogen bonding as a self assembling motif and is expected to benefit from simple catalyst synthesis and desir ed metal metal distance for dual activation. Those bis urea (salen) Co(II I ) catalysts showed significant rate acceleration (4.2 to 13.7 times) compared to the unfunctionalized (salen) Co(II I ) catalyst in the HKR of epichlorohydrin in THF. The rate accelerati on was caused by self assembly of catalytic units which was verified by control experiments, IR and NMR experiments X ray analysis and MM2 calculations. As an extension of this promising strategy, we also developed nov e l bis urea spacing dimeric (salen)C o catalysts. In t hi s ligand design two salen units are linked by a bis urea spacer The resulting complexes have been found to efficiently catalyze asymmetric hydrolysis reaction of meso epoxide s which is known to be very challenging with the monomeric (s alen)Co catalyst. Those results demonstrate th e novel self assembled approach can provide a powerful tool for the generation of bimetallic catalysts.

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18 CHAPTER 1 INTRODUCTION Cooperative A ctivation in A symmetric C atalysis Catalytic asymmetric reactions hav e been one of the most powerful and economical methods to prepare a variety of enantio enriched compounds. In order to achieve the reactivity and selectivity in asymmetric catalysis, the single activation strategy has been utilized over the past four decade s In this context, a number of chiral Lewis acid and Lewis base catalysts have been devised to activate electrophiles or nucleophiles by coordination. The resulting electrophile/Lewis acid complex (or nucleophile/Lewis base complex) reacts with a nucleoph ile (or electrophile) in an enantioselective manner to afford enantio enriched products While remarkable advances have been achieved with this approach over the years, there are still a number of important asymmetric transformations that lack efficien t cat alytic methods Synergistic, c ooperative activation through multiple reaction centers in close proximity is a general strategy in biological system. 1 P ositioning two reaction partners in optimal geometry through coordination or non covalent interactions a llows for high efficiency and selectivity under mild reaction condition s This cooperative activation make s the reaction occur in an intramolecular fashion, which generally give s superior reactivity and selectivity compared to the reaction in an intermolec ular fashion with single activation catalysts Inspired by th is remarkable efficiency of biocatalysts, there has been much interest in designing and developing highly efficient catalyst s to explore the concept of cooperative activation over the past decade 2 In this catalyst design, two catalytic moieties that can activate both reaction partners ar e integrated into one molecule, resulting in high reactivity and selectivity.

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19 Two general approaches toward efficient dual activation systems have been currentl y utilized in asymmetric catalysis In o ne approach carefully designed chiral dinucleating ligands are used to host two metallic or functional moieties in one molecule. This type of catalysts includes bimetallic catalysts, Lewis acid/base and organocataly tic bifunctional catalysts (Figure 1 1) Among those catalysts, bimetallic catalysts will be described in detail in the next section. Figure 1 1. Schematic illustration of bifunctional catalytic systems In another approa ch, two catalyst entities are often linked together by covalent tethers for the reaction displaying a second order rate dependence on catalysts (Figure 1 2) This linking approach allows for the development of much more efficient catalysts than the monomer ic catalyst This attempt will be described in detail later in C hapter 1 Figure 1 2 Schematic illustration of tethering strategy for bimetallic catalysts

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20 Bimetallic C atalysts in A symmetric S ynthesis Catalytic systems i nvolving two metal centers are ubiquitously found in enzymes such as methane monooxygenase, aminopeptidase, urease, and phosphoesterases. 3 The catalytic system utilizing two metal centers has been proved highly effective for many type s of transformation s In this context, there have been growing efforts to develop bimetallic catalysts enabling cooperative and simultaneous activation of two reaction partners in asymmetric catalysis. 4 As an early attempt, Kumada and co wor kers reported new chiral ligand 1 2 f or the asymmetric palladium catalyzed allylic alkylation, which ha s a chelation control motif (Scheme 1 1) 5 By employin g those additional control groups, moderate selectivity was achieved (52% ee) When they tested the ligand lacking the ester functional group ( 1 3 ) selectivity was significantly decreased (15% ee) Thus, the chelation of a nucleophile through the alkali metal cation was a crucial factor to achieve the improved stereoselection (Figure 1 3 ) Scheme 1 1 E nantioselective ally l ic alkylation

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21 Figure 1 3 Proposed transition state for the Pd catalyzed allyl i c alkylation From this initial experiment, more improved ligand s bearing other directing group have been reported. Ito a nd co workers devised aza crown ether bearing bisphosphine ligand 1 5 which showed improved enantioselectivity (72%) in the allylic alkylation of diketone (Figure 1 4 ) 6 The other related ligand 1 6 has been also successfully expanded to asymmetric allylic alkylation of nitroesters in the presence of RbF and RbClO 4 wherein good ee (80%) was achieved. 7 Figure 1 4 Crown ether substituted ferrocenylphosphine ligands In 1992, Shibasaki and co workers report ed lanthanide based heterobimetallic systems that contain one rare earth metal, three alkali metals and three 1,1 bi 2 naphthols (BINOL) for asymmetric nitroa ldol reaction (Figure 1 5 ) 8 The reaction is promoted by the combination of the Br nsted basicity of the alkali metal portion (generation of nucleophiles) and the Lewis acidic lanthanide center (activation of electrophiles), and high selectivity (90% ee) w as obtained. This rare earth alkali metal BINOL (REMB) complex 1 7 has been successfully extended to other asymmetric

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22 transformation s such as cyano ethoxycarbonylation 9 conjugate addition 10 hydrophosphonylation, 11 Tishchenko aldol 12 and direct aldol reaction 13 Figure 1 5 Structure of 1 7 and the enantioselective Henry reaction A few years later, t he same group also developed a BINOL derived aluminum /alkali metal bimetallic system (Scheme 1 2 ) 14 The alkali metal heterobimet allic catalyst was found to be efficient for the conjugate addition of malonates, wherein the aluminum center played as a Lewis acid and alkali metal alkoxide behave d as a Br nsted base (Figure 1 6 ) Scheme 1 2 Enantios elective conjugate addition

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23 Figure 1 6 Proposed bimetallic activation for the enantioselective conjugate addition Kozlowski and co workers reported a salen based bimetallic complex that incorporates two chiral binol moi eties. 15 This Ni/Cs bimetallic complex was an effective catalyst for the enantioselective Michael addition of benzyl malonate to cyclohex 2 enone (Scheme 1 3) Similarly, the Lewis acid/alkali metal cooperative effects are crucial for the high enantiosel ect ivity (90% ee) observed in this cataly tic system. Scheme 1 3 Conjugate addition of malonate to cyclic enone In addition to transition metal/alkali metal bimetallic systems, there is another type of bimetallic catalyst s in which two transition metals are involved. The TMSCN addition reactions to carbonyl compounds via bimetallic activation were reported by Belokon North and co workers (Scheme 1 4) 16 It was found that the bridged bimetallic oxo titanium species 1 16 is the actual precatalyst, which simultaneously activates both the electrophile and the nucleophile (Figure 1 7 ) This bimetallic oxo titanium species 1 16 is in equilibrium to monometallic species 1 15 which is catalytically inactive, relying on concentr ation. This catalyst has been proven to be highly efficient for the synthesis of

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24 optically active cyanohydrins derivatives because good to excellent enantiomeric excesses (52 92%) can be achieved using as low as 0.1 mol% of catalyst. Scheme 1 4 Asymmetric trimethylsilylcyanation of aldehydes Figure 1 7 Proposed transition state of cyanohydrin reaction Jacobsen and co workers reported the first example of asymmetric catalysis in the co njugate addition reactions of cyanide (Scheme 1 5) 17 In this reaction, chiral (salen)AlCl complex 1 20 was used as a catalyst, and high yields and enantioselectivity

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25 were observed with unsaturated imides. Preliminary kinetic study show s that a bimetall ic, dual activation mechanism is involved. Scheme 1 5 Conjugate addition of TMSCN to unsaturated imides catalyzed by (salen)AlCl complex The use of two different chiral metal catalysts is beneficial for dual activation in some cases Jacobsen and co workers reported that the combination of oxo dimeric (salen)Al complex 1 2 2 and (pybox)ErCl 3 complex 1 2 3 improved catalytic efficiency further in the same cyanide conjugate addition (Scheme 1 6) 18 In contrast to (salen)AlCl complex 1 20 oxo analogue 1 2 2 was found to be i nactive owing to th e lack of the cyanide activation. They found that the addition of (pybox)ErCl 3 complex 1 2 3 in the presence of 1 2 2 efficiently promotes th is reaction through the dual activation of the cyanide nucleophile by 1 2 3 and the imide by 1 2 2 Compared to the (sa len)AlCl system, total catalyst loadings in the dual catalysis system were decreased from 10 mol% to 5 mol% without any loss of enantioselectivity. The cyanide addition to imine electrophiles is also a very useful reaction because the resulting compounds can be transformed into various compounds. Shibasaki and co workers have reported gadolinium complex 1 2 5 Gd for the asymmetric Strecker reaction of ketimines (Scheme 1 7). 19 This chiral Gd complex was prepared from Gd(O i Pr) 3 and D glucose derived ligand 1 2 5 in a 1:2 ratio, and the resulting complex

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26 showed high enantioselectivity in the asymmetric TMSCN addition to a wide range of N diphenylphosphinoyl ket imines This glucose based gadolinium catalyst was very useful for other various reactions, including t he cyanosilylation of ketones, 20 the conjugate addition of TMSCN to unsaturated N acyl pyrroles, 21 and ring opening reactions of meso aziridines with TMSCN and TMSN 3 22 Scheme 1 6 Conjugate addition of TMSCN to unsatur ated imides Scheme 1 7 Catalytic enantiosel ective Strecker reaction of ket im i nes The results of mechanistic and ESI MS studies indicated that the active catalyst is a self assembled Gd/ 1 2 5 = 2:3 complex Thus, the mech anism involving bimetallic activation wa s proposed as a working model (Figure 1 8 ). 23 In this cooperative system, one gadolinium metal activates the electrophile, and the cyanide nucleophile is activated by the other gadolinium metal ions rather than by the phosphane oxide moiety.

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27 Figure 1 8 Proposed mechanism for Strecker reaction To gain structural information they attemp t ed to obtain the crystal structure of the actual catalytic species (Gd/ 1 2 5 = 2:3 complex) Howev er, the single crystal obtained from the 1 2 5 Gd complex ( Gd(O i Pr 3 ) / 1 2 5 = 2:3) in propionitrile/hexane solution was a 4:5 complex (Gd/ 1 2 5 = 4:5) with a oxo atom (Scheme 1 8 1 2 7 ) 24 Interestingly, ESI MS study of 1 2 7 indicates that this tetranuclear structure is maintained in a solution state. Unexpectedly, when higher order aggregated crystal 1 2 7 was employed to the same Strecker reaction of N diphen ylphosphinoyl ket imines much slower reaction and opposite ena n tioinduction were observed. Thus, they conclude d that the assembly mode is the determining factor for the function of asymmetric induction in polymetallic catalysi s, not the structure of each c hiral ligand module. Trost and co workers developed a dinuclear zinc catalyst that was successfully applied to enantioselective direct aldol reactions (Scheme 1 9). 25 This chiral semi crown/Zn catalyst promotes the reaction of acetophenone and bulky aldehyd es with high enantioselectivity, wherein one zinc metal acts as a Lewis acid and the other zinc metal acts as a Br nsted base. The use of this dinuclear zinc catalyst has been successfully applied to desymmetrization of meso diol, 26 enantioselective Henry, 27 aza Henry, 28 alkynylation, 29 Friedel Crafts, 30 Mannich, 31 and conjugate addition reactions. 32

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28 Scheme 1 8 E nantioselective Strecker reaction of ketim i nes catalyzed by 1 2 7 Scheme 1 9 Chir al dinuclear zinc catalyst for asymmetric aldol reaction s

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29 Recently, Shibasaki and co workers reported salen based hetereobimetallic catalysts ( Scheme 1 10) 33 They showed that this heterobimetallic Cu Sm Schiff base complex 1 33 efficiently catalyze nitro M annich reactions with high syn diastereoselectivity and enantioselectivity. The cooperative activation of the imine and the nitroalkane by two different metals is the key to achieving such high selectivities. The interesting feature of this Schiff base lig and system is that a smaller transition metal can be selectively installed into the inner N 2 O 2 cavity and an oxophilic rare earth metal with a large ionic radius into the outer O 2 O 2 cavity Scheme 1 10 Shibasaki s Cu S m Schiff base system The same group successfully expanded this dinucleating Schiff base ligand system to other catalytic asymmetric reactions. Th e bench stable homodinuclear Ni 2 Schiff base complex ( 1 3 6 ) works well for the anti diaster e oselective formatio n of tetrasubstituted anti diamino acid surrogates with high enantioselectivity (Scheme 1 11) 34 The introduction of 1,1 binaphth yl 2,2 diamine backbone in 1 3 6 allows for the incorporation of metals with a smaller ionic radius into the O 2 O 2 outer c avity in contrast to 1 3 3 This dinucleating Schiff base system proved to be highly efficient for a variety of different asymmetric reactions and often different combination s of inner and outer metals were used

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30 Scheme 1 11 Diastereoselective nitro Mannich reaction catalyzed by 1 3 6 A h ighly efficient heterogeneous bimetallic catalyst has been introduced by Shibas a ki and co workers. 35 T he amide based ligand bearing a m oriented phenolic hydroxyl group was utilized as a p latform to form a heterobimetallic complex with a rare earth metal and an alkali metal (Scheme 1 12) This heterogeneous Nd/Na heterobimetallic catalytic system demonstrates excellent anti selectivity and en a ntioselectivity in nitroaldol reaction for a bro ad range of aldehydes and nitroalkanes Scheme 1 1 2 H eterogeneous bimetallic system for anti selective nitroaldol reaction s Recently, Peters and Jautze reported bispalladacycle complex 1 4 2 for the enantioselective Mi chael addition of aryl substituted cyanoacetates to vinyl ketone s

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31 (Scheme 1 13) 36 This soft bimetallic complex is capable of simultaneously activating both substrates in a highly stereocontrolled manner, resulting in the formation of a quaternary stere ocenter with high ena n tiomeric excess. As shown in Figure 1 9, the enone electrophile can be activated by the carbophilic Pd cente r, and the cyanoacetate nucleophile can be activated by the other Pd center. The use of this bispalladacycle catalyst has be en successfully applied to tandem azlactone formation Michael addition reaction. 37 Scheme 1 13 Bispalldacycle catalyzed asymmetric Michael addition Figure 1 9 Proposed cooperative bim etallic activation mechanism Enhancement of C ooperative B imetallic A ctivation As described in the previous section there ha ve been growing efforts to construct more efficient catalytic systems using dual activation concept. Mechanistic and kinetic

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32 studies have disclosed that certain types of metal catalyzed reaction s involve a bimetallic reaction pathway between individual catalytic units. However, this intermolecular bimetallic activation often led to low efficiency and selectivity at low catalyst loading or at the late stage of reactions. To overcome this limitation the covalent ly linking or merging strategy has been utilized, in which two or multiple catalytic units are linked through an appropriate linker or merging within a single framework. In this s ection, those attempts will be discussed. The asymmetric ring opening (ARO) of epoxides has emerged as a powerful method for the preparation of synthetically useful aminoalcohols, diols, and related compounds in an optically active form. 38 The asymmetric r ing opening of meso epoxide s with TMSN 3 catalyzed by (salen) Cr(III) complex es was reported by Jacobsen and co workers in 199 5 which affords 1,2 azido silylethers with good to excellent enantioselectivity (Scheme 1 14) 39 Scheme 1 1 4 Asymmetric ring opening of meso epoxide with TMSN 3 It was found that catalyst 1 4 5 a wa s a precatalyst, and the actual catalytic species was 1 4 5 b The kinetic studies revealed the second order rate dependence on catalyst and significant non linear effects were observed in th e (salen)Cr(III) catalyzed ARO of epoxides with TMSN 3 Those studies show that a bimetallic mechanism is operating,

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33 wherein simultaneous activation of the nucleophile and the electrophile by distinct catalyst molecules occ urs (Figure 1 10 ) Figure 1 10 Bimetallic mechanism for ARO of epoxides with TMSN 3 The afore mentioned mechanistic studies led to design of new catalysts that could enforce bimetallic cooperative activation. C ovalent te thering has been employed to construct dimeric salen systems for the purpose of increasing bimetallic environment. In this re gard Jacobsen and co workers devised dinuclear salen complexes using flexible tethers (Figure 1 1 1 ) 40 This bimetallic complex enfo rced cooperativity between catalysts. It was also shown that the length of tether significantly impact the reactivity where the dimeric catalyst with medium tether (n = 5) displayed a maximu m value of k intra and enantioselectivity. Figure 1 1 1 D imeric (salen) Cr catalyst for ARO of epoxides

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34 As with the ARO of epoxides with TMSN 3 the hydrolytic kinetic resolution (HKR) of terminal epoxides using (salen) Co(III) complex es follows similar bimetallic mechanism. Due to its im portance of HKR a great deal of effort ha s been made to develop more efficient catalytic system. The achievement of HKR of epoxide will be described in more detail in C hapter 3. I n the previous section the chiral (salen) Al cat a lyzed conjugate cyanation w as described as a n example of bimetallic cooperative catalysis To enforce bimetallic activation the similar strategy has been taken Jacobsen and Mazet reported tethered dinuclear (salen)Al Cl complex 1 48 for the conjugate cyanation of unsaturated imides (Scheme 1 15) 41 Compared to the monomeric Al Cl complex, this covalently linked dinuclear catalyst 1 4 8 showed superior efficiency in terms of reactivity without loss of enantioselectivity Kinetic studies of this reaction proved tha t an intramolecular pathway is two orders of magnitude greater than the second order component of the reaction catalyzed by 1 4 8 Scheme 1 1 5 Covalent ly tethered d inuclear (salen)Al catalyst for conjugate addition

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35 Coate s and co workers reported a highly efficient bimetallic catalyst for the enantioselective polymerization of epoxides (Scheme 1 16) 42 The b imetallic catalyst 1 50 featuring a chiral binaphthol linker proved to be highly active and selective for the preparat ion of stereoregular polyethers By X ray analysis, Co Co separations are found to be 5.963 and 5.215 which are very close to the ideal metal metal separation of 6 for epoxide opening reactions they suggest Scheme 1 1 6 Enantioselective polymerization of epoxides Very recently, Ding and co workers reported highly efficient dimeric titanium com plex 1 5 2 for the cyanohydrin synthesis, in which two salen units were connected through a covalent tether (Scheme 1 17) 43 As described in Scheme 1 4, t he catalytically active oxo titanium(salen) species is in equilibrium to the inactive oxo species. To minimize th e catalytically unfavorable dissociation of oxo species, the cis 5 norbornene endo 2,3 dicarboxylate bridge was e mployed between two salen units The resulting dimeric catalyst showed excellent reactivity and enantioselectivity in the asymmetric cyanohydrins synthesis even at as low as 0.0005 mol% of catalyst loading. This remarkable catalytic efficiency can be attri buted to the reinforcement of cooperative dual activation by reducing the dissociation of catalytic species.

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36 Scheme 1 1 7 Bridged b imetallic titanium complex for enantioselective cyanohydrin synthesis Optically pure bina phthol ( BINOL ) and its deriv atives constitute the core structure of many highly effective chiral ligands for a wide range of asymmetric catalysis 44 as well as biaryl natural products. 45 The catalytic oxidative coupling of 2 naphthols has drawn much attention lately as an atom efficient, mild, and direct synthetic route to enantiomerically pure BINOL. 46 Several metal based catalysts involving copper, iron, cobalt, and vanadium have been developed for this reaction where either monometallic or bimetallic mechan ism ha s been proposed depending on the catalytic system 45,46 Martell and co workers reported dinuclear Cu complex 1 5 4 for the enantioselective oxidative coupling (Scheme 1 18) 47 In this catalyst design, two Cu metals are bound to two N 2 O 2 cavities in the fused macrocyclic Schiff base ligand. This bimetallic Cu complex efficiently catalyze s the oxidative coupling to afford BINOL product s with high enantioselectivity. A h omolytic coupling of two radical species that were generated through one electron trans fer from substrate to the Cu(II) center, was suggested as a plausible mechanism.

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37 Scheme 1 1 8 D inuclear Cu catalyst for the enantioselective oxidative coupling The chiral vanadium complexes have been also employed to asy mmetric oxidative coupling of 2 naphthols. Chen and Uang independently reported the chiral vanadium complexes derived from naphthyl backbone, which can catalyze the oxidative coupling of 2 naphthol and its derivative s (Figure 1 1 2 ) 48 However, moderate ee v alues (51 87%) were obtained for the 2 naphthol substrates lacking an ester functionality at the C 3 position Figure 1 1 2 Chiral vanadium complexes for oxidative coupling To improve the catalytic efficiency, dinuclear vanadium complexes have been devised. Gong and co workers reported dinuclear bis vanadium complex 1 60 for the highly enantioselective oxidative coupling of 2 naphthol (Scheme 1 19) 49 The structural feature of this catalyst is the V O V linkage. Their kine tic and mechanistic studies suggest that the catalytic oxidative coupling reaction occurs through intramolecular

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38 radical radical coupling pathways involving two vanadium metals. Sasa i and co workers also developed similar chiral dinuclear vanadium catalyst 1 61 50 With the dinuclear catalyst, up to 91% ee was achieved for the formation of ( S ) BINOL. From kinetic analysis, they found that the coupling reaction rate using dinuclear catalyst is 48 times faster than that of the mononuclear catalyst. Interestingl y, the catalyst of which the absolute configuration is same as that of Gong s catalyst gave the opposite enantiomer as a major product. Although t he reason for the reversed enantioselectivity is not clear at this point, the authors suggest that the generat ion of oligomeric dinuclear complexes could be involved. Scheme 1 1 9 Dinuclear vanadium catalyzed oxidative coupling of 2 naphthol s

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39 Supramolecular C atalysis Supramolecular chemistry has grown into an important area in or ganic and inorganic chemistry over the last three decades. Large and complex structures can be obtained through the self assembly of relatively simple subunits without using covalent bonds. These subunits are programmed to form the supramolecular structure by the utilization of weak and reversible interactions such as metal coordination, hydrogen bonds, interactions, and van der Waals interactions between the components. Indeed, nature largely utilizes those weak interactions for recognition of substrates as well as organization of catalytic systems. Therefore, the application of supramolecular chemi stry to catalysis has drawn much attention to develop more efficient and selective catalyst s 51 However, despite the recent progress in supramolecular catalysis, successful examples of supramolecular cata l ysis are still rare compared to the conventional cat alysis. The reason is that the prediction and control of weak interactions is still challenging and those interactions can affect and often inhibit the catalytic site. However, if it is possible to control and predict those interactions in supramolecular catalysis, this approach could provide a lot of opportunities to develop powerful and selective catalytic systems In general, two main approaches are considered in the field of supramolecular catalysis. First, the reversible non covalent interactions hav e been utilized to recognize substrates. Second, more sophisti cated catalysts can be constructed via self assembly of relatively simple units through non covalent interactions Both approaches have offered a great opportunity to find the efficient catalyti c system for challenging reactions or even to enable completely unknown chemical transformations. This section will focus on the second approach and recent examples will be described in detail.

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40 Coordination Driven Supramolecular Catalysts The metal coordin ation has been utilized to build supramolecular catalytic systems. In 2002, Lin and co workers developed a chiral organometallic triangle for the dialkylzinc addition to aldehydes (Scheme 1 20) 52 This macrocyclic ligand features three platinum metals at th e vertices of the triangle formed by the three BINOL edges The macrocyclic triangle ligand 1 62 gave high ee (91%) for the addition of diethylzinc to 1 naphthaldehyde, whereas monomeric ligand 1 63 showed a slightly lower ee (80%). Scheme 1 20 Asymmetric dialkylzinc addition to aldehyde An interesting feature of the metal coordination based supramolecular catalysts is that the allosteric regulation is possible owing to its reversible nature Mirkin and co workers repo rted the salen based dinuclear Cr catalyst in which two Rh metals were used as the allosteric, structural motifs (Figure 1 1 3 ) 53 In the closed dimeric form 1 65 the Rh metal site is chelated by both phosphine and sul fur atoms, and the two catalytic metal (CrCl) s ites are in close proximity (~5.2 separation) T his coordination driven supramolecular catalyst 1 65 reveals the significant 20 fold rate enhancement in the

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41 asymmetric ring opening of cyclohexene oxide with TMSN 3 as compared to a corresponding m onomeric (salen) Cr(III) analogue In addition, the observed enantiomeric excess is much higher under the same reaction conditions (68% vs 12% for monomer). By addition of the external ligands Cl and CO to the closed form, the cooperative activity between catalytic metal (CrCl) sites can be regulated. Because the thioether sulfur atoms are relatively poor donors, the ligand exchange readily occurs to give the open dimeric form 1 6 6 The open macrocyclic catalyst exhibits two fold rate increase for the same epoxide opening reaction compared to the closed dimeric catalyst. This remarkable result demonstrates that the reactivity and selectivity of the supramolecular catalysts can be modulated by the addition of controllers such as Cl or CO. Figure 1 1 3 Mirkin s supramolecular allosteric catalyst

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42 The utilization of metal coordination or hydrogen bonds in the formation of supramolecular bidentate ligands is highly attractive, because large libraries can be easily accessed and rapid screening is possible by simply varying components. Two general methods have been recently developed : template mediate assembly and direct assembly (Figure 1 1 4 ) Three components are required in the template mediated assembly to make rather complic ated systems. Nevertheless large ligand libraries are easily accessible by this approach (10 x 10 x 10 = 1000 members based on 30 components). In contrast, t he direct assembly provides a simpler system because it requires only t wo components However, to achieve large ligand libraries, more building blocks are required in this approach (30 x 30 = 900 members based on 60 components) Figure 1 1 4 Schematic illustration of supramolecular bidentate ligands In this regard Reek and co workers developed template mediated bidentate ligands for the rhodium catalyzed hydroformylations for the first time (Scheme 1 21) 54 In this ligand assembly, bis (porphyrin)Zn complex was employed as a template and Zn pyridine coordinations wer e utilized Although this supramolecular catalyst did not give

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43 good enantioselection (33% ee) it display ed unusual ly high regioselectivity for the branched product in hydroformylation (branched:linear = >100:1) Scheme 1 21 Asymmetric hydroformylation using supramolecular rhodium catalyst Based on the direct ligand assembly approach through metal coordination, Reek and co workers developed zinc porphyrin /pyridine based ligands for rhodium catalyzed asymmetric hydrogenat ion reactions (Scheme 1 22) 55 The optimal combination of component s ( 1 72 ) was chosen after rapid screening of a library of 64 ligands, which was readily accessible with this strategy. Based on a similar strategy, Takacs and co workers developed self assem bled chiral bidentate bis phosphite ligands for the asymmetric Pd catalyzed allylic amination (Scheme 1 23). 56 Treating two monophosphite ligands bearing a pendant bisoxazoline with Zn(OAc) 2 led to the preferential formation of the heteroleptic (box) 2 Zn com plex, in which the Zn metal served as a structural element. Like other supramolecular bidentate

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44 ligands, this modular and combinatorial approach allowed for rapid screening of 50 different combinations of spacers and backbones to find optimal catalytic eff iciency. As a consequence, Pd complex 1 75 was found to be the optimal combination which efficiently catalyzed the allylic amination with high enantioselectivity. Scheme 1 22 Asymmetric hydrogenation using supramolecul ar rhodium catalyst Scheme 1 23 Self assembled chiral diphosphite palladium catalyzed a symmetric allyl i c amination s Another interesting use of metal coordination in supramolecular chemistry is the build ing of cage like macromolecules, which can accommodate small molecules inside the cavity. The resulting molecular cages can function as a n a noreactor by providing a confined reaction environment. 57 In 1995, Fujita and co workers reported the formation

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45 of M 6 L 4 assembling enc apsulated cage by mixing tridentate 4 pyridyl ligands and Pd precursors in aqueous solution (Figure 1 1 5 ) 58 The resulting supramolecular cage is thermodynamically stable and is able to accommodate guest molecules such as adamant yl carboxylate ion. In addit ion, the well defined, hydrophobic cavity of this coordination driven cage can provide a microenviron ment that promote s reactions such as trimerization of trialkoxysilanes, 59 alkane oxidation s 60 and Diels Alder reaction s 61 Quite impressively, the unusual re activity and selectivity inside the cavity led to discover new transformations which were otherwise inaccessible. Figure 1 1 5 Fujita s M 6 L 4 supramolecular assembly In 2002, the same group showed that this cage could be a good encapsulated cat alyst for photo catalyzed [2+2] cycloaddition of sterically demanding olefins 62 This cage can nicely accommodate reactants in side the cavity in the head to tail syn configuration through aromatic interactions (Scheme 1 24). After irrad iation of 1 7 7 a 1 7 8 complex, as a result, the head to tail syn isomer 1 7 9 was obtained in excellent yield

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46 without any other regio and stereoisomers. Without the cage, no photoaddition products were observed even at a very high concentration. Scheme 1 2 4 [2+2] Photocycloaddition within encapsulated catalyst Very recently, the enantioselective catalysis with this cage catalyst has been accomplished In 2008, Fujita and co workers utilized their chiral M 6 L 4 cage catalyst 1 7 7 b for enantioselective [2+2] cross photocycloaddition reactions of fluoranthrene with a maleimide (Scheme 1 25) 63 To build a chiral cage, (1 R ,2 R ) N N diethyl 1,2 diaminocyclohexane ligands were used. Good asymmetric induction (50% ee) and regioselect ion w ere observed considering the remote location of the chiral ligand. Scheme 1 2 5 Asymmetric [2+2] photocycloaddition within a cage

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47 Raymond and co workers reported M 4 L 6 self assembled system (M = Ga 3+ Al 3+ Fe 3+ Ge 4 + Ti 4+ L = 1,5 bis(2 ,3 dihydroxybenzamido)naphthalene) with metal coordination bond (Figure 1 1 6 ) 64 This cavity containing metal assembly provides well defined polyanionic and hydrophobic cavity, which allows for encapsulation of cationic species The self assembled cage 1 83 has been used as a nanoreactor for the C H activation, 65 acidic hydrolysis of orthoformates 66 and isomerization of allylic alcohols. 67 Figure 1 1 6 Raymond s M 4 L 6 supramolecular assembly In this co ntext Raymond and co workers also showed that self assembled cage 1 83 can catalyze the unimolecular [3,3] aza cope rearr angement of allyl enammonium sa lts (Figure 1 1 7 ) 68 This host assembly accelerates the rates fo r rearrangement by up to 3 orders of mag nitude, and independence of rates with solvents support this reaction occur r ing inside the cavity. Although the building blocks for this [Ga 4 L 6 ] 12 assembly are achiral, 1 83 is chiral as a result of the three bidentate catecholates binding to each gallium centers. Those two enantiomeric forms 1 83 and 1 83 were successfully separated by addition of ( ) N methylnicotinium iodide (Scheme 1 26). 69 After treating with ion exchange chromatography, both enantiomers were obtained as the tetramethyl

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48 ammo nium salts. With this chiral capsule, they performed the enantioselective version of the aza Cope rearrangement, which afforded the resulting rearranging product with high enantioselectivity (78%). This ee value is the highest ee by synthetic supramolecula r hosts to date. Figure 1 1 7 Aza Cope rearrangement within a self assembled cavity Scheme 1 2 6 Enantioselective aza Cope rearrangement by a chiral supramolecular assembly

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49 Hydrogen Bo nding Mediated Supramolecular Catalysts Hydrogen bonding interaction represents probably the most important non covalent interaction used in the supramolecular chemistry owing to their pronounced directionality and relatively high strength. Although hydrog en bond itself is a much weaker bond compared to the covalent bond, it can be utilized to build strongly assembled structures by combining multiple hydrogen bonds In this context, hydrogen bonding interactions have been re co gnized as one of the main force s to construct supramolecular structure s and recognize specific guest molecules. However, the successful application of this interaction for supramolecular catalysis has been rarely developed so far As an early example, Yano and co workers developed a sel f assembled catalytic system by the use of hydrogen bonds and electrostatic interactions. 70 The 2,6 diaminopyridine moiety has been known as a thymine receptor through three hydrogen bonds. 71 Based on this idea, they devised a supramolecular system in which thymine bearing thiazolium ion 1 8 9 and 2,6 diaminopyridine derivative 1 8 8 are self assembled via hydrogen bonds (Figure 1 1 8 ) The pyruvate anion can be attracted via ionic interaction s to the alkali metal cation bound into the crown ether moiety of 1 8 8 rendering the reaction intramolecular in nature This catalytic system exhibited rate acceleration up to 160 times for the thiazolium catalyzed oxidative decarboxylation of pyruvate. Like metal coordination driven capsules, properly oriented multiple hyd rogen bonding interactions can be utilized to construct the molecular capsule having a well defined cavity. In contrast to metal coordination cages, those hydrogen bonds mediated

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50 cages are generally not stable in polar or aqueous media due to the nature of hydrogen bonds. Rebek and co workers reported molecule 1 90 which can self assemble through Figure 1 1 8 Supramolecular oxidative decarbo x ylation of pyruvate multiple hydrogen bonds to form a molecular capsule in nonpol ar solvent (Figure 1 1 9 ) 72 The dimerization constant of 1 90 is very large (>10 6 M 1 ) in benzene and the resulting self assembled capsule possess an interior volume of ~300 3 This self assembled capsule provides a well defined hydrophobic cavity that can accommodate more than one small guest molecule, and certain type of intermolecular reactions can be accelerated inside the cavity. Indeed, t his encapsulated catalyst displays 200 times rate acceleration for Diels Alder reaction compared to non catalyzed r eaction. A few years later, Rebek and Chen also reported a self assembled cylindrical cavity for 1,3 dipolar cycloaddition reactions (Figure 1 20). 73 The resorcinarene based molecule ( 1 94 ) can dimerize through twelve hydrogen bonds. The cavity size of the self assembled capsule is calculated as ~450 3 which is larger than that of previous self assembled systems. In the presence of this molecular capsule, the rate acceleration was observed in the 1,3 dipolar cycloaddition between phenyl azide 1 95 and phe nylacetylene 1 96 In addition, a single regioisomer ( 1 97 ) was formed

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51 exclusively in this system. However, due to the product inhibition, substoichiometric catalysis was not accomplished. Figure 1 1 9 S elf assembled mol ecular capsule for Diels Alder reaction Figure 1 20 S elf assembled cylindrical capsule for cycloaddition reaction

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52 Aida and co workers utilized hydrogen bonds to assemble dimeric bifunctional catalyst (Figure 1 2 1 ) 74 In this catalyst design, 2 ureidoisocytosine motif was employed to assemble two catalytic units in close proximity through quadruple hydrogen bonds This interesting catalyst showed rate acceleration up to 4.7 fold in the epoxide opening reaction with thiol Figure 1 2 1 S upramolecular catalyst via multiple hydrogen bonds Another example of supramolecular organocatalyst has been reported by Clarke and Fuentes 75 The feature of this system is that a chiral precatalyst and an a chiral additive are self assembled through complementary hydrogen bonds, in which achiral additives would alter the steric environment around the catalytic site (Scheme 1 27) This modular approach allows the enantioselectivity to be fine tuned easily by s imply changing achiral additives. In this report, aminonaphthyridine derived proline was used as a chiral catalyst unit, and a library of achiral pyridinone compounds was used as an achiral additive. As a consequence, the optimal combination ( 1 100 ) enhanc ed the reaction rate as well as diastereo and enantioselectivity compared to a simple proline catalyst in the asymmetric conjugate addition of cyclic ketones to nitroalkene s Ionic interactions are generally stronger than hydrogen bonding interactions, th us they have been used for supramolecular assembly. Recently, Ooi and co workers reported a unique ion pair catalyst which is assembled through hydrogen bonding

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53 Scheme 1 2 7 Self assembled organo catalyst for asymmetric c onjugate addition networks for asymmetric conjugate addition (Scheme 1 28). 76 S upramolecular ion pair catalyst 1 104 (OPh) 3 H 2 was prepared by ion exchange of tetraaminophosphonium chloride 1 104 Cl with hydroxide, and subsequent neutralization with phenol. The self assembled structure of 1 104 (OPh) 3 H 2 was confirmed by a single crystal X ray analysis. The authors proposed that enolate 1 102 could replace the phenoxide anion of 1 104 (OPh) 3 H 2 maintaining similar hydrogen bonding networks. When the modified self assembled catalyst 1 104 ( 3,5 Cl 2 C 6 H 3 O ) 3 H 2 was employed in the asymmetric conjugate addition of azlactone 1 102 the desired adduct 1 105 was obtained in excellent yield with high dr and ee. The same reaction with 1 104 Cl gave much lower enantiosele ctivity (34% ee ), indicating that all components are necessary for high selectivity. Zhao and Mandal reported modularly designed organocatalytic assemblies through ionic interactions (Scheme 1 29) 77 They utilized quinidine thiourea and proline as component s to build self assembled catalysts. This multicomponent catalyst was very efficient for direct nitro Michael addition reactions of ketones to nitroalkenes.

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54 Scheme 1 28 Chiral ion pair catalyst for the conjugate additio n Scheme 1 2 9 Multicomponent catalyst for the asymmetric conjugate addition Ionic interactions also can be used for the construction of main chain functionalized polymers. Recently, Itsuno and co workers developed main chain chiral polymer 1 10 9 containing a quaternary ammonium sulfonate as a repeating unit (Scheme 1 30) 78 This chiral polymer can function as a chiral organocatalyst, displaying good efficiency and enantioselectivity in the asymmetric benzylation of N diph enylmethylid e ne glycine ester in biphasic conditions. In addition, owing to its

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55 insoluble nature, the catalyst could be easily separated from the reaction mixture and recycled. Scheme 1 30 Main chain ionic polymer catal yst Transition metal catalyst s ha ve been a key player for numerous asymmetric transformations. Therefore, it would be interesting to construct supramolecular transition metal catalysts using hydrogen bonds However, the control of H bonds in metal catal y ti c systems is difficult because hydrogen bond donors/acceptors are also generally good ligands for the metals 79 Neverth e less, some pioneering research has been reported with this approach Among those attempts, supramolecular bidentate ligands through hydr ogen bonding interactions have been successfully developed Like coordination driven approach, this strategy allows an easy access to various combination s of ligand libraries In some cases, hydrogen bonded bidentate ligands showed comparable or even bette r performance compared to those o f covalently bonded diphosphine ligands Breit and Seiche realized the self assembled bidentate ligand system through hydrogen bonding s for the first time. 80 They utilized the 2 pyridone/2 hydroxypyridine tautomer s 81 to

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56 const ruct self assembled bidentate phosphine ligand s which can form a bidentate chelate wit h a transition metal (Scheme 1 31) The resulting supramolecular rhodium(I) catalyst 1 1 14 proved to be eff i cient and highly regioselective for the hydroformylation of t erminal alkenes. Scheme 1 3 1 S upramolecular bidentate catalyst for hydroformylation As mentioned earlier hydrogen bonds can be utilized to generate supramolecular bidentate ligand libraries. Based on this concept, the Breit group developed a heterodimeric bidentate ligand system in which the 2 aminopyridine/isoquinolone H bonding pair was utilized as an A T base pair analogue (Figure 1 2 2 ) 82 Owing to its array of H bonding donor/acceptor, the formation of homodimeric s pecies would be suppressed. This supramolecular heterobidentate system allowed for facile generation of a 4 x 4 library. From the screening of this library for the rhodium catalyzed hydroformylation of terminal alkenes, the optimal catalyst combination s we re successfully identified. Figure 1 2 2 Self assembled heterobidentate ligand

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57 This highly modular approach has been extended to asymmetric catalysis by employing chiral ligands. The same group reported chiral hetero bid entate ligands for rhodium catalyzed asymmetric hydrogenati on reaction, where the same 2 aminopyridine/isoquinolone H bonding motif was incorporated into chiral phosphonite ligands (Scheme 1 32). 83 The most efficient catalyst combination ( 1 11 8 ) displayed e xcellent performance in the asymmetric hydrogenation of acetamidoacrylates with up to 99% enantiomeric excess. Scheme 1 3 2 Self assembled heterobidentate catalyst for asymmetric hydrogenation Ding and co workers reporte d supramolecular phosphoramidite ligand for the rhodium catalyzed asymmetric hydrogenation of ( Z ) and ( E ) acrylates and itaconate derivatives (Scheme 1 3 3 ) 84 In this report, monodentate phosphoramidite ligands bearing a n N H bond was found to be very react ive and selective. Theoretical calculations and NMR studies reveal that the intermolecular H bonds between adjacent mono phosphoramidite ligands around the Rh metal center c ould reduce the inter ligand bite angle for the exceptional reactivity. Based on a similar concept, Reek and co workers recently developed a series of supramolecular bidentate ligand systems using hydrogen bonds for the asymmetric hydrogenation reactions. In one example, they reported supramolecular bidentate

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58 Scheme 1 3 3 Asymmetric hydrogenation catalyzed by 1 1 21 phosphine ligand s ( UREAphos ), by the use of intermolecular urea urea hydrogen bonding interaction (Scheme 1 34) 85 The resulting UREAphos rhodium complex showed impressive efficiency for asy mmetric hydrogenation of aceta midoacrylates Scheme 1 3 4 Supramolecular bidentate ligand for asymmetric hydrogenation The same group also utilized a single hydrogen bond between the NH group of the phosphoramidite and t he urea carbonyl group of a functionalized phosphine to build supramolecular hetero bidentate system (Scheme 1 35) 86 The resulting rhodium complex 1 125 exhibited very high enantioselectivity (>99% ee) for the asymmetric hydrogena tion of methyl 3 hydroxy 2 methylpropionate 1 124 (Roche ester) An interesting supramolecular bidentate system based on ligand tautomerism was also developed by Reek and co workers. The authors disclosed that sulfonamide derived phosphine compound 1 1 27 a has a stable tautomer 1 1 2 7 b in CDCl 3 (Scheme

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59 Scheme 1 35 Supramolecular Rh catalyst for asymmetric hydrogenation 1 36) 87 These two tautomers can form hydrogen bonded bis ligated metal complex 1 1 28 Solution IR and NMR studies revealed that th e hydrogen bonding interaction exists between the NH group of coordinated 1 1 27 a and the S O group of 1 1 27 b The chiral version of th e adaptive supramolecular catalyst 1 1 29 showed excellent enantioselectivity (99% ee) in the asymmetric hydrogenation of m ethylacrylamide 1 117 (MAA). Scheme 1 3 6 A daptive supramolecular catalyst for asymmetric hydrogenation

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60 Recently, Gennari and co workers reported novel chiral supramolecular ligands, PhthalaPhos, which were utilized for enantioselective rhodium catalyzed hydrogenation reactions (Scheme 1 3 7 ) 88 The PhthalaPhos ligand was self assembled through amide hydrogen bonds, and the resulting rhodium complex 1 131 showed excellent efficiency for the enantioselective hydrogenatio n of challenging cyclic enamide 1 1 30 Scheme 1 3 7 Asymmetric hydrogenation catalyzed by PhthalaPhos Rh complex Immobi lization of catalyst on organic or inorganic solid supports has been an important ar ea, because separatio n and recy cling of precious catalysts is highly desirable 89 Traditionally, the catalysts were anchored on the support throug h covalent linker. Although the covalent linking approach enabled the catalyst recycling the preparation of such immobilized cataly sts generally required long synthetic steps and time consum ing purification s Thus, as an alternative, non covalent anchoring approach has emerged. 90 The non covalent approach c ould offer facile modulation of catalytic sites and reuse of catalysts. Bianchin i and co workers reported tripodal polyphosphine rhodium catalysts immobilized on silca via hydrogen bonding (Figure 1 2 3 ) 91 The authors found that the immobilized Rh catalyst is more chemoselective in the hydrogenation and hydroformylation reactions and m ore easily recyclable than the unsupported analogue.

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61 Figure 1 2 3 Supported hydrogen bonded catalyst s Reek Meijer and co workers utilized hydrogen bonds and ionic interactions to anchor phosphine ligand s on a soluble po ly(propylene imine) dendrimer backbone (Figure 1 2 4 ) 92 The binding studies revealed that the acid contain in g phosphine ligand was tightly bound to the periphery of the dendrimer through the combination of H bonds and ionic interaction The resulting supram olecular Pd complex showed similar activity and selectivity in the allylic amination reaction of crotyl acetate and piperidine to that of the monomeric complex. In addition, this large supramolecular catalyst can be easily separated from the reaction mixtu re using nanofiltration techniques. Figure 1 2 4 Supramolecular anchoring of catalysts on dendrimer As an extension of this approach to heterogen e ous catalys is Ding and co workers reported immobilized Rh catalyst by ort hogonal self assembly through hydrogen bonding and ligand to metal coordination interactions (Scheme 1 38) 93 They integrated MonoPhos ligand and 6 methyl 2 ureido 4[1 H ]pyrimidone (UP) group into one molecule. This UP moiety has been known to form very stro ng dimer ( K a = 6 10 7 M 1 in CHCl 3 )

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62 through complementary, quadruple H bonding interactions. By addition of [Rh(cod) 2 ]BF 4 to the resulting ligand, the orthogonal self assembled polymer 1 1 33 can be formed, which is thermally stable and insoluble in less p olar organic solvents such as toluene. Th e resulting heter ogen e ous polymeric Rh(I) catalyst displayed excellent asymmetric induction in the catalytic hydrogenation of dehydro amino acid and enamide derivatives. In addition, an efficient recovery and reu se of catalyst was achieved Scheme 1 3 8 Self supported Rh complex through hydrogen bonds Recently, W rnmark and co workers reported a dynamic supramolecular heterobimetallic (salen) Mn (porphyrin) Zn system, where multip le hydrogen bond interactions were introduced to assemble two units (Scheme 1 3 9 ) 94 In this catalyst design, complementary pyridone/isoquinolone hydrogen bonds are used to assemble (salen)Mn complex 1 1 38 and (porphyrin) Zn complex 1 1 39 This catalytic sys tem wa s designe d to give substrate selectivity in the catalytic epoxidation reaction of olefin, as the (porphyrin)Zn could bind pyridine containing substrates preferentially However, the observed selectivity between pyridine cont a ining substrate 1 1 36 and phenyl derived

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63 substrate 1 1 37 was not high but noticea ble in competing experiment ( 1.5 5:1 ). Although the observed selectivities are not high, this approach showed that weak, kinetically labile hydrogen bonding interactions can be applied to build supramo lecular dinuclear catalyst s containing transition metals. Scheme 1 3 9 Catalytic epoxidation by supramolecular catalytic system Supramolecular Bioconjugate Systems Nature offers a great deal of chiral environment, genera ting chiral molecules with high selectivity in biotransformation. T he combination of metal catalysis and biocatalysis could be a highly attractive strategy toward efficient asymmetric catalysis. Covalent attachment of metal catalyst to biopolymers such as antibody and protein has been achieved by several groups however this approach gave very limited success with respect to efficiency and stereoselectivity. 95 Alternatively, one can conceive a supramolecular anch oring strategy, where multiple weak interactio ns such as hydrogen bonds, ionic interaction, and stacking interactions are utilized in lieu of covalent bonds 96 The supramolecular strategy can be advantageous because many different

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64 combinations can be easily tested like other supramolecular catalysis a nd the chemical conversion with biomolecules which is sometimes troublesome, can be avoided. As early as 1978 Wilson and Whitesides reported an achiral rhodium avidin hybrid catalyst for enantioselective hydrogenation (Scheme 1 40 ) 97 The biotin avidin non covalent interactions is very strong in biological systems ( K a = 10 15 M 1 ). 98 Although the enantioselection was moderate (39% ee), this research demonstrated that the chiral environment of biomolecules could be utilized for asymmetric reaction s catalyzed b y achiral metal complex. Recently, Ward and co workers have improved the enantioselectivity of this catalytic system up to 96% ee by changing avidin to streptavidin, which is known to possess a deeper binding pocket 99 Sc heme 1 40 Enantioselective hydrogenation catalyzed by biotin/avidin hybrid Rh complex Ward and co workers expand ed this approach to other enantioselective reactions. They reported ruthenium complex/streptavidin hybrid for the enantioselective reduction of acetophenone to 1 phenylethanol by transfer hydrogenation (Scheme 1 4 1 ) 100 To obtain the best catalytic efficiency, a combined structural variation of both chemical and

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65 biological components was utilized. As such, the artificial metalloenzyme substantia lly improved the performance of metal complex/protein hybrids. After screening, they found the combination of 6 p cymene capping arene and the mutant Pro64Gly gave the de s ired product in the highest conversion (92%) and ee (94%). Scheme 1 4 1 Ruthenium complex/streptavidin hybrid catalyzed asymmetric reduction Reetz and Jiao re p orted copper phthalocy anine conjugates of bovine serum albumins for the Diels Alder cyclization (Scheme 1 4 2 ) 101 In this hybrid system, polysulfonic acid mediated ionic interaction was employed to anchor Cu phthalocyanine 1 1 48 into the protein The result ing protein conjugate catalyze d Diels Alder reaction s with high e nantioselectivity up to 93% ee Scheme 1 4 2 Albumin conjugated copper complex for Diels Alder reaction s

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66 The use of double helix DNA s has recently emerge d as a new area of bioconjugate catalyst. As a pioneering work, Feringa and Roefles demonstrate d hybrid DNAzymes in asymmetric catalysis for the first time (Scheme 1 4 3 ). 102 An acridine moiety was utilized as an intercalator, and was responsible for supramol ecular assembly with the rig ht handed double helix DNA. The resulting 1 152 Cu / DNA hybrid catalyst showed good endo stereo selectivity for D i els Alder cyclization of cyclopentadiene with pyridine containing dienophiles. Sc heme 1 4 3 DNA based hybrid catalysts for the stereoselective Diels Alder cyclization In the last decade, we have witnessed advances in the design and application of supramolecular catalysts. Since the non covalent bonds have an inherent dynamic character the supramolecular approach provides new opportunities in catalysis. Particularly, this concept has been effectively applied for the generation of ligand libraries, recyclable catalysts, and nanoreactors. However, it is still very challenging to

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67 rational ly design efficient catalytic system using a supramolecular strategy due to the lack of understanding of catalytic mechanism and non covalent interactions Nonetheless, by considering the apparent advantage such as easy access to large libraries the supra molecular approach could find more applications in catalysis.

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68 CHAPTER 2 SELF ASSEMBLED DINUCLEAR CATALYST THROUGH HYD ROGEN BONDS FOR ASYMMETRIC HENRY REA CTIONS Ligand D esign and S ynthesis Inspired by previous research on cooperative activation and supramo lecular catalys i s, we devised a new bimetallic system in which hydrogen bonds were utilized to co nnect two chiral metal catalyst units By introducing hydrogen bonding motifs to chiral metal framework with an appropriate linker, chiral bimetallic catalyst c ould be readily formed in solution via self a ssembly (Figure 2 1) 103 Figure 2 1 Design of s elf assembled dinuclear catalyst via H bonding interactions The apparent advantage of this approach is that various homodimeric heterodimeric, or even heterobimetallic catalysts can be obtained by mixing monomeric units in solution (Figure 2 2) If we can access various bimetallic catalysts without having to synthesize individual ligands, it would dramatically increase chances of finding new bimetallic catalysts and new synthetic methodologies which are not currently available. In addition, we can modulate the metal metal distance and the strength of association of catalytic units by varying hydrogen bonding motif and linker parts

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69 Figure 2 2 Homodimeric, heterodimeric, and heterobimetallic catalysts mediated by hydrogen bonding interaction s In 1994, Wuest and Ducharme reported that the self aggregation behavior of di pyridone scaffold s 104 Accordi ng to this report unsymmetric al di pyridone compound 2 1 discretely forms dimer ic structure through two comple mentary hydrogen bonding interaction s in both dilute CHCl 3 solution ( G > 6.5 kcal/mol) and in the solid state (Figure 2 3 a ) In contrast, symmetrical di pyridone compound 2 2 prefer s the formation of linear oligomeric aggregated structures (Figure 2 3b) Inspired by the pioneering work of Wuest and co workers, we initially decided to utilize this complementary 2 pyridone/ 2 pyridone hydrogen bonding pair for novel self assembled catalyst. Figure 2 3 S elf compl e ment a ry di pyridone system

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70 The chiral salen (tetradentate Schiff base) framewor k has been recognized as a privileged class of ligands in asymmetric catalysis. 105 The metal salen complexes have exhibited excellent efficiency in a wide range of asymmetric transformation such as epoxidation, kinetic resolution of epoxides, sulfoxidations, cycloadditions, conjugate additions, and Mannich reactions with good to excellent levels of asymmetric induction. 106 The metal salen complex es preferentially adopt a planar geometry. It has been known that the metal salen complex also can have cis or ci s conformation depending on the type of backbone and metal 107 However, the metal salen complex es with diaminocyclohexane backbone generally exhibit a square planar geometry, where one of the apical positions is available for substrate binding. Another advan tage of salen catalysts is their accessibility. Salen ligands are generally obtained by condensation of chiral diamine backbone and salicylaldehydes in nearly quantitatively yield. Subsequent meta lation allows a variety of metal salen complexes from first and second row transition metal s as well as ma in group metals. In this regard we decided to use salen as a chiral framework to develop self assembled catalyst s In the initial catalyst design, two symmetrical salens were devised to f orm a hetero dimeric st ructure. In s ymmetrical salen 2 3 2 pyridone ring is connected to the salen core through an acetylene linker on 6 position of pyridone ring The other symmetrical salen 2 4 ha s the connection on 3 position of the pyridone ring (Figure 2 4a) Owing to thei r H bond ing array two symmetrical salen compound s can not form homodimeric structures; i nstead, the heterodimeric structures are expected to form when they are employed together In contrast, unsymmetrical salen 2 5 is expected to

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71 form a homodimeric struct ure through two compl e mentary hydrogen bonding interactions (Figure 2 4b) Figure 2 4 Design of pyridone /pyridone H bonding self assembled salen catalyst s The synthesis of symmetrical (salen) Co complex 2 3 began with th e reaction of 2 8 and trimethylsilylacetylene under typical Sonogashira coupling conditions (Scheme 2 1) After removal of trimethylsilyl group using K 2 CO 3 the resulting compound ( 2 9 ) was reacted under Sonogashira coupling conditions with iodosalicylalde hyde 2 7 which was prepared using a known method 108 After removal of the benzyl group with TMSI, t he resulting salicylaldehyde ( 2 11 ) was condensed with ( R R ) 1,2 diaminocyclohexane to furnish symmetrical salen ligand 2 12 The salen ligand was then reacte d with

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72 Co(OAc) 2 4H 2 O in MeOH at room temperature under argon to give 2 pyridone incorporated (salen)Co complex 2 3 in 78% yield. Scheme 2 1 Synthesis of symmetrical (salen) Co complex 2 3 To prepare another symmetrical s alen complex 2 4 a similar synthetic strategy was applied (Scheme 2 2) 3 Bromo 2 hydroxypyridine 2 13 was selectively benz ylated on O position using Ag 2 CO 3 in hexane to afford 2 14 in 74% yield. The resulting product ( 2 14 ) was coupled with trimethylsily l acet y l ene under Sonogashira coupling conditions, followed by the removal of TMS group with KOH in aqueous MeOH The resulting compound ( 2 15 ) was then coupled with iodosalicylaldehyde 2 7 under Sonogashira coupling conditions to give 2 1 6 in 71% yield. To afford deprotected pyridone

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73 intermediate 2 17 iodotrimethylsilane was used in CH 2 Cl 2 Although 2 17 was isolated in 57% yield this compound was unstable in solution and in the solid state According to the literature, 109 this array of pyridone acetylene f unctional groups is prone to cyclize to form fused furan ring as described in Figure 2 5. Therefore, ( salen )Co complexes 2 4 and 2 5 might not be suitable for catalysis because of the instability Scheme 2 2 Synthesis of intermediate 2 17 Figure 2 5 Plausible i ntramolecular cyclization of intermediate 2 17 The replace ment of hydrogen bonding motif was necessary to a d dress the stability issue with our initial design Adenine/thymine ( AT) hydrogen bonding motif was found ubiquitously in nature. In addition, a s described in C hapter 2 Breit and co workers successfully utilized pyridone/aminopyridine hydrogen bonding motif as an AT base pair mimic for the supramolecular bidentate ligands (Figure 2 6a) 82,83 Inspired by those examples we designed new symmetrical salen complex 2 18 that can form a heterodimeric structure with another symmetrical salen 2 3 (Figure 2 6 b ) In addition unsymmetrical ( salen )Co complex 2 19 was newly designed I n both cases the 2

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74 aminopyridine motif was introduced as a suitable hydrogen bonding pa r tner with the 2 pyridone motif. Figure 2 6 New catalyst design using a pyridone/aminopyridine H bonding pair The synthesis of sym metrical salen complex 2 18 began by reacting commercial 2 aminopyridine 5 boronic ester 2 20 with pivaloyl chloride (Scheme 2 3) The resulting compound was transformed into salicylaldehyde 2 21 using Suzuki coupling reaction protocol s The desired symmet rical ( salen )Co complex ( 2 18 ) was easily prepared using similar metal ation condition s from symmetrical salen ligand 2 22 For the synthesis of unsymmetrical salen ligand 2 23 two different salicylaldehydes were reacted with ( R R ) 1,2 diaminocyclohexane i n the direct condensation protocol (Scheme 2 4). Interestingly, the yield of this reaction (53 78%) was more than the statistical maximum (50%). Usually, such direct condensation protocols gave the unsymmetrical salen products in less than 50% yields. 110 Thi s result

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75 could be rationalized by a template effect through hydrogen bonding interactions (Figure 2 7). Finally, the desired unsymmetrical (salen)Co complex ( 2 19 ) was obtained by metalation of 2 23 Scheme 2 3 Synthesi s of symmetrical (salen)Co complex 2 18 Scheme 2 4 Synthesis of unsymmetrical (salen)Co complex 2 19 Figure 2 7 Template effect in the synthesis of 2 23

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76 To gain insight s about the s tructure and the mode of self assembly of th e s e (salen) Co complexes we tried to obtain single crystal s of sel f assembled (salen)Co complex 2 19 for X ray analysis However, m any attempts to grow a single crystal of cobalt complex 2 19 were unsuccessful. T hus other metal salen complexes such as Ni and Zn were prepared (Scheme 2 5) Scheme 2 5 Synthesis of (salen) Ni and (salen) Zn complexes Among them, an orange colored, single crystal of (salen) Ni complex 2 24 suitable for X ray analysis was finally obtained by slow diffusion of hexane to CH 2 Cl 2 solution The ORTEP view of Ni complex 2 2 4 is shown in Figure 2 8 The Ni metal is coordinated in a N 2 O 2 coordination compartment and adopts a near square planar geometry. The X ray packing structure of the (salen)Ni complex 2 24 clearly indicated the proposed self assembly through complementary hydrogen bonding (Figure 2 9). The self assembled dimer 2 24 2 24 adopts the head to tail conformation where the metal metal distance is determined as 4.054(2) This result suggests that the geometry and

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77 place of hydrogen bonding motifs was nicely arranged to form a strong dimeric structure, as we anticipated. Figure 2 8 ORTEP view of the crystal st ructure of 2 24 with the t hermal ellipsoids drawn at 50% probability Figure 2 9 X ray structure of self assembled dimeric (salen) Ni complex 2 24 2 24 Catalytic E nantioselective Henry ( N itro A ldol) R eaction The asymmetric Henry (nitro aldol ) reaction represents a powerful C C bond forming reaction to provide chiral nitro alcohol s which are highly valuable building blocks in asymmetric synthesis. In addition, the nitro alcohols can be further transformed in to amino alcohol s and hydroxy acids In 199 2, Shibasaki and co

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78 workers reported the first asymmetric Henry reactions using the heterobimetallic catalyst as des c ribed in C h apter 1. 8 Since then, a number of excellent catalysts including metal complexes, phase transfer catalysts, and organocatalysts have been employed for this reaction 111 It is important to note that both aldehydes and nitronates can coord inate to the metal centers, which might enable dual activation for this reaction. Chiral (salen)metal complexes have been also applied to asymmetric Henry reactions. In 2004, Yamada and co workers reported (salen) Co(II) catalyzed Henry reactions for the first time (Scheme 2 6) 112 However, only ortho halogenated benzaldehydes gave nitroaldol adducts with good enantioselectivity. A few years later, Skar e wski and co workers showed that (salen) Cr(III ) complex can catalyze asymmetric Henry reactions with moderate enantioselectivity (Scheme 2 6) 113 Although both (salen)metal complexes can catalyze Henry reaction smoothly, those catalysts suffer from low reacti vity and moderate enantioselectivity. Scheme 2 6 (Salen)metal catalyzed asymmetric Henry reaction Interestingly, the introduction of sterically demanding groups at the 5,5 positions of salen ligands has a beneficial ef fect on enantioselectivity as well as reactivity.

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79 Skar ewski and co workers recently reported sterically modified (salen) Cr(III ) complex 2 29 which showed improved reactivity and enantioselectiv ity compared to the t butyl substituted (salen)Cr(III) complex (Scheme 2 7) 114 Scheme 2 7 Sterically modified (salen)Cr complex for asymmetric Henry reaction s Very recently, Shibasaki and co workers reported heterobimetallic Pd/La/Schiff base complex es for anti selective asymmetric n itroaldol reactions. 115 This dinucleating Schiff base complex displayed high anti diastereo selectivity which was very challenging with conventional methods. Using this catalyst ( ) ritodrine ( 2 3 1 ) and adrenoreceptor agonist ( 2 3 2 ) were synthesized in a short reaction sequence (Scheme 2 8 ). Scheme 2 8 The anti selective catalytic asymmetric nitroaldol reaction s promoted by a Pd/La heterobimetallic catalyst

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80 Although no mechanistic pr o of was provided at the outset of this research, it was conceivable that metal salen catalyzed Henry reactions could proceed via a bimetallic mechanism. Therefore, we decided to evaluate our self assembled catalysts for the asymmetric Hen ry reactions. Self A ssembled D inuclear (Salen) Co(II) C atalyzed Henry R eaction To determine the catalytic effici e ncy, n ewly prepared symmetrical and unsymmetrical (salen) Co complexes were tested in the reaction of o methoxy benzaldehyde and nitromethane in the presence of 2 mol% of DIPEA in CH 2 Cl 2 at 30 C (Table 2 1). While unsymmetrical (salen) Co (II) catalyst 2 19 afforded nitroaldol adduct 2 33 a in 87% yield with 96% ee (entry 1), monomeric (salen) Co(II) catalyst 2 26 provided the product in 11% yield wit h 55 % ee under the same reaction conditions (ent r y 8 ). To see the effect of the metal oxidation state on reactivity, monomeric Co(III) acetate 2 26(OAc) was prepared by a known method. 116 In this test, Co(III) catalyst 2 26(OAc) gave the product in less than 10% yield with 64% ee (entry 9). Two s ymmetrical (salen) Co complexe s ( 2 3 and 2 18 ) gave the product in low yields (12 and 16%) and that were similar to those of monomeric Co catalyst (entries 5 6). As described in the previous section, both s ymmetri cal ( salen )Co complexes are expected to form oligomeric or polymeric aggregates owing to their arrays of hydrogen bonding donors and acceptors. When MeOH was used as a solvent, a loss of enantioselectivity was observed and shorter reaction times (40 h) wer e required (entries 3 and 10). Interestingly when an equimolar mixture of (salen) Co complexe s 2 3 and 2 18 was used as a heterodimeric catalyst, the product was obtained with good ee (87%), but the yield was low (18%) as when they are used alone (entry 7 ). This result suggests that those two symmetrical salen complexes would form a relatively weak hetero dimeric

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81 species. When 100 mol% of base were used, the reaction was accelerated with the slight loss of enantioselectivity (entry 2). Scheme 2 9 (Salen)Co catalyzed asymmetric Henry reaction Table 2 1. Henry reaction of o methoxybenzaldeh yd e entry (salen) Co DIPEA (mol%) solvent time (h) yield (%) ee (%) 1 2 19 2 CH 2 Cl 2 90 87 96 2 2 19 100 CH 2 Cl 2 40 91 91 3 2 19 2 MeO H 40 89 25 4 2 19 + 2 23 (6 mol%) 2 CH 2 Cl 2 90 59 96 5 2 3 2 CH 2 Cl 2 90 12 72 6 2 18 2 CH 2 Cl 2 90 16 69 7 2 3 + 2 18 2 CH 2 Cl 2 90 18 87 8 2 26 2 CH 2 Cl 2 90 11 55 9 2 26 (OAc) 2 CH 2 Cl 2 90 <10 64 10 2 26 2 MeOH 40 93 5 11 2 34 2 CH 2 Cl 2 90 14 70 Interesti ngly, when free ligand 2 23 (6 mol%) was added to the reaction mixtur e in the presence of 2 19 (2 mol%) yield was lowered noticeably without loss of enantioselectivity ( Table 2 1, entry 4) This result suggest s that free ligand 2 23 might play a role as a competitive inhibitor for the bimetallic species formation ( Figure 2 10 ).

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82 Figure 2 10 Metal complex/ligand self assembly The substrate scope was then examined with 2 mol% of (salen) Co 2 19 (Scheme 2 10) The results ar e shown in Table 2 2. To reduce the reaction time further, slightly more concentrated conditions were used o rtho S ubstituted benzaldehydes were found to be more reactive and selective in general (entry 1 3) Although more catalyst loading (5 mol%) and lon ger reaction time (110 h) was required, electron rich p methoxy benzaldehyde was smoothly converted to the nitroaldol adduct in 77% yield and 81% ee (entry 6) Overall, various aryl aldehydes afforded h igh enantiomeric excesses (81 96% ee) and good to exc ellent yield (65 99%) Scheme 2 10 Self assembled (salen)Co catalyzed asymmetric Henry reaction Table 2 2 Substrate scope of self assembled (salen) Co catalyzed Henry reaction entry aldehyde (salen) Co (mol%) time (h) y ield (%) ee (%) 1 o MeOC 6 H 4 ( 1 17 a ) 2 48 89 96 2 o ClC 6 H 4 ( 1 17 b ) 2 14 97 93 3 o FC 6 H 4 ( 1 17 c ) 2 14 97 94 4 p CF 3 C 6 H 4 ( 1 17 d ) 2 40 99 82 5 p FC 6 H 4 ( 1 17 e ) 2 40 65 90 6 p MeOC 6 H 4 ( 1 17 f ) 5 110 77 81 7 1 naphthyl ( 1 17 g ) 2 40 92 91 8 2 naphthyl ( 1 17 h ) 2 65 88 87

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83 Kinetic S tudy To verify our hypothesis of bimetallic activation, kinetic studies of the Henry reaction catalyzed by 2 19 were conduct ed by monitoring initial reaction rates ( consumption of o methoxybenzaldehyde). M esitylene was us ed as an in ternal standard. The reaction progress was monitored by the rem mixture and HPLC analysis for the first 15 45% of the reaction. The slopes of the least square lines for the plots of ([SM] 0 [SM]) v ersus time were determined (Figure 2 11) Same kinetic experiments were also perfor med with the monomeric (salen)Co catalyst 2 26 for comparison (Figure 2 12). Figure 2 11 Initial rates of the asymmetric Henry reaction with 2 19 In these experiments, reaction r ate s were determined over a 5 10 fold range of catalyst concentrations. A linear correlation between rates vs [ catalyst ] 2 was obtained in both cases (Figure 2 13 ), indicating a second order dependence on catalyst. This result supports that two (salen)Co(II) catalysts are involved in the rate determining transition state. The mea sured rate constant k obs with self assembled catalyst 2 19 is found to be

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84 Figure 2 12 Initial rates of the asymmetric Henry reaction with 2 26 289 M 1 h 1 which is 48 times larger than that with monomeric catalyst 2 26 ( k obs = 6.02 M 1 h 1 ). The rate ac celeration by 2 19 can be attributed to the facile formation of bimetallic species through two complementary hydrogen bonds in non polar media. Figure 2 13 Rate dependence on catalyst concentration However, after the c areful inspection of rate laws, we found that the catalyst order in the reaction can change depending on the self association strength of catalyst and its concentration Thus further kinetic and mechanistic stud ies might be needed to obtain

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85 more precise r eaction model of this self assembled catalyst. More d etailed discussion will be provided in C h apter 3. Self A ssembly S tudy NMR spectroscopy is particularly useful in the study of self assembly in solution. It would be desirable to perform NMR experiment s w ith (salen) Co(II) complex 2 19 but th e (salen)Co(II) complex exhibited broad signals due to the paramagnetism of Co(II) Although the Co(III) complexes are diamagnetic the signal of corresponding Co(III)( OAc ) complex was still broad For this reason we decided to use metal free ligand 2 23 as a model compound to estimate self association strength. First, we tried to determine the dimerization constant of 2 23 in CDCl 3 at room temperature However, n o obvious chemical shift change (< 0.02 ppm) was observe d for the pivalamide N H proton at the three representative concentrations (0.15, 1.5, and 10 mM) as shown in Figure 2 14 Assuming more than 90% dimer formation at the lowest concentration measured Figure 2 14 Stacked 1 H NMR (300 MHz) spectra of aromatic region of salen ligand 2 23 at the concentration of 0.15, 1.5 and 10 mM in CDCl 3 at 25 C

PAGE 86

86 (0.15 mM) the dimerization constant K dim can be estimated as exceeding 3.0 10 5 M 1 in CDCl 3 at 25 C. Aforementioned 1 H NMR exper iment in CDCl 3 indicates the strong hydrogen bonding interaction s in the 2 pyrid on e / aminopyridine functionalized salen ligand. To obtain more precise information on the strength of self assembly in this system, more polar medi um was chosen. When 25% v/v CD 3 NO 2 in CDCl 3 was used as a medi um which is similar to the actual Henry reaction conditions, the N H signal of the pivalamide group and the signals of three protons of the pyridine ring in the free ligand were changed upon variation of concentration (0.14 1 9.09 mM). As depicte d in Figure 2 15 downfiel d shifts of those signals were observed upon increasing concentration. Figure 2 15 Stacked 1 H NMR (300 MHz) spectra of aromatic region of diluted samples (0.14 19.1 mM) of 2 23 in 25% v/v CD 3 NO 2 in CDCl 3 at 25 C

PAGE 87

87 Table 2 3 Measured chemical shifts of pivalamide N H H a H b and H c using 25% v/v CD 3 NO 2 in CDCl 3 at 25 C concentrations (N H ) (H a ) (H b ) (H c ) 0.14 mM 8.311 8.216 8.050 7.619 0.26 mM 8.311 8.217 8.050 7.620 0.40 mM 8.314 8.218 8.051 7.621 0.66 mM 8.318 8.219 8.052 7.622 0.93 mM 8.320 8.220 8.053 7.623 1.58 mM 8.327 8.221 8.055 7.625 2.22 mM 8.335 8.223 8.056 7.627 2.85 mM 8.343 8.225 8.058 7.629 3.48 mM 8.349 8.226 8.059 7.631 4.70 mM 8.359 8.228 8.061 7.633 5.90 mM 8.373 8.230 8.063 7.635 8.20 mM 8.392 8.234 8.066 7.638 10.39 mM 8.408 8.237 8.067 7.641 12.49 mM 8.415 8.238 8.069 7.642 14.48 mM 8.426 8.240 8. 071 7.644 19.09 mM 8.457 8.244 8.073 7.647 Assuming a fast exchange condition in this system, the resulting data were fitted using a nonlinear curve fitting method to find three parameters ( K dim mono and dim ) in the following equation, where the standard deviation ( ( obs cal ) 2 ) shows a minimum value. [mono] = [ dim ] + {[1 (8 K dim [mono] 0 + 1)1/2]) / 4 K dim [mono] 0 }/ ( dim mono ) The dimerization constant ( K dim ) of the self assembled salen l igand 2 23 was estimated as 53 21 M 1 by using non linear cu rve fitting methods. The calculation result was shown in Figure 2 16. After our report, 103 W rnmark and co workers reported dynamic supramolecular (salen)CrCl catal ysts for epoxide ring opening reactions with trimethylsilyl azide based on similar concept (Figure 2 17). 117 In this research, they utilized self complementary 2

PAGE 88

88 Figure 2 16 Complexation induced chemical shift changes of proton signals in metal free salen ligand 2 23 in 25% v/v CD 3 NO 2 in CDCl 3 at 25 C Figure 2 17 Self assembled (salen)CrCl catalyst for epoxide opening reactions pyridone containing isoquinone/quinolinone motif to assem ble two (salen)Cr catalysts, and a 6 fold rate acceleration was observed in the asymmetric ring opening of epoxides

PAGE 89

89 with azide nucleophile. However, the enantioselectivity observed was generally less than 10% ee. Summary In summary we developed a novel ch iral dinuclear (salen)Co catalyst self assembled through hydrogen bonds, and this catalyst successfully mediated the enantioselective Henry reaction. The self assembled dinuclear (salen) Co(II) catalyst results in significant rate acceleration (48 times fas ter) as well as high enantioselectivity compared to the non functionalized (salen) Co(II) catalyst. The observed rate acceleration can be rationalized by the facile formation of dimeric catalyst through H bonds. To the best of our knowledge, this is the fir st example of chiral bimetallic system using hydrogen bonds In addition, we also suggest that bimetallic mechanism is operating in (salen)Co(II) catalyzed Henry reaction. Experimental General Remarks All reactions were conducted in flame dried glassware under an inert atmosphere of dry argon. THF, CH 2 Cl 2 Et 2 O and toluene were purified under positive pressure of dry nitrogen by Meyer Solvent Dispensing System prior to use. All the chemicals used were purchased from Sigma Aldrich Co., Acros Organics, TCI A merica, and Strem Chemic al Incs. and were used as recei ved without further purification. NMR spectra were recorded using a Me r cury 300 FT NMR, 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 residual signals from CDCl 3 (1H) 7.26 ppm and (13C) 77.23 ppm. High resolution mass spectra were recorded on a GC/MS spectrometer or a TOF LC/Ms spectrometer. Optical rotations were recorded on a Perkin Elmer 241 polarimeter.

PAGE 90

90 Enantiomeri c ratios were determined by chiral HPLC analysis (Shimadzu) using Chiralpak IA and IB columns. Catalyst Preparation 3 tert B utyl 2 hydroxy 5 iodobenzaldehyde ( 2 7) 3 t Butoxy 2 hydroxy benzaldehyde 2 6 (2.50 g, 14.03 mmo l) was dissolved in glacial acetic acid (15 mL), and then iodine monochloride (3.18 g, 19.59 mmol) in glacial acetic acid (15 mL) was added to the resulting solution at room temperature. The mixture was heated to reflux for 3 h, and then cooled to room tem perature. This solution was poured into water (100 mL), and then extracted into CH 2 Cl 2 (2 x 50 mL). After extraction, the organic layer was washed with aqueous sodium thiosulfate solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressur e. The resulting crude product was purified by column chromatography on silica gel (10% ethyl acetate in n hexane) to give 2 7 (4.25 g, 100%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ) 11.74 (s, 1 H), 9.80 (s, 1 H), 7.72 (d, J = 2.3 Hz, 1 H), 7.69 (d, J = 2.3 Hz, 1 H), 1.41 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 196.1 161.1, 142.8, 141.6, 140.2, 122.7, 80.8, 35.3, 29.2 ; HRMS (DIP CI MS) c alcd for C 11 H 13 IO 2 [M] + : 303.9960, f ound: 303.9939 2 (Benzyloxy) 6 ((trimethylsilyl)ethynyl)pyridine (2 3 5 ) A stirred mixture of 2 bromo 6 benzyloxypyridine 2 8 (2.02 g, 7.65 mmol), CuI (58 mg, 0.30 mmol), PdCl 2 (PPh 3 ) 2 (63 mg, 0.15 mmol), (trimethylsilyl)acetylene (1. 3 mL, 9.14 mmol), and

PAGE 91

91 triethylamine (5 mL, 35.87 mmol) in THF (5 mL) was heated at reflux under argon for 12 h. The mixture was cooled to room temperature, diluted with Et 2 O (100 mL), and washed with H 2 O, and then dried over anhydrous Na 2 SO 4 Volatiles wer e removed by evaporation under reduced pressure, the residue was then purified by column chromatography on silica gel (10% ethyl acetate in n hexane) to give 2 3 5 (2.12 g, 98%) as a pale yellow liquid. 1 H NMR (300 MHz, CDCl 3 ) 7.44 7.58 (m, 3 H), 7.31 7.4 4 (m, 3 H), 7.11 (d, J = 7.4 Hz, 1 H), 6.77 (d, J = 9.1 Hz, 1 H), 5.42 (s, 2 H), 0.31 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 163.5, 140.1, 138.8, 137.4, 128.7, 128.5, 128.1, 121.6, 111.9, 104.2, 94.3, 68.2, 0.1; HRMS (APCI TOF) c alcd for C 17 H 20 NOSi [M+H] + : 28 2.1309, f ound: 282.1314. 2 (Benzyloxy) 6 ethynylpyridine (2 9) A mixture of 2 3 5 (2.12 g, 7.53 mmol), 2 O (2.85 g, 9.03 mmol), and 1N HCl (7.6 mL) in THF (20 mL) was stirred overnight at room temperature. The resul ting mixture was diluted with ethyl acetate (100 mL), washed with H 2 O (2 x 100 mL), and dried over anhydrous Na 2 SO 4 Volatiles were removed by evaporation under reduced pressure, the residue was then purified by column chromatography on silica gel (10% eth yl acetate in n hexane) to give 2 9 (1.53 g, 97%) as a pale yellow li quid. 1 H NMR (300 MHz, CDCl 3 7.44 7.61 (m, 3 H), 7.29 7.43 (m, 3 H), 7.13 (d, J = 6.5 Hz, 1 H), 6.81 (d, J = 8.5 Hz, 1 H), 5.40 (s, 2 H), 3.14 (s, 1H); 13C NMR (75 MHz, CDCl 3 ) 163.6, 139.3, 138.9, 137.2, 128.7, 128.4, 128.1, 121.4, 112.4, 83.2, 76.7, 68.2; HRMS (APCI TOF) c alcd for C 14 H 12 NO [M+H] + : 210.0913, f ound: 210.0914.

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92 5 ((6 (Benzyloxy)pyridin 2 yl)ethynyl) 3 tert butyl 2 hydroxybenzaldehyde (2 10) A stirred mixture of 2 9 (1.53 g, 7.31 mmol), CuI (56 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (60 mg, 0.15 mmol), 3 tert butyl 2 hydroxy 5 iodobenzaldehyde 2 7 (2.22 g, 7.32 mmol), and triethylamine (5 mL, 35.87 mmol) in THF (10 mL) was heated at reflux under a rgon for 12 h. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with H 2 O, and then dried over anhydrous Na 2 SO 4 Volatiles were removed by evaporation under reduced pres s ure the residue was then purified by column chromatography on silica gel (10% ethyl acetate in n hexane). The combined fractions were then triturated with ethyl acetate to give 2 10 (1.70 g, 60%) as a pale yellow solid. 1 H NMR (300 MHz, CDCl 3 11.98 (s, 1 H), 9.88 (s, 1 H), 7.74 (d, J = 2.0 Hz, 1 H), 7.70 (d, J = 2.3 Hz, 1 H), 7.58 (dd, J = 8.5, 7.4 Hz, 1 H), 7.44 7.52 (m, 2 H), 7.31 7.44 (m, 3 H), 7.17 (d, J = 7.1 Hz, 1 H), 6.79 (d, J = 8.2 Hz, 1 H), 5.44 (s, 2 H), 1.44 (s, 9 H); 13 C NMR (7 5 MHz, CDCl 3 ) 196.8, 163.7, 161.9, 140.4, 139.3, 138.9, 137.6, 137.3, 135.9, 128.7, 128.4, 128.1, 121.1, 120.7, 113.7, 111.6, 88.1, 87.9, 68.2, 35.3, 29.3; HRMS (APCI TOF) c alcd f or C 25 H 24 NO 3 [M+H] + : 386.1751, f ound: 386.1750. 3 tert Butyl 2 hydroxy 5 ((6 oxo 1,6 dihydropyridin 2 yl)ethynyl) benzaldehyde (2 11) TMSI (0.29 mL, 2.03 mmol) was added to a solution of 2 10 (600 mg, 1.56 mmol) in CH 2 Cl 2 (10 mL), and allowed to stir overnight at room temperature

PAGE 93

93 under argon. A fter the addition of MeOH (5 mL) to the reaction mixture, and then volatiles were removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel (10% ethyl acetate in n hexane, then pure ethyl acetate), and t hen the combining fraction was triturated with ethyl acetate to give 2 11 (379 mg, 82%) as a pale yellow solid. 1 H NMR (300 MHz, CDCl 3 ) 12.45 (br s, 1 H), 12.04 (s, 1 H), 9.89 (s, 1 H), 7.73 (d, J = 2.1 Hz, 1 H), 7.71 (d, J = 2.1 Hz, 1 H), 7.39 (dd, J = 9.2, 6.9 Hz, 1 H), 6.59 (d, J = 9.3 Hz, 1 H), 6.47 (d, J = 6.8 Hz, 1 H), 1.47 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 196.8, 164.9, 162.4, 141.1, 139.5, 137.5, 136.2, 129.8, 121.1, 120.7, 112.5, 111.2, 94.0, 81.7, 35.3, 29.3; HRMS (APCI TOF) c alcd f or C 18 H 18 NO 3 [M+H] + : 296.1281, f ound: 296.1284. 2 12 To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine (55 mg, 0.48 mmol) in THF (8 mL), 2 11 (298 mg, 1.01 mmol) was added at room temperature, and then allowed to stir for 3 h. The s olution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate) to give 2 12 (321 mg, 100%) as a yellow solid. 1 H NMR (300 MHz, DMSO d 6 ) 14.80 (br s, 2 H), 11.86 (br s, 2 NH), 8.53 (s, 2 H), 7.33 7.46 (m, 6 H), 6.43 (d, J = 6.8 Hz, 2 H), 6.36 (d, J = 9.1 Hz, 2 H), 3.42 3.64 (m, 2 H), 1.98 (d, J = 5.9 Hz, 2 H), 1.75 1.87 (m, 2 H), 1.56 1.75 (m, 2 H), 1.40 1.54 (m, 2 H), 1.31 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 165.5, 164.8, 162.6, 141.0, 138.5, 133.8, 133.7, 130.7, 119.9, 118.5, 111.4, 110.5, 95.3, 81.2,

PAGE 94

94 72.4, 35.1, 32.8, 29.4, 24.4; HRMS (ESI TOF) c alcd for C 42 H 45 N 4 O 4 [M+H] + : 669.3435, f ound: 669.3504; [ ] D 21 +80.0 ( c 0.54, CH 2 Cl 2 ). 2 3 To a solution of 2 12 (140 mg, 0.21 mmol) in MeOH (5 mL), Co(OAc) 2 2 O (52 mg, 0.21 mmol) in MeOH (3 mL) was added, and allowed to stir at room temperature for 1 h under argon. Precipitate was collected by filtration, an d then dried under vacuum for 24 h to give 2 3 (123 mg, 81%) as a reddish brown solid. HRMS (ESI TOF) c alcd for C 42 H 42 CoN 4 O 4 [M] + : 725.2538, f ound: 725.2533. N (5 (4,4,5,5 Tetramethyl 1,3,2 dioxaborolan 2 yl)pyridin 2 yl) pivalamide (2 3 6 ) Pivaloyl chloride (0.30 mL, 2.44 mmol) was added to a solution of 2 aminopyridine 5 boronic acid pinacol ester 2 20 (446 mg, 2.03 mmol), and triethylamine (0.37 mL, 2.63 mmol) in CH 2 Cl 2 (3 mL) at 0C, the resulting mixture was allowed to warm to room temperature, and then allowed to stir overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with Et 2 O (30 mL), and then washed with water, 1N HCl (5 mL), and water. The combined aqueous fractions were back extracted with CH 2 Cl 2 (4 x 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and then concentrated under reduced pressure to give 2 3 6 (599 mg, 87%) as a white solid. This crude product was used for next step without further purification. 1 H NMR (300 MHz, CDCl 3 ) 9.73 (br s, 1 H), 8.52 (d, J = 1.1 Hz, 1 H), 8.44

PAGE 95

95 (d, J = 8.5 Hz, 1 H), 8.21 (dd, J = 8.8, 1.7 Hz, 1 H), 1.34 (s, 9 H), 1.23 (s, 12 H); 13 C NMR (75 MHz, CDCl 3 ) 178.3, 152.7, 149.8, 147.7, 114.6, 84.8, 75.3, 40.6, 27.4, 25.1; HRMS (( ) ESI TOF) c alcd fo r C 16 H 24 BN 2 O 3 [M H 2 Cl] : 303.1889, f ound: 303.1878. N (5 (3 tert Butyl 5 formyl 4 hydroxyphenyl)pyridin 2 yl)pivalamide (2 21) A stirred mixture of 2 20 (303 mg, 0.89 mmol), 3 tert butyl 2 hydroxy 5 iodobenzaldehyde 2 7 (302 mg, 0.99 mmol), Na 2 CO 3 (316 mg, 2.98 mmol), Pd(PPh 3 ) 4 (23 mg, 0.02 mmol), water (0.5 mL), and 1,4 dioxane (3 mL) was heated at reflux under argon for 12 h. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with H 2 O, and then dried over anhydrous Na 2 SO 4 Volatiles were removed by evaporation under reduced pressure, then the residue was purified by column chromatography on silica gel (10%, then 33% ethyl acetate in n hexane) to give 2 21 (185 mg, 59%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ) 11.83 (s, 1 H), 9.96 (s, 1 H), 8.45 (d, J = 2.3 Hz, 1 H), 8.33 (d, J = 8.8 Hz, 1 H), 8.07 (s, NH), 7.86 (dd, J = 8.6, 2.4 Hz, 1 H), 7.69 (d, J = 2.3 Hz, 1 H), 7.56 (d, J = 2.3 Hz, 1 H), 1.46 (s, 9 H), 1.35 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 197.3, 177.3 161.2, 150.9, 145.7, 139.6, 136.6, 132.8, 132.1, 129.9, 129.0, 121.0, 114.0, 40.1, 35.3, 29.4, 27.7; HRMS (ESI TOF) c alcd for C 21 H 26 N 2 O 3 [M+H] + : 355.2016, f ound: 355.2022.

PAGE 96

96 2 22 To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine (19 mg, 0.17 mmol) in THF (5 mL), 2 21 (116 mg, 0.33 mmol) was added at room temperature, and allowed to stir overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica g el (33% ethyl acetate in n hexane) to give 2 22 (83 mg, 65%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ) 14.01 (br s, 2 H), 8.36 (s, 2 H), 8.33 (d, J = 1.7 Hz, 2 H), 8.25 (d, J = 8.8 Hz, 2 H), 8.03 (s, 2 NH), 7.74 (dd, J = 8.6, 2.4 Hz, 2 H), 7.40 (d, J = 2.3 Hz, 2 H), 7.15 (d, J = 2.3 Hz, 2 H), 3.38 (dd, J = 5.7, 3.7 Hz, 2 H), 2.05 2.01 (m, 2 H), 1.93 1.91 (m, 2 H), 1.66 1.84 (m, 2 H), 1.46 1.57 (m, 2 H), 1.43 (s, 18 H), 1.32 (s, 18 H); 13 C NMR (75 MHz, CDCl 3 ) 177.2, 165.7, 160.5, 150.3, 145.5, 138.4, 13 6.5, 133.0, 128.1, 128.0, 127.3, 119.0, 113.8, 72.7, 40.0, 35.2, 33.2, 29.5, 27.7, 24.5; HRMS (APCI TOF) c alcd for C 48 H 62 N 6 O 4 Na [M+Na] + : 809.4725, f ound: 809.4765; [ ] D 21 41.1 ( c 0.57, CH 2 Cl 2 ). 2 18 To a solution of 2 2 2 (47 mg, 0.06 mmol) in MeOH (3 mL), Co(OAc) 2 2 O (15 mg, 0.06 mmol) in MeOH (1 mL) was added, and the resulting dark brown solution allowed to stir at room temperature for 3 h under argon. The reaction mixture was concentrated under reduced pressure, an d the residue was dissolved in CH 2 Cl 2 The resulting solution was filtered through celite, and then concentrated under reduced pressure. The resulting solid was dried under vacuum for 24 h to give bisaminopyridine (salen)Co 2 18 (50 mg, 100%) as a reddish brown solid. HRMS (APCI TOF) c alcd for C 48 H 60 CoN 6 O 4 [M] + : 843.4003, f ound: 843.4054.

PAGE 97

97 2 23 To a suspension of 2 11 (110 mg, 0.37 mmol) and 2 21 (132 mg, 0.37 mmol) in anhydrous THF (10 mL), a solution of (1 R ,2 R ) cyclohexa ne 1,2 diamine (42 mg, 0.37 mmol) in THF (5 mL) was added at room temperature, and allowed to stir for 15 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel column (33% ethyl acetate in n hexane, and then pure ethyl acetate) to give 2 23 (212 mg, 78%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ) 14.59 (br s, 1 H), 13.96 (s, 1 H), 10.72 (br s, NH, 1 H), 8.61 (s, NH, 1 H), 8.35 (d, J = 2.3 Hz, 1 H), 8.24 (d, J = 8.8 Hz, 1 H), 8. 21 (s, 1 H), 8.13 (s, 1 H), 7.73 (dd, J = 8.6, 2.4 Hz, 1 H), 7.30 7.43 (m, 3 H), 7.13 (d, J = 1.7 Hz, 1 H), 6.98 (d, J = 2.0 Hz, 1 H), 6.55 (d, J = 9.1 Hz, 1 H), 6.38 (d, J = 6.8 Hz, 1 H), 3.24 3.40 (m, 2 H), 2.01 2.1 4 (m, 2 H), 1.87 1.98 (m, 2 H), 1.72 1. 87 (m, 2 H), 1.51 1.69 (m, 2 H), 1.43 (s, 9 H), 1.37 (s, 9 H), 1.35 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 177.7, 165.9, 165.1, 164.4, 162.9, 160.5, 150.6, 145.2, 141.1, 138.6, 138.4, 136.8, 133.8, 133.4, 133.1, 129.8, 128.5, 127.9, 127.4, 120.8, 118.8, 118.5, 114.4, 111.0, 110.0, 95.5, 80.7, 72.2, 71.9, 40.1, 35.2, 35.1, 33.0, 33.0, 29.5, 29.3, 27.6, 24.4, 2 4.4; HRMS (ESI TOF) c alcd for C 45 H 54 N 5 O 4 [M+H] + : 728.4170, f ound: 728.4192; [ ] D 21 +108.4 ( c 0.31, CH 2 Cl 2 ).

PAGE 98

98 2 19 To a solution of 2 23 (100 mg, 0.14 mmol) in MeOH (5 mL), Co(OAc) 2 2 O (34 mg, 0.14 mmol) in MeOH (1 mL) was added, and allowed to stir at room temperature for 3 h under argon. Precipitate was collected by filtration, washed with MeOH, and then dried under vacuum for 24 h to give unsymmetrical (salen)Co 2 19 (91 mg, 83%) as a brown solid. HRMS (ESI TOF) c alcd for C 45 H 51 CoN 5 O 4 [M] + : 784.3268, f ound: 784.3297. 2 24 To a solution of 2 23 (30 mg, 0.04 mmol) in MeOH (3 mL), Ni(OAc) 2 2 O (10 mg, 0.04 mmol) in MeOH (1 mL) was added, and allowed to stir at room temperature overnig ht under argon. Precipitate was collected by filtration, washed with MeOH, and then dried under vacuum for 24 h to give unsymmetrical (salen)Ni 2 24 (24 mg, 74%) as a greenish yellow solid. Red single crystals suitable for X ray analysis were obtained by l ayering chloroform solution with n hexane and allowing slow diffusion at room temperature. 1 H NMR (300 MHz, DMSO d 6 ) 11.91 (s, 1 H), 9.77 (s, 1 H), 8.51 (s, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.95 (d, J = 8.1 Hz, 1 H), 7.80 (s, 1 H), 7.74 (s, 1 H), 7.67 (s, 1 H), 7.59 (s, 1 H), 7.41 (s, 1 H), 7.35 7.39 (m, 1 H), 6.39 (s, 1H), 6.32 (d, J = 9.6 Hz, 1 H), 3.13 3.17 (m, 2 H) 2.52 2.56 (m, 2 H), 1.73 1.81 (m, 2H), 1.36 (s, 9 H), 1.32 (s, 9 H), 1.23 1.37 (m, 4 H), 1.23 (s, 9 H) ; HRMS (ESITOF) c alcd for C 45 H 52 NiN 5 O 4 [M+H]+: 784.3367, f ound: 784.3370 Refinement details for 2 24 : C 22 H 24 Cl 0.50 N 8 NiO 0.75 ; M r = 488.93; T = 173(2) K ; wavelength = 0.71073 ; crystal system: t riclinic ; space group P 1 ; a = 13.8471(18) b = 16.144(2) c = 24.435(3) ; = 88.172(3) =

PAGE 99

99 88.307(3) = 87.923(2) ; V = 5454.0(12) 3 ; Z = 8; calcd = 1.191 Mg/m 3 ; = 0.786 mm 1 ; F (000) = 2036; crystal size = 0.15 x 0.07 x 0.04 mm 3 ; range = 0.83 to 22.50 ; index ranges: 14 h 14, 16 k 17, 26 l 24; reflections collecte d 24770, independent reflections 14238 [ R (int) = 0.0645] completeness to = 22.50 99.8%; absorption correction: integration; max./min. transmission 0.9692 / 0.8912 ; data/restraints/parameters 14238/0/989 ; goodness of fit on F 2 0.955; final R indices [ I >2 ( I )]; R 1 = 0.0783, wR 2 = 0.1905 [7574] ; R indices (all data): R 1 = 0.1212, wR 2 = 0.2047 ; largest diff. peak/hole 1.042 and 0.378 e 3 5 tert Butyl 4 hydroxybiphenyl 3 carbaldehyde (2 3 7 ) A stirred mixture of phenylbo ronic acid (334 mg, 2.74 mmol), 3 tert butyl 2 hydroxy 5 iodobenzaldehyde 2 7 (757 mg, 2.50 mmol), Na 2 CO 3 (529 mg, 4.99 mmol), PdCl 2 (PPh 3 ) 2 (58 mg, 0.14 mmol), water (5 mL), and 1,4 dioxane (15 mL) was heated at reflux under argon for 2 h. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with H 2 O, and then dried over anhydrous MgSO 4 Volatiles were removed by evaporation under reduced pressure, the residue was then purified by column chromatography on silica gel (2 .5% ethyl acetate in n hexane) to give 2 3 7 (532 mg, 84%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ) 11.80 (s, 1 H), 9.96 (s, 1 H), 7.78 (d, J = 2.0 Hz, 1 H), 7.60 (d, J = 2.3 Hz, 1 H), 7.53 7.59 (m, 2 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.36 (t, J = 7.1 Hz, 1 H), 1.49 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 197.5, 160.9, 140.4, 139.0, 133.4, 132.7, 130.3, 129.2, 127.4, 127.0, 121.0, 35.3, 29.5; HRMS (ESI TOF) c alcd for C 17 H 19 O 2 [M+H] + : 255.1380, f ound: 255.1397.

PAGE 100

100 5,5' (1 E ,1' E ) (1 R ,2 R ) Cyclohexane 1,2 diylbis(azan 1 yl 1 ylidene)bis(methan 1 yl 1 ylidene)bis(3 tert butylbiphenyl 4 ol) (2 3 8 ) To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine (25 mg, 0.22 mmol) in THF (3 mL), 2 37 (110 mg, 0.43 mmol) was added at room temperature, an d allowed to stir for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (2.5% ethyl acetate in n hexane) to give 2 38 (109 mg, 86%) as a yellow solid. 1 H NMR (300 MHz, CDC l 3 ) 13.96 (br s, 2 H), 8.35 (s, 2 H), 7.48 (d, J = 2.5 Hz, 2 H), 7.34 7.46 (m, 6 H), 7.23 7.31 (m, 4 H), 7.20 (d, J = 2.3 Hz, 2 H), 3.29 3.45 (m, 2 H), 1.96 2.09 (m, 2 H), 1.86 1.95 (m, 2 H), 1.71 1.84 (m, 2 H), 1.49 1.55 (m, 2 H), 1.46 (s, 18 H); 13 C NM R (75 MHz, CDCl 3 ) 166.0, 160.1, 141.3, 137.7, 131 .1, 128.9, 128.7, 128.4, 126.9, 126.7, 118.9, 72.6, 35.2, 33.3, 29.6, 24.5; HRMS (ESI TOF) c alcd for C 40 H 47 N 2 O 2 [M+H] + : 587.3632, f ound: 587.3634; [ ] D 21 131.2 ( c 0.17, CH 2 Cl 2 ). 2 34 To a solution of 2 38 (83 mg, 0.14 mmol) in CH 2 Cl 2 (5 mL), Co(OAc) 2 2 O (35 mg, 0.14 mmol) in MeOH (3 mL) was added, and allowed to stir at room temperature for 1 h under argon. Precipitate was collected by filtration, and then dried

PAGE 101

101 under vacuum for 24 h to give bisphenyl (salen)Co 2 34 (52 mg, 58%) as a dark red solid. HRMS (ESI TOF) c alcd for C 40 H 45 CoN 2 O 2 [M+H] + : 643.2729, f ound: 643.2724. General Procedure for Asymmetric Henry Reaction To the mixture of (salen)Co catalyst (2 mol%) in CH 2 Cl 2 (0.2 mL), aldehyde (0.25 mmol) and nitromethane (0.13 mL, 10 equiv.) were added at room temperature. The resulting mixture was cooled to 30C, stirred at this temperature for 30 min, and followed by the addition of 0.1 M DIPEA (50 L, 2 mol%) in CH 2 C l 2 After 14 110 h reaction time, the reaction mixture was purified by column chromatography on silica gel column (20% ethyl acetate in n hexane) to give the desired nitroaldol adduct. Ena n tiomeric excesses were determined by chiral HPLC analysis using Chi ralpak IA or Chiralpak IB columns. Absolute configuration of major isomer was determined to be ( S ) by comparison of the rete ntion time with literature data and by analogy. ( S ) 1 (2 Methoxyphenyl) 2 nitroethanol (2 33 a) C olorless oil. 1 H NMR (300 MHz, CDCl 3 ) 7.44 (dd, J = 7.6, 1.7 Hz, 1 H), 7.33 (td, J = 7.9, 1.7 Hz, 1 H), 7.01 (t, J = 7.5 Hz, 1 H), 6.91 (d, J = 8.2 Hz, 1 H), 5.55 5.69 (m, 1 H), 4.64 (dd, J = 13.0, 3.4 Hz, 1 H), 4.56 (dd, J = 13.0, 9.1 Hz, 1 H), 3.88 (s, 3 H), 3.20 (br s, 1 H); 13 C NMR (75 MHz, CDCl 3 ) 156.2, 130.0, 127.4, 126.1, 121.4, 110.7, 80.1, 68.0, 55.6; HRMS (GC CI) c alcd for C 9 H 11 O 4 [M] + : 197.0688, f ound: 197.0688; Ee was determined by HPLC with a Chiralpak IB column (90:10 hexane: i PrOH 0.8 mL /min, 215 nm); minor t r = 10.7 min; major t r = 11.6 min; 96% ee.

PAGE 102

102 ( S ) 1 (2 Chlorophenyl) 2 nitroethanol (2 33 b) Colorless oil. 1 H NMR (300 MHz, CDCl 3 ) 7.65 (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 ) 135.8, 131.7, 130.2, 129.9, 127.8, 79.6, 68.1; HRMS (GC CI) c alcd for C 8 H 8 ClNO 3 [M] + : 201.0193, f ound: 201.0208; Ee was determined by HPLC with a Chiralpak IB column (97.5:2.5 hexane: i PrOH 0.8 mL/min, 215 nm); minor t r = 21.2 min; major t r = 22.0 min; 93% ee. ( S ) 1 (2 Fluorophenyl) 2 nitroethanol (2 33 c) Colorless oil. 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 ) 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 TOF MS) c alcd for C 8 H 7 FNO 3 [M H] : 184.0415, f ound: 184.0411; Ee was determined by HPLC with a Chiralpak IA column (95:5 he xane: i PrOH 0.8 mL/min, 215 nm); major t r = 16.7 min; minor t r = 17.7 min; 94% ee.

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103 ( S ) 2 Nitro 1 (4 (trifluoromethyl)phenyl)ethanol (2 33 d) Colorless oil. 1 H NMR (300 MHz, CDCl 3 ) 7.68 (d, J = 7.9 Hz, 2 H), 7.56 (d, J = 7.9 Hz, 2 H), 5.55 (d, J = 8.9 Hz, 1 H), 4.60 (dd, J = 13.6, 8.8 Hz, 1 H), 4.52 (dd, J = 13.6, 3.7 Hz, 1 H), 3.05 (br s, 1 H); 13 C NMR (75 MHz, CDCl 3 ) 142.1 (q, J CF = 1.3 Hz), 131.4 (q, J CF = 32.0 Hz), 126.6, 126 .2 (q, J CF = 3.8 Hz), 122.2, 81.1, 70.5; HRMS (DART TOF MS) c alcd for C 9 H 7 F 3 NO 3 [M H] : 234.0384, f ound: 234.0373; Ee was determined by HPLC with a Chiralpak IB column (85:15 hexane: i PrOH 0.8 mL/min, 215 nm); minor t r = 8.2 min; major t r = 9.2 min; 82% e e. ( S ) 1 (4 Fluorophenyl) 2 nitroethanol (2 33 e) Colorless oil. 1 H NMR (300 MHz, CDCl 3 ) 7.31 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 ) 163.1 (d, J 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 TOF MS) c alcd for C 8 H 7 FNO 3 [M H] : 184.0415, f ound: 184.0413; Ee was determined by HPLC with a Chiralpak IB column (90:10 hexane: i PrOH 0.8 mL/min, 215 nm); minor t r = 11.5 min; major t r = 12.6 min; 90% ee. ( S ) 1 (4 Methoxyphenyl) 2 nitroethanol (2 33 f) Colorless oil. 1 H NMR (300 MHz, CDCl 3 ) 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

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10 4 H); 13 C NMR (75 MHz, CDCl 3 ) 160.3, 130.4, 127.5, 114.6, 81.5, 70.9, 55.6; HRMS (DART TOF MS) c alcd for C 9 H 10 NO 4 [M H] : 196.0615, f ound: 196.0608; Ee was determined by HPLC with a Chiralpak IB column (85:15 hexane: i PrOH 0.8 mL/min, 215 nm); minor t r = 12.0 min; major t r = 13.6 min; 81% ee. ( S ) 1 (Naphthalen 1 yl) 2 nitroethanol (2 33 g) Yellow oil. 1 H NMR (300 MHz, CDCl 3 ) 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); 13 C NMR (75 MHz, CDCl 3 ) 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) c alcd for C 12 H 10 NO 3 [M H] : 216.0666, f ound: 216.0658; Ee was determined by HPLC with a Chiralpak IB column (85:15 hexane: i PrOH 1.0 mL/min, 215 nm); minor t r = 8.3 min; major t r = 10.7 min; 91% ee. ( S ) 1 (Naphthalen 2 yl) 2 nitroethanol (2 33 h) White solid. 1 H NMR (300 MHz, CDCl 3 ) 7.82 7.93 (m, 4 H), 7.46 7.56 (m, 3 H), 5.65 (dt, J = 9.3, 3.4 Hz, 1 H), 4.71 (dd, J = 13.6, 9.3 Hz, 1 H), 4.61 (dd, J = 13.3, 3.1 Hz, 1 H), 2.86 (d, J = 3.1 Hz, 1 H); 13 C NMR (75 MHz, CDCl 3 ) 135.6, 133.6, 133.4, 129.2, 128.3, 128.0, 126.9, 126.9, 125. 5, 123.4, 81.4, 71.4; HRMS (DART TOF MS) c alcd for C 12 H 10 NO 3 [M H] : 216.0666, f ound: 216.0664; Ee was determined by HPLC with a Chiralpak IB column (85:15 hexane: i PrOH 0.8 mL/min, 215 nm); minor t r = 18.0 min; major t r = 23.3 min; 87% ee.

PAGE 105

105 Kinetic Exper iments To a vial equipped with sealed cap, the cobalt salen catalyst and CH 2 Cl 2 (1.0 mL) were charged, and then followed by the addition of o methoxybenzaldehyde (34 mg, 0.25 mmol), nitromethane (0.13 mL, 10 equiv.), and mesitylene (30 mg, 0.25 mmol, inter nal standard). The reaction does not occur without external base. The resulting mixture was cooled to 30C, and then allowed to stir for 30 min at that temperature. The reaction was initiated by the addition of 1.0 M DIPEA (25 L, 0.1 equiv.) in CH 2 Cl 2 T he reaction progress was monitored by the removal of 20 L aliquots from the reaction mixture, filtration through silicagel with 10% isopropanol in n hexane as the eluent, and HPLC analysis (Chiralpak IB column, 95:5 hexane: i PrOH 0.8 mL/min, 215 nm, mesi tylene: 4.1 min, o methoxybenzaldehyde: 7.9 min) for the first 30% or 40% of the reaction. The slopes of the least square lines for the plots of ([SM] 0 [SM]) vs. time were determined.

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106 CHAPTER 3 SELF ASSEMBLED CATALYSTS THROUGH UREA UREA HYDROGEN BONDS FO R EPOXIDE OPENING REAC TIONS Backgrounds The u rea functional group is composed of one hydrogen bond acceptor (C=O) and two hydrogen bond donors (NH) Owing to its unique ability of H bonding interaction s to anion s and electrophile s the urea moiety and its congeners have been widely employed in the development of anion receptors 118 and H bond donor organocatalyst s 119 for the past decade. Besides those abilities, symmetrical or unsymmetrical disubstituted ureas can form strong and directional hydrogen bond s with other urea molecule s in solution and in the solid state 120 More interesting ly, the good complementarity between donors and acceptors of urea motifs often lead to the formation of robust one dimensional H bonded chains (Figure 3 1). Figure 3 1 Urea self assembly Those intermolecular interactions can be further strengthened and controlled by the introduction of multiple urea motifs in the molecule. In this regard the compounds bearing bis tris or tetra urea motifs have been reported, and they can form dimer or higher aggregates through multiple intermolecular hydrogen bonds in solution and in the solid state By employing multiple urea motifs, a number of self assembled supramolecular architectures such as capsules columns, nanotubes, channels, supramolecular polymers, and organogel s have been developed.

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107 Rebek and B hmer indepen den tly and extensively studied self assembled dimeric calix [4] arenes in which tetra urea motifs have been utilized. 121 The attachment of four urea groups at the upper rim of calix[4]aren e s led to formation of a reversible dimeric capsule through a circular array of eight hydrogen bonded ureas in nonpolar solvents (Figure 3 2). T he cavities generated by reversible dimerization can accommodate sm all solvent molecules such as benzene. Figure 3 2 Dimeric self assembly of tetra urea calix[4]arene Similarly, Steed and co workers reported dimeric self assembling capsules derived from the tribenzylamine skeleton (Fig ure 3 3) 122 T his molecular self assembly consist of a circular array of six hydrogen bonded ureas. The dimerization constant of 3 2 3 2 was found to be very high in CDCl 3 ( K 2 = ~83000 M 1 ). The X ray structure showed that the resulting cavity of the self a ssembled dimer could accommodate one molecule of CH 2 Cl 2 There has been considerable interest in building self assembled hollow columnar and tubular stacks which can be applicable to ion transport and sensing, antibacterial agents, and reaction vessels. 123 Owing to the strong tendency to form hydrogen bonded

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108 Figure 3 3 Dimeric self assembly of tris urea compounds one dimensional network, macrocyclic N N oligoureas have been shown to form various supramolecular structures possessing channel s (Figure 3 4) 124 Those macrocyclic bis or tetra urea compounds 3 3 3 4 3 5 and 3 6 were stacked through 3 points urea urea H bonding and 4.61~4.72 of intermolecular space was created in the solid state. The dimension of the channe l can be controlled by variation of the length and the type of spacer in the ring. Interestingly, oligomeric urea s with a large ring such as 3 6 can accommodate small guest molecules in the pore. Gelation is becoming an important area for developing new ma terials in solar cells, tissue engineering, vehicles for drug release, and pollutant removal. 125 Traditionally, covalently cross linked polymers were used to prepare gels. Recently, low molecular weight organic gelators have been developed. The gelation by t hese organic gelators involves the self assembly of individual molecules through non covalent interactions such as hydrogen bonding and hydrophobic interactions, followed by trapping of solvent molecules. In the pioneering work by Hanabusa, Hamilton, and F eringa, cyclic or acyclic bis urea molecules serve as a good gelator in a variety of

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109 Figure 3 4 X ray packing structures of macrocy c lic bis and tetra urea compounds

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110 solvent systems (Figure 3 5). 126 With a high propensit y to form infinite H bonded networks, urea motifs were shown to be effective in gelation in organic and aqueous solution. In addition, urea functionality is easy to incorporate Figure 3 5 Some examples of bis urea gel ators Another interesting application of bis urea self assembly is the forma tion of supramolecular polymers which are a chain of small molecules held together through reversible noncovalent interactions. The bis urea based supramolecular polymers have been extensively studied by Bouteiller and co workers. 127 In contrast to bis urea gelators some bis urea compounds such as 3 10 and 3 1 1 have a tendency to form dynamic supramolecular polymers through urea urea hydrogen bonds in nonpolar solvents (Figure 3 6) The molar mass of th e s e unconventional polymers depends on concentration, solvent polarity, and temperature, and they are potentially useful for a wide range of applications including self healing polymers and stimuli responsive materials Figure 3 6 Bis urea monomers for supramolecular polymer

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111 The urea based self assembled struc tures generally formed in non polar media. However, some bis and tetra urea compounds can also self assemble in polar media such as THF or even in aqueous solution through the combination of hydrogen bonding and hydrophobic interactions (Figure 3 7) 128 This behavior is advantageous for the development of effective hydrogelators and supramolecular polymers in aqueous solution. Figure 3 7 Urea monomers for the self assembly in polar media Although many urea based self assembly system s ha ve been report ed, examples of the urea system containing transition metal s are relatively rare As one of the few example s Shink ai and co workers reported a tetra urea incorporated (porphyrin)Cu complex 3 1 5 that form s thermally stable organometallic gel through one dimensional molecular self assembly by means of urea urea hydrogen bonds and porphyrin p orphyrin interactions (Fi gure 3 8 ) 129 Although 3 1 5 was not tested as a catalyst, this molecular design could have the potential to be a new self assembling, transition metal catalyst. In summary, the urea functional group has proved to have a strong tendency to form self assemble d structures with neighboring urea molecules in a predictive and directional way. This self assembled structure includes dimer oligomer and higher

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112 Figure 3 8 ( P orphyrin ) Cu based tetra urea gelator aggregate s It seems possible to develop self assembled bimetallic or multimetallic catalysts if the urea motifs are introduced to the catalytic cores through an appropriate linker. Hydrolytic K inetic R esolution (HKR) of T erminal E poxides Ena ntio pure terminal epoxides are val uable intermediates for the synthesis of important pharmaceuticals and agricultural compounds Although a number of excellent methods have been developed for the catalytic enantioselective epoxidation of unfunctionalized alkenes 130 terminal alkenes are stil l very challenging substrates for enantioselective epoxidation As an alternative, Jacobsen and co workers develop ed (salen) Co(III) catalyzed hydrolytic kinetic resolution (HKR) of racemic epoxides (Scheme 3 1) 131 This reaction represents one of the most su ccessful applications of chiral ( salen )metal catalyst. In this reaction, the Co(II) precatalyst should be oxidized to the active Co(III) species by addition of acid in the air. The chiral (salen)Co(III) complexes efficiently resolve those epoxides up to 99 % ee using water as a nucleophile under highly concentrated or solvent free conditions. In addition, this reaction generates

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113 optically pure 1,2 diol as a by product which is also a synthetically valuable intermediate. Because racemic epoxides are relativel y inexpensive and water is the sole reagent in this reaction the hydrolytic kinetic resolution (HKR) has b ecame the most powerful and practical method to obtain enantiopure terminal epoxides. Scheme 3 1 Hydrolytic kinet ic resolution using a (salen)Co c atalyst Preliminary mechanistic and kinetic studies by Jacobsen and co workers have revealed a second order dependence on cobalt concentration, which suggests that two metal centers are involved in the rate limiting transit ion state in a cooperative manner 131 In this dual activation mechanism, epoxide is activated by one metal salen unit and cobalt hydroxide species is delivered by the second catalyst unit. Therefore, this reaction c ould be second order with respect to cata lyst concentration In addition, two limiting geometries were proposed, as described in Figure 3 9 Among them, head to tail geometry seem ed to give better enantioselectivity. Recently, a more detailed kinetic profile of the HKR of epoxides was disclosed by Jacobsen and Blackmond, where significant counterion dependence was found on the rate of the HKR (Figure 3 10). 116 Their kinetic studies reveal that the maximum rate can be obtained when [Co OH] tot is equal to [Co X] tot Th us, it is important to maintain this partitioning during the course of reaction to achieve the maximum reaction rate. The partitioning of the Co OH ( B ) and Co X ( A ) is highly dependent on the nature of counterion. Although acetate could be a reasonable cho ice as a counterion, weaker

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114 nucleophilic tosylate was the much better alternative. Note that Co(OTs) complex displays better catalytic efficiency in HKR of epoxides compared to Co(OAc) in most cases. Figure 3 9 Two limi ting geometries in HKR of epoxides Figure 3 10 Counterion effect in HKR

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115 Despite the aforementioned advantages, there is also a disadvantage associated with this methodology, arising from the second order kinetics. The l oss of activity is often observed at the late stage of HKR and the catalytic efficiency is exponentially decreased at low catalyst loadings. T here have been numerous attempts to overcome this limitation for the past decade The general approach to improve catalytic efficiency in HKR is linking multiple salen catalytic units together using a covalent tether The resulting oligomeric, dendritic, and polymeric multinuclear salen catalysts, indeed, showed improved reactivity and selectivity in HKR reaction by increasing local concentration of the catalytic site. M any of them showed better performance than monomeric catalyst in the HKR to afford lower catalyst loading. As a pioneering work Jacobsen and co workers developed dendritic multinuclear salen complexes for HKR, and the dendritic salen complexes showed dramatic improvement of catalytic efficiency compared to the monomeric salen catalyst (Figure 3 1 1 ) 132 They utilized NH 2 terminated PAMAM dendrimers as a backbone that was attached by multiple chiral (salen )Co units through covalent linkages. D endri t ic catalyst 3 1 7 demonstrated much enhanced reactivity and lower catalyst loading in HKR of epoxides resulting from intramolecular cooperative reactivity between catalytic units. Cyclic oligomers have also been r ealized as a good platform to enhance cooperative activity between the catalytic units. Jacobsen and co workers reported highly efficient cyclic oligomer salen complexes 3 1 8 for HKR of epoxides (Figure 3 12). 133 This catalyst was prepared as a mixture of di fferent ring sizes. These complexes exhibited lower catalyst loading (up to 50 fold) and shorter reaction times, compared to the monomoric catalyst. This remarkable catalytic efficiency can be attributed to the

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116 Figure 3 1 1 Dendrimeric multinuclear ( salen ) Co complex 3 1 7 facile formation of the head to tail bimetallic geometry within flexible macrocyclic structures. The kinetic analysis of HKR with 3 1 8 revealed a first order dependence on catalyst, consistent with this intramolecular activation. Weck and co workers reported macrocyclic oligomeric (salen)Co(III) complexes which were derived from cyclooctene salen monomers using an olefin metathesis strategy (Figure 3 13). 134 These oligomeric (salen)Co(III) complexes that we re prepared as a mixture of cyclic oligomers with different ring sizes, showed remarkable efficiency in the HKR of terminal epoxides. Later, further studies reveal that the ring size is crucial to achieve high efficiency in HKR of terminal epoxides. 135 They found that the dimeric

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117 (salen)Co complex was the least reactive catalyst, whereas larger ring size macrocycles (tetramer to hexamer mixture) showed superior reactivity in the HKR of epoxides. Figure 3 1 2 Macrocyclic o li gomeric ( salen )Co complexes Figure 3 1 3 Weck s macrocyclic o ligomeric ( salen )Co complexes T he cataly tic efficiencies of those oligomeric multinuclear (salen)Co complexes and the monomeric complex are summarized in Table 3 1. Indeed, two oligomeric (salen)Co complexes 3 1 8 and 3 1 9 display superior catalytic efficiency and lower catalyst loading. For example, in the HKR of ( rac ) epichlorohydrin, relatively high catalyst loading (0.2 0.5 mol%) and longer reaction time (16 18 h) are required with

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118 monomeric catalyst s 2 26(OAc ) and 2 26( OTs) whereas only 0.01 mol% catalyst loading is required by the multinuclear (salen)Co complexes to achieve the same level of resolution (entry 1). In addition, reaction time (2.5 11 h) is als o much shorter than that of the monomeric catalyst (16 18 h). S imilarly good results are also obtained with the multinuclear (salen)Co complexes for the HKR of various terminal epoxides (entries 2 5). It is important to note that t his remarkable catalytic efficiency is originated from the enforcement of cooperative activation by tethering catalytic units. Table 3 1 Catalyst efficiency of multinuclear salen systems entry epoxide solvent catalyst Co (mol%) time (h) ee (%) yield (%) 1 neat 2 26(OAc) 0.5 18 99 42 neat 2 26(O Ts ) 0.2 16 99 42 neat 3 1 9 0.01 2.5 99 44 neat 3 1 8 0.01 11 99 45 2 1,2 hexanediol 2 26(OAc) 2.0 48 99 41 neat 2 26(O Ts ) 2.0 48 99 40 neat 3 1 9 0.25 48 99 42 3 THF 2 26(OAc) 0.8 48 99 44 neat 3 1 9 0.1 24 99 45 CH 3 CN/CH 2 Cl 2 3 1 8 0.08 2.5 99 44 4 neat 2 26(OAc) 0.5 18 99 43 neat 2 26(O Ts ) 0.05 16 99 45 neat 3 1 9 0.01 2 99 43 5 THF 2 26(OAc) 0.5 18 99 47 neat 3 1 9 0.01 20 99 46 Immobilization of salen molecules on polymer backbone s and inorganic supports is also a well known strategy for reinforcing the bimetallic activation as well as re cycling catalysts. In 1999, Jacobsen and Annis reported polystyrene and silica bound (salen) Co complexes for this purpose (Figure 3 1 4 ) 136 This polymer supported system has been proved to be beneficial particularly for purification step and allows repeated recycling without loss of reactivity and enantioselectivity.

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119 Figure 3 1 4 Polymer suppor ted (salen)Co complexes Weberskirch and co workers developed self assembled nanoreactors for the HKR of terminal epoxides and they utilized amphiphilic block copolymers as a backbone (Scheme 3 2 ) 137 The miscellar aggregation of this polymer backbone generates a hydrophobic core which provides high local concentration of catalysts under homogeneous conditions. This catalyst resolves ef ficiently various terminal epoxides with very low catalyst loading. In addition, this catalyst can be easily separated and recycled without loss of enantioselectivity. Scheme 3 2 Hydrolytic kinetic resolution catalyzed by 3 22 In general, it is more challenging to precisely control cooperative activation on solid support than on the soluble support. To overcome this limitation, Wec k and co w or kers have developed polymer bound ( salen )Co complexe s bearing oligo(ethylene

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120 gl ycol) linker or a dendron backbone (Figure 3 1 5 ). 138 Those approaches have been found to provide constant cooperative activation over the entire catalyst structures As a result, t hose polymer bounded catalyst s 3 23 and 3 2 4 also showed high efficiency in th e HKR of terminal epoxides at low catalyst loadings (0.01 0.06 mol%) Figure 3 1 5 Polymer supp or ted (salen) Co complexes by Weck Similarly, Jones and co workers reported a polystyrene supported multinuclear ( salen )Co com plex where two salen units are linked through a styryl functionalized bridge (Scheme 3 3) 139 Notably, like Weck s polystyrene based (salen)Co complex, this catalyst can provide constant local concentration of cooperative bimetallic environment. This solubl e polymeric catalyst 3 2 5 showed superior reactivity compared to the monomeric catalyst. For example, racemic 1,2 epoxyhexane can be completely resolved within 2 h with only 0.02 mol% of catalyst loading. In 2008, Jacobsen and Belser reported (salen)Co(III ) complexes immobilized on gold colloids (Figure 3 16). 140 Th e self assembled thiolate monolayers (SAMs) showed remarkable efficiency in the HKR of 1,2 epoxyhexane. Only 0.01 mol% catalyst was needed to complete the resolution within 4 h.

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121 Scheme 3 3 P olystyrene based dimeric salen developed by Jones Figure 3 1 6 Gold immobilized colloidal salen Recently, nanocage s of mesoporous materials have been utilized for this reaction. Li and co wor ke r s developed nano cage materials in which (salen)Co complexes were

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122 accom m odated in the cagelike mesoporous silica SBA 16 (Figure 3 1 7 ) 141 As a consequence of high local concentration of catalytic units in the confined space, dramatic rate enha n cement was observed in the HKR of racemic propylene oxide. In addition, this solid catalyst can be easily recycled by filtration without significant loss of catalytic efficiency. Figure 3 1 7 HKR on (salen)Co catalysts confined in nanocages Very recently, Kleij and co workers used olefin metathesis as a coupling tool for constructing dinuclear cobalt salen complex es (Figure 3 1 8 ) 142 They tested the resulting dimeric catalyst for the HKR and methanolysis of epoxides, however cooperat ive effect was not significant. The same group also reported a bis (salen)Co calix[4]arene hybrid catalyst for the HKR. 143 Similarly, this dimeric catalyst also did not show significant enhancement of the reaction rate. Both results suggest that the precise control of the orientation of catalytic units is challenging but crucial to achieve the effective cooperative activation.

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123 Figure 3 1 8 Kleij s dimeric (salen) cobalt complexes Although there have been tremendous efforts t o develop efficient HKR catalyst s covalent tethering or immobilization approach es w ere mainly pursued However, those strategies generally require a relatively long sy nthesis and difficult purification. Thus, the self assembly approach using non covalent interactions would be a promising alternative for the efficient catalytic system in many respects. Design and P reparation of Bis U rea (Salen) Co C atalyst s Based on a wealth of literature precedence on self assembly of the urea motifs, we envisioned that the urea functional group can be utilized as a hydrogen bonding motif to design new self assembled catalysts As described above, tremendous efforts have been devoted into developing more efficient catalysts for HKR of terminal epoxides mainly by the use of a covalent tether. Thus, it would be interesting to utilize non covalent bonds, particularly hydrogen bonds in designing a multinuclear (salen)Co catalyst. For those reasons, we devised a new bis urea functionalized (salen)Co complex which can be self assem bled through ur ea urea H bonding interactions to offer a cooperative activity (Figure 3 19). 144

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124 Figure 3 1 9 Self assembly of b is urea incorporated (salen) Co complexes The readily accessible linkers such as p phenylene, m phenylene, and methylene groups have been chosen to install the urea group into the salen core (Figure 3 20 ) Phenylen e type linker s would provide relatively rigid structural framework wh ile the methylene linker would give more flexibility All t hose bis urea incorporated salen structures were easily synthesized from commercial starting materials Figure 3 20 D esign of bis urea (salen)Co complexes The synthesis of bis urea (salen)Co complexes 3 28(a f) with the p pheny lene linker is summarized in Scheme 3 4. 4 A minophenylboronic ester 3 31 was reacted with an appropriate isocyanate to afford the urea derived boronic esters in 70 99% yield. Then the urea boronic ester was converted to the urea incorporated salicylaldehyd es 3 33 under the Suzuki coupling conditions. After condens ation of salicylaldehydes with

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125 ( R R ) 1,2 diaminocyclohexane, the resulting salen s were reacted with Co(OAc) 2 4H 2 O under argon atmosphere to afford the corresponding bis urea (salen) Co(II) complexes 3 2 8 (a f) Scheme 3 4 Synthesis of bis urea (salen)Co complexes containing the p phenylene linker The synthesis of m phenylene linked bis urea (salen)Co(II) complexes 3 29(a c) was also performed in a similar way from 3 aminophenylboronic ester 3 35 (Scheme 3 5). For this series, three different end groups (4 CF 3 C 6 H 4 4 MeOC 6 H 4 and 3,5 (CF 3 ) 2 C 6 H 3 ) were employed.

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126 Scheme 3 5 Synthesis of bis urea (salen)Co complexes containing the m phenylene linker M ethylene linked bis urea (salen)Co complexes were prepared in five steps from commercial t butyl salicylaldehyde 2 6 (Scheme 3 6) Compound 3 3 9 was obtained by reactin g 2 6 with formaldehyde in concentrated HCl for 2 days at 40 C. After converting 3 39 to azide compound 3 40 t he urea functional group was conveniently introduced by the reaction of 3 40 with an appropriate isocyanate under catalytic hydrogenation conditions. For the urea compounds bearing reducible functional groups under catalytic hydrogenation conditions, an alternative route should be taken. Thus, the acetal protected amine 3 43 was prepared in a two step sequence 145 Then, 3 43 was treated

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127 with a corresponding isocyanate followed by the removal of the acetal protecting g roup to afford salicylaldehydes 3 41 i and 3 41 j in good overall yields. Scheme 3 6 Synthesis of urea functionalized salicylaldehyde T he resulting salicylaldehydes 3 41 ( a k ) were condensed with ( R R ) 1,2 diaminocyclohexa ne to afford bis urea salen ligands 3 4 4 ( a k ) (Scheme 3 7) Finally, bis urea (salen)Co(II) complexes 3 30 ( a k ) were obtained by the reaction of Co(OAc) 2 4H 2 O with the corresponding salen ligands in EtOH under argon atmosphere. It is interesting to note th at the yield was improved by the replacement of ethanol with iso propanol in the metal ation of 3 44k (37% vs 77%). Those methylene link ed bis urea (salen)Co(II) complexes 3 30 ( a k ) were characterized by high resolution mass spectroscopy and elemental analy sis.

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128 Scheme 3 7 Synthesis of bis urea (salen) Co complexes containing the methylene linker Self A ssembled B is U rea (Salen) Co(II I ) C atalyzed HKR To assess the catalytic performance of bis urea (salen) Co complex es, HKR of ( rac ) allyl glycidy l ether was performed under solvent free cond i tions at 23 C with 0.55 equivalent s of H 2 O (Scheme 3 8) For this initial study, two different types of bis urea (salen)Co complexes 3 2 8 e ( p phenylene) and 3 30 f (methylene) were chosen. As mentioned earlier, the counter ion effect is crucial in the HKR of epoxides. To avoid potential disruption of self assembly by binding of acetate to the urea NHs t osylate was chosen as a counterion for this study. Thus, prior to the catalytic reactions, C o(II) precatalyst 3 28e and 3 30f were oxidized to active Co(III) species 3 28e(OTs) and 3 30f(OTs) B oth bis urea (salen)Co (OTs) catalysts showed much superior reactivity compared to monomeric catalyst 2 26 (OTs) at the initial stage (Figure 3 2 1 a ) Howeve r,

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129 we later found t hat an induction period exist ed in HKR of some epoxides such as allyl glycidyl ether and benzyl glycidyl ether at low catalyst loading (0.05 mol%) when monomeric catalyst 2 26 (OTs) was used As shown in Figure 3 2 1 a in the HKR of allyl glycidyl ether using 0.05 mol% of the monomeric catalyst almost no reaction occurs for the first 9 h under solvent free conditions. However, after the induction period, monomeric catalyst 2 26 (OTs) exhibited comparable reaction rates (Figure 3 21b). This induction period might be attributed to the immiscibility of allyl glycidyl ether with the water. According to the lite rature, 131 to avoid the immiscibility issue, the addition of 10 mol% of 1,2 hexanediol to reaction mixture c ould be helpful to obtain more reliable kinetic profile. However, at 0.05 mol% catalyst loading of monomeric catalyst 2 26 (OTs) the induction period was still observed (~5 h) even with the addition of 10 mol% of 1,2 hexanediol Interestingly, this inducti on period was not observed with both bis urea catalyst s 3 2 8 e (OTs) and 3 30 f (OTs) at 0.05 mol% catalyst loading, which can be an advantage of bis urea (salen)Co catalyst s Scheme 3 8 HKR of ( rac ) allyl glyci d yl ether c atalyzed by bis urea (salen) Co complexes

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130 Figure 3 2 1 Induction period of HKR of allyl glycidyl ether Although we found that bis urea (salen)Co complexes had apparent advantage over the monomeric catalyst from the s e ini tial experiment s th e induction period made it difficult to precise evaluate efficiency of the catalysts. Later w e found that such induction period can be eliminated by choosing ( rac ) epichlorohydrin as a substrate at 0.05 mol%

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131 catalyst loading in THF. Thu s, we decided to use the s e induction period free conditions for better analysis. A series of bis urea salen catalysts were reevaluate d in the HKR of ( rac ) epichlorohydrin in THF at 23 C with 0.55 equiv. of H 2 O (Scheme 3 9) Tosylate was chosen as a counter ion for this study and bromobenzene was added as an internal standard for GC analysis. The results are shown in Table 3 2. Rather unexpectedly the aminopyri di ne/pyridone self assembled catalyst 2 19(OTs) showed much slower reaction rate (entry 1, relative rate = 0.2) compared to monomeric catalyst 2 26(OTs) The m phenylene linked bis urea (salen)Co complex 3 2 9 b (OTs) also showed similarly slow reaction ( entry 2, relative rate = 0.3). However, the p phenylene linked bis urea complex 3 2 8 e(OTs) disclose d no ticeable rate acceleration ( entry 3, relative rate = 2.6) and the methylene linked bis urea complex 3 30 f(OTs) showed most significant rate enhancement ( entry 4, relative rate = 9.7). From these results, we confirmed that the orientation and geometry of bi s urea functional groups were pivotal to exhibit the cooperative effect. It is not clear why 2 19(OTs) showed rate deceleration in HKR of epoxide in contrast to the rate acceleration in Henry reaction. Presumably, the metal metal separation (~4 ) of the 2 pyridone/aminopyridine system might not be optimal for the epoxide opening reactions (5 6 ) Aforementioned kinetic studies revealed that methylene linked bis urea (salen)Co complexes would be optimal for epoxide opening reactions. Thus, we decided to s tudy further with this rather flexible bis urea scaffold. To evaluate the end group effect, a series of bis urea (salen)Co complexes 3 30( a k ) were tested for the HKR of ( rac ) epichlorohydrin under same reaction conditions (Scheme 3 10). We were pleased t o

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132 Scheme 3 9 HKR of ( rac ) epichlorohydrin catalyzed by (salen)Co (OTs) complexes Table 3 2 Kinetic data for the HKR of ( rac ) epichlorohydrin entry catalyst k obs (h 1 ) r elative rate 1 2 19(OTs) 1.8 x 10 2 0.2 2 3 2 9b (OTs) 2.0 x 10 2 0.3 3 3 2 8e (OTs) 2.0 x 10 1 2.6 4 3 30f (OTs) 7.4 x 10 1 9.7 5 2 26(OTs) 7.6 x 10 2 1.0 Figure 3 2 2 Rate plots of the HKR of ( rac ) epichlorohydrin in THF

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133 find that bis urea (salen)Co ( OTs ) catalysts showed significant rate acceleration (4.2 13 times) compared to monomeric catalyst 2 26( OTs ) (Table 3 3) It is not e worthy that all bis urea salen complexes showed rate acceleration regardless of the end groups T he N aryl end groups show greater rate acce leration than the N alkyl end groups (entries 1 3 vs 4 11) Electron withdrawing groups on the phenyl ring show more rate acceleration. However, t he substituent effect does not linearly correlate with the Hammett parameter The bis urea (salen)Co complex es 3 30h(OTs) and 3 30k(OTs) prove to be the best from the survey (entries 8 and 11), and 3 30k(OTs) was selected for the further studies. Scheme 3 10 HKR of ( rac ) epichlorohydrin catalyzed by (salen)Co(OTs) complexes T able 3 3 Kinetic data for the HKR of ( rac ) epichlorohydrin entry catalyst R k obs (h 1 ) r elative rate 1 3 30 a(OTs) Bn 3.2 x 10 1 4.2 2 3 30 b (OTs) n C 6 H 13 3.5 x 10 1 4.6 3 3 30 c (OTs) n C 18 H 37 5.4 7.2 4 3 30 d (OTs) C 6 H 5 6.5 8.6 5 3 30 e (OTs) 4 CH 3 O C 6 H 4 6.5 8.6 6 3 30 f (OTs) 3,5 (CF 3 ) 2 C 6 H 3 7.4 9.7 7 3 30 g (OTs) 4 F C 6 H 4 6.7 8.8 8 3 30 h (OTs) 4 Cl C 6 H 4 1.00 13 9 3 30 i (OTs) 4 Br C 6 H 4 7.2 9.5 10 3 30 j (OTs) 4 CN C 6 H 4 5.1 6.7 11 3 30 k (OTs) 4 CF 3 C 6 H 4 1.04 13.7 12 2 26(OTs) 7.6 x 10 2 1.0 One of the im pressive features of the (salen)Co(III) catalyzed HKR is that this reaction can be performed under solvent free conditions, which is beneficial in terms of waste reductions and cost savings. 146 Because epoxide substrates and 1,2 diol products are generally l iquid, it is possible to use solvent free or highly concentrated

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134 conditions. In addition, since the remaining epoxides are generally isolated by vacuum transfer, it is highly desirable to avoid the use of solvent. Kinetic resolution of ( rac ) Figure 3 2 3 Rate plots of the HKR of epichlorohydrin ( 3 30 (a f) and 2 26 ) Figure 3 2 4 Rate plots of the HKR of epichlorohydrin ( 3 30 ( g k ) and 2 26 ) epichlorohydrin (5 mmol ) was performed at 23 C with 0.7 equiv alents of H 2 O and 0.05 mol% of 3 30 k ( O T s ) and under solvent free conditions (Figure 3 25) It should be note d that bis urea catalyst 3 30 k(OTs) display ed significantly better performance than

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135 monomeric catalyst 2 26( OTs ) both in THF (Figure 3 25a) and under solvent free conditions (Figure 3 25 b ) After 8 h, 3 30k(OTs) gave 92% ee (THF) and 93% ee (solvent free) for the remaining epoxide, while 2 26(OTs) gave only 35% ee (THF) and 47% ee (solvent free) at the same catalyst loading (0.05 mol%). Figure 3 2 5 HKR of ( rac ) epichlorohydrin with 0.05 mol% 3 30 k(OTs) and 2 26(OTs) in THF and under solvent free conditions B is urea (salen)Co catalyst 3 30 k(OTs) was employed in the HKR of a variety of terminal epoxides under solvent free conditions and as low as 0.03 0.05 mol% catalyst loading (Scheme 3 11) After the reaction was completed, the enantioenriched epoxide was isolated by vacuum transfer. B is urea (salen)Co catalyst 3 30 k(OTs) displayed

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136 improved performance for all four terminal epoxides examined compared to monomeric catalyst 2 26(OTs) (Table 3 3) B is urea (salen)Co catalyst 3 30 k(OTs) completed the reaction in 8 14 h whereas the monomeric catalyst require a prolonged reaction time (24 71 h) at the same l ow catalyst loadings (0.03 0.05 mol%). Scheme 3 11 HKR of ( rac ) epoxides catalyzed by (salen)Co(OTs) complexes Table 3 4 HKR of terminal epoxides under solvent free conditions entry R c atalyst (mol%) t ime (h) e e (%) y ield (%) 1 CH 2 Cl ( 1 4 9 b ) 3 30 k(OTs) (0.05) 14 99 41 2 CH 2 Cl ( 1 4 9 b ) 2 26(OTs) (0.05) 71 96 42 3 CH 2 O(allyl) ( 1 4 9 a ) 3 30 k(OTs) (0.05) 8 99 43 4 CH 2 O(allyl) ( 1 4 9 a ) 2 26(OTs) (0.05) 32 98 43 5 CH 2 CH 3 ( 1 4 9 c ) 3 30 k(OTs) (0.0 3 ) 8 99 43 6 CH 2 CH 3 ( 1 4 9 c ) 2 26(OTs) (0.0 3 ) 24 99 43 7 (CH 2 ) 3 CH 3 ( 1 4 9 d ) 3 30 k(OTs) (0.0 3 ) 14 99 41 8 (CH 2 ) 3 CH 3 ( 1 4 9 d ) 2 26(OTs) (0.0 3 ) 42 99 42 Kinetic and M echanistic S tudy In order to investigate the origin of the observed rate acceleration a series of kinetic/mechanistic s tudies were performed mainly in THF. First, t he rate constants ( k obs ) of the HKR of epichlorohydrin with 3 30f (OTs) were measure d by changing catalyst loadings in THF (Figure 3 2 6 ).

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137 Figure 3 2 6 Rate plots of the HKR of epichlorohydrin (5.0 mmol) using the bis urea (salen)Co 3 30f (OTs) (0.02, 0.03, 0.04, and 0.05 mol%) in THF The kinetic study reveal ed that the rate laws were second order in catalyst concentration for bis urea (salen)Co complex 3 30f (OTs) (Figure 3 27) W hile t his result might suggest that the same bimetallic mechanism is operating with the bis urea (salen)Co complex as with monomeric (salen)Co complex 2 26(OTs) we can not rule out completely other mechanism such as intermolecular metal/urea activation. Figure 3 2 7 Kinetic dependence on catalyst concentration

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138 Assuming the dimeric aggregate of (salen)Co units is an actual catalytic species, the rate law can be expressed in terms of monomer dimer equilibrium constant K 2 ( E qs 3 1 3 2, and 3 3). Meanwhile, the initial catalyst concentration [(salen)Co] 0 can be written as the sum of monomer concentration [(salen)Co] and dimer concentration [ (salen)Co] (Eq. 3 4). By assuming that monomer concentration would be equal to the initial catalyst concentration i n relatively weak self assembled system s ( K 2 << 10 2 ), the second order like kinetic dependence on the initial catalyst concentration [(salen)Co] 0 is expected ( E q. 3 5) In contrast, the first order like kinetic depen dence is expected from strong self assembled systems ( K 2 >> 10 3 ) or covalently tethered systems ( E q. 3 6) Thus, the observed second order kinetic dependence might suggest that the self association constant of the bis urea (salen)Co would be moderate in cu rrent reaction media. K 2 = (salen)Co] / [(salen)Co] 2 ( 3 1) Rate = k obs (salen)Co] ( 3 2) Rate = k obs K 2 [(salen)Co] 2 ( 3 3) [(salen)Co] 0 = 2[ (salen)Co ] + [(salen)Co] ( 3 4) i) K 2 << 10 2 0 Rate = k obs K 2 [(salen)Co] 0 2 ( second order ) ( 3 5) ii) K 2 >> 10 3 : [(salen)Co 0 /2 Rate = ( k obs /2)[(salen)Co] 0 ( first order ) ( 3 6)

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139 Second, to determine whether the accessible urea NH groups are pi votal for such rate acceleration, we synthesized two other (salen)Co complexes that might not readily form self assembled dimer because of their bulky end group or N Me substitution. For this purpose, 2,6 diisopropylphenylurea derived (salen)Co complex 3 3 0 l was prepared as shown in S cheme 3 12 Scheme 3 12 Synthesis of 2,6 diisopropyl phenyl urea ( salen ) Co complex Synthesis of N N dim e thylated urea (salen)Co com plex was summarized in Scheme 3 13. The urea i ntermediate 3 41 d was reacted with excess MeI after deprotonation by NaI to afford N N dimethylurea 3 4 6 The methyl group on aryl oxygen of 3 4 6 was removed by the treatment with B Br 3 in CH 2 Cl 2 to afford salicylaldehyde 3 4 7 This resulting intermediate was converted to N N di methylated bis urea (salen)Co complex 3 4 9 using the routine condensation and meta lation methods. Both catalysts 3 30l(OTs) and 3 49(OTs) lacking accessible N H were tested for the HKR of ( rac ) epichlorohydrin under the standard reaction conditi ons, much slower reaction rates were observed (Figure 3 28). This result clearly indicates that accessible urea NH groups are crucial for the observed rate acceleration.

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140 Scheme 3 1 3 Synthesis of N N dimethylated urea ( salen)Co complex Figure 3 2 8 Relative rate s of H bonds blocked catalysts Third, mono substituted urea (salen)Co complex 3 51 was synthesized using Weck s protocol for unsymmetrical salens as described in S cheme 3 1 4 147 T his complex was expected to show slower reaction rate compared to bis urea catalyst because of the lack of additional H bonding interactions. The resulting mono urea (salen)Co complex 3 51 (OTs) showed less rate acceleration in the HKR of epichlorohydrin (F igure 3 29). However, the rate acceleration (relative rate = 8.4) was still significant compared to that of the corresponding bis urea (salen)Co catalyst (relative rate = 13.7), which suggests even the mono urea (salen)Co complex can provide self assembled structure in a desired orientation with comparable association strength. This phenomenon will be discussed further in later sections.

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141 Scheme 3 1 4 Synthesis of mono urea (salen)Co complex 3 51 Figure 3 2 9 Relative rate of mono urea (salen)Co complex Finally additio nal control experiment was performed to rule out an alternative mechanism involving electrophilic activation of epoxides by the neighboring urea group through double hydrog en bonding. According to recent report by Sch r ei n er and co workers, (thio)urea functional groups can catalyze a certain types of epoxide opening r eaction by double hydrogen bonding activation (Scheme 3 1 5 ) 148 Scheme 3 1 5 Epoxide opening reaction catalyzed by thiourea

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142 Becaus e previous kinetic analysis can not discriminate intermolecular electrophil i c activation by the neighboring urea group (Figure 3 30 ) another control experiment would be required to ensure that bimetall ic activation through self assembly is responsible for observed rate acceleration. Figure 3 30 Possible urea/metal dual activation scenario Thus, to examine possible electrophilic activation, two different simple N N d isubstituted urea compounds were added to the reaction mixture in the presence of monomeric catalyst 2 26( OTs ) (Scheme 3 16) However, the addition of b oth urea additives decreased reaction rates in the HKR of ( rac ) epic hlorohydrin (Table 3 5 ) The additio n of electron rich dibenzylurea 3 52 exhibited a much slower reaction (entry 2). I ncreasing the amount of urea additive also resulted in slowe r reaction (entry 4). These results suggest that the urea additive might function as a competitive inhibitor, pres umably through co ordination to the metal center Therefore, it is highly unlikely that the rate acceleration originated from the electrophilic activati on of epoxides by the urea moiety It also explains why electron deficient end groups showed generally be tter reactivity in the bis urea (salen)Co catalyzed HKR.

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143 Scheme 3 1 6 Kinetic data for the HKR of ( rac ) epichlorohydrin catalyzed by 2 26(OTs) and urea additives Table 3 5 Kinetic data for the HKR of ( rac ) epichlorohy drin entry a dditive (mol%) k obs (h 1 ) r elative rate 1 none 7.6 x 10 2 1.0 2 3 52 (0.1) 3.8 x 10 2 0.5 3 3 53 (0.1) 6.7 x 10 2 0.9 4 3 53 (0.4) 3.2 x 10 2 0.4 Self A ssembly S tudy To verify the self assembly of bis urea salen structures in solution, FT IR and 1 H NMR dilution experiment s were performed. IR spectroscopy has been widely applied for studying self assembly of urea compounds because it has been known that free N H and hydrogen bonded N H ha ve different frequencies. Figure 3 3 1 depicts the NH stretching region of the FT IR spectra of 3 26k ( 3 mM, cyan line) in THF and reveals strong hydrogen bonded N H stretching vibrations (3347 and 3295 cm 1 ) in comparison to free N H stretching vibrations (3571 and 3505 cm 1 ) The intensity of hydrogen bonde d N H stretching vibrations was decreased with lowering concentration, but they were still significant even in diluted ( 1 mM, dark blue line) solution This result demonstrates that the urea N H groups of the bis urea (salen)Co complex are involved in inte rmolecular H bonding events in THF.

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144 Figure 3 3 1 The NH stretching region of the FTIR spectra of 3 26 k in THF To gain further insight into the self association strength, 1 H NMR dilution experiments were also performed us ing (salen)Ni complexes in THF d 8 Both bis and mono urea (salen)Ni complexes 3 5 4 and 3 5 5 were readily prepared as a model compound from the corresponding salen ligands (Figure 3 3 2 ) Figure 3 3 2 Bis urea (salen)Ni complex and mono urea (salen)Ni complex Two NH proton signals of the urea group in the (salen) Ni complexes were monitored upon increasing the concentration (0.76 to 19.1 mM), and the observed chemical shift of the N H group shifted downfield as shown in Figure 3 33. By using the simple monomer dimer model, t he dimerization constants of 3 54 and 3 55 were estimated as 56 22 M 1 and 32 3 M 1 respectively As mentioned earlier, it is also possible that mono and bis urea (sale n)Ni complexes can exist as higher aggregates like many other urea derived compounds To evaluate the association

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145 strength of the higher aggregate, two mathematical models such as equal K model ( K 2 = K n = K ) and two K model ( K 2 K n = K ) have been generall y used. 149 When the equal K model ( K 2 = K n = K ) was applied K a values of 3 5 4 and 3 5 5 were determined as 70 29 M 1 and 32 M 1 respectively. Th e s e result s indicate that both urea (salen)Ni complexes are self assembled in THF through hydrogen bonds with mo derate Figure 3 3 3 Concentration dependent 1 H NMR shift s of two urea protons

PAGE 146

146 association strength ( K a = 32~70 M 1 ) In addition, as discussed before, this moderate association values are consistent with the observed se cond order kinetic dependence on catalyst concentration in this system. It is also worthwhile to mention that the self association strength of Ni complexes (56 M 1 vs 32 M 1 ) can be translated into the rate enhancement by the corresponding Co(III) catalyst s (13 vs 8.4) X R ay P acking S t ructure s and MM2 C alculation To obtain the structural information on th e self assembly of bis urea (salen)Co complexes we attempted to grow single crystals. However, our attempts to crystallize (salen)Co complexes were unsu ccessful. Instead, a single crystal of the bis urea (salen)Ni complex 3 56 (R = Bn) was obtained by slow evaporation in DMF The ORTEP view of 3 56 is shown in Figure 3 34. Figure 3 3 4 ORTEP view of the crystal structu re of 3 5 6 The H atoms of the framework are omitted for clarity In the crystal packing, t he interstack arrangement between two extensive H bond networking layers was observed (Figure 3 35). However, the desired head to tail dimer suitable for bimetallic a ctivation is not found within this H bonding network (Figure 3 36).

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147 Figure 3 3 5 X ray packing structures of 3 5 6 showing interstack arrangement between two h ydrogen bond networks Figure 3 3 6 H bonded network in the packing structure of 3 5 6 Thus, M M2 calculation s were performed by using C A Che program (Fujitsu) to look at the feasibility of the self assembled dimer capable of bimetallic activation. To simplify the calculation, the bis urea (salen)Ni structure having the methyl end groups (R = Me) was used. The atomic coordinates in the (salen)Ni fragment were obtained from the crystal structure data of 3 5 6 and t he (salen)Ni fragment was locked during optimization

PAGE 148

148 After calculation s two possible energy minimized structures in the head to tail arran gement were obtained as shown in Figure 3 3 7 T wo (salen)Ni units can be assembled through two urea urea H bonding interactions either in a parallel ( P ) or an anti parallel ( A ) mode Interestingly, the Ni Ni separation was calculated as approximately 6 i n both mode s which is the optimal metal metal separation for epoxide opening reactions. 42 Figure 3 3 7 Two plausible structures of bis urea (salen)Ni dimer: antiparallel (A) and parallel (P ) After performing MM2 calculations, we could obtain a n X ray suitable single crystal of bis urea (salen)Ni complex 3 5 7 by slow evaporation in DMF (Figure 3 3 8 ) The end group of this bis urea (salen)Ni complex is the electron poor and sterically demandin g 3,5 (CF 3 ) 2 C 6 H 3 moiety In the crystal packing, the bis urea (salen)Ni complex 3 57 forms a self assembled dimer which adopts anti parallel head to tail conformation (Figure 3 39 and 3 40). In this structure, the intermolecular hydrogen bonding interacti ons between urea groups are observed (N H O = 2.06, 2.08 A) at the both ends of the salen and two urea planes are significantly twisted (57.9(8) ). The metal metal distance was determined as 5.3

PAGE 149

149 Figure 3 3 8 X ray crystal structure of bis urea (salen) Ni complex 3 5 7 Figure 3 3 9 Self assembled dimeric structure of 3 57 (side view) Figure 3 40 Self assembled dimeric structure of 3 57 (top view)

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150 This dimeric structure interacts with the neighboring dimer throug h extended urea urea hydrogen bonds (Figure 3 4 1 ) However, in this association only the alkyl urea N H involves in the formation of intermolecular N H O interaction of 2.05 with the neighboring dimer. The aryl urea N H forms N H O interactions of 2 .28 with one DMF molecule. The urea urea plane i s also twisted with the angle of 53.4(1) The metal metal distance between neighboring dimers was measured as 4.9 Figure 3 4 1 Hydrogen bond packing structure of bis urea (salen) Ni complex Inter e stin gly, less reactive bis urea salen complex (R = Bn) reveals the oligomeric structure in the solid state whereas more reactive bis urea salen (R = 3,5 (CF 3 ) 2 C 6 H 3 ) shows the desired dimeric structure. This result is rather unexpected, because it is generall y accepted that the electron rich al k yl urea can form more stable self assembled structures Although it is possible to have different self association pattern in solution, the bis urea salen bearing the electron deficient end group may h ave a stronger tend ency to form the dimeric structure adopting the desired conformation. Taken together those MM2 calculations and X ray packing structures demonstrate that

PAGE 151

151 the current bis urea salen scaffold provide s optimal metal metal separation (5~6 ) through H bonds f or effective bimetallic activation Asymmetric H ydrolysis of C yclohexene O xide Although the chiral (salen)Co(III) complexes are very efficient for the HKR of terminal epoxides, the asymmetric hydrolysis of meso epoxides still remains a challenge. Thus, we investigated asymmetric hydrolysis of cyclohexene oxide 3 58 as a model reaction to explore the scope of the bis urea (salen)Co catalyst (Scheme 3 17) After 45 h, bis urea (salen)Co complex 3 30 k(OTs) afforded the desired trans 1,2 cyclohexane diol product with much higher yield (62%) and enantiomeric excess (75%) compared to monomeric catalyst 2 26(OTs) (9% yield and 45% ee) This result demonstrate s that our approach will be applicable to more challenging substrate s as well. Scheme 3 1 7 Asymmetric hydrolysis of cyclohexene oxide Design of B is U r ea Spacing Dimeric ( S alen)Co C omplexes In the previous section, we successfully developed the self assembled catalyst mediated b y urea urea hydrogen bonds for HKR of epoxides. Th us, i t is interesting to utilize the urea motif for a new self assembled system. We envis i oned that the bis urea motif could be used as a spacer for linking two (salen)Co units (Figure 3 42). As a result two bimetallic reaction sites can be generated at t he both ends of the self assembled dimer We expected that the resulting dimeric catalysts c ould provide stronger but more flexible self assembling system for bimetallic reactions.

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152 Figure 3 4 2 Conceptual design of the bis urea dimeric ( salen )Co complex Based on this idea, various bis urea spacing dimeric ( salen ) cobalt complexes were prepared. B is urea spacing salicylaldehyde s 3 61 ( a e ) were readil y synthesized by reacting amine compound 3 43 with an appropriate commerc ial diisocyanate followed by deprotection (Scheme 3 18 ) Scheme 3 1 8 Synthesis of bis urea spacing salicylaldehyde intermediates

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153 From this salicyla l dehyde intermediate s the corresponding bis urea dimeric salen ligands were obtained using Weck s protocol 147 as depicted in Scheme 3 1 9 Subsequent meta lation of the resulting dimeric salen ligands afforded the desired bis urea spacing dimeric (salen)Co complexes 3 62 (a e) Scheme 3 1 9 Synthesis of bis urea spacing dimeric ( salen )Co complexes It is also interesting to see the catalytic efficiency and the self assembly of the analogous mono urea spacing dimeric (salen) Co complex. For this reason, mono urea int ermediate 3 63 was prepared by the reaction of amino compound 3 43 with carbodiimidazole ( CDI ) followed by deprotection of acetal group (Scheme 3 20 ) From salicyla l dehyde intermediate 3 63 mono urea dimeric (salen)Co complex 3 6 4 was obtained by using W eck s protocol 147 and subsequent meta lation. Those newly prepared dimeric (salen)Co complexes were tested for the hydrolytic desymmetrization of cyclohexene oxide (Scheme 3 21). As mentioned earlier, this reaction has been know n for very challenging with the simple monomeric (salen)Co catalyst. As low as 0.25 mol% of catalyst loading and 1.2 equivalent of H 2 O were used for this reaction. In the initial screening, those all bis urea spacing dimeric (salen)Co

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154 complexes demonstrate d superior reactivity and enantioselectivity compared to monomeric catalyst 2 26(OTs) (Table 3 6, entry 1 vs entries 3 7). Among them, the Scheme 3 20 Synthesis of mono urea spacing dimeric ( salen )Co complex 3 6 4 dimeri c catalysts linked with 1,3 phenylene type spacers ( 3 62 a(OTs) and 3 62 b(OTs) ) showed better performance than bis urea monomeric catalyst 3 26k(OTs) in terms of reactivity and enantioselectivity (entry 2 vs entries 3 4) Linear aliphatic and 1,4 phenylene spacer s were found to be less efficient than bis urea monomeric catalyst 3 26k(OTs) in terms of reactivity (entry 2 vs entries 5 7). Interestingly, the mono urea analogue 3 6 4 (OTs) exhibited slightly low but com parable reactivity and similar enantioselecti vity (entry 8). Those promising results demonstrate that the bis urea spacing dimeric scaffolds can provide a versatile and powerful self assembled catalytic system for epoxide opening reactions. In addition, the different types of chiral ligands such as tridentate Schiff base can be easily installed at the both ends of the bis urea spacer. Although more detailed structural and mechanistic studies are required to elucidate this novel

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155 self assembled catalytic system, it would be a powerful solution for effi cient bimetallic catalysis. Scheme 3 21 Desymmetrization of cyclohexene oxide catalyzed by (salen)Co complexes Table 3 6 Desymmetrization of cyclohexene oxide entry catalyst (mol%) yield (%) e e (%) 1 2 26(OTs) (0.5) 9 45 2 3 30 k(OTs) (0.5) 62 75 3 3 62 a(OTs) (0. 2 5) 69 81 4 3 62 b(OTs) (0. 2 5) 72 81 5 3 62 c(OTs) (0. 2 5) 45 71 6 3 62 d(OTs) (0. 2 5) 38 72 7 3 62 e(OTs) (0. 2 5) 43 76 8 3 6 4 (OTs) (0. 2 5) 59 80

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156 Summary In summary we developed novel chiral bis urea (salen)C o catalysts which were self assembled through intermolecular urea urea hydrogen bonds in the solution. These catalysts were successfully employed to hydrolytic kinetic resolution of racemic epoxides exhibiting significant rate acceleration up to 13 times compared t o the unfunctionalized analogue. The observed rate acceleration can be rationalized by the self assembly of catalytic units through intermolecular hydrogen bonds To the best of our knowledge, this is the first example of H bonded self assembling catalyst for the hydrolytic kinetic resolution of epoxides. In addition, a s an extension of this strategy, bis urea spacing dimeric (salen)Co catalysts were de veloped. These catalysts exhibited superior performance in the hydrolytic desymmetrization of me so epoxide in terms of reactivity and enantioselectivity. Experimental General Remarks All reactions were conducted in flame dried glassware under an inert atmosphere of dry argon. THF, CH 2 Cl 2 Et 2 O and toluene were purified under positive pressure of dry nitrogen by Meyer Solvent Dispensing System prior to use. All the chemicals used were purchased from Sigma Aldrich Co., Acros Organics, TCI America, and Strem Chemical Incs. and were used as recei ved without further purification. NMR spectra were recorded using a Me r cury 300 FT NMR, 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 residual signals from CDCl 3 (1H) 7.26 ppm and (13C) 77.23 ppm. High resolution mass spectra were recorded on a GC/MS spectrometer or a TOF LC/Ms

PAGE 157

157 spectrometer. Enantiomeric ratios were determined by chiral GC MS analysis using a Chiraldex TA column General Proced ure for the Preparation of Ureidophenyl Boronic Ester s To a solution of 4 a minophenylbo ronic acid pinacol ester (161 mg, 0.74 mmol) in CH 2 Cl 2 (2 mL), isocyanate (0.74 mmol) was added at room temperature, and then allowed to stir for 2 h. The solution was concentrated under reduced pressure, and the residue was then triturated with ethyl acet ate/ n hexane to give 3 32 as a soli d 1 B enzyl 3 (4 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)phenyl)urea (3 32 a). W h ite solid (95%); 1 H NMR ( 300 MHz, DMSO d 6 ) 8.69 (s, 1 H) 7.52 (d, J = 8.5 Hz, 2 H) 7.40 (d, J = 8.5 Hz, 2 H) 7. 35 7. 18 (m, 5 H) 6.66 (t, J = 5.8 Hz, 1 H) 4.28 (d, J = 5.7 Hz, 2 H) 1.25 (s, 12 H) ; 13 C NMR (75 MHz, DMSO d 6 ) 155.6, 144.1, 140.9, 136.1, 129.0, 127.9, 127.5, 127.4, 117.3, 83.9 43.4, 25.4; HRMS (ESI TOF) c alcd for C 20 H 2 6 BN 2 O 3 [M +H ] + : 353.2035 f ound: 353.2042. 1 H exyl 3 (4 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)phenyl)urea (3 32 b). White solid (100%); 1 H NMR ( 300 MHz, DMSO d 6 ) 8.53 (s, 1 H) 7.51 (d, J = 8.5 Hz, 2 H) 7.38 (d, J = 8.5 Hz, 2 H) 6.16 (t, J = 5.5 Hz, 1 H) 3.05 ( q J = 6. 6 Hz, 2 H) 1. 50 1. 35 (m, 6 H) 1. 25 (s, 12 H) 0. 84 ( t J = 6.6 Hz, 3 H) ; 13 C NMR (75 MHz, DMSO d 6 )

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158 155.6, 144.3, 136.0, 117.1, 83.9, 39.7, 31.7, 30.4 26.8, 25.4, 22.8, 14.6; HRMS (APCI TOF) c alcd for C 19 H 3 2 BN 2 O 3 [M +H ] + : 347.2500 f ound: 347.2530. 1 P henyl 3 (4 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)phenyl)urea (3 32 c). W hite solid (97%) 1 H NMR ( 300 MHz, DMSO d 6 ) 8.80 (s, 1 H) 8.69 (s, 1 H) 7. 65 7. 53 (m, 2 H) 7.4 7 ( d, J = 6.2 Hz, 2 H) 7.4 4 ( d, J = 6.2 Hz, 2 H) 7.27 (t, J = 7.8 Hz, 2 H) 7.03 6.90 (m, 1 H) 1.26 (s, 12 H) ; 13 C NMR (75 MHz, DMSO d 6 ) 153.0, 143.4, 140.2, 136.1, 129.5, 122.7, 122.6, 119.0, 117.8 84.0, 25.4; HRMS (ESI TOF) c alcd for C 19 H 2 4 BN 2 O 3 [M +H ] + : 33 9 .18 78 f ound: 339.1888. 1 (4 M ethoxyphenyl) 3 (4 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)phenyl)urea (3 32 d). W hite solid (99%); 1 H NMR ( 300 MHz, DMSO d 6 ) 8.71 (s, 1 H) 8.49 (s, 1 H) 7.56 (d, J = 8.5 Hz, 2 H) 7.44 (d, J = 8.5 Hz, 2 H) 7.34 (d, J = 9.1 Hz, 2 H) 6.85 (d, J = 9.1 Hz, 2 H) 3. 70 ( s 3 H) 1.26 (s, 12 H) ; 13 C NMR (75 MHz, DMSO d 6 ) 155.3, 153.2, 143.6, 136.1, 133.2, 120.8, 117.6, 114.7, 8 4.0, 55.8, 25.4; HRMS (APCI TOF) c alcd for C 20 H 2 6 BN 2 O 4 [M +H ] + : 369.1984 f ound: 369.1999.

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159 1 (3,5 B is(trifluoromethyl)phenyl) 3 (4 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)phenyl)urea (3 32 e). White solid (90%); 1 H NMR ( 300 MHz, DMSO d 6 ) 9.40 (s, 1 H), 9.12 (s, 1 H), 8.12 (s, 2 H), 7.63 (s, 1 H), 7. 60 (d, J = 7.8 Hz, 2 H) 7. 50 ( d J = 7.8 Hz, 2 H) 1. 27 (s, 12 H) ; 13 C NMR (75 MHz, DMSO d 6 ) 152.9, 142.7, 142.4, 136.1, 131.4 (q, J = 32 Hz), 124.0 (q, J = 272 Hz), 118.8, 118.7, 118.4, 84 .1, 25.4; HRMS (APCI TOF) c alcd for C 21 H 2 2 BF 6 N 2 O 3 [M +H ] + : 475.1626 f ound: 475.1639. 1 (4 (4,4,5,5 T etramethyl 1,3,2 dioxaborolan 2 yl)phenyl) 3 (4 (trifluoromethyl) phenyl)urea (3 32 f). White solid (100%); 1 H NMR ( 300 M Hz, DMSO d 6 ) 9.11 (s, 1 H), 8.94 (s, 1 H), 7. 62 (d, J = 3.0 Hz, 4 H) 7. 59 ( d J = 8.1 Hz, 2 H) 7. 47 ( d J = 8.1 Hz, 2 H) 1. 27 (s, 12 H) ; 13 C NMR (75 MHz, DMSO d 6 ) 152.8, 144.0, 143.0, 136.1, 126.8 (d, J = 3.7 Hz), 125.2 (q, J = 270 Hz), 122.6 (q, J = 32 Hz), 118 .6, 118.0, 84.1, 25.4; HRMS (APCI TOF) c alcd for C 20 H 2 3 BF 3 N 2 O 3 [M +H ] + : 407.1752 f ound: 407.1760. General Procedure for the Preparation of Ureidophenyl Salicylaldehydes A stirred mixture of urea functionalized boronic acid pinacol ester 3 32 (0.50 mmol), 3 tert butyl 2 hydroxy 5 iodobenzaldehyde 2 7 (0.50 mmol, 1 equiv.), K 2 CO 3 (1.50 mmol, 3 equiv.), PdCl 2 (PPh 3 ) 2 (0.02 mmol, 4 mol%), water (2 mL), and CH 3 CN (5 mL) was heated at 70 C under argon for 3 12 h. The mixture was cooled to room temperature, dilute d with ethyl acetate (50 mL), and washed with H 2 O, and then dried over anhydrous Na 2 SO 4 Volatiles were removed by evaporation under reduced

PAGE 160

160 pressure, then the residue was purified by column chromatography on silica gel (10%, then 33% ethyl acetate in n he xane) to give the resulting salicylaldehydes 3 33 (38 72% yield) as a solid. The yields were not optimized. 1 B enzyl 3 (3' tert butyl 5' formyl 4' hydroxybiphenyl 4 yl)urea (3 33 a). Yellow solid (66%); 1 H NMR ( 300 MHz, DM SO d 6 ) 11. 76 (s, 1 H) 10.04 (s, 1 H) 8.66 (s, N H ), 7.90 (d, J = 2 3 Hz, 1 H) 7.73 (d, J = 2.3 Hz, 1 H) 7.56 7.48 (m, 4 H), 7.35 7.20 (m, 5 H), 6.63 (t, J = 5.9 Hz, N H ), 4.30 (d, J = 5.9 Hz, 2 H), 1.42 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 199.7, 159. 5, 155.9, 141.0, 140.5, 138.3, 132.6, 132.4, 132.1, 130.3, 129.0, 127.8, 127.4, 127.2, 121.6, 118.8, 43.5, 35.3, 29.8; HRMS (APCI TOF) c alcd for C 25 H 2 7 N 2 O 3 [M +H ] + : 403.2016 f ound: 403.2043. 1 (3' tert B utyl 5' formyl 4' hydroxybiphenyl 4 yl) 3 hexylurea (3 33 b). Yellow solid (50%); 1 H NMR ( 300 MHz, DMSO d 6 ) 11. 76 (s, 1 H) 10.03 (s, 1 H) 8.48 (s, N H ), 7.89 (d, J = 2 3 Hz, 1 H) 7.72 (d, J = 2.3 Hz, 1 H) 7.58 7.42 (m, 4 H), 6.12 (t, J = 5.5 Hz, N H ), 3.07 (q, J = 5.9 Hz, 2 H), 1.42 (s, 9 H), 1.26 (m, 8 H), 0.86 (t, J = 6.6 Hz, 3 H); 13 C NMR (75 MHz, DMSO d 6 ) 199.7, 159.5, 155.8, 140.7, 138.2, 132.4, 131.1, 130.3,

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161 127.2, 121.6, 118.6, 39.7, 35.3, 31.7, 30.4, 29.8, 26.8, 22.8, 14.6; HRMS (APCI TOF) c alcd for C 24 H 3 2 N 2 O 3 Na [M +Na ] + : 419.2305 f ound: 419.2327. 1 (3' tert B utyl 5' formyl 4' hydroxybiphenyl 4 yl) 3 phenylurea (3 33 c). Beige solid (72%); 1 H NMR ( 300 MHz, DMSO d 6 ) 11. 79 (s, 1 H) 10.05 (s, 1 H) 8.77 (s, N H ), 8.67 (s, N H ), 7.92 (d, J = 2 3 Hz, 1 H) 7.74 (d, J = 2.3 Hz, 1 H) 7.57 (m, 4 H), 7.45 (m, 2 H), 7.27 (t, J = 7.9 Hz, 2 H), 6.96 (m, 2 H), 1.43 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 199.7, 159.6, 153.2, 140.3, 139.7, 138.3, 133.3, 132.5, 132.0, 130.4, 129.5, 127.4, 122.6, 121.6, 119.3, 118.9, 35.3, 29.8; HRMS (ESI TOF) c alcd for C 24 H 2 5 N 2 O 3 [M +H ] + : 389.1860 f ound: 389.1879. 1 (3' tert B utyl 5' formyl 4' hydroxybiphenyl 4 yl) 3 (4 methoxyphenyl)urea (3 33 d). Yellow solid (38%); 1 H NMR ( 300 MHz, DMSO d 6 ) 11. 77 (s, 1 H) 10.05 (s, 1 H) 8.68 (s, N H ), 8.47 (s, N H ), 7.92 (d, J = 2 3 Hz, 1 H) 7.74 (d, J = 2.3 Hz, 1 H) 7.64 7.46 (m, 4 H), 7.43 7.27 (m, 2 H), 6.77 6.95 (m, 2 H), 3.70 (s, 3 H), 1.43 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 199.7, 159.6, 155.2, 153.4, 139.9, 138.3, 133.3, 133.1, 132.5, 130.4, 127.3, 121.7, 120.8, 119.2 114.7, 55.9, 35.3, 29.8; HRMS (APCI TOF) c alcd for C 25 H 2 7 N 2 O 4 [M +H ] + : 419.1965 f ound: 419.1972.

PAGE 162

162 1 (3,5 B is(trifluoromethyl)phenyl) 3 (3' tert butyl 5' formyl 4' hydroxybi phenyl 4 yl)urea (3 33 e). Yellow solid (60%); 1 H NMR ( 300 MHz, DMSO d 6 ) 11. 78 (s, 1 H) 10.05 (s, 1 H) 9.39 (s, N H ), 9.09 (s, N H ), 8.14 (s, 2 H), 7.93 (d, J = 2 1 Hz, 1 H) 7.75 (d, J = 2.1 Hz, 1 H) 7.63 7.56 (m, 5 H), 1.43 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 199.7, 159.7, 153.1, 142.5, 139.0, 138.3, 134.0, 132.5, 131.8, 131.4 (q, J = 33 Hz), 130.8, 130.5, 127.3, 124.0 (q, J = 272 Hz), 121.7, 120.0, 118.7, 35.3, 29.8; HRMS (ESI TOF) c alcd for C 26 H 2 3 F 6 N 2 O 3 [M +H ] + : 525.1607 f ound: 525.1613. 1 (3' tert B utyl 5' formyl 4' hydroxybiphenyl 4 yl) 3 (4 (trifluoromethyl) phenyl) urea (3 33 f). Yellow solid (59%); 1 H NMR ( 300 MHz, DMSO d 6 ) 11. 78 (s, 1 H) 10.05 (s, 1 H) 9.10 (s, N H ), 8.90 (s, N H ), 7.93 (d, J = 2 0 Hz, 1 H) 7.75 (d, J = 2.3 Hz, 1 H) 7.68 7.55 (m, 8 H), 1.43 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 199.6, 159.7, 152.9, 144.1, 139.3, 138.3, 133.7, 132.5, 131.9, 130.5, 127.4, 126.8, 125.2 (q, J = 270 Hz), 122.5 (q, J = 32 Hz), 121.7, 119.6, 118.6, 35.3, 29.8; HRMS (ESI TOF) c alcd for C 25 H 2 4 F 3 N 2 O 3 [M +H ] + : 457.1734 f ound: 457.1749.

PAGE 163

163 General Procedure for the Preparation of Ureidophenyl Salen Ligand s To a solution of (1 R ,2 R ) cyclo hexane 1,2 diamine (0.20 mmol) in THF (8 mL), urea functionalized salicylaldehyde 3 33 (0.40 mmol) was added at room temperature, and then allowed to stir for 3 20 h. The solution was concentrated under reduced pressure, and the residue was purified by col umn chromatography on silica gel (ethyl acetate) to give the resulting salen as a yellow solid. The yields were not optimized. 3 3 4 a. Yellow solid (71%); 1 H NMR ( 300 MHz, DMSO d 6 ) 14.15 (s, 2 H), 8.60 (s, 2 H), 8.52 (s, 2 H), 7.43 7.20 (m, 12 H), 6.59 (t, J = 6.0 Hz, 2 H), 4.30 (d, J = 5.7 Hz, 4 H), 3.46 3.38 (m, 2 H), 2.01 1.91 (m, 2 H), 1.86 1.76 (m, 2 H), 1.75 1.60 (m, 2 H), 1.52 1.41 (m, 2 H), 1.36 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) 167.1, 159.6, 155.8, 141.0, 13 9.9, 137.3, 133.5, 130.4, 129.0, 128.0, 127.8, 127.4, 127.4, 126.9, 119.0, 118.7, 71.6, 43.4, 35.2, 33.1, 29.8, 24.5; HRMS (APCI TOF) c alcd for C 56 H 6 2 N 6 O 4 Na [M +Na ] + : 905.4725 f ound: 905.4718 3 3 4 b. Yellow solid (72%); 1 H NMR ( 300 MHz, DMSO d 6 ) 14.14 (s, 2 H), 8.52 (s, 2 H), 8.41 (s, 2 H), 7.42 7.28 (m, 8 H), 6.08 (t, J = 5.7 Hz, 2 H), 3.47 3.40 (m, 2 H), 3.06 (q, J = 6.5 Hz, 4 H), 2.02 1.91 (m, 2 H), 1.88 1.76 (m, 2 H), 1.75 1.60 (m, 2 H), 1.50 1.47 (m, 2 H), 1.35 (s, 18 H), 1.31 1.19 (m, 16 H ), 0.86 (t, J = 6.5 Hz, 6 H); 13 C NMR (75

PAGE 164

164 MHz, DMSO d 6 ) 167.1, 159.6, 155.8, 140.0, 137.3, 133.2, 130.4, 127.9, 127.8, 126.8, 119.0, 118.5, 71.6, 39.7, 35.2, 33.0, 31.7, 30.4, 29.8, 26.7, 24.5, 22.8, 14.6; HRMS (APCI TOF) c alcd for C 54 H 7 5 N 6 O 4 [M +H ] + : 871 .5844 f ound: 871.5858. 3 3 4 c. Yellow solid (88%); 1 H NMR ( 300 MHz, DMSO d 6 ) 14.18 (s, 2 H) 8.70 (s, 2 H) 8.64 (s, 2 H), 8.54 (s, 2 H), 7.48 7.35 (m, 16 H), 7.27 (t, J = 7.6 Hz, 4 H), 6.95 (t, J = 7.2 Hz, 2 H), 3.51 3.41 (m, 2 H), 2.02 1.92 (m, 2 H), 1.88 1.78 (m, 2 H), 1.75 1.62 (m, 2 H), 1.54 1.43 (m, 2 H), 1.37 (s, 18 H) ; 13 C NMR (75 MHz, DMSO d 6 ) 167.1, 159.7, 153.1, 140.3, 139.1, 137.4, 134.2, 130.2, 129.4, 128.0, 127.9, 127.0, 122.5, 119.1, 119.0, 118.9, 71.6 35.2, 33.1, 29.8, 24.5; HRMS (APCI TOF) c alcd for C 54 H 5 9 N 6 O 4 [M +H ] + : 855.4594 f ound: 855.4593. 3 3 4 d. Yellow solid (83%); 1 H NMR ( 300 MHz, DMSO d 6 ) 14.14 (s, 2 H), 8.59 (s, 2 H), 8.51 (s, 2 H), 8.41 (s, 2 H), 7.41 (d J = 8.7 Hz, 4 H), 7.35 7.29 (m, 12 H), 6.82 (d, J = 8.9 Hz, 4 H), 3.66 (s, 6 H), 3.44 3.42 (m, 2 H), 1.97 1.91 (m, 2 H), 1.82 1.77 (m, 2 H), 1.70 1.60 (m, 2 H), 1.49 1.39 (m, 2 H), 1.33 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) 167.6, 159.7, 155.1, 153.3, 1 39.3, 137.3, 133.9, 133.3, 132.2, 130.3, 128.2, 127.0, 120.7, 119.1, 119.0, 114.6, 71.1, 55.9, 35.2, 33.1, 29.8, 23.1; HRMS (APCI TOF) c alcd for C 56 H 6 3 N 6 O 6 [M +H ] + : 915.4804 f ound: 915.4817

PAGE 165

165 3 3 4 e. Yellow solid (86%); 1 H NMR ( 300 MHz, DMSO d 6 ) 14.20 (s, 2 H), 9.37 (s, 2 H), 9.02 (s, 2 H), 8.54 (s, 2 H), 8.12 (s, 4 H), 7.62 (s, 2 H), 7.52 7.37 (m, 12 H), 3.46 3.44 (m, 2 H), 1.99 1.96 (m, 2 H), 1.83 1.81 (m, 2 H), 1.70 1.68 (m, 2 H), 1.50 1.47 (m, 2 H), 1.37 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) 167.1, 159.9, 153.0, 142.5, 138.4, 137.4, 134.9, 132.0, 131.4 (q, J = 32 Hz), 130. 1, 128.1, 127.9, 127.0, 124.0 ( q, J = 271 Hz), 199.8, 119.1, 118.6, 71.6, 35.2, 33.0, 29.8, 24.9; HRMS (APCI TOF) c alcd for C 58 H 5 5 F 12 N 6 O 4 [M +H ] + : 1127.4088 f ound: 1127.409 8. 3 3 4 f. Yellow solid (46%); 1 H NMR ( 300 MHz, DMSO d 6 ) 14.19 (s, 2 H), 9.07 (s, 2 H), 8.84 (s, 2 H), 8.54 (s, 2 H), 7.69 7.58 (m, 8 H), 7.52 7.34 (m, 12 H), 3.49 3.42 (m, 2 H), 2.03 1.92 (m, 2 H), 1.87 1.79 (m, 2 H), 1 .75 1.63 (m, 2 H), 1.54 1.44 (m, 2 H), 1.37 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) 167.1, 159.8, 152.9, 144.1, 138.7, 137.4, 134.6, 130.2, 128.1, 128.0, 127.0, 126.7, 125.2 (q, J = 270 Hz), 122.4 (q, J = 32 Hz), 119.4, 119.1, 118.5, 71.6, 35.2, 33.1, 29.8, 24.5; HRMS (APCI TOF) c alcd for C 56 H 5 7 F 6 N 6 O 4 [M +H ] + : 991.4340 f ound: 991.4364 General P rocedure for the P reparation of B is U rea ( S alen ) Co Complex es To a solution or suspension of an appropriate salen ligand 3 3 4 (0.21 mmol) in EtOH (5 mL), Co(OAc) 2 4H 2 O (0.21 mmol, 1.0 equiv) was added and heated at reflux

PAGE 166

166 for 3 h under argon. Precipitate was collected by filtration, washed by EtOH, and then dried under vacuum for 24 h to give a (salen)cobalt complex. 3 2 8 a Reddish br own solid (72%); HRMS (APCI TOF) c alcd for C 56 H 60 CoN 6 O 4 [M] + : 939.400 3 f ound: 939.3999. 3 2 8 b Brown solid (81%); HRMS (ESI TOF) c alcd for C 54 H 72 CoN 6 O 4 [M] + : 927.494 2 f ound: 927.4896 3 2 8 c Reddish brown solid (87%); HRMS (ESI TOF) c alcd for C 54 H 56 CoN 6 O 4 [M] + : 911.369 0 f ound: 911.3704. 3 2 8 d Reddish brown solid (57%); HRMS (ESI TOF) c alcd for C 56 H 60 CoN 6 O 6 [M] + : 971.390 1 f ound: 971.3861.

PAGE 167

167 3 2 8 e Reddish brown solid (81%); HRMS (APCI TOF) c alcd for C 58 H 52 CoF 12 N 6 O 4 [M] + : 1183.3190 f ound: 1183.3168. 3 2 8 f Red solid (83%); HRMS (ESI TOF) c alcd for C 56 H 54 CoF 6 N 6 O 4 [M] + : 1047.34 37 f ound : 1047.3419 General Procedure for the Preparation of Ureidom ethylene salicylaldehydes This reaction was carr ied out using known procedures. To a solution of 5 (azidomethyl) 3 tert butyl 2 hydroxybenzaldehyde 3 40 (1.26 mmol) in ethyl acetate (10mL), an ap propriate isocyanate (1 .26 mmol, 1.0 equiv) was added. After addition of Pd C (10 wt %, ~30 mg), the mixture was then allowed to stir overn ight under a hydrogen balloon. This reaction mixture was filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 2:1) to give the resulting salicylaldehyde. Yields were not optimized.

PAGE 168

168 1 Benzyl 3 (3 t ert butyl 5 formyl 4 hydroxybenzyl)urea (3 40 a) White solid (63%). 1 H NMR (300 MHz, DMSO d 6 ) 11.72 (s, 1 H), 9.93 (s, 1 H), 7.50 7.46 (m, 2 H), 7.31 7.18 (m, 5 H), 6.46 (t, J = 6.0 Hz, 2 H), 4.22 (d, J = 6.6 Hz, 2 H), 4.20 (d, J = 6.3 Hz, 2 H), 1.36 (s 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 198.5, 158.7, 158.1, 140.9, 137.1, 133.7, 132.0, 130.3, 128.2, 126.9, 126.5, 120.3, 42.9, 42.3, 34.4, 29.0; HRMS (ESI TOF) c alcd for C 20 H 25 N 2 O 3 [M+H] + : 341.1860, f ound: 341.1861. 1 (3 t ert Butyl 5 formyl 4 hydroxybenzyl) 3 hexylurea (3 40 b) Colorless oil (83%). 1 H NMR (300 MHz, CDCl 3 ) 11.65 (s, 1 H), 9.70 (s, 1 H), 7.33 (d, J = 2.3 Hz, 1 H), 7.18 (d, J = 2.3 Hz, 1 H), 5.75 (t, J = 5.3 Hz, 1 H), 5.37 (t, J = 5.3 Hz, 1 H), 4.15 (d, J = 5.7 Hz, 2 H), 3.04 (q, J = 6.7 Hz, 2 H), 1.41 1.36 (m, 2 H), 1.34 (s, 9 H), 1.27 1.14 (m, 6 H), 0.83 (t, J = 6.8 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ) 196.8, 160.1, 158.8, 138.4, 133.3, 130.2, 129.9, 120.2, 43.4, 40.4, 34.7, 31.5, 30.2, 29.1, 26.5, 22.5, 14. 0; HRMS (APCI TOF) c alcd for C 19 H 31 N 2 O 3 [M+H] + : 335.2329, f ound: 335.2318. 1 (3 tert Butyl 5 formyl 4 hydroxybenzyl) 3 octadecylurea (3 40 c) White solid (66%) 1 H NMR (300 MHz, CDCl 3 ) 11.73 (s, 1 H), 9.84 (s, 1 H), 7.4 3 (d, J = 2.3 Hz, 1 H), 7.34 (d, J = 2.3 Hz, 1 H), 4.70 (t, J = 5.8 Hz, 1 H), 4.40 (t, J = 5.5 Hz, 1 H), 4.32 (d, J = 5.9 Hz, 2 H), 3.19 3.13 (m, 2 H), 1.49 1.45 (m, 2 H), 1.40 (s, 9 H), 1.25 (s, 30 H), 0.88

PAGE 169

169 (t, J = 6.8 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ) 197.0, 160.5, 158.0, 138.7, 133.7, 130.5, 130.0, 120.4, 43.9, 40.7, 34.9, 31.9, 30.2, 29.7, 29.7, 29.6, 29.6, 29.4, 29.4, 29.2, 26.9, 22.7, 14.1; HRMS (ESI TOF) c alcd for C 31 H 55 N 2 O 3 [M+H] + : 503.4207, f ound: 503.4200. 1 (3 tert Butyl 5 formyl 4 hydroxybenzyl) 3 phenylurea (3 40 d) White solid (72%) 1 H NMR (300 MHz, DMSO d 6 ) 11.75 (s, 1 H), 9.96 (s, 1 H), 8.54 (s, 1 H), 7.55 7.52 (m, 2 H), 7.40 (d, J = 8.4 Hz, 2 H), 7.22 (t, J = 8.0 Hz, 2 H), 6.88 (t, J = 7.4 Hz, 1 H), 6.61 (t, J = 6.0 Hz), 4.26 (d, J = 6.0 Hz, 2 H), 1.35 (s, 9 H); 13 C NMR (125 MHz, DMSO d 6 ) 198.6, 158.9, 155.2, 140.4, 137.1, 133.5, 131.4, 130.5, 128.6, 121.1, 120.4, 117.7, 42.1, 34.4, 29.0; HRMS (ESI TOF) c alcd for C 19 H 23 N 2 O 3 [M+H] + : 327.1703, f ound: 327.1702. 1 (3 tert Butyl 5 formyl 4 hydroxybenzyl) 3 (4 methoxyphenyl)u rea (3 40 e) White solid (42%) 1 H NMR (300 MHz, CDCl 3 ) 11.69 (s, 1 H), 9.73 (s, 1 H), 7.37 (d, J = 2.0 Hz, 2 H), 7.23 (s, 1 H), 7.12 (d, J = 8.8 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 5.40 (s, 1 H), 4.27 (d, J = 5.7 Hz, 2 H), 3.74 (s, 3 H), 1.37 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 196.9, 160.4, 156.9, 156.8, 1 38.6, 133.4, 130.7, 130.3, 129.7, 124.4, 120.3, 114.5, 55.4,

PAGE 170

170 43.4, 34.8, 29.1; HRMS (ESI TOF) c alcd for C 20 H 24 N 2 O 4 Na [M+Na] + : 379.1628, f ound: 379.1634. 1 (3,5 Bis(trifluoromethyl)phenyl) 3 (3 tert butyl 5 formyl 4 hydrox ybenzyl) urea (3 40 f) White solid (68%) 1 H NMR (300 MHz, DMSO d 6 ) 11.77 (s, 1 H), 9.98 (s, 1 H), 9.38 (s, 1 H), 8.11 (s, 2 H), 7.56 7.55 (m, 3 H), 7.05 (t, J = 5.7 Hz, 1 H), 4.31 (d, J = 5.9 Hz, 2 H), 1.38 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 198.6, 158.9, 154.8, 142.5, 137.2, 133.4, 131.2, 131.0, 130.6 (q, J = 32 Hz) 130.5, 123.4 (q, J = 271 Hz), 120.4, 117.3, 42.2, 34.4, 29.0; HRMS (ESI TOF) c alcd for C 21 H 24 F 6 N 3 O 3 [M+NH 4 ] + : 480.1716, f ound: 480.1743. 1 (3 tert Butyl 5 formyl 4 hydroxybenzyl) 3 (4 fluorophenyl)urea (3 40 g) White so lid (73%) 1 H NMR (300 MHz, DMSO d 6 ) 11.77 (s, 1 H), 9.97 (s, 1 H), 8.60 (s, 1 H), 7.55 7.53 (m, 2 H), 7.43 7.38 (m, 2 H), 7.09 7.03 (m, 2 H), 6.62 (t, J = 5.9 Hz, 1 H), 4.27 (d, J = 5.9 Hz, 2 H), 1.38 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 198.6, 158.9, 156.9 (d, J = 236 Hz), 155.3, 137.1, 136.8 (d, J = 2.6 Hz), 133.5, 131.4, 130.5, 120.4, 119.3 (d, J = 7.7 Hz), 115.1 (d, J = 22 Hz), 42.2, 34.4, 29.1; HRMS (ESI TOF) c alcd for C 19 H 22 FN 2 O 3 [M+H] + : 345.1609, f ound: 345.1614.

PAGE 171

171 1 (3 tert Butyl 5 formyl 4 hydroxyb enzyl) 3 (4 chlorophenyl)urea (3 40 h) White solid (65%) 1 H NMR (300 MHz, DMSO d 6 ) 11.76 (s, 1 H), 9.97 (s, 1 H), 8.71 (s, 1 H), 7.54 7.53 (m, 2 H), 7.45 7.42 (m, 2 H), 7.27 7.24 (m, 2 H), 6.67 (t, J = 5.9 Hz, 1 H), 4.27 (d, J = 5.9 Hz, 2 H), 1.38 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 198.6, 158.9, 155.0, 139.4, 137.1, 133.5, 131.2, 13 0.5, 128.4, 124.5, 120.4, 119.2, 42.1, 34.4, 29.0; HRMS (ESI TOF) c alcd for C 19 H 22 N 2 O 3 [M+H] + : 361.1313, f ound: 361.1325. 1 (3 tert Butyl 5 formyl 4 hydroxybenzyl) 3 (4 (trifluoromethyl)phenyl)urea (3 40 k) White solid (7 1%) 1 H NMR (300 MHz, DMSO d 6 ) 11.77 (s, 1 H), 9.97 (s, 1 H), 9.03 (s, 1 H), 7.63 7.54 (m, 6 H), 6.81 (t, J = 5.9 Hz, 1 H), 4.29 (d, J = 5.9 Hz, 2 H), 1.38 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 198.6, 158.9, 154.9, 144.2, 137.2, 133.5, 131.1, 130.5, 126.0, 124.6 (q, J = 270 Hz), 121.0 (q, J = 32 Hz), 120.4, 117.3, 42.2, 34.4, 29.0; HRMS (ESI TOF) c alcd for C 20 H 22 F 3 N 2 O 3 [M+H] + : 395.1577, f ound: 395.1580.

PAGE 172

172 1 (3 tert Butyl 5 formyl 4 hydroxybenzyl) 3 (2,6 diisopropylphenyl)urea (3 40 l) White solid (66%) 1 H NMR (300 MHz, DMSO d 6 ) 11.71 (s, 1 H), 9.95 (s, 1 H), 7.57 (s, 1 H), 6.64 (s, 1 H), 4.24 (s, 2 H), 3.13 (m, 2 H), 1.38 (s, 9 H), 1.09 (d, J = 6.8 Hz, 12 H); 13 C NMR (75 MHz, DMSO d 6 ) 198.2, 158.7, 157.0, 146.7, 137.0, 133.2, 133.0, 132.2, 130.3, 126.9, 122.7, 120.2, 42.3, 34 .4, 29.0, 27.9, 23.6; HRMS (ESI TOF) c alcd for C 25 H 35 N 2 O 3 [M+H] + : 411.2642, f ound: 411.2632. Synthesis of 4 ( A minomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol 4 (Azidomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol (3 42 ) To a mixture of 5 (azidomethyl) 3 tert butyl 2 hydroxybenzaldehyde 3 40 (596 mg, 2.56 mmol), 1,3 propanediol (0.74 mL, 10.23 mmol), and a catalytic amount of tetra n butylammonium tribromide (123 mg, 0.25 mmol) was added. After stirring at room temperat ure for 20 h, the reaction was quenched by adding saturated aq ueous NaHCO 3 solution. The mixture was extracted twice with EtOAc and the combined organic layers were washed with brine. After drying over anhydrous Na 2 SO 4 the solvent was removed in vacuo. Th e residue was purified by column chromatography on silica gel ( n hexane:EtOAc 5:1) to give 3 42 (506 mg, 68%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ) 8.20 (s, 1 H), 7.18 (d, J = 2.0 Hz, 1 H), 7.03 (d, J = 2.3 Hz, 1 H), 5.63 (s, 1 H), 4.34 4.28 (m, 2 H), 4.23 (s, 2 H), 4.05 3.96 (m, 2 H), 2.33 2.21 (m, 1 H), 1.54 1.47 (m, 1H), 1.42 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 154.4, 137.9, 127.9, 125.7, 125.6, 122.7, 103.2, 67.5, 54.8,

PAGE 173

173 34.9, 29.4, 25.6; HRMS (ESI TOF) c alcd for C 15 H 22 N 3 O 3 [M+H] + : 292.1656, f ound: 292.1656. 4 (Aminomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol (3 43 ) To a solution of 3 42 (506 mg, 1.74 mmol) i n ethyl acetate (10 mL), Pd C (10 wt %, 40 mg) was added. The mixture was then allowed to stir overn ight under a hydrogen balloon. This reaction mixture was filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated under reduce d pressure to give 3 43 ( 446 mg, 77%) as a white solid. This crude compound was used for the next step without further purification. 1 H NMR (300 MHz, CDCl 3 ) 8.01 (s, 1 H), 7.17 (d, J = 1.7 Hz, 1 H), 7.01 (d, J = 2.3 Hz, 1 H), 5.62 (s, 1 H), 4.35 4.29 (m, 2 H), 4.01 (t, J = 12.2 Hz, 2 H), 3.75 (s, 2 H), 2.32 2.22 (m, 1 H), 1.54 1.47 (m, 1 H), 1.40 (s, 9H); 13 C NMR (75 MHz, CDCl 3 ) 153.1, 137.5, 133.5, 126.8, 124.3, 122.4, 103.6, 67.5, 46.2, 34.9, 29.6, 25.6. General Procedure for the Preparation of 3 41g and 3 41h To a solution of 4 (aminomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol 3 43 (0.25 mmol) in CH 2 Cl 2 (3.0 mL) at 0 C, an appropriate isocyanate (0.25 mmol, 1.0 equiv) was added. After stirring at this temperature for 1 h, the reaction mixture was a llowed to warm up to room temperature. After stirring overnight at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (10 mL), and then the organic layer was washed with aqueous 2 N HCl (10 mL). After remov ing the solvent under reduced pressure, the residue was dissolved in THF (3 mL), and then

PAGE 174

174 10% HCl (0.2 mL) was added to this solution at room temperature. After stirring for 2 h at this temperature, the solvent was removed under reduced pressure. The resid ue was dissolved in EtOAc (10 mL), and then the organic layer was washed with water and saturated aqueous NaHCO 3 After drying over anhydrous Na 2 SO 4 the solvent was r emoved under reduced pressure. The residue was purified by column chromatography on silic a gel ( n hexane:EtOAc 2:1) to give the resulting salicylaldehyde. 1 (4 Bromophenyl) 3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea (3 41 g) Beige solid (66%) 1 H NMR (300 MHz, DMSO d 6 ) 11.76 (s, 1 H), 9.97 (s, 1 H), 8.72 (s, 1 H), 7.55 (s, 1 H), 7.54 (s, 1 H), 7.39 (s, 4 H), 6.68 (t, J = 5.8 Hz, 1 H), 4.27 (d, J = 5.9 Hz, 2 H), 1.38 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 198.5, 158.8, 155.0, 139.8, 137.1, 133.4, 131.3, 131.2, 130.4, 120.3, 119.6, 112.4, 42.1, 34.4, 29.1; H RMS (ESI TOF) c alcd for C 19 H 22 BrN 2 O 3 [M+H] + : 405.0808, f ound: 405.0812. 1 (3 tert Butyl 5 formyl 4 hydroxybenzyl) 3 (4 cyanophenyl)urea (3 41 h) White solid (85%) 1 H NMR (300 MHz, DMSO d 6 ) 11.77 (s, 1 H), 9.98 (s, 1 H) 9.14 (s, 1 H), 7.68 7.65 (m, 2 H), 7.60 7.56 (m, 2 H), 7.56 (d, J = 2.4 Hz, 1 H), 7.54 (d, J = 2.4 Hz, 1 H), 6.87 (t, J = 5.7 Hz, 1 H), 4.29 (d, J = 5.9 Hz, 2 H), 1.38 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) 198.5, 158.9, 154.6, 144.8, 137.1, 133.5, 133.1, 131.0, 130.5, 120.3,

PAGE 175

175 119.4, 117.5, 102.4, 42.2, 34.4, 29.0; HRMS (ESI TOF) c alcd for C 20 H 21 N 3 O 3 Na [M+Na] + : 374.1475, f ound: 374.1468. General P rocedure for the P reparation of B is U rea S alen L igands (3 44) To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine ( 0.18 mmol) in THF (5 mL), salicylaldehyde 3 41 (0.36 mmol, 2.0 equiv) was added at room temperature, and then allowed to stir for 3 20 h. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 5:1 then 2:1 or 1:2) to give the resulting bis urea salen as a yellow solid. 3 4 4 a Y ellow solid (99%) 1 H NMR (300 MHz, DMSO d 6 ) 14.03 (s, 2 H), 8.44 (s, 2 H), 7.29 7.14 (m, 12 H), 7.00 (s, 2 H), 6. 33 6.25 (m, 4 H), 4.19 (d, J = 6.0 Hz, 4 H), 4.06 (d, J = 5.4 Hz, 4 H), 3.45 3.38 (m, 2 H), 1.93 1.83 (m, 2 H), 1.83 1.74 (m, 2 H), 1.69 1.56 (m, 2 H), 1.49 1.38 (m, 2 H), 1.32 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) 165.9, 158.6, 157.9, 140.9, 136.1, 129.7 128.4, 128.4, 128.1, 126.9, 126.5, 117.7, 71.0, 42.9, 42.6, 34.3, 32.5, 29.1, 23.8; HRMS (APCI TOF) c alcd for C 46 H 59 N 6 O 4 [M+H] + : 759.4592, f ound: 759.4620.

PAGE 176

176 3 4 4 b Y ellow solid (94%) 1 H NMR (300 MHz, CDCl 3 ) 13.57 (s, 2 H), 7.94 (s, 2 H), 6.97 (d, J = 2.0 Hz, 2 H), 6.03 (s, 2 H), 5.90 (s, 2 H), 5.74 (s, 2 H), 3.74 3.53 (m, 4 H), 3.28 3.25 (m, 2 H), 3.04 (q, J = 6.3 Hz, 4 H), 2.17 2.11 (m, 2 H), 1.97 1.94 (m, 2 H), 1.81 1.72 (m, 2 H), 1.55 1.46 (m, 2 H), 1.44 1.37 (m, 4 H), 1.28 1.23 (m, 12 H), 1.21 (s, 18 H), 0.85 (t, J = 6.8 Hz, 6 H); 13 C NMR (75 MHz, CDCl 3 ) 166.4, 159.4, 158.9, 137.0, 128.3, 128.2, 128.0, 117.6, 72.8, 43.2, 40.3, 34.6, 32.7, 31.6, 30.3, 29.5, 29.1, 26.7, 22.6, 14.0; HRMS (ESI TOF) c alcd for C 44 H 71 N 6 O 4 [M+H] + : 747.5531, f ound: 747.5526. 3 4 4 c Y ellow solid (92%) 1 H NMR (300 MHz, CDCl 3 ) 13.71 (s, 2 H), 8.01 (s, 2 H), 7.07 (s, 2 H), 6.34 (s, 2 H), 5.21 (s, 2 H), 5.13 (s, 2 H), 3.97 3.74 (m, 4 H), 3.28 3.25 (m, 2 H), 3.11 (td, J = 6.5, 6.5 Hz, 4 H), 2.13 1.79 (m, 6 H), 1.54 1.38 (m, 6 H), 1.31 (s, 18H), 1.26 (s, 60 H), 0.88 (t, J = 6.8 Hz, 6 H); 13 C NMR (75 MHz, CDCl 3 ) 166.3, 159.2, 158.7, 137.2, 128.4, 128.1, 117.8, 72.5, 43.8, 40.5, 34.7, 32.7, 32.0, 30.4, 29.7, 29.5, 29.4 29.3, 27.0, 24.4, 22.7, 14.1; HRMS (ESI TOF) c alcd for C 68 H 119 N 6 O 4 [M+H] + : 1083.92 87, f ound: 1083.9223. 3 4 4 d Y ellow solid (81%) 1 H NMR (300 MHz, DMSO d 6 ) 14.09 (s, 2 H), 8.48 (s, 2 H), 8.39 (s, 2 H), 7.36 7.16 (m, 10 H), 7.07 (s, 2 H), 6.88 (t, J = 7.2 Hz, 2 H), 6.43 (t, J

PAGE 177

177 = 5.7 Hz, 2 H), 4.12 (d J = 5.7 Hz, 4 H), 3.45 3.38 (m, 2 H), 1.93 1.83 (m, 2 H), 1.83 1.74 (m, 2 H), 1.69 1.56 (m, 2 H), 1.49 1.38 (m, 2 H), 1.31 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) 165.9, 158.7, 155.0, 140.4, 136.2, 129.1, 128.7, 128.5, 121.0, 117.8, 117.6, 71.0, 42.4, 34. 3, 32.5, 29.1, 23.8; HRMS (APCI TOF) c alcd for C 44 H 55 N 6 O 4 [M+H] + : 731.4279, f ound: 731.4291. 3 4 4 f Y ellow solid (67%) 1 H NMR (300 MHz, CDCl 3 ) 13.63 (s, 2 H), 7.95 (s, 2 H), 7.62 (s, 2 H), 7.05 7.00 (m, 6 H), 6.66 (d, J = 9.1 Hz, 4 H), 6.12 (s, 2 H), 6.03 (s, 2 H), 3.73 3.63 (m, 4 H), 3.70 (s, 6 H), 3.31 3.28 (m, 2 H), 2.18 2.14 (m, 2 H), 2.00 1.97 (m, 2 H), 1.84 1.81 (m, 2 H), 1.63 1.55 (m, 2 H), 1.18 (s, 18 H); 13 C NMR (75 MHz, CDCl 3 ) 166.4, 159.0, 157.5, 155.5, 137 .1, 131.9, 128.2, 127.7, 122.2, 117.6, 114.0, 73.0, 55.3, 43.0, 34.5, 32.7, 29.1, 24.6; HRMS (APCI TOF) c alcd for C 46 H 59 N 6 O 6 [M+H] + : 791.4491, f ound: 791.4493. 3 4 4 f Y ellow solid (86%) 1 H NMR (300 MHz, DMSO d 6 ) 14.10 (s, 2 H), 9.22 (s, 2 H), 8.47 (s, 2 H), 8.07 (s, 4 H), 7.53 (s, 2 H), 7.16 (d, J = 2.0 Hz, 2 H), 7.06 (d, J = 1.7 Hz, 2 H), 6.87 (t, J = 5.9 Hz, 2 H), 4.14 (d, J = 6.2 Hz, 4 H), 3.45 3.38 (m, 2 H), 1.93 1.83 (m, 2 H), 1.83 1.74 (m, 2 H), 1.69 1.56 (m, 2 H) 1.49 1.38 (m, 2 H), 1.25 (s, 18 H);

PAGE 178

178 13 C NMR (75 MHz, DMSO d 6 ) 165.8, 158.7, 154.6, 142.5, 136.2, 130.5 (q, J = 32 Hz), 128.9, 128.6, 128.4, 123.4 (q, J = 271 Hz), 117.7, 117.1, 113.4, 71.1, 42.4, 34.2, 32.5, 29.0, 23.8; HRMS (APCI TOF) c alcd for C 48 H 51 F 12 N 6 O 4 [M+H] + : 1003.3775, f ound: 1003.3801. 3 4 4 g Y ellow solid (52%) 1 H NMR (300 MHz, DMSO d 6 ) 14.09 (s, 2 H), 8.48 8.45 (m, 4 H), 7.39 7.35 (m, 4 H), 7.18 (s, 2 H), 7.07 7.01 (m, 4 H), 6.41 (s, 2 H), 4.13 (s, 4 H), 3.43 (m, 2 H), 1.93 1.83 (m, 2 H), 1.83 1.74 (m, 2 H), 1.69 1.56 (m, 2 H), 1.49 1.38 (m, 2 H), 1.30 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) 165.9, 158.8, 156.8 (d, J = 237 Hz), 155.1, 136.8 (d, J = 2.6 Hz), 136.2, 129.1, 128.7, 128.6, 119.2 (d, J = 7.4 Hz), 117.8, 115.0 (d, J = 22 Hz), 71. 0, 42.4, 34.3, 32.5, 29.1, 23.8 ; HRMS (ESI TOF) c alcd for C 44 H 53 F 2 N 6 O 4 [M+H] + : 767.4091, f ound: 767.4087. 3 4 4 h Y ellow solid (85%) 1 H NMR (300 MHz, CDCl 3 ) 13.69 (s, 2 H), 7.95 (s, 4 H), 7.06 6.94 (m, 10 H), 6.28 (s, 2 H), 6.04 (s, 2 H), 3.71 3.64 ( m, 4 H), 3.31 3.28 (m, 2 H), 2.17 2.13 (m, 2 H), 2.00 1.97 (m, 2 H), 1.84 1.81 (m, 2 H), 1.63 1.55 (m, 2 H), 1.15 (s, 18 H); 13 C NMR (75 MHz, CDCl 3 ) 166.1, 159.2, 157.0, 137.4, 128.8, 128.1, 127.8,

PAGE 179

179 127.4, 127.0, 121.3, 121.0, 117.7, 73.0, 43.0, 34.6, 32. 7, 29.0, 24.5; HRMS (APCI TOF) c alcd for C 44 H 53 Cl 2 N 6 O 4 [M+H] + : 799.3500, f ound: 799.3531. 3 4 4 i Y ellow solid (91%) 1 H NMR (300 MHz, DMSO d 6 ) 14.09 (s, 2 H), 8.57 (s, 2 H), 8.48 (s, 2 H), 7.44 7.36 (m, 8 H), 7.17 (d, J = 2.0 Hz, 2 H), 7.06 (d, J = 2.0 Hz, 2 H), 6.50 (t, J = 5.8 Hz, 2 H), 4.12 (d, J = 5.8 Hz, 4 H), 3.46 (m, 2 H), 1.92 1.88 (m, 2 H), 1.88 1.80 (m, 2 H), 1.76 1.60 (m, 2H), 1.54 1.44 (m, 2 H), 1.30 (s, 18H); 13 C NMR (75 MHz, DMSO d 6 ) 165.9, 158.9, 155.0, 139.9, 136.4, 131.6, 131.4, 129.1, 128.7, 119.7, 117.9, 112.5, 71.1, 42.5, 34.4, 32.6, 29.2, 23.9; HRMS (ESI TOF) c alcd for C 44 H 53 Br 2 N 6 O 4 [M+H] + : 887.2490, f ound: 887.2469. 3 4 4 j Y ellow solid (55%) 1 H NMR (300 MHz, DMSO d 6 ) 14.10 (s, 2 H), 8.99 (s, 2 H), 8.47 (s, 2 H), 7.67 7.64 (m, 4 H), 7.57 7.54 (m, 4 H), 7.18 (d, J = 2.0 Hz, 2 H), 7.07 (d, J = 2.0 Hz, 2 H), 6.69 (t, J = 5.8 Hz, 2 H), 4.14 (d, J = 5.7 Hz, 4 H), 3.46 (m, 2 H), 1.94 1.90 (m, 2 H), 1.88 1.80 (m, 2 H), 1.76 1.60 (m, 2H), 1.54 1.44 (m, 2 H), 1.29 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) 165.9, 158.9, 154.5, 144.9, 136.3, 133.1, 128.8, 128.7, 119.4, 117.8, 117.4, 102.4, 71.0, 42.4, 34.3, 32.5, 29.1, 23.8; HRMS (ESI TOF) c alcd for C 46 H 53 N 8 O 4 [M+H] + : 781.4184, f oun d: 781.4170.

PAGE 180

180 3 4 4 k Y ellow solid (89%) 1 H NMR (300 MHz, DMSO d 6 ) 14.10 (s, 2 H), 8.87 (s, 2 H), 8.48 (s, 2 H), 7.60 7.53 (m, 8 H), 7.18 (d, J = 2.0 Hz, 2 H), 7.08 (d, J = 2.0 Hz, 2 H), 6.62 (t, J = 5.7 Hz, 2 H), 4.15 ( d, J = 5.7 Hz, 4 H), 3.44 (m, 2 H), 1.93 1.83 (m, 2 H), 1.83 1.74 (m, 2 H), 1.69 1.56 (m, 2 H), 1.49 1.38 (m, 2 H), 1.29 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) 165.9, 158.8, 154.7, 144.2, 136.3, 128.9, 128.7, 128.6, 125.9, 124.6 (q, J = 270 Hz), 121.0 (q, J = 32 Hz), 117.8, 117.2, 71.0, 42.4, 34.3, 32.5, 29.0, 23.8; HRMS (ESI TOF) c alcd for C 46 H 53 F 6 N 6 O 4 [M+H] + : 867.4027, f ound: 867.4024. 3 4 4 l Y ellow solid (92%) 1 H NMR (300 MHz, DMSO d 6 ) 14.02 (s, 2 H), 8.43 (s, 2 H), 7.37 (s, 2 H), 7.23 (s, 2 H), 7.17 (d, J = 7.9 Hz, 2 H), 7.08 (m, 4 H), 7.03 (s, 2 H), 6.46 (s, 2 H), 4.11 (s, 4 H), 3.46 (m, 2 H), 3.10 (m, 2 H), 1.94 1.90 (m, 2 H), 1.88 1.80 (m, 2 H), 1.76 1.60 (m, 2H), 1.54 1.44 (m, 2 H), 1.34 (s, 18 H), 1.07 (d, J = 6 .8 Hz, 24 H); 13 C NMR (75 MHz, DMSO d 6 ) 165.7, 158.6, 156.9, 146.7, 136.1, 133.0, 129.9, 128.3, 126.8, 122.7, 117.6, 71.0, 42.5, 34.3, 32.6, 29.1, 27.8, 23.8, 23.6; HRMS (ESI TOF) c alcd for C 56 H 79 N 6 O 4 [M+H] + : 899.6157, f ound: 899.6165.

PAGE 181

181 General P rocedure for the P reparation of B is U rea (S alen )C o Complexe s (3 30) To a solution or suspension of an appropriate salen ligand (0.21 mmol) in EtOH (5 mL), Co(OAc) 2 4H 2 O (0.21 mmol, 1.0 equiv) was added and heated at reflux for 3 h under argon. Precipitate was collected by filtration, washed by EtOH, and then dried under vacuum for 24 h to give a (salen)cobalt complex. 3 30 a Red solid (68%) HRMS (ESI TOF) c alc d for C 46 H 56 CoN 6 O 4 [M] + : 815.3690, f ound: 815.3678; elemental analysis calcd (%) for C 46 H 56 CoN 6 O 4 : C 55.73, H 5 .46, N 8.12; found C 55.73, H 5.46, N 8.12. 3 30 b Red solid (39%) HRMS (ESI TOF) c alcd for C 44 H 68 CoN 6 O 4 [M] + : 803.4629, f ound: 803.4629; elemental analysis calcd (%) for C 44 H 68 CoN 6 O 4 : C 65.73, H 8.53, N 10.45; found C 6 5.40, H 8.86, N 10.26.

PAGE 182

182 3 30 c Reddish brown solid (56%) HRMS (MALDI TOF) c alcd for C 68 H 116 CoN 6 O 4 [M] + : 1139.8385, f ound: 1139.8399; elemental analysis calcd (%) for C 68 H 116 CoN 6 O 4 : C 71.60, H 10.25, N 7.37; found C 71.61, H 10.56, N 7.19. 3 30 d Red solid (60%) HRMS (ESI TOF) c alcd for C 44 H 52 CoN 6 O 4 [M] + : 787.3377, f ound: 787.3343; elemental analysis calcd (%) for C 44 H 52 CoN 6 O 4 : C 67.08, H 6.65, N 10.67; found C 66.79, H 6.88, N 10.48. 3 30 e Reddish brown solid (67%) HRMS (ESI TOF) c alcd for C 46 H 56 CoN 6 O 6 [M] + ; 847.3588, f ound: 847.3569; elemental analysis calcd (%) for C 46 H 56 CoN 6 O 6 : C 65.16, H 6.66, N 9.91; found C 65.39, H 6.92, N 9.81. 3 30 f Reddish brown solid (55%) HRMS (ESI TOF) c alcd for C 48 H 48 CoF 12 N 6 O 4 [M] + ; 1059.2872, f ound: 1059.2975; elemental analysis calcd (%) for C 48 H 48 CoF 12 N 6 O 4 : C 54.40, H 4.56, N 7.93; found C 54.18, H 4.53, N 7.58.

PAGE 183

183 3 30 g. Orange red solid (79%) HRMS (ESI TOF) c alcd for C 44 H 50 CoF 2 N 6 O 4 [M] + ; 823.3188, f ound: 823.3181; elemental analysis calcd (%) for C 44 H 50 CoF 2 N 6 O 4 : C 64.15, H 6.12, N 10.20; found C 64.39, H 6.54, N 9.95. 3 30 h Reddish brown solid (61%) HRMS (ESI TOF) c alcd for C 44 H 50 Cl 2 CoN 6 O 4 [M] + ; 855.2592, f ound: 855.2546; elemental analysis calcd (%) for C 44 H 50 Cl 2 CoN 6 O 4 : C 61.68, H 5.88, N 9.81; found C 61.28, H 5.98, N 9.59. 3 30 i Reddish brown solid (75%) HRMS (ESI TOF) c alcd for C 44 H 50 Br 2 CoN 6 O 4 [M] + : 945.1572, f ound: 945.1591; elemental analysis calcd (%) for C 44 H 50 Br 2 CoN 6 O 4 : C 55.88, H 5.33, N 8.89; found C 55.95, H 5.46, N 8.63.

PAGE 184

184 3 30 j Redd ish brown solid (32%) HRMS (ESI TOF) c alcd for C 46 H 50 CoN 8 O 4 [M] + : 837.3287, f ound: 837.3290; elemental analysis calcd (%) for C 46 H 50 CoN 8 O 4 : C 65.94, H 6.01, N 13.37; found C 65.56, H 6.06, N 13.03. 3 30 k Reddish brown s olid (37%) The r eplacement of ethanol with isopropanol in the general procedure afforded 3 30 k in higher yield (77%). HRMS (ESI TOF) c alcd for C 46 H 50 CoF 6 N 6 O 4 [M] + ; 923.3124, f ound: 923.3140; elemental analysis calcd (%) for C 46 H 50 CoF 6 N 6 O 4 : C 59.80, H 5.46 N 9.10; found C 59.57, H 5.46, N 8.87. 3 30 l Red solid (56%) HRMS (ESI TOF) c alcd for C 56 H 76 CoN 6 O 4 [M] + : 955.5255, f ound: 955.5250; elemental analysis calcd (%) for C 56 H 76 CoN 6 O 4 : C 70.34, H 8.01, N 8.79; found C 70.46 H 8.37, N 8.72. Synthesis of Mono Urea ( Salen )Co Complex (3 51)

PAGE 185

185 3 50 To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine (55 mg, 0.48 mmol) in absolute EtOH (3 mL), 2 M HCl in ethyl ether (0.24 mL, 0.48 mmol, 1.0 equiv) w as added at 0 C, and then allowed to stir for 3 h at this temperature under argon. To this reaction mixture 3,5 di tert butyl 2 hydroxybenzaldehyde (113 mg, 0.48 mmol, 1.0 equiv ) in EtOH (3 mL) was added at 0 C. Then, the reaction mixture was stirred for a n additional 3 h at this temperature, followed by the addition of 3 41 k (190 mg, 0.48 mmol, 1.0 equiv) in EtOH (5 mL) and NEt 3 (0.13 mL, 0.96 mmol, 2 equiv). The reaction mixture was allowed to stir at room temperature overnight. The solution was concentra ted under reduced pressure, and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 5:1 then 2:1) to give the resulting mono urea salen 3 50 (216 mg, 63%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ) 13.90 (s, 1 H), 13.73 (s, 1 H), 8.31 (s, 1 H), 8.20 (s, 1 H), 7.44 (d, J = 6.2 Hz, 2 H), 7.36 7.27 (m, 2 H), 7.30 (d, J = 2.5 Hz, 1 H), 7.13 (s, 1 H), 6.98 (d, J = 2.5 Hz, 1 H), 6.91 (s, 1 H), 6.37 (s, 1 H), 5.09 (s, 1 H), 4.27 4.13 (m, 2 H), 3.37 3.20 (m, 2 H), 1.96 1.85 (m, 4 H), 1 .79 1.62 (m, 2 H), 1.49 1.40 (m, 2 H), 1.38 (s, 9 H), 1.37 (s, 9 H), 1.21 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 165.8, 164.9, 159.8, 158.0, 155.1, 142.0, 140.2, 137.7, 136.6, 128.8, 128.6, 127.0, 126.9, 126.1 (q, J = 3.6 Hz), 126.0, 124.4 (q, J = 33 Hz), 124.2 (q, J = 270 Hz), 118.5, 118.3, 117.7, 72.4, 72.2, 43.9, 34.9, 34.7, 34.0, 33.1, 33.0, 31.3, 29.4, 29.2, 2 4.2; HRMS (APCI TOF) c alcd for C 41 H 54 F 3 N 4 O 3 [M+H] + : 707.4143, f ound: 707.4173.

PAGE 186

186 3 51 To a solution of salen ligand 3 50 (79 mg, 0.11 mmol) in isopropanol (3 mL), Co(OAc) 2 4H 2 O (28 mg, 0.11 mmol) was added, and heated at r eflux for 3 h under argon. Precipitate was collected by filtration, washed by isopropanol, and then dried under vacuum for 24 h to give 3 51 (70 mg, 83%) as a reddish brown solid. HRMS (APCI TOF) c alcd for C 41 H 52 CoF 3 N 4 O 3 [M+H] + : 764.3318, f ound: 764.3336. elemental analysis calcd (%) for C 41 H 51 CoF 3 N 4 O 3 : C 64.47, H 6.73, N 7.34; found C 64.26, H 6.95, N 7.09. Synthesis of Urea (Salen) Ni Complexes To a solution or suspension of an appropriate salen ligand (0.1 mmol) in MeOH (3 mL), Ni(OAc) 2 4H 2 O (0.1 mmol, 1. 0 equiv) was added, and stirred at room temperature for 6 h under argon. Precipitate was collected by filtration, washed by MeOH, and then dried under vacuum for 24 h to give a (salen) Ni complex. 3 5 4 Greenish yellow sol id (86%). 1 H NMR (300 MHz, DMSO d 6 ) 8.91 (s, 2 H), 7.66 (s, 2 H), 7.62 7.55 (m, 8 H), 7.16 (s, 2 H), 7.11 (s, 2 H), 6.59 (t, J = 5.5 Hz, 2 H), 4.14 (d, J = 5.1Hz, 4 H), 3.07 (s, 2 H), 1.76 (s, 2 H), 1.32 (s, 18 H), 1.25 (s, 6 H); 13 C NMR (75 MHz, DMSO d 6 ) 162.2, 158.7, 154.7, 144.3, 139.3, 130.3, 130.0, 126.0, 124.7 (q, J = 270 Hz), 124.1, 120.9 (q, J = 32 Hz), 120.1, 117.2, 69.7, 42.6, 35.1, 29.5, 28.4, 24.0; HRMS (APCI TOF) c alcd for C 46 H 51 F 6 N 6 NiO 4 [M+H] + : 923.3224, f ound: 923.3228.

PAGE 187

187 3 5 5 Greenish yellow solid (81%) 1 H NMR (300 MHz, DMSO d 6 ) 8.93 (s 1 H), 7.67 (s, 1 H), 7.66 (s, 1 H), 7.62 7.55 (m, 4 H), 7.18 (s, 2 H), 7.15 (s, 1 H), 7.11 (s, 1 H), 6.60 (t, J = 5.5 Hz, 1 H), 4.14 (d, J = 4.8 Hz, 2 H), 3.06 (s, 2 H ), 1.77 (s, 2 H), 1.32 (s, 18 H), 1.26 (s, 6 H), 1.23 (s, 9 H); 13 C NMR (125 MHz, DMSO d 6 ) 162.3, 161.1, 159.1, 158.6, 154.7, 144.3, 139.3, 138.4, 134.8, 130.3, 129.9, 127.6, 127.2, 126.0 (q, J = 3.6 Hz), 125.4 (q, J = 271 Hz), 124.7, 120.9 (q, J = 32 Hz ), 120.0, 119.7, 117.2, 69.7, 69.6, 42.6, 35.3, 35.1, 33.5, 31.3, 29.6, 29.5, 28.5, 28.3, 24.0, 23.9; HRMS (APCI TOF) c alcd for C 41 H 52 F 3 N 4 NiO 3 [M+H] + : 763.3340, f ound: 763.3354. 3 5 6 Greenish yellow solid (84%) Orange s ingle crystals suitable for X ray analysis were obtained by slow evaporation in DMF at room temperature. 1 H NMR (300 MHz, DMSO d 6 ) 7.61 (s, 2 H), 7.29 7.16 (m, 10 H), 7.08 (s, 4 H), 6.34 (s, 2 H), 6.24 (s, 2 H), 4.22 (d, J = 5.4 Hz, 4 H), 4.06 (d, J = 3.4 Hz, 4 H), 3.08 (s, 2 H), 1.77 (s, 2 H), 1.31 (s, 18 H), 1.28 1.21 (m, 6 H); 13 C NMR (125 MHz, DMSO d 6 ) 162.1, 158.6, 158.1, 141 .0, 139.2, 130.0, 129.8, 128.2, 127.0, 126.6, 125.0, 119.9, 69.7, 42.9, 42.8, 35.1, 29.5, 28.4, 24.0; HRMS (APCI TOF) c alcd for C 46 H 57 N 6 NiO 4 [M+H] + : 815.3789, f ound: 815.3763. Refinement details for 3 56 : C 46 H 56 N 6 NiO 4 ; M r = 815.68; T = 1 00 (2) K ;

PAGE 188

188 wavelength = 0.71073 ; crystal system: t riclinic ; space group P 1; a = 8.6817 (1 1 ) b = 1 5 721 (2) c = 15.803 ( 2 ) ; = 76.708 (3) = 86.868 (3) = 78.889 ( 3 ) ; V = 2059.6 ( 5 ) 3 ; Z = 2 ; calcd = 1. 315 Mg/m 3 ; = 0. 523 mm 1 ; F (000) = 868 ; crystal size = 0. 20 x 0.0 8 x 0.04 mm 3 ; range = 1.35 to 25.00 ; index ranges: 1 0 h 1 0 1 8 k 1 4 18 l 18 ; reflections collected 20352 independent reflections 7262 [ R (int) = 0.0 729 ] completeness to = 25.00 100.0 %; absorption correction: none ; max./min. transmission 0. 9819 / 0. 9031 ; data/restraints/parameters 7262 /0/ 502 ; goodness of fit on F 2 1.116 ; final R indices [ I >2 ( I )]; R 1 = 0.0 692 wR 2 = 0.1 456 [ 4506 ] ; R indices (all data): R 1 = 0.1 136 wR 2 = 0. 1542 ; largest diff. peak/hole 0.373 and 0. 414 e 3 3 5 7 Greenish yellow solid (80%) Orange single crystals suitable for X ray analysis were ob tained by slow evaporation in DMF at room temperature. Refinement details for 3 57 : C 51 H 55 F 12 N 7 Ni O 5 ; M r = 1132.73; T = 1 00 (2) K ; wavelength = 0.71073 ; crystal system: t riclinic ; space group P 1; a = 9.3525 (1 3 ) b = 1 3 0965 ( 17 ) c = 20.515 ( 3 ) ; = 9 1.018 (3) = 97.294 ( 2 ) = 94.674 ( 3 ) ; V = 2483.2 ( 6 ) 3 ; Z = 2; calcd = 1. 515 Mg/m 3 ; = 0. 492 mm 1 ; F (000) = 1172; crystal size = 0. 31 x 0. 12 x 0.0 5 mm 3 ; range = 1.56 to 27.50 ; index ranges: 12 h 12, 14 k 17, 26 l 24; reflections collected 2791 3, independent reflections 11151 [ R (int) = 0.0 294 ] completeness to = 27.50 97.9 %; absorption correction: none; max./min. transmission 0. 9 768 / 0. 8632 ; data/restraints/parameters 11151 /0/ 686 ; goodness of fit on F 2 1.1 58 ; final R indices

PAGE 189

189 [ I >2 ( I )]; R 1 = 0 .0 551 wR 2 = 0.1 103 [ 9198 ] ; R indices (all data): R 1 = 0.0695 wR 2 = 0. 1 151 ; largest diff. peak/hole 0. 585 and 0. 615 e 3 Preparation of B is ( N N D imethyl P henylurea) ( S alen) C obalt Complex 1 (3 tert Butyl 5 formyl 4 m ethoxybenzyl) 1,3 dimethyl 3 phenylurea (3 4 6 ) 1 (3 tert Butyl 5 formyl 4 hydroxybenzyl) 3 phenylurea 3 41 d (214 mg, 0.66 mmol) was dissolved in dry DMF (3.0 mL) and 60% NaH (105 mg, 2.63 mmol) was added at room temperature under argon. After stirring for 30 min at this temperature, iodomethane (0.4 mL, 6.41 mmol) was added, and then the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with EtOAc (20 mL) and washed with water and brine. After drying over anhydrous Na 2 SO 4 the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel ( n hexane:EtOAc 10:1 then 5:1) to give 3 4 6 (173 mg, 72%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ) 10.30 (s, 1 H), 7.48 (d, J = 2.3 Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.34 7.29 (m, 2 H), 7.12 7.07 (m, 3 H), 4.37 (s, 2 H), 3.93 (s, 3 H), 3.25 (s, 3 H), 2.47 (s, 3 H), 1.41 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 190.3, 162.6, 162.0, 146.7, 144.0, 133.1, 132.9, 129.5, 126.9, 124 .7, 124.2, 66.1, 53.0, 40.1, 36.4, 35.1, 30.7 ; HRMS (ESI TOF) c alcd for C 22 H 29 N 2 O 3 [M+H] + : 369.2173, f ound: 369.2183.

PAGE 190

190 1 (3 tert Butyl 5 formyl 4 hydroxybenzyl) 1,3 dimethyl 3 phenylurea (3 4 7 ) 1 (3 tert Butyl 5 formyl 4 methoxybenzyl) 1,3 dimethyl 3 phenylurea 3 4 6 (153 mg, 0.42 mmol) in dry CH 2 Cl 2 (2.0 mL) was cooled to 78C and 1 M BBr 3 in CH 2 Cl 2 (0.5 mL, 1.2 eq.) was added. After stirring at this temperature for 1 h, the reaction mixture was allowed to warm up to room temperature and then stirred overnight. After quenching by adding saturated NaHCO 3 the mixture was extracted with CH 2 Cl 2 The organic layer was dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure. The residue was purified by co lumn chromatography on silica gel ( n hexane:EtOAc 5:1 then 2:1) to give 3 4 7 (117 mg, 80%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3 ) 11.73 (s, 1 H), 9.82 (s, 1 H), 7.37 (d, J = 2.3 Hz, 1 H), 7.34 7.28 (m, 2 H), 7.23 (d, J = 2.0 Hz, 1 H), 7.13 7.07 (m, 3 H), 4.34 (s, 2 H), 3.23 (s, 3 H), 2.46 (s, 3 H), 1.39 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) 197.0, 161.9, 160.4, 146.7, 138.4, 134.0, 131.0, 129.4, 128.3, 124.6, 124.1, 120.2, 52.8, 40.0, 36.1, 34.7, 29.1 ; HRMS (ESI TOF) c alcd for C 21 H 27 N 2 O 3 [M+H] + : 355.2016 f ound: 355.2022. 3 4 8 To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine (17 mg, 0.15 mmol) in THF (3.0 mL), salicylaldehyde 3 4 7 (108 mg, 0.30 mmol, 2.0 equiv) was added at room temperature, and then allowed to stir for 20 h. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 5:1 then 2:1) to give 3 48 (100 mg, 84%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ) 13.80 ( s, 2 H), 8.24 (s, 2 H), 7.28 7.22 (m, 4 H), 7.06 7.03 (m, 6 H),

PAGE 191

191 7.01(s, 2 H), 6.81(d, J = 2.3 Hz, 2 H), 4.20 (s, 4 H), 3.33 3.30 (m, 4 H), 3.21 (s, 6 H), 2.37 (s, 6 H), 1.98 1.87 (m, 2 H), 1.74 1.71(m, 2 H), 1.64 1.55 (m, 2 H), 1.50 1.43 (m, 2 H), 1.37 (s, 18 H); 13 C NMR (7 5 MHz, CDCl 3 ) 165.2, 161.9, 159.6, 146.8, 137.3, 129.4, 129.3, 129.2, 126.4, 124.2, 123.9, 118.2, 72.3, 53.1, 39.8, 35.8, 34.7, 33.1, 29.3, 24.2; HRMS (ESI TOF) c alcd for C 48 H 62 N 6 O 4 Na [M+Na] + : 809.4725, f ound: 809.4711. 3 4 9 To a solution of salen 3 4 8 (73 mg, 0.093 mmol) in EtOH (2.0 mL), Co(OAc) 2 4H 2 O (23 mg, 0.093 mmol) was added, and heated at reflux for 2 h under argon. Precipitate was collected by filtration, washed by EtOH, and then dried under vacuum for 24 h to give 3 49 (50 mg, 64%) as a red solid. HRMS (ESI TOF) c alcd for C 48 H 60 CoN 6 O 4 [M] + : 843.4003, f ound: 843.3989; elemental analysis calcd (%) for C 48 H 60 CoN 6 O 4 : C 68.31, H 7.17, N 9.96; found C 67.94, H 7.44, N 9.69. Reaction Rate Determination A vial equippe d with stir bar was charged with (salen) Co mol%). A solution of p toluenesulfonic acid monohydrate in THF (0.01 M, 0.55 mL, 1.1 equiv per catalyst) was added and the solution was stirred in air for 30 min. After removing solvent by rotary evaporation, racemic epichlorohydrin (426 mg, 5.0 mmol), (salen)Co complex. The vial was placed into a water bath at 23 C and H 2 equiv) was added in one portion. The reaction progress was monitored by the removal of aliquots from the reaction mixture, filtration through silica gel with diethylether as an

PAGE 192

192 eluent, and chiral GC MS analysis ( Chiraldex TA 70 C, isothermal, t R (major) = 4.24 min, t R (minor ) = 4.68 min). The slopes of the least square lines for the plots of ln([epoxide]/[epoxide] 0 ) vs. time were determined. General Procedure for Hydrolytic Kinetic Resolution of Epoxides ( S ) Epichlorohydrin ( 1 4 9 b ) A vial equipped with a stir bar was charge d with 3 30 k p toluenesulfonic acid monohydrate in THF (0.01 M, 1.1 mL, 1.1 equiv per catalyst) was added and the solution was stirred in the open air for 30 min. After removing solvent by rotary evaporation, race mic epichlorohydrin (925 mg, 10 mmol) was added. The reaction mixture became homogeneous within 30 min. The vial was placed into a water bath at 23C and H 2 O 14 h, th e remaining epoxide was isolated by vacuum transfer (rt, 0.5 Torr) into a receiving flask pre cooled at 78C. The recovered epoxide was dried over anhydrous MgSO 4 and filtered to give ( S ) epichlorohydrin 1 4 9 b (390 mg, 42%) as a colorless liquid. The ee o f the recovered epichlorohydrin was determined to be 99% by chiral GC MS analysis (Chiraldex TA, 70C, isothermal, t R (major) = 4.24 min, t R (minor) = 4.68 min). Absolute configuration of the major isomer was determined to be ( S ) by comparison of the reten tion time with literature data. ( R ) Allyl glycidyl ether ( 1 4 9 a ) A vial equipped with a stir bar was charged with 3 30 k p toluenesulfonic acid monohydrate in THF (0.01 M, 0.55 mL, 1.1 equiv per catalyst) was adde d and the solution was stirred in the open air for 30 min. After removing solvent by rotary evaporation, racemic allyl glycidyl ether (1.14 g, 10 mmol) was added. The vial was placed into a water bath at 23C and H 2 ortion. After the reaction was

PAGE 193

193 stirred at 23C for 9 h, the remaining epoxide was isolated by vacuum transfer (40C, 0.1 Torr) into a receiving flask pre cooled at 78C. The recovered epoxide was dried over anhydrous MgSO 4 and filtered to give ( R ) allyl g lycidyl ether 1 4 9 a (491 mg, 43%) as a colorless liquid. The recovered allyl glycidyl ether was determined to be 99% ee by chiral GC MS analysis (Chiraldex TA, 75C, isothermal, t R (minor) = 7.35 min, t R (major) = 8.69 min). Absolute configuration of the major isomer was determined to be (R) by comparison of the retention time with literature data. ( R ) 1,2 Epoxybutane ( 1 4 9 c) A vial equipped with a stir bar was charged with 3 30 k p toluenesulfonic acid monohydrat e in THF (0.01 M, 0.66 mL, 1.1 equiv per catalyst) was added and the solution was stirred in the open air for 30 min. After removing solvent by rotary evaporation, racemic 1,2 epoxybutane (1.44 g, 20 mmol) was added. The vial was placed into a water bath a t 23C and H 2 stirred at 23C for 8 h, the remaining epoxide was isolated by vacuum transfer (rt, 0.5 Torr) into a receiving flask pre cooled at 78C. The recovered epoxide was dried o ver anhydrous MgSO 4 and filtered to give ( R ) 1,2 epoxybutane 1 4 9 c (615 mg, 43%) as a colorless liquid. The recovered ( R ) 1,2 epoxybutane was determined to be 99% ee by chiral GC MS analysis (Chiraldex TA, 28C, isothermal, t R (major) = 4.91 min, t R (minor ) = 5.36 min). Absolute configuration of the major isomer was determined to be (R) by comparison of the retention time with literature data. ( R ) 1,2 Epoxyhexane ( 1 4 9 d) A vial equipped with a stir bar was charged with 3 30 k solution of p toluenesulfonic acid monohydrate in THF (0.01 M, 0.33 mL, 1.1 equiv per catalyst) was added and the solution was stirred in

PAGE 194

194 the open air for 30 min. After removing solvent by rotary evaporation, racemic 1,2 epoxyhexane (1.0 g, 10 mmol) was ad ded. The vial was placed into a water bath at 23C and H 2 the reaction was stirred at 23 C for 14 h, the remaining epoxide was isolated by vacuum transfer (rt, 0.5 Torr) into a receiving flask pre coole d at 78C. The recovered epoxide was dried over anhydrous MgSO 4 and filtered to give ( R ) 1,2 epoxyhexane 1 4 9 d (410 mg, 41%) as a colorless liquid. The recovered ( R ) 1,2 epoxyhexane was determined to be 99% ee by chiral GC MS analysis (Chiraldex TA, 50 C, isothermal, t R (minor) = 8.29 min, t R (major) = 8.87 min). Absolute configuration of the major isomer was determined to be ( R ) by comparison of the retention time with literature data Asymmetric Hydrolysis of Cyclohexene O xide (1 S ,2 S ) trans 1,2 Cyclohex anediol ( 3 5 9 ) A vial equipped with a stir bar was charged with 3 30 k p toluenesulfonic acid monohydrate in THF (0.01 M, 0.33 mL, 1.1 equiv per catalyst) was added and the solution was stirred in the open air for 30 min. After removing solvent by rotary evaporation, TBME (0.5 mL) was charged to dissolve the catalyst. Cyclohexene oxide 3 58 (49 mg, 0.5 mmol) and H 2 1.2 equiv) was added and solution was stirred for 45 h at 23C. The reaction mixture was appl ied to a pad of silica gel and the pad was washed with EtOAc. The solvent was removed under reduced pressure to give 3 5 9 (36 mg, 62 %) as a white solid. The bis TFA ester derivative was prepared to determine enantiomeric excess (Chiraldex TA, 90C, isot hermal, t R (minor) = 8.29 min, t R (major) = 8.87 min). The ester derivative was determined to be 75% ee. Absolute configuration of the major isomer was determined to be (1 S ,2 S ) by comparison of the retention time with literature data.

PAGE 195

195 Molecular Mechanics Cal culations Molecular mechanics calculations were performed using augmented MM2 force field parameters, as implemented in CAChe version 6.1.1. Calculations were performed using a simplified b is urea (salen)nickel complex (R = Me) The atomic coordinates in t he (salen)Ni fragment were obtained from the crystal structure data of 3 5 6 (R = Bn) The (salen)Ni fragment was locked during computation. Steepest descent search will be used to locate the energy minimum. Optimization continues until the energy change is less than 0.001 kcal/mol. General P rocedure for the P reparation of B is U rea S alicylaldehydes To a solution of 4 (aminomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol 3 43 (0.25 mmol 2 equiv ) in CH 2 Cl 2 (3.0 mL) at room temperature an appropriate di isocyan ate (0.25 mmol, 1 equiv) was added. After stirring ove rnight at room temperature, precipitate was filtered and washed with CH 2 Cl 2 The resulting solid was dissolved in THF (3 mL), and then 10% HCl (0.2 mL) was added to this solution at room temperature. Af ter stirring for 2 h at this temperature, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (10 mL), and then the organic layer was washed with water and saturated NaHCO 3 After drying over anhydrous Na 2 SO 4 the solvent was r emoved under reduced pressure. The residue was triturated with CH 2 Cl 2 /hexanes to give the resulting bis urea salicylaldehyde.

PAGE 196

196 1,1' (1,3 P henylene)bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3 61 a) White solid ( 54 %). 1 H NMR ( 300 MHz, DMSO d 6 ) 11.77 (s, 2 H) 9.97 (s, 2 H) 8.50 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 = 6.0 0.2 Hz, 4 H) 1.38 (s, 18 H); 13 C NMR (75 MHz, DMSO d 6 ) 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) c al cd for C 32 H 38 N 4 O 6 Na [M+Na] + : 597.2684, found 597.2702 1, (4 M ethyl 1,3 phenylene)bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3 61 b) White solid (48%). 1 H NMR ( 300 MHz, DMSO d 6 ) 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 ) 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, 3 4.4, 29.1, 17.2; HRMS (APCI) c al cd for C 33 H 4 1 N 4 O 6 [M+H] + : 589.3021, found 589.303 1. 1,1' (1,4 P henylene)bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3 61 c) White solid (44%). 1 H NMR ( 300 MHz, DMSO d 6 ) 11.75 (s, 2 H), 9.95 (s, 2 H), 8.35 (s, 2 H), 7.52 (d, J = 2.9 Hz, 2 H), 7.24 (s, 4 H), 6.5 2 (t, J = 5.9 Hz, 2 H), 4.24 (d, J = 5.8 Hz,

PAGE 197

197 4 H), 1.36 (s, 1 8 H); 13 C NMR (75 MHz, DMSO d 6 ) 199.3, 159.5, 156.1, 137.8, 135.0, 134.2, 132.2, 131.2, 121.0, 119.2, 42.8, 35.1, 29.7 ; HRMS (APCI) calcd for C 32 H 3 9 N 4 O 6 [M+H] + : 575.2864, found 575.2861 1,1' ( H exane 1,6 diyl)bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3 61 d) White solid (47%). 1 H NMR ( 300 MHz, DMSO d 6 ) 11.73 (s, 2 H) 9.94 (s, 2 H) 7.47 (s, 4 H) 6.26 6.32 (m, 2 H) 5.90 5.96 (m, 2 H) 4.16 (d, J = 6.1 Hz, 4 H) 2.98 3.03 (m, 4 H) 2.48 2.52 (m, 4 H) 1.36 (s, 18 H) 1.25 (m, 4 H); 13 C NMR (75 MHz DMSO d 6 ) 198.6, 158.8, 158.1, 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 4 7 N 4 O 6 [M+H] + : 583.3490, found 583.3484 1,1' ( D odecane 1,12 diyl)bis(3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea) (3 61 e) White solid (62%). 1 H NMR ( 300 MHz, DMSO d 6 ) 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 = 6.1 0. 1 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 ) 198.5, 158.8, 158.1, 137.0, 133.3, 132.1, 130.3, 120.3, 42.3, 34.4, 30.1, 29.1, 28.9, 26.4; HRMS (APCI) c al cd for C 38 H 5 9 N 4 O 6 [M +H]+: 667.4429, found 667.4447

PAGE 198

198 1,3 B is(3 tert butyl 5 formyl 4 hydroxybenzyl)urea (3 63 ). White solid ( 47 %). 1 H NMR ( 300 MHz, CDCl 3 ) 11.7 1 (s, 2 H) 9.77 ( s 2 H) 7.4 0 ( d J = 2.1 Hz, 2 H) 7.28 ( d J = 2.1 Hz, 2 H) 4.90 (br s 2 H), 4.29 (d, J = 5.7 Hz, 4 H), 1.37 (s, 18 H) ; 13 C NMR (75 MHz, CDCl 3 ) 197.1 160.8, 139. 1, 133.9, 130.7, 129.9, 120.6, 44.2, 35.1, 29.4. Bis Urea Spacing Dimeric (Salen)Co Complexes 3 62 a. HRMS (ESI) ca lcd for C 74 H 98 N 8 O 6 Co 2 [M] + :1312.6268, found 1320.6265 3 62 b HRMS (ESI) calcd for C 75 H 100 N 8 O 6 Co 2 [M] + :1326.6424, found 1326.6344 3 62 c HRMS (ESI) calcd for C 74 H 98 N 8 O 6 Co 2 [M] + : 1312.62 68, found 1312.6226

PAGE 199

199 3 62 d HRMS (ESI) calcd for C 74 H 106 N 8 O 6 Co 2 [M] + :1320.6894, found 1320.6885 3 62 e HRMS (ESI) calcd for C 80 H 11 9 N 8 O 6 Co 2 [M+H] + :1405.7911, found 1405.7878

PAGE 200

200 CHAPTER 4 CONCLUSION The synergistic dual activation has emerged as a powerful theme to develop more efficient and selective asymmetric catalysis. As one of those approaches, chiral bimetallic catalysts linked by a covalent tether have been extensively reported an d studied. Indeed, those catalysts have show n imp r oved efficiency and enantioselectivity for a number of bimetallic transformations Recently, the merge of supramolecular chemistry and catalysis has been envis i oned as a powerful new strategy to achieve mul tifunctional catalysis because of the facile construction of complicated systems through self assembly. Based on this concept, we devised a novel self assembled dinuclear catalytic system mediated by hydrogen bonds. The key to success of this approach was the identification of suitable intermolecular interactions that are strong enough to hold two metal centers in close proximity and that are still compatible with the metal substrate interactions. In addition, the orientation and geometry of the self assemb led catalyst shoul d be controlled to posit ion two metal centers within the optimal distance for cooperative activation Chapter 2 described the development of the self assembled dinuclear (salen)Co (II) complex featuring two complementary 2 pyridone/aminopy ridine hydrogen bonding interactions. Th is self assembled dinuclear (salen) Co(II) catalyst results in significant rate acceleration (48 times faster) as well as high enantioselectivity compared to the non functionalized (salen) Co(II) catalyst. The single c rystal X ray analysis reveals that the self assembled dimer adopts the antiparallel head to tail geometry where the metal metal distance was measured as 4.05 The strength of

PAGE 201

201 self association ( K dim ) was estimat ed as 53 21 M 1 in 25% CD 3 NO 2 /CDCl 3 from 1 H NMR experiments. Chapter 3 discussed the development of novel bis urea (salen)Co catalysts that can self assemble through intermolecular urea urea hydrogen bonding interactions. These catalysts successfully promoted hydrolytic kinetic resolution of rac emic epoxides, exhibiting significant rate acceleration up to 13 times compared to the unfunctionalized analogue. The single crystal X ray analysis and MM2 calculation reveal that the bis urea salen scaffold can provide the optimal metal metal distance (5~ 6 ) for epoxide opening reactions through intermolecular H bonds. In addition, as an extension of this strategy, the bis urea spacing dimeric (salen)Co catalysts were developed, and they showed superior performance in the hydrolytic desymmetrization of cy clohexene epoxide in terms of reactivity and enantioselectivity. In all cases, t he observed rate acceleration can be rationalized by the facile formation of the dimeric catalyst through intermolecular hydrogen bonds. Thus, t his novel self assembly strategy represents a powerful approach to develop more efficient dual activation catalysts and can be applicable to wide range of asymmetric reactions.

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213 BIOGRAPHICAL SKETCH Jongwoo Park was born and grew up in Seoul, Korea. After getting BS and MS in chemistry at Yonsei University in Seoul, he joined LG chemical company as a research scientist. After working for LG Chem and LG Life sciences, Jongwoo went on to pursue his PhD in organic chemistry at the University of Florida under the super vision of Dr. Sukwon Hong. He received his Ph. D. from the University of Florida in December 2011.