Development of Bifunctional Lewis Acid Catalysts for Asymmetric Henry Reactions

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Development of Bifunctional Lewis Acid Catalysts for Asymmetric Henry Reactions
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english
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Lang,Kai
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University of Florida
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Gainesville, Fla.
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Doctorate ( Ph.D.)
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University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
Hong, Sukwon
Committee Members:
McElwee-White, Lisa A
Stewart, Jon D
Castellano, Ronald K
Douglas, Elliot P

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Subjects / Keywords:
activation -- bifunctional -- bis -- diastereoselective -- dual -- enantioselective -- henry -- reaction -- salen -- urea
Chemistry -- Dissertations, Academic -- UF
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Chemistry thesis, Ph.D.
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theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
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Abstract:
Base-functionalized aza-bis(oxazoline) ligands were developed to explore the concept of dual activation through the Lewis acid and a tethered tertiary amine base. The catalytic activity of the Cu complex was evaluated for the asymmetric Henry reaction. Compared with a corresponding unfunctionalized ligand complex with external base, the base-functionalized aza-bis(oxazoline) CuTC complex exhibited higher activity and selectivity. Kinetic studies revealed that the rate constant (kobs) for the base-functionalized complex was 2.5 times greater than that of the corresponding unfunctionalized complex with external base. Novel urea-(salen) cobalt bifunctional catalysts were developed for asymmetric Henry reactions. Broad substrate scope, good yield, and excellent enantioselectivity were obtained for nitromethane Henry reactions (82-99% yield; 91-97% ee). anti-Diastereoselectivity (up to 48/1 anti/syn with 90-98% ee (anti) ) were observed for diastereoselective Henry reactions. A new dual activation mode, cooperative activation by urea (H-bond) and the cobalt (Lewis acid) is suggested from mechanistic studies. This methodology was applied to the efficient synthesis of (1R,2S)-methoxamine hydrochloride.
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by Kai Lang.
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Thesis (Ph.D.)--University of Florida, 2011.
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Adviser: Hong, Sukwon.
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1 DEVELOPMENT OF BIFUNCTIONAL LEWIS ACID CATALYSTS FOR ASYMMETRIC HENRY REACTIONS By KAI LANG A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE D EGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2011

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2 2011 K ai L ang

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3 To Yidan Jiang, Meihua Q iao and Daihuan Lang

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4 ACKNOWLEDGMENTS I would like to thank my grandfather who spent lots of time and patience cultivating my curiosity for sc ience when I was young My wife (Yidan Jiang) my mother in law, father in law and my parents support me in my everyday l ife and encourage me in my research. Without th ese efforts I could not finish my research so smoothly. My supervisor P rofessor Sukwon Hong has been very supportive throughout my five years PhD study. He was a great mentor and sp ared no efforts teaching me all the necessary knowledge for my future independent research in terms of providing and suggest ing the helpful reading material s wr iting and presenting skill, and how to think scientifically H is guidance and advice will be the me n tal wealth for my whole life. I will be always thankful to him for that. I want to thank especially Jongwoo Park for helping me to solve lots of tough quest ions during my research and giving me his excellent suggestions over the past years. I really appreciate his literature sent by email to me every time I had new research questions and his help for proofing my manuscript with great patience Also I want to thank all the other former and current Hong group members: Dr. Dimitri Hirsh Weil, Dr. David Snead, Sebastien Inagaki, Dr. Hwimin Seo and Mike Rodig for interesting discussion on my research particularly Dr. David Snead and Dr. Dimitri Hirsh Weil who disc ussed with me on a lot of wonderful chemistry literatures in the past 5 years

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 8 LIST OF FIGURES ................................ ................................ ................................ ........ 11 LIST OF SCHEMES ................................ ................................ ................................ ...... 13 ABSTRACT ................................ ................................ ................................ ................... 15 CHA PTER 1 INTRODUCTION ................................ ................................ ................................ .... 17 Cooperative Dual Activation ................................ ................................ .................... 17 Enzyme Model for Dual Activation Catalysi s ................................ ........................... 17 Abiotic Bifunctional Catalysts ................................ ................................ .................. 20 Metal Involved Bifunctional Catalysts ................................ ............................... 2 0 Homodinuclear Catalysts ................................ ................................ .................. 21 Heterodinuclear Catalysts ................................ ................................ ................ 28 Lewis Acid Tertiary Amine Bifunctional Catalysts ................................ ............. 32 Lewis Acid Lewis Base Bifunctional Catalysts ................................ .................. 34 Bifunctional Organocatalysts ................................ ................................ ............ 36 Lewis Acid/Lewis Base Bifunctional Organocatalysts ................................ ....... 37 Br nsted Acid/Lewis Base Catalysts ................................ ................................ 37 Hydrogen Bond Donor Cata lysts ................................ ................................ ...... 38 Hydrogen Bond Donor/Tertiary Amine Catalysts ................................ .............. 41 Bifunctional Catalysts through Ion Pair Interaction ................................ ........... 45 The Difference between Dual Activation Catalysts and Mixed Binary Catalysts ..... 47 The Difference between Dual Activation Catalysts and Supramolecul ar Catalysts ................................ ................................ ................................ .............. 49 Design of Dual Activation Catalysts ................................ ................................ ........ 50 Asymmetric Henry Reaction ................................ ................................ ................... 51 Synthetic Application of Asymmetric Henry Reactions ................................ ............ 51 Summary and Outlook ................................ ................................ ............................ 55 2 DEVELOPMENT OF BIFUNCTIONAL AZA B IS(OXAZOLINE) COPPER CATALYSTS FOR ENANTIOSELECTIVE HENRY R EACTION ............................. 57 Design of Dual Activation Ligands Using Aza Bis(oxazoline) Units ........................ 57 Results and Discussion ................................ ................................ ........................... 58 Synthesis of Dimeric A za Box and B ifunctional A za Box L igands .................... 58 Reaction Optimization with Unfunctionalized Aza Box ................................ ..... 60 D ual A ctivation C atalyst Design ................................ ................................ ....... 64 Kinetic Study for CuTC and Ligand 2 9 Complex ................................ ............. 65

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6 Kinetic Study for T ertiary A mine B ase 2 14 ................................ ...................... 68 Development of Dual Activation Catalyst ................................ ................................ 71 Mononuclear vs Dinuclear Catalyst for Asymmetric Henry Reaction ................ 73 Base Tethered Bifunctional Catalyst for Asymmetric Henry Reaction .............. 75 Summary and Conclusion ................................ ................................ ....................... 81 Experimental Section ................................ ................................ .............................. 82 General Procedure for Enantioselective Henry Reaction ................................ ........ 83 General Procedure for Diastereoselective Henry Reaction ................................ ..... 88 Ligand Synthesis ................................ ................................ ................................ .... 92 General Procedure for the Synthesis of Aminooxazoline ................................ 92 General Procedure for the Synthesis of Oxazolidinone ................................ .... 94 General Procedure for the Synthesis of Ethoxyoxazoline ................................ 96 General Procedure for the Synthesis of Aza Bis(oxazolines) ........................... 99 General Procedure for Alkylation of Aza Box Ligand ................................ ....... 99 Synthesis of Dimeric Aza Box Ligand 2 2 ( a f) ................................ ................ 104 General Procedure for Synthesis of Backbone of Bifunctional Catalyst ......... 108 General Procedure for the Synthesis of Bifunctional Ligands ......................... 110 General Procedure for K inetic Study of Base 2 14 (Table 2 11 Table 2 15) .. 112 Kinetic Comparison between Bifunctional Catalyst and Non Functional Catalyst (for Figure 2 13) ................................ ................................ ............ 113 3 UREA (SALEN)CO BALT BIFUNCTIONAL CATALYST FOR ANTI SELECTIVE ASYMMETRIC HENRY REACTIONS ................................ ................................ ... 115 Background and Introduction ................................ ................................ ................ 115 Results and Discussion ................................ ................................ ......................... 117 Ligand Structure Survey ................................ ................................ ................. 117 Diastereoselective Henry Reaction ................................ ................................ 120 Ligand Structure Survey under Final Optimized Conditions ........................... 123 Enantioselective Henry Reaction ................................ ................................ .... 124 Diastereoselective Henry Reaction ................................ ................................ 126 Mechanism Study ................................ ................................ ................................ 131 Discussion on Monometallic vs Bimetallic Pathway ................................ ....... 131 Nonlinear Effect ................................ ................................ .............................. 131 Kinetic Studies ................................ ................................ ................................ 132 Control Experiments ................................ ................................ ....................... 133 Proposed Transition State ................................ ................................ .............. 135 Conclusion ................................ ................................ ................................ ............ 136 Experimental S ection ................................ ................................ ............................ 136 General Remarks ................................ ................................ ........................... 136 Ligand and Catalyst Preparation ................................ ................................ .... 137 General Procedure for Enantioselective Henry Reaction ............................... 170 General Procedure for Diastereoselective Henry Reaction ............................ 178 Mechani sm Study ................................ ................................ ................................ 209 General Procedure for Kinetic Study ................................ .............................. 209 General Procedure for Nonlinear Effect Study ................................ ............... 212

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7 4 CONCLUSION ................................ ................................ ................................ ...... 214 LIST OF REFERENCES ................................ ................................ ............................. 216 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 225

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8 LIST OF TABLES Table page 1 1 Dinuclear nickel catalyst promoted asymmetric Mannich type reactions ............ 22 1 2 Dinu clear nickel catalyst promoted asymmetric vinylogous Mannich type reactions ................................ ................................ ................................ ............. 22 1 3 Dinuclear Mn(III) catalyst for asymmetric 1,4 additions of oxindoles to nitroalkenes ................................ ................................ ................................ ........ 23 1 4 Dinuclear Co(III) catalyst for asymmetric 1,4 keto esters to a l kynones ................................ ................................ ............................. 24 1 5 Heterodinuclear catalyst promoted r ing o pening of meso a ziridines .................. 29 1 6 addition of isocyanides to aldehydes ................................ ................................ ................................ ........... 30 1 7 Dinuclear vs mixed mononuclear catalysts for Nozaki Hi yama Kishi Coupling .. 32 2 1 Conditions tested for aromatic functionalization of aza Box ............................... 59 2 2 Synthesis of dinucleating and bifu nctional aza Box ligands through alkylation .. 60 2 3 Cu precursor and reaction temperature optimization ................................ .......... 62 2 4 Ligand structure su rvey ................................ ................................ ...................... 63 2 5 Reaction scope using unfunctionalized aza Box 2 9 ................................ .......... 64 2 6 Kinetic data for 3 mol % loading of aza Box catalyst 2 9 Cu TC [9.1 mM] .......... 66 2 7 Kinetic data for 1.5 mol % loading of aza Box catalyst 2 9 CuTC [4.5 mM] ....... 66 2 8 Kinetic data for 0.75 mol % l oading of aza Box catalyst 2 9 CuTC [2.3 mM] ..... 67 2 9 Kinetic data for 0.325 mol% loading of aza Box catalyst 2 9 CuTC [1.1 mM] .... 67 2 10 Kinetic data for Figure 2 6 ................................ ................................ .................. 68 2 11 Kinetic data for 2 mol % loading of base 2 14 [0.0095M] ................................ ... 69 2 12 Kinetic data for 5 mol % loading of base 2 14 [0.024M] ................................ ..... 69 2 13 Kinetic data for 10 mol% loading of base 2 14 [0.048M] ................................ .... 70 2 14 Kinetic data for 20 mol % loading of base 2 14 [0.096M] ................................ ... 70

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9 2 15 Kinetic data for 30 mol % loading of base 2 14 [0.144M] ................................ ... 70 2 16 Kinetic data for Figure 2 10 ................................ ................................ ................ 71 2 17 Screening of d imer ic l igand ................................ ................................ ................ 73 2 18 Enantioselective Henry reaction (mononuclear vs dinuclear catalyst) ................ 74 2 19 Diastereoselective Henry reaction using 10 equiv of nitroethane (mononuclear vs dinuclear catalyst) ................................ ................................ ... 74 2 20 Diastereoselective Henr y reaction using 5 equiv of nitroethane (mononuclear vs dinuclear catalyst) ................................ ................................ .......................... 75 2 21 Enantioselective Henry reaction (bifunctional 2 4a CuTC vs 2 9 CuTC & 2 14 ) ................................ ................................ ................................ ........................... 77 2 22 Brief substrate scope survey using 2 4a CuTC ................................ .................. 77 2 23 Enantioselective Henry reaction (bifunctional 2 4c CuTC vs 2 9 CuTC & i Pr 2 NEt) ................................ ................................ ................................ ............... 79 2 24 Diastereoselective Henry reactions catalyzed by bifunctional catalyst ............... 80 2 25 Kinetic data for 2 mol% l oading of bifunctional catalyst 2 4a [0.0095M] ........... 114 3 1 Screening of urea moieties and linkers ................................ ............................. 118 3 2 Catalyst survey under further optimized reaction conditions ............................ 119 3 3 Base, solvent and counterion survey for the diastereoselective Henry reaction ................................ ................................ ................................ ............. 122 3 4 Counterion optimization for diastere oselective Henry reactions ....................... 123 3 5 Catalyst structure survey under the final optimized conditions ......................... 124 3 6 Enantioselective Henry reactions (reaction scope) ................................ ........... 125 3 7 Diastereoselective Henry reactions (reaction scope) ................................ ........ 127 3 8 Control experiments (hydrogen bo nd effect) ................................ .................... 13 4 3 9 Kinetic data for 5 mol % loading of 3 3c O 2 CAr F [27.0 mM] ............................. 210 3 10 Kinetic data for 2.5 mol % loading of 3 3c O 2 CAr F [13.5 mM] ........................... 210 3 11 Kinetic data for 1.25 mol % loading of 3 3c O 2 CAr F [6.75 mM] ........................ 211

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10 3 12 Kinetic data for 0.625 mol % lo ading of 3 3c O 2 CAr F [3.375 mM] .................... 211 3 13 Kinetic data for Figure 3 5 ................................ ................................ ................ 211

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11 LIST OF FIGURES Figure page 1 1 Type II aldolase promoted aldol condensation (cooperative catalysis) ............... 18 1 2 Acceleration of amide hydrolysis by base/hydrogen bond donor bifunctional catalysis ................................ ................................ ................................ .............. 19 1 3 Mechanism proposed for the polymerase reaction ................................ ............. 19 1 4 Proposed dual activation model for phosphate ester hydrolysis by the kidney b ean purple acid phosphatase. ................................ ................................ ........... 20 1 5 Dinucleating Schiff base ligands and their complexes ................................ ........ 21 1 6 Dinucleating Schiff base complex es for heterodinuclear catalysts ..................... 29 1 7 Hajos Parrish reaction ................................ ................................ ........................ 37 1 8 Cinchona alkaloids for bifunctional catalyst design ................................ ............. 42 2 1 Design of dual activation ligands using aza bis(oxazoline) units ........................ 57 2 2 Box ligand structures and solvent optimizations from Ev ans work ..................... 61 2 3 Optimized reaction condition using less reactive benzaldehyde 2 5b ................ 63 2 4 Kinetic study of 2 9 CuTC complex prom oted reaction 2 5c 2 6c .................. 65 2 5 Kinetic study of ligand 2 9 CuTC complex ................................ .......................... 67 2 6 Determination of reaction order in aza Box Cu c oncentration for the Henry reaction ................................ ................................ ................................ ............... 68 2 7 Kinetic study of base 2 14 concentration vs rate for the reaction 2 5 e 2 6 e .. 68 2 8 Design of bifunctional aza Box ligand 2 4a by tethering 1 benzyl 4 ethylpiperazine 2 14 to the aza Box core ................................ ........................... 69 2 9 Kinetic study of base 2 14 ................................ ................................ .................. 71 2 10 Determination of reaction order in tertiary amine concentration ......................... 71 2 11 Mononucleating ligand 2 9 vs dinucleating ligand 2 2a ................................ ...... 73 2 12 Amine tethered aza Box ligand 2 4a vs unfunctionalized ligand 2 9 with external base additive 2 14 ................................ ................................ ................ 75

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12 2 13 Kinetic plots of 2 4a versus 2 9 and 2 14 ................................ ........................... 76 2 14 Amine tethered aza Box ligand 2 4b or 2 4c vs unfunctionalized ligand 2 9 with external base i Pr 2 NEt ................................ ................................ ................. 78 2 15 Plausible transition stat e model for bifunctional catalyst 2 4a CuTC .................. 81 2 16 Reaction rate comparison between 2 4a vs 2 9 and 2 14 ................................ 113 3 1 Dual activatio n catalysts ................................ ................................ ................... 115 3 2 Dual activation catalyst developed for hydrolytic kinetic resolution of epoxides and asymmetric Henry reactions ................................ ................................ ...... 117 3 3 Strategies for syn or anti diastereoselective Henry reaction ........................... 121 3 4 Nonlinear effect study ................................ ................................ ....................... 132 3 5 Kinetic study ................................ ................................ ................................ ..... 133 3 6 Dual activation working model ................................ ................................ .......... 135 3 7 Known ligands reported by our previous study ................................ ................. 137 3 8 Kinetic study of ligand 3 3c O 2 CAr F complex ................................ .................... 211 4 1 Bifunctional base tethered aza bis(oxazoline) CuTC catalyst for asymmetric Henry reaction ................................ ................................ ................................ .. 214

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13 LIST OF SCHEMES Scheme p age 1 1 Dinuclear unsaturated imides and ARO of cyclopentene oxide ................................ .............................. 25 1 2 Dinuclear Cu(II) sal a n catalyzed enantioselective oxidative coupling of 2 naphthol ................................ ................................ ................................ .............. 25 1 3 Self dimerization of vanadium complexes for asymmetric 2 naphthol oxidative coupling ................................ ................................ ............................... 26 1 4 Dinuclear vanadium catalysts f or oxidative coupling of 2 naphthols ................... 27 1 5 D Glucose derived/Gd(O i Pr) 3 complex for enantioselective Strecker reaction of ketoimines ................................ ................................ ................................ ...... 28 1 6 Dinuclear Zn(II) catalyst developed by Trost et al ................................ .............. 28 1 7 Proposed mechanism by Kishi for Nozaki Hiyama Kishi Coupling ..................... 31 1 8 Application of bimetallic catalyst 1 48a in total synthesis ................................ ... 32 1 9 tertiary amine bifunctional catalyst ................................ ...... 33 1 10 ................................ ................................ .................... 33 1 11 ................................ ................................ 34 1 12 Lewis acid/base bifunctional c atalyst for Strecker reaction ................................ 35 1 13 VAPOL phosphate calcium catalyst for asymmetric chlorination ........................ 35 1 14 Self assembled bifunc tional catalysis ................................ ................................ 36 1 15 CBS reduction of ketone ................................ ................................ ..................... 37 1 16 Bifunctional chiral phosphoric acid catalyst for direct alkylation of diazoester ................................ ................................ ................................ ........... 38 1 17 Bifunctional DMAP thiourea catalyst for Michael addition of nitroalkanes to nitroalkenes ................................ ................................ ................................ ........ 39 1 18 Guanidine t hiourea bifunctional catalyst ................................ ............................. 40 1 19 A bifunctional organocatalyst by Takemoto ................................ ........................ 41 1 20 Bifunctional organocatalytic oxy Michael addition ................................ .............. 42

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14 1 21 Bifunctional organocatalytic asymmetric Henry reaction ................................ .... 43 1 22 S quaramide bifunctional organocatalyst ................................ ............................. 44 1 23 Jacobsen ................................ ........... 44 1 24 ................................ ................................ ............ 45 1 25 Chiral crown ether rubidium/phosphine palladium complexes ........................... 46 1 26 Lewis acid/ion pair dual activation catalyst by Peters ................................ ......... 46 1 27 Example of the parallel dual catalytic system with partially shared cycle ........... 48 1 28 Example of sequential binary catalysis ................................ ............................... 49 1 29 Supramolecular catalyst engineered by Bach ................................ ..................... 50 1 30 Henry reaction and related conversion ................................ ............................... 51 1 31 First tandem Henry reaction for the indanone derivative synthesis .................... 52 1 32 Substrate/chiral catalyst induced diastereoselective Henry reaction .................. 52 1 33 syn Diastereoselective Henry reaction by Arai ................................ ................... 53 1 34 Synthetic application of the Henry reaction between methyl 4 nitrobutyrate and aldehyde ................................ ................................ ................................ ...... 54 1 35 The short synthesis of codonopsinines through asymmetric Henry reaction ...... 55 1 36 Examples of bioactive molecules synthesized by Henry reactions ..................... 55 3 1 Expedited synthesis of methoxamine ................................ ............................... 130 3 2 Attempted cleavage of methoxy group on aromatic ring through nickel chemistry ................................ ................................ ................................ .......... 131 4 1 Bis urea (salen)cobalt catalyst for asymmetric Henry reaction ......................... 215

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15 Abstract of Dissertation Presented to the Graduate School of the University of Flor ida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy DEVELOPMENT OF BIFUNCTIONAL LEWIS ACID CATALYSTS FOR ASYMMETRIC HENRY REACTIONS By Kai Lang August 2011 Chair: Sukwon Hong Major: Chemistry Base fun ctionalized aza bis(oxazoline) ligands were developed to explore the concept of dual activation through the Lewis acid and a tethered tertiary amine base The catalytic activity of the Cu complex was evaluated for the asymmetric Henry reaction. Compared with a corresponding unfunctionalized ligand complex with external base, the base functionalized aza bis(oxazoline) CuTC complex exhibited higher activity and selectivity. Kinetic studies revealed that the rate constant ( k obs ) for the base functionalized complex was 2.5 times greater than that of the corresponding unfunctionalized complex with external base. Novel urea (salen) cobalt bifunctional catalysts were developed for asymmetric Henry reactions. Broad substrate scope, good yield, and excellent enant ioselectivity were obtained for nitromethane Henry reactions (82 99% yield; 91 97% ee). anti Diastereoselectivity (up to 48/1 anti / syn with 90 9 8 % ee ( anti ) ) were observed for diastereoselective Henry reactions. A new dual activation mode, cooperative ac tivation by urea (H bond) and the cobalt (Lewis acid) is suggested from mechanistic studies

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16 This methodology was applied to the efficient synthesis of (1 R ,2 S ) methoxamine h ydrochloride

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17 CHAPTER 1 INTRODUCTION Cooperative Dual Act i v a tion Modern organic ch emistry heavily rel ie s on the development of effective catalyst s t o build s tructur ally compl ex molecules with high chemo and stereoselectivity 1 C ooperative dual activation catalys ts have attracted more attention recently, because they can activate both r eaction partners and hold them in an optimal arrangement to achieve fast rates and high stereoselectivities. Currently, there are t wo types of dual activation catalysts: dual activation enzyme and abiotic dual activation catalysts. In C hapter 1 we first g o through an Following that, a main focus is on abiotic dual activation catalysts including dinuclear catalysts, metal/base bifunctional catalysts, bifunctional organocatalysts and bifunctional catalyst s b y ion pair interaction. Then for better understanding of the dual activation concept, a comparison between dual activation catalysts and mixed binary catalysts or supramolecular catalysts is made At the end, the asymmetric Henry reaction is briefly review ed to provide the background for C hapter 2 and C hapter 3 which are about the development of the dual activation catalysts for the asymmetric Henry reaction. Enzyme M odel for D ual A ctivation C atalysis As the most efficient and successful catalysts in natu re the enzymes usually mediate their cataly tic process es through multi ple functional sites 2 a which is generally called synergistic dual activation or bifunctional activation T h e dual activation catalysts are expected to be more eff ective than the corres ponding catalysts with single active site s in terms of catalytic activity regio and stereoselectivity based on the following

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18 reasons: 1) From an energy point of view, two substrates are activated at the same time. 2) From an entropy aspect, the formation of well organized transition state is facilitated through an intramolecular path way ( S inter < S intra < 0 where a minimum decrease of entropy of activation is preferred ). I n th e case of bifunctional enzymes, the functionalities of two active sites in a single enzyme are compl e mentary by nature. For example, in the Type II zinc enolate a l dolase promoted electrophile/nucleophile reaction (Figure 1 1) the Zn (II) Lewis acid center is in charge of inducing and stabilizing the formation of enolate and directing th is enolate c lose to the aldehyde. 2 Simultaneously the hydrogen bond don or in t his a l dolase activates the aldehyde for aldol condensation. T he two orthogonal activating group s and the structure around the two active sites are important for high reacti vity and stereo selectivity As a functional alternative to Lewis acid, amines can generate and stabilize nucleophile and be effective bifunctional sites with proton donors. For example, i n the case of amide hydrolys is by s erine protease the two pivotal active sites, amine and hydrogen bond donors activate both the nucleophile and the e lectrophile at the same time and accelerate this reaction (Figure 1 2). 3 Figure 1 1 Type II a l dolase promoted aldol condensation (cooperative catalysis)

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19 Figure 1 2. Acceleration of ami de hydrolysis by base/hydrogen bond donor bifunctional cataly sis Figure 1 3 Mechanism proposed for the polymerase reaction Another mode of dual activation enzymes is through bimetallic catalysis 3 c For example, in polyme rase promoted multiple substrates involved reaction, two Mg 2+ ions were responsible for activating reactants and stabilizing trans i tion state in a cooperative way (Figure 1 3). 3 c P hosphate ester s hydroly ze in the presence of kidney bean purple acid phospha tase through the bimetallic dual activation catalysis (Figure 1 4). 3 d According to the proposed mechanism, the two active sites Fe(III) and Zn(II) worked together to bind and activate the two substrates. One key factor for effective cooperative catalysis i s t he distance between two active sites. According to the X ray structure s in most of bimetallic enzymes, the two

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20 metal ions are separated by 2.9 5.0 to facilitate the dual activation 3 c Corresponding model system calculation s also support the same conc lusion. 3 c Figure 1 4 Proposed dual activation model for phosphate ester hydrolysis by the kidney bean purple acid phosphatase. Abiotic Bifunctional Catalysts Enlighten by t he concept of enzymatic dual activation there h ave been growing efforts to develop abiotic dual activation catalysts. Compared to the enzymatic catalys ts the artificially designed dual activation catalysts exhibit broad substrate scope usually work in organic solvent instead of aqueous solution and p ossess better stability Metal involved bifunctional catalysts such as dinuclear catalysts, 4 5 6 7 8 9 metal/base bifunctional catalysts 10 11 were developed for highly effective d ual activation Meanwhile, there are many excellent examples of bifunctional or ganocatalysts 12 13 showing dual activation. Metal Involved Bifunctional Catalysts For the reactions where the transition states are stabilized by two Lewis acid centers, bimetallic catalyst s usually work better than corresponding monometallic catalysts. Like the enzymatic systems, the most common bimetallic catalysts are homo bimetallic catalysts considering that the formation of these metal complexes is

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21 relative ly simple and from the single metal source s By comparison the synthesis of heterobimetallic catal ysts is generally difficult and usually depends on the ligand affinity ( to interact with ox o philic metal or nitro philic metal) to distinguish the metal coordination Homodinuclear C atalysts D inucleating Schiff base ligands 1 4 and 1 5 were developed by Shibasaki and co workers (Figure 1 5 ) In terms of cavity size in 1 4 outer O 2 O 2 binding pocket is more spacious than the inner N 2 O 2 Two different metal ions with different ionic radii would fit into these two cavities accordingly By comparison, the tw o cavities in 1 5 are similar in size and therefore can accommodate well the same metal ions with a medium size radius such as Ni (II), Co (III) or Mn (III). Meanwhile, although these two metal ion s are same, the ligands with different electronic propertie s endow these two metal centers with different functionalities in terms of acid/base character. As such, the two metals are able to interact with electrophilic/nucleophilic substrates selectively. Figure 1 5 D inucleati ng Schiff base ligands and their complexes Shibasaki et al reported that Schiff base ligand 1 5 and Ni( OAc ) 2 form ed bench stable dinuclear catalyst ( R ) Ni 2 1 7 a This catalyst is highly efficient for a symmetric Mannich t ype of r eactions with up to 97 : 3 ( anti : syn ) diastereoselectivity and 91 98% ee

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22 ( anti ). 4 d The control experiment s using mono metallic catalyst s Ni 1 6 a Ni 1 6 b and Ni 1 6 c exhibited low er yields and stereoselectivi ti es (T able 1 1 entries 2 4 vs entry 1), which indicated that it was the two the simple bulkiness effect that br ought th ese high yield s and stereoselectivities. Dinuclear c atalyst ( R ) Ni 2 1 7 a worked for asymmetric vinylogous Mannich type reactions with > 30 : 1 dr and 99% ee (Table 1 2) 4 e Compared to the mono metallic catalysts Ni 1 6 a Ni 1 6 b and Ni 1 6 c t he dinuclear catalyst ( R ) Ni 2 1 7 a was superior in terms of selectivity and reactivity ( Table 1 2 entry 1 vs entries 2 4). Table 1 1 Dinuclear n ickel c atalyst promoted a symmetric Manni ch t ype r eactions Table 1 2 Dinuclear n ickel c atalyst promoted a symmetric v inylogous Mannich t ype r eactions

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23 Mn(II) is also able to form bench stable complex Mn (III) 1 7a with Schiff ba se 1 5 (Figure 1 5) which promot ed the a symmetric 1,4 a dditions of o xindoles to n itroalkenes (Table 1 3) 4 f Choosing the different metal ions made a big difference to the result. Dinuclear Ni(II) gave 96% yield with 2 : 1 dr and 57% ee (Table 1 3, entry 1) Cu(II) catalyst gave 3% ee for the same reaction (entry 2). ( R ) Mn 2 1 7 a gave 98% yield with >30 : 1 dr and 97% ee (entry 3). B oth Mn (III) centers are essential for high stereoselectivity The control experiments using mono metallic catalysts Mn(III) 1 6a Mn(III) 1 6b and Mn(III) 1 6c gave low yield s and stereoselectivities (entries 4 6 ). Table 1 3 Dinuclear Mn(III) c atalyst for a symmetric 1,4 a dditions of o xindoles to n itroalkenes Dinuclear Co(III) c atalyst 1 7 a catalyz ed the a symmetric 1 ,4 a ddition r eactions of k eto e sters to a l kynones with high yields and enantioselectivity (Table 1 4 entry 1 ). 4 g The follow ing one pot E / Z isomerization by Ph 2 PMe gave only E product. Control experiment s again highlighted the importan ce of two metal centers, as the mono metallic catalysts gave either low 38 % ee or 0% yield (entries 2 4).

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24 Table 1 4. Dinuclear Co(III) c atalyst for a symmetric 1,4 a ddition r eactions of k eto e sters to a l kynones Schiff base dimeric salen systems were success fully de veloped by Jacobsen et al for conjugate addition to unsaturated imides and for the asymmetric ring opening reaction ( ARO ) of cyclopentene oxide (Scheme 1 1). 5 g, 5 a T he covalent ly linked dinuclear catalysts 1 20a and 1 20b exhibited higher yield and better selectivity than the corresponding mononuclear catalysts in both reactions The kinetic study clearly show ed that when monomeric salen metal complex was used reaction rates were second order dependent on the catalyst concentration whe re as the tether ed s ale n complex changed the reaction kinetic s more towards the first order pathway. The rationale for these observations was that the bimetallic transition state could be better realized by the covalent ly linked dinuclear catalyst intramolecularly than by two separate mononuclear catalysts intermolecularly. The dinuclear Cu(II) salan derivatives was reported to effectively promote the e nantioselective o xidative c oupling r eaction of 2 naphthol. 8 g In comparison with monometallic analogue 1 25a the bimetallic c atalyst 1 25 b exhibited up to 88% ee and

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25 85 % yield. A diradical working model involving two metal centers was proposed based on the stereoselectivity and reactivity (Scheme 1 2). Scheme 1 1 Dinuclear salen catalyst prom oted c onjugate c yanation of u nsaturated i mides and ARO of cyclopentene oxide Scheme 1 2. Dinuclear Cu(II) sal a n catalyzed e nantioselective o xidative c oupling of 2 naphthol

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26 T ridentate Schiff base o xovanadium catalysts were reported to be effecti ve for t he oxidative coupling reaction of 2 naphthol s However, t he moderate enantioselectivity (up to 68% ee) was obtained when catalyzed by the monomeric catalysts. 14 The first highly enantioselective reaction was promoted by the heterogeneous self assem bled dimeric catalyst 1 2 8 b on silica support. 8 h B ased on the ESR spectra analysis of this catalyst 1 2 8 b a ~ 0.40 0.05 nm distance (~ 4 ) between two vanadium metal centers were inferred which favored a dinuclear transition state according to the enzym atic model study A dual activation mechanism was proposed to explain this high stereoselectivity. To prove this hypothesis, a control catalyst 1 28a was studied under the h omogeneous condition In comparison with monomer catalyst 1 2 8 a which gave only 12% yield and 14% ee this silica supported self assembled dimer ic catalyst 1 2 8 b gave excellent ee ( 90% ) and yield ( 93% ) (Scheme 1 3) which is still the highest ee reported for this reaction until now Scheme 1 3. S elf di merization of vanadium complexes for asymmetric 2 naphthol oxidative coupling

PAGE 27

27 The homogeneous versions of dinuclear tridentate oxovanadium catalysts were further developed by the research groups of Gong and Sasai i ndependently. 8 i j Excellent catalytic acti vity and enantioselectivity for oxidative coupling reactions (Scheme 1 4) were achieved by these catalysts. The control experiment and kinetic study implied a bimetallic mechanism. Scheme 1 4. Dinuclear vanadium catalyst s for oxidative coupling of 2 naphthols D G lucose deriv ed homo dinuclear catalyst 1 30 was developed by Shibasaki et al for asymmetric Strecker reactions. Two metal centers in this catalyst are in different electronic environment. Thus, a more electron ric h metal center is involved in the delivery of CN nucleophile, whereas the other Lewis aci dic center is activating the im ine electrophile (Scheme 1 5). 4 l Trost et al reported that ( S S ) b is p ro p henol ligand reacted with Et 2 Zn or Me 2 Zn to form dinuclear ca talyst 1 33 This catalyst proved to be highly effective for asymmetric direct aldol reactions, nitro aldol reactions, Mannich reactions, nitro Mannich reactions, alkynylation and v inylogous n ucleophilic Micha e l addition. 6 Two Zn(II) metal centers are

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28 pro posed to work cooperatively towards the activation, stabilization and orientation of two active species to give the high yield and stereoselectivity (Scheme 1 6). Scheme 1 5. D G lucose deriv ed / Gd(O i Pr) 3 complex for enant ioselective S trecker reaction of ketoimines Scheme 1 6. Dinuclear Zn(II) ca talyst developed by Trost et al Heterodinuclear C atalysts D inucleating Schiff base ligands 1 4 1 5 were used to form heterodin uclear complexes b y sequential expos ure to two different metal sources (Figure 1 6). In addition to main group metals (Figure 1 6, 1 4a ), 4 b rare earth metals were very sui table

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29 for the formation of this type of complexe s The inner cavity is relatively small er an d interacts easily with nitro philic metal ions. The outer cavity is big ger and accommodates the more ox o philic metal ions. Therefore, two functionally compl e mentary metal ions are expected to fit into these two cavities, for which the Br nsted ba se goes to the inner one and Lewis acid stays in the outer. Schi ff base h eterobimetallic Lanthanide complex 1 7 a w as reported by the Shibasaki group for highly enantioselective ring opening of meso aziridines 4 h In the absence of either La (O i Pr) 3 or Yb(OTf) 3 the reactions were not able to proceed effectively (Table 1 5), which proved the importance of both metals participation. Figure 1 6 D inucleating Schiff base complexes for heterodinuclear catalysts Table 1 5. Heterodinuclear catalys t promoted r ing o pening of meso a ziridines

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30 Another attractive feature of this type of Schi ff base ligands is the tunab i l ity of the chiral backbon e to meet the geometry requirement in various transition state s Anthracene derived diamine unit is a valid candidate to build the Schi ff base 1 7 b ( Figure 1 6 ) The bimetallic Ga(III)/Yb(III) 1 7b complex was developed for highly effective c atalytic a symmetric a ddition of i socyanides to a ldehydes (Table 1 6) 4 i The inner metal ion Ga(O i Pr) is believed to interact with the isocyanoacetamide to effectively control its orientation for high enantioselectivity. The cationic Yb(III) activated the aldehyde and made this nucleophilic addition possible. Table 1 6 Heterodinuclear ca talyst promoted addition of isocyanides to aldehydes Hetero bimetallic catalysts also found application in the reactions promoted by transition metal catalys i s. One example is using linked Cr(II)/Ni(II) bimeta llic catalyst to improve the chemo and stereoselectivity in c hromium mediated 1,2 addition of an alkenyl halide to an aldehyde ( Nozaki Hiyama Kishi Coupling ) 8 k According to the mechanism by Kishi et al the transmetalation step is the key to get desired cross

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31 coupling product (Scheme 1 7). However, this process was compromise d by the dimerization pathway which gave undesired byproduct 1 4 7 The most straightforward way to improve the yield of the desired product is to use large excess of Cr(II) catalyst and aldehyde 1 45 to outcompete the un desir able pathway A n obvious drawback would be the lack of atom economy : For the coupling between two reaction components with complicated structure in the total synthesis large excess of aldehyde 1 45 means a lot o f extra work for making aldehyde 1 45 Another solution is to change intermolecular transmetalation between the two Cr(II)/Ni(II) centers into the intramolecular process through a linked bimetallic catalyst and use a dilute solution to suppress the intermo lecular Ni(II)/Ni(II) pathway. The catalyst 1 4 8 a was developed by Kishi et al for this purpose (Table 1 7 ) Scheme 1 7. Proposed mechanism by Kishi for Nozaki Hiyama Kishi Coupling As can be seen in T able 1 7, the link ed bimetallic catalyst 1 4 8 a (2 mol%) promoted this coupling reaction not only with excellent chemoselectivity but also with improved stereoselectivity when an exact 1: 1 ratio of two reaction components were used (Table 1 7, entr y 1 vs 2). For the mixed ca taly tic system of 1 48b / 1 48c 10 mol%

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32 of Cr(II) catalyst 1 48b and 0.5 equiv excess of aldehyde 1 45a were needed to get comparable and slightly worse results (entry 3 vs 1). This methodology was applied to the fragment syn thesis of 1 51 for the total syn thesis of halichondrin/E7389 (Scheme 1 8). Table 1 7 Dinuclear vs mixed mononuclear catalysts for Nozaki Hiyama Kishi Coupling Scheme 1 8. Application of bimetallic catalyst 1 4 8a in t otal synthesis Lewis A cid T ertiary A mine B ifunctional C atalyst s Another type of metal involved dual activation is through the Lewis acid tertiary amine bifunctional catalyst Th is type of catalysis is challenging to develop. One concern is that Lewis acid s and tertiary amines can potentially quench each other and

PAGE 33

33 lose activity. 10 a To avoid this self sequestering problem, a non coordinating bulky base is usually used Lectka et al developed a n In (III)/ benzoylquinine deriv ed bifunctional catalyst 1 52 for enantioselective synthesis of lactams. 10 a Substantial kinetic stereochemical NMR UV Vis and IR evidence s suggested a cooperative dual activation mechanism by a Lewis acid and the chiral ketene enolate nucleophile (Scheme 1 9). Scheme 1 tertiary amine bifunctional catalyst Lin incorporated quinine an easily accessible chiral base into a salen ligand to build a bifunctional catalyst 1 56 which worked excellent ly for lactone synthesis (Scheme 1 10) 10 d A Lewis acid/tertiary amine dual activation model was suggested. Scheme 1 Kozlowski et al developed a n amine functionalized Ti(III) salen catalyst 1 60 b (Scheme 1 11) 7 Through th e dual activation mechanism, this catalyst promoted rapid, chemoselective alkylations of ketoesters. Meanwhile, the control experiment using

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34 either no catalyst or simple Lewis acid salen gave poor chemoselectivities. Kinetic study, nonlinear study and control experiment supported this dual activation mechanism. Scheme 1 11. Kozlowski Lewis A cid Lewis B ase B ifunctional C atalyst s Lewis base s such as phosphine/sulfur o xide are known to coordinate and activate silylated nucleophile s and therefore are good candidates to make bifunctio nal catalysts together with Lewis acid sites Shibasaki et al developed Lewis base tethered bifunctional catalyst 1 6 5 b which is highly effective for asymmetric cyanosilylation of aldehydes. 11 a In comparison with unfunctionalized catalyst 1 6 5 a this du al activation catalyst gave higher yield and enantioselectivity. According to the proposed working model (Scheme 1 12) t he Lewis base phosphine oxide played two roles: 1) Coordinating with aluminum to form a rigid structure 2) Activating the TMSCN for CN deliver y

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35 Scheme 1 12. Lewis acid/base bifunctional catalyst for Strecker reaction Antilla et al reported that the chiral anion VAPOL phosphate c alcium effectively promoted asymmetric chlorination and Michael reactions of 3 substituted oxindoles (Scheme 1 13) 11 d A Lewis acid / base cooperative mechanism was suggested Brnsted bas ic oxygen in the chiral phosphate is believed to activate the oxindole tautomer and calcium activated and directed NCS to the desired position for enantioselective chloride transf er Scheme 1 13. VAPOL phosphate calcium catalyst for asymmetric chlorination

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36 C inchonidine / 1,1' binaphthyl 2,2' diol chiral anion Ti(IV) complex 1 70 was reported by You and co workers for e nantioselective h ydrophosphonylation 11 h A Lewis acid/base dual activation working model was proposed (Scheme 1 14). Scheme 1 14. Self a ssembled b ifunctional c atalysis B ifunctional O rgano catalyst s The bifunctional or ganocatalyst s are capable of dual activation; and they have been intensely investigated. 12 Due to the metal free environment, the organocatalytic process is preferred by the pharmaceutical industry to the metal involved process In addition the chiral sou rces for these organo catalysts are usually readily a cc ess i ble from natur al resources, such as amino acids cinchona alkaloids brucine or from inexpensive commercial product resolved by natur al biomolecules such as 1,2 cyclohexyldiamine tartrate salt, BINO L, etc. Alt hough in some cases, high catalyst loading is necessary due to the low turnover efficiency, the bifunctional organocatalysts are usually inexpensive to prepare and highly useful for large scale asymmetric synthesis.

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37 Lewis A cid/Lewis B ase B ifunc tional O rganocatalyst s O xazaborolidine (CBS) catalyst is an excellent example of dual activation organocatalyst for ketone reduction. 12 d Both a Lewis acid site and base site exist in this catalyst, where the borane center activates the carbonyl group and a mine lone pair coordinates to BH 3 to facilitate hydride transfer to the carbonyl group. During this process, the stereochemistry was realized by orienting the substrates th r ough the chiral backbone (Scheme 1 15) Scheme 1 15. CBS reduction of ketone Br nsted A cid /Lewis B ase C atalysts Hajos et al reported that proline 1 7 8 is an effective catalyst for i ntramolecular a ldol r eactions (Figure 1 7 ) 15 a Mechanistic study by Houk et al suggested a transition state involving bot h the amine and the acid 15 b where the amine form ed an enamine nucleophile to attack carbonyl group activated by the acid Figure 1 7 Hajos Parrish reaction

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38 Terada group reported that c hiral p hosphoric a cid 1 80 promote d the d irect a lkylation of d iazoester with high yields and stereoselectivities (Scheme 1 16) 12 e A c hiral p hosphoric a cid is a dual activation catalyst bear ing two sites : 1) Lewis base site for internal proton transfer for facilitating the new NH bond fo rmation and the catalyst recycling 2) Br nsted acid site for electrophile activation. In the absence of this bifunctional catalyst, t he intramolecular proton transfer would be very slow and nonproductive 12 c Recent NMR study by Gschwind group proved the importance of hydrogen bond OH N for the p hosphoric a cid catalyzed imine addition type of reaction s 12 y Scheme 1 16. Bifunctional c hiral p hosphoric a cid catalyst for d irect a lkylation of d iazoester H ydrogen B ond D onor C atalysts Compared to ureas, t hioureas are better hydrogen bond donors to activate electrophile s owing t o the ir more acidic NH proton s and negligible deactivating self assembly Wulff et al successfully incorporate d thiour ea and aminopyridine into a single catalyst 1 8 4 (Scheme 1 1 7 ) 12 m The d irect Michael a ddition of nitroalkanes to

PAGE 39

39 nitroalkenes proceeded smoothly in the presence of this catalyst. Control experiment s indicated that an aminopyridine moiety is crucial to mak e this reaction proceed. The same thiourea and chiral scaffold attached to a simple base unit such as dimethylamino group failed to promote this reaction. They proposed that the aminopyridine worked as a base to deprotonate nitroalkane and after its proto nation, it can work as a two point hydrogen bond donor to stabilize and direct the nitronate nucleophile close to the electrophile. Simultaneously the thiourea moiety activated the nitroalkene. In the enantioselectiv ity determining step, both reactant s we re well organized by the two active sites tethered through the chiral backbone Therefore both the high yield and stereoselectivity could be achieved from the dual activation process Scheme 1 1 7 Bifunctional DMAP thio urea catalyst for Michael a ddition of nitroalkanes to nitroalkenes Nagasawa et al reported that guanidine thiourea bifunctional catalyst 1 87 mediated the syn selective asymmetric Henry reaction in good enantioselectivity. 12 n A dual activation working mod el through double two point hydrogen bond donors w as proposed (Scheme 1 1 8 ).

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40 Scheme 1 1 8 G uanidine thiourea bifunctional catalyst The highly versatile thiourea /tertiary amine bifunctional catalyst was first developed b y Takemoto et al The initial Takemoto catalyst features inexpensive trans 1,2 cyclohexyldiamine as a chiral source. Catalyst 1 91 a was highly effective for enantio and diastereoselective Michael addition of nitrostyrene 1 13 with diethyl malonate 1 92 (Scheme 1 19). 13 a c The control experiment using base Et 3 N gave 17% yield and addition of thiourea 1 91b improved the yield to 57%. Meanwhile, the base tethered chral thiourea catalyst 1 91a gave 86% yield implying a dual activation mechanism where the li n ker effectively brings the two active sites (thiourea and base) in close proximity A ccording to Takemoto mechanism (Scheme 1 19) the base activated /stabilized enol electrophile and the thiourea recognized/activated the nitro group with two point hydro gen b o nding An alternative mechanism was suggested by Ppai et al in which the protonated base activated/directed the nitro group and thiourea recognized/activated the enol. 13 c Currently it is not clear which functional group activate s the nucleophile because both mechanisms were valid based on theoretical calculation according to Ppai et al. 13 c

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41 H ydrogen B ond D onor / T ertiary A mine C atalysts Scheme 1 19. A b ifunctional organocatalyst by Takemoto Cinchona alkaloids are excellent chiral building block s for constructing bifunctional organocatalysts. These compounds are relatively inexpensive and easily available as both pseudo enantiomer s In addition, the tertiary amine moieties together with the rigid chiral scaffold mak e th is type of compounds ideal candidates for the bifunctional catalys t design. Since Chen and co workers developed the first thiourea substituted cinchonidine catalyst for asymmetric addition of thiophenol to unsaturated imide 12 f several other groups of So s, 12 g Connon 12 h and Dixon 12 i have independently developed the c inchona alkaloids C 9 isomer /thiourea bifunctional catalytic systems (Figure 1 8 ) C inchona alkaloid C 9 isomer/thiourea bifunctional organo catalysts were effective to promote a series of transformations. 12 For example, Falck et al. developed highly enantioselective o rganocatalytic o xy Michae l addition s (Scheme 1 20). 12 o Both ( R ) and ( S ) chirality for the product were easily accessible from tw o pseudo enantiomer ic

PAGE 42

42 catalysts 1 102 a (quinine derivative) and 1 102 b (quinidine derivative). A push pull dual activation mechanism was proposed, where the tertiary amine activated the boronic acid hemiester for the hydroxyl group transfer to the doubl e bond and the thiourea moiety increased the electrophilicity of the Michael acceptor. The chrial scaffold between the two active sites made the reaction proceed on either R e face or S i face of the h ydroxy enones Figure 1 8 Cinchona alkaloids for bifunctional catalyst design Scheme 1 20 Bifunctional o rganocatalytic o xy Michael a ddition

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43 T hiourea b ifunctional organocatalysts derived from C 6 isomer of c inchona alkaloid were devel oped by Hiemstra et al. for the asymmetric Henry reaction. 12 j Both pseudo enantiomer ic catalyst s 1 10 6 a (quinine derivative) and 1 10 6 b (quinidine derivative) worked equally efficiently for the formation of the ( R ) and ( S ) product respectively (Scheme 1 2 1 ) The proposed transition state involved a cooperative activation by this thiourea and the tertiary amine T hus, t he tertiary amine can deprotonate the nitromethane and stabilize the resulting nitronate ion for the further nucleophillic attack while t he thiourea can activate the aldehyde through the two point hydrogen bonding interaction Scheme 1 21 Bifunctional o rganocatalytic asymmetric Henry reaction As the thiourea surrogate in terms of structure and functionality s quaramide was also an effective moiety for bifunctional catalyst design (Scheme 1 2 2 ) Rawa l group successfully incorporated a s quaramide into the cinchona alkaloid to form a bifunctional catalyst 1 1 09 for enantioselective Michael addition. 12 q Although i n terms of cooperative activation, catalyst 1 109 behaves similar ly 1 91a s quaramide

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44 moiety enriched bifu nctional organocatalyst family which is currently dominated by the thiourea as H bond donors. Scheme 1 22 S quaramide bifunctional organo catalyst P hosphine s are well known nucleophilic catalyst s Jacobsen et al. developed a p hosphinothiourea dual activation catalyst 1 1 1 2 for highly enantioselective i mine a llene [3 + 2] c ycloadditions 12 p The ph osphine center converted the a llene into a highly active nucleophile in the Baylis Hillman type reaction A t the same time, the phosphinoyl imine was activated and directed by the thiourea moiety to accept the nucleophilic attack from the enolate (Scheme 1 23). Scheme 1 23. Jacobsen s p hosphinothiourea bifunctional catalyst

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45 B ifunctional C atalyst s through Ion P air I nteraction Hayashi et al. developed chiral gold catalyst 1 11 6 [Au (c HexNC) 2 ]BF 4 for the asymmetric aldol rea ction. 16 a The key to obtain high stereoselectivity is the two point binding of the isocyanate enolate substrate through the isocyanate gold coordination and the ion pair interaction between the ammonium cation and the enolate anion (Scheme 1 24) Both the m etal ion selection and catalyst geometry are crucial to get good results: 1) The phosphinephilic Au (I) might leave the amine groups available to deprotonate acidic substrates and form an ion pair stabilized intermediate for further reaction In terestingly corresponding Cu (II) or Ag (I) 1 116 complexes did not w or k 2) When the extended morpholine moiety was removed t he catalyst analogue with an only proximal amine gave poor ee. This is the first dual activation catalyst through the charge stabilization. Scheme 1 24. Hayashi Sawamura et al. developed a chiral crown ether phosphine palladium complex 1 11 9 for the e nantioselective a llylation of n itro g roup s tabilized c arbanions (Scheme 1 25). 16 b Aft er the proton deprotonation in ester 1 1 20 by RbF, t he positive ly charge d

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46 Rb(I) crown ether complex stabilized and directed th e ester enolate intermediate in the enantio determining step Scheme 1 25. Chiral crown ether rubid ium/phosphine palladium complexes Peters et al. developed catalyst 1 1 23 c for the lactones through Lew is acid and ion pair cooperative catalysis (Scheme 1 26). 16 c Whether or not this charge directing group is present made a big di fference to the reaction results. Only 28% yield and racemic product was obtained using the simple salen catalyst 1 123b whereas the dual activation catalyst gave 82% yield and 88% ee. Scheme 1 26. Lewis acid/ ion pair du al activation catalyst by Peters

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47 The D ifference b etween D ual A ctivation C atalyst s and M ixed B inary C atalyst s D ual activation is different from the mixed binary cataly sis : 1) T he rate determin ing step for d ual activation catalysis requires the participation from both catalytic sites (Figure 1 9 A) whereas in a mixed binary catalytic system two catalysts are usually involved either in parallel (Figure 1 9 B) or a sequen ce (Figure 1 9 C) in two catalytic cycles 2) E ven if there is some catalytic period shared by two catalysts in binary catalysis it is usually very fast step. Figure 1 9 Dual activation catalysis vs binary catalysis Therefore, a linker is very crucial for the dual activation catalysis to bring two catalytic si tes to a desired geometry for the rate and stereo determining steps while for binary catalysis, a linker is not necessary. An excellent example of binary catalysis with the parallel catalytic cycles is the organocatalyst/metal complex binary catalytic sys tem developed by MacMillan et al. for a series of functionalization of aldehydes For example, in the benzylation of aldehydes a binary catalys i s : p hotoredox /o rganocatalysis was involved (Scheme 1 27) 17 a According to the proposed mechanism, the catalytic cycle promoted by organocatalyst 1 128 for en amine generation and the subsequent reaction with the benzyl radical is in linked with the transition metal 1 129 mediated photoredo x catalytic cycle which produced the benzyl radical and an oxidant. Although these two cycles

PAGE 48

48 shared some common part s (rapi d single electron transfer oxidation of the amino radical), these parts are fast process and do not contain cooperative activation mechanis m Therefore, instead of using a catalyst with dual activation sites, a mixture of two separate catalysts is sufficient to make these catalytic cycles producti ve. Scheme 1 27. Example of the parallel dual catalytic system with partially shared cycle An example of the sequential binary catalysis can be found in the work of Gong and co workers in which gold catalyst 1 133 and c h iral p hosphoric a cid 1 134 were combined to mediate the h ydroamination and hydr ide transfer in a one pot cascade fashion. 17 b For this transformation, two catalytic cycle s worked one after another and no overlapped cycle existed Therefore, the reaction cou ld be conducted in two separate steps without significant difference The opposite situation is usually the case:

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49 sequential catalysis was integrated into one step for simplicity with a combination of two different catalysts. Scheme 1 28. Example of sequential binary catalysis The Difference between Dual Activation Catalysts and S upramolecular Catalysts Dual activation catalysts are similar to s upramolecular cataly sts in sofar as that the two functional sites are involved i n the transition state 18 Meanwhile, the difference can be seen between these two types of catalysis: For a s upramolecular catalyst only o ne site participates in the substrate activation while the other site brings the substrate close to the catalytic site through molecular recognition. O n the other hand, in the dual activation catalysis, both of the two active sites are responsible for substrate recognition, direction and activation. For example, Bach et al. developed metalloporphyrin /amide supramolecular catalyst for the regio and enantioselective e poxidation r eaction (Scheme 1 29). 18 d Both the activation by Ru and the molecular recognition from the amide hydrogen bond played crucial roles for high regio and enantio selectivity and reactivity. With the h elp of hydrogen bonding between amides, the inherent chemoselectivity was reversed. L ess reactive electron deficient double bond attached to the C3 position was

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50 chemoselectively oxidized over the more electron rich double bond at C7, as the former was loca ted at the catalytic cente r through the molecular recogni tion. Scheme 1 29. Supramolecular catalyst engineered by Bach Design of Dual Activation Catalysts Compared to the binary catalytic systems, the dual activation cat alytic systems are more challenging to design and study : 1) The synthesis of bifunctional catalysts containing two active sites is usually longer than that of monofunctional catalysts. 2) It is very difficult to design effective bifunctional ligands, as th e desired dual activation transition state can only be accessed by proper arrangement of two sites. Often, poorly designed bifunctional catalysts display no advantage over the binary systems, and the search for the optimal design is rather a hit or miss pr ocess. S everal factors should be considered for the success of dual activation catalyst development : 1 ) The two active sites (Lewis acid, base, transition metal) need to be compatible with each other. 2 ) A linker portion through which two active sites are brought to the right distance for new stereoselective bond formation need to be wisely designed and optimized in terms of length, geometry and flexibility Such process

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51 usually requires the systematic screening of a library of catalysts varied by one fact or each time. Asymmetric Henry R eaction Asymmetric nitro aldol (Henry) reactions 19 20 have drawn much attention as an important carbon carbon bond formation method owing to the synthetic versatility of the nitro group in the nitroalcohol products Ideally, in a highly enantioselective and diastereoselective Henry reaction, up to two chiral centers can be formed in a single step (Scheme 1 30) The Henry reaction product 1 142 could be converted into various useful chiral buil ding blocks for pharmaceutical drugs, for example, amino alcohol s ( 1 143 ) through reduction, 19 b, 21 e, 21 f hydroxy ketone s ( 1 145 ) by TiCl 3 reduction 21 g or chiral alcohol s ( 1 144 ) by removing the nitro group 21 f It is also interesting to note that t he asymmetric nitro aldol (Henry) reactio n has provided a good platform to develop dual activation c atalysts. M any catalysts including bimetallic 4 c 6 b and bifunctional designs, 12 j, 19 b, 19 g exhibited high enantioselectivity in nitromethane Henry reactions. Scheme 1 30. Henry reaction and related conversion S ynthetic Application of Asymmetric Henry Reactions T he f irst c atalytic a symmetric t andem i nter i ntramolecular n itro aldol r eaction for the synthesis of the indanone deriv ative 1 148

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52 (Scheme 1 31) 21 a The bifunctional catalyst ( R ) PrLB 1 146 was used in this reaction. A good ee ( 79% ) was observed and the ee of product 1 148 was improved to 96% after recrystallization A fter the first interm olecular Henry reaction, the resulting nitroalcohol intermediate underwent a second intramolecular Henry reaction with the ketone carbonyl group which is usually less reactive Similar concept was also applied to the synthesis of dideoxy D mannopyranose de rivatives by Barbas III et al. 21 d Scheme 1 31. F irst t andem Henry reaction for the indanone derivative synthesis Recently, a partially substrate controlled diastereoselective Henry reaction was reported by Shibasaki et al I n the presence of chiral catalyst 1 149 (Scheme 1 32) 21 b m ore than 20 : 1 dr and 97% yield were obtained for nitro alcohol 1 152 which is a potential ly useful chiral building block Scheme 1 32. Substrate/chiral cataly st induced diastereoselective Henry reaction Arai group also reported highly diastereoselective Henry reaction s using chiral sulfonyldiamine catalyst 1 153 and chiral substrate 1 154 21 c The stereochemistry of the major products ( 1 155a and 1 157a ) indicat ed that the newly formed hydroxyl group and

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53 the nitro group are all syn relationship to the methyl group (Scheme 1 33). The absolute configuration of 1 154a and 1 154b dict ated the stereochemical outcome in the product 1 155a and 1 15 6 a Scheme 1 3 3 s yn D iastereoselective Henry reaction by Arai Pedro et al. developed camphor derived C 1 symmetric amino pyridine ligand 1 15 7 / Cu(OTf) 2 complex for the asymmetric Henry reaction, and demonstrated the facile conversion of the Henry reaction product s into highly versatile chiral building blocks such as aza muricatacin 1 15 8 5 h ydroxy 5 phenyllevulinic a cid m ethyl e ster 1 1 59 and l actones 1 16 4 (Scheme 1 34). 21 f T he shortest asymmetric synthesis of aza muricatacin 1 15 8 thus far was achieved using this method ( o nly 3 steps from commercial materials) One excellent example of applying asymmetric Henry reactions to the natural pro duct synthesis was reported by Ooi group. 21 e Chiral tetraaminophosphonium salt 1 167 was developed by Ooi et al. and exhibited excellent stereoselectivity for anti diastereoselective asymmetric Henry reactions (Scheme 1 35). This methodology was applied to the reaction of aldehyde 1 16 5 with nitroalkane 1 89 and anti product 1 16 6 was obtained in 99% yield and > 20:1 anti : syn ratio. This Henry reaction adduct 1 16 6

PAGE 54

54 was subjected to the selective reduction of alkynes to give either E or Z alkenyl nitro alco hols. Directed by chiral allylic hydroxy group, epoxidation of the double bonds in compounds 1 16 7 and 1 17 0 in the presence of m CPBA led to the e poxide with the desired stereochemistry. Then Boc protected nitrogen underwent the regioselective epoxide ope ning reaction with the help of para Red Al reduced the N Boc all the way to N methyl and gave ( ) codonopsinine 1 1 68 and ( ) 2 epi codonopsinine 1 17 1 (5 6 steps, 4 chiral centers). Scheme 1 34. S ynthetic application of the Henry reaction between methyl 4 nitrobutyrate and aldehyde Several aminoalcohol containing bioactive molecules were successfully synthesized by Shibasaki, Trost and Wolf groups via the asymmetric Henry reactions (Scheme 1 36). 4 c, 6 c, 19 f g, The obvious advantage of using Henry reaction over other method is the highly straightforward synthetic pathway. From achiral commercial product, it takes only two steps to make the desired amino alcohols. In addition, the

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55 chira l alkyl group and the absolute configuration of these amino alcohols are not limited to the availability of corresponding natural amino acids and analogues. Scheme 1 35. The short synthesis of codonopsinines through asym metric Henry reaction Scheme 1 36. Examples of bioactive molecules synthesized by Henry reaction s Summary and Outlook To summarize metal based dual activation catalysts and bifunctional organocatalysts have been intensi vely explored in the past 10 years. Compared to the

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56 traditional catalysts with a single active site dual activation catalysts exhibit un parallel reactivity and stereo selectivity under mild conditions Therefore, it would be desirable to develop new dual a ctivation catalysts for the challenging transformations. The dual activation catalysts can be classified into t hree types: metal/metal, metal/base, proton donor/base. I t is reasonable to predict that another type of dual activation metal/proton donor cat alysis c ould exist. As an example of metal/base bifunctional catalyst, C hapter 2 describes the development of bifunctional base tethered aza bis(oxazoline) CuTC catalysts for asymmetric Henry reaction Then, C hapter 3 is about the metal/proton donor catal ysts through a urea functionalized ( salen ) C o bifunctional catalysts for asymmetric Henry reaction. E nantioselective Henry reaction s ha ve been widely studied owing to the synthetic value of the nitroalcohol products Nevertheless the diastereoselective asy mmetric Henry reaction is still challenging to achieve because of the low reactivity of nitroalkanes other than nitromethane and the difficulties in controlling diastereoselectivity Several successful cases rely on the existing chirality of the substrates The most successful non substrate induced cases involve the use of dinuclear catalyst s organocatalyst s and bifunctional catalyst s In the following chapters, development of the bifunctional base tethered aza bis(oxazoline) CuTC catalysts and urea tether ed ( salen ) Co catalysts will be discussed for highly enantioselective Henry reactions. As a demonstration o f the unique effect from these bifunctional catalysts, the high ee and anti diastereoselectivity were achieved by the urea tethered ( salen )Co catalyst s and the synthetic utility of this method was applied to the short synthesis of m ethoxamine

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57 CHAPTER 2 DEVELOPMENT OF BIFUNCTIONAL AZA B IS( O XAZOLINE) COPPER CATALYSTS FOR ENANTIOSELECTIVE HENRY R EACTION Design of D ual A ctivation L igands U sing A za B is(oxa zoline) U nits One focus of our research is on the development of dual activation catalysis through dinuclear, bifunctional catalysts 8 a, 22 b Considering the facile functionalization of the central nitrogen in the aza bis(oxazoline) (aza Box) we envisioned t hat a series of novel dual activation catalysts (either bimetallic or bifunctional catalysts) could be developed based on the aza Box units (Figure 2 1 ). F igure 2 1 Design of dual activation ligands using aza bis(oxaz oline) units (a) dimeric aza Box and (b) base functionalized aza Box A za Box is one of the members in b is(oxazoline) family. As versatile bidentate imine ligands, b is(oxazoline) and its related structures such as pyBox and bora Box have been intensively st udied for a broad variety of enantioselective reactions in the past two deca d es 23 24 Reiser and co workers developed and applied aza B ox to a number of asymmetric transformations such as cyclopropanation reactions, kinetic resolutions of 1,2 diols, conjugat unsaturated carbonyl compounds and Michael additions of indole. 25 A useful feature related to the structure of aza Box is that the central nitrogen of aza B ox ligands is easy to functionalize by alkylation Reiser and co workers success fully immobilized the aza Box units on the solid support for the recyclable chiral catalysts 26 Therefore, it is an interesting topic to explore the bifunctional or dinuclear

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58 catalysts built f ro m bis(oxazoline) ligand units taking advantage of convenient f unctionaliza ti on at the center nitrogen in aza B ox. H istorically the asymmetric Henry reaction has provided a good platform for testing the concept of dual activation for the development of bimetallic catalysts or bifunctional organocatalysts 4 e, 6 c, 8 a, 12 j, 12 n, 19 b, 19 g The starting materials for the Henry reaction are usually commercial available and the products are easy to handle Most importantly, as discussed in C hapter 1, the nitro alcohols can be easily converted into useful chiral building blocks for pharmaceutical drugs. Aza B ox might be potentially effective for the asymmetric Henry reaction based on the fact that its analogues, Box ligands and Cu(II) catalysts have been independently reported by Evans 19 c and Jrgensen 27 a c for highly enantioselect ive Henry and aza Henry reactions respectively. More in terestingly, i n Evans and Jrgensen the base play s a crucial role to enhance the catalytic efficiency Therefore, we envisioned that through a cooperative dual activation mechanism, the novel functionalized aza Box Cu catalysts such as either bimetallic catalysts or base tethered bifunctional catalysts would introduce catalytic efficiency over the known monomeric, non functionalized Box Cu catalysts. Results and Discussion Synthesis of Dimeri c A za Box a nd B ifunctional A za Box L igands The aza Box ligands, for example ligand 2 1, were synthesized according to C hap t er 1 ) without any modification. 25 b In a hope to access highly rigid dimeric aza Box lig ands, our first plan is to functionalize the center nitrogen in aza Box 2 1 using aromatic ring (Table 2 1). If this step could be achieved, we will build the aromatic ring bridged dimeric aza Box ligands. However, all

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59 the typical coupling reactions using either bromobenzene or iodobenzene failed to give the desired aromatic aza Box (Table 2 1). Table 2 1. Conditions tested for aromatic functionalization of aza Box E ntry Ar X C onditions P roduct 1 Ph Br Pd 2 (dba) 3 (4mol%), BINAP (8mol%), NaO t Bu, toluene, 110 C, 20h No Rxn 2 Ph Br CuI, N N dimethyl ethane 1,2 diamine, K 2 CO 3 toluene, 110 C, 23 h No Rxn 3 Ph Br CuI, trans N N dimethyl cyclohexane 1,2 diamine, K 2 CO 3 toluene, 110 C, 23 h No Rxn 4 Ph I CuI (1 equiv), Cs 2 CO 3 (2.5 equiv), DMSO (0.25 M), 90 C, 16h No Rxn 5 Ph I CuI, N N dimethyl ethane 1,2 diamine, K 3 PO 4 toluene, 110 C, 20h No Rxn 6 Ph I CuI (50 mol%), trans cyclohexan e 1,2 diamine, NaO t Bu, toluene, 110 C, 23 h No Rxn 7 Ph I CuI (3 equiv), trans cyclohexane 1,2 diamine, NaO t Bu, toluene, 110 C, 23 h Complex M ixture 8 Ph I CuI (5 mo l%), biphenyl 2 ol ( 10 mol%), Cs 2 CO 3 THF, reflux, 20h No Rxn T raditional method to functionalize the center nitrogen in aza Box is through the nucleophilic substitution as described by Reiser and co workers. 25 a Table 2 2 showed the summary of the synthesis of dinucleating aza Box ligand 2 2 a and tertiary amine functionalized aza Box ligands 2 4a / 2 4b / 2 4c through alkylation of the known lithium amide of 2 1 with dibromide and amine functionalized benzyl bromides 2 3a / 2 3b / 2 3c respectively. It need s to be mention ed that a catalytic amount of KI (2 mol%) turned out to be crucial for making this reaction proceed because o ur original study indicated that in the abs en c e of KI, no reaction was observed

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60 Table 2 2. Synthesis of dinucleating and bifunctional aza B ox ligands through alkylation Reaction O ptimization with Unfunctionalized A za Box By the time we initiated this project, there was no report on aza Box complex promot ing asymmetric Henry reaction. 28 The aza Box for Henry reac ti on has originally been tested with Evans condition using Cu(OAc) 2 2 O as metal precursor and EtOH as solvent 19 c Evans reported that either the i Pr Box or the inda Box ligand with

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61 Cu(OAc) 2 2 O gave the nitro aldol product of 4 nitrobenzaldehyde in 67% ee and 74% ee, respectively (Figure 2 2 ). Switching the solvent from MeOH to EtOH further improved enantioselectivity to 81% ee. F igure 2 2 B ox ligand structures and solvent optimizations from Evans work U nder the similar conditions reported by Evans and co workers i Pr aza Box ligand 2 9 was also effective (Table 2 3 ) Th e reaction conditions were further explored with resp ect to monomeric az a Box ligand 2 9 Table 2 3 summarized the preliminary results of screening reaction conditions. In the absence of the metal, this Henry reaction gave the racemic product (entry 1). The overall trend seems to be that Cu (I) precatalysts show ed better react ivity than Cu (II) precatalysts (entries 2 6 vs entries 7 1 1). T he counterion is also an important factor Among these copper precursors, CuTC (TC = thiophene 2 carboxylate) proved to be the most promising A t room temperature a 69% ee and 95% yield were obtained after only 4 h (entry 11). W hen the temperature was lowered to 20 C t he reaction selectivity was further improved to 87% ee (entry 12). Whether Cu (I) or Cu (II) is the actual reactive species in the aza Box CuTC catalyzed system is still not clear. At the beginning all the vials for Cu (I) promoted reactions were charged with argon. Later it turned out that the aza Box CuTC system made no difference in terms of reactivity and enantioselectivity whether the reaction was

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62 run under inert atmos phere or not (entry 10 vs entry 11). Therefore, all Henry reactions were carried out under air atmosphere unless noted otherwise. Table 2 3 Cu p recursor and r eaction t emperature o ptimization E ntry Cu p recursor T emp (C) T ime (h) Y ield (%) E e (%) 1 No Cu rt 5 90 racemic 2 Cu(OTf) 2 rt 48 0 3 Cu(OAc) 2 2 O rt 1 6 95 75 4 Cu(OAc) 2 2 O 20 36 trace 5 CuF 2 rt 48 69 5 6 CuCl 2 rt 48 0 7 2 S) rt 4 99 42 8 CuCl rt 5 87 59 9 CuCl 0 12 87 67 10 CuTC (argon) rt 4 92 69 11 CuTC (air) rt 4 95 69 12 CuTC 20 24 83 87 T he optimized conditions with para nitrobenzaldehyde (Table 2 3 entry 12) failed to promote the less reactive benzaldehyde (Figure 2 3) Ac c ording to Jrgensen and 19 d 27 a tertiary am ine base can facilitate the deprotonation of nitromethane and boost the catalytic activity for Lewis acid catalyzed (aza) Henry reactions In addition, t o minimize the possible racemic background reaction from the base the amount of base is usually less t han or equal to the loading of Lewis acid Therefore, 5 mol% loading of i Pr 2 NEt and 4 molecular sieve s were used to further improve the activity of aza box cat alytic systems U nder the base involved conditions the reaction temperature was able to be f urther low er ed to 30 C and the aza Box 2 9 CuTC c omplex effectively catalyzed the reaction between benzaldehyde 2 5 b and nitromethane with 95% yield and 92% ee

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63 (Table 2 4 entry 2 ). F our additional aza B ox ligands as well as the original Evans i Pr Box li gand 2 7 (Table 2 4 ) were tested under this condition H igh enantioselectivity w as obtained by using b oth i Pr substituted Box 2 7 and corresponding aza Box 2 9 (entries 1 2) More bulk y substitu ent on aza Box mainly brought lower yields and/or ee ( entries 3 6). C 1 symmetric substituted aza Box ligand 2 13 also afforded high selectivity (93% ee) H owever the yield was significantly lower than that of C 2 symmetric i Pr aza Box 2 9 Therefore, the best l igand was 2 9 and was used for further study. Figure 2 3. Optimized r eaction condition using less reactive benzaldehyde 2 5b T able 2 4 Ligand structure s urvey E ntry L igand T ime (h) Y ield (%) % E e ( a bs. c onfig.) 1 2 7 36 77 93 ( S ) 2 2 9 36 95 92 ( S ) 3 2 10 36 57 74 ( S ) 4 2 11 48 12 73 ( S ) 5 2 12 48 56 89 ( R ) 6 2 13 48 41 93 ( R ) S ubstrate scope for enantioselective Henry reaction was explored using ligand 2 9 with CuTC (Table 2 5) in the presence of i Pr 2 NEt and 4 molecular sieve s at 30 C

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64 Several representative types of aldehydes such as benzaldehydes bearing electron withdrawing groups and electron donating groups and aliphatic aldehyde were tested under these conditions H igh yield s (88 99%) and excellent enantioselectivit ies (7 0 97% ee) were obtained (entries 1 8 ). The se results served as reference points upon evaluati on of novel bimetallic and bifunctional aza Box systems T able 2 5 Reaction s cope using unfunctionalized aza Box 2 9 E ntry S u bstrate T ime (h) Y ield (%) E e (%) 1 2 5a Y = 4 NO 2 16 99 70 2 2 5b Y = H 36 95 92 3 2 5c Y = 4 F 24 99 94 4 2 5d Y = 4 MeO 36 88 96 5 2 5e Y = 2 MeO 20 95 97 6 2 5f 24 95 93 7 2 5g 24 91 90 8 2 5h 60 85 90 D ual A ctivation C atalyst Design In order to design an effective dual ac tivati on catalyst, gathering enough mechanism information is crucial. One simpl e but useful method to probe reaction mechanism is kinetic study with the help of either HPLC or 1 H NMR. Using HPLC is more convenient for us due to the fact that th is Henry reaction was run at 30 C and the

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65 reaction was monitored for up to 7 hour which wo uld require extra work for cooling down the system when using the low temperature 1 H NMR. Th erefore by using HPLC, kinetic studies on [ 2 9 CuTC] vs time and [ b ase 2 14 ] vs time were conducted to identify the nuclearity of the catalytically active species in this reaction K inetic S tudy for CuTC and L igand 2 9 C omplex K inetic study of the reaction 2 5c 2 6c was conducted using HPLC by varying the catalyst concentration (Figure 2 4 ). The data of time vs conversion of 2 5c were collected under different catalyst concentration (Table 2 6 Table 2 9 ). Figure 2 4 Kinetic study of 2 9 CuTC complex promoted reaction 2 5c 2 6c T o minimize the human error from weighing tiny amount of catalyst precursor a copper complex stock solution was used for kinetic study. The g eneral procedure for making this complex stock solution is as follows (m aking a 3 mol% loading complex solution as an example) To a vial equipped with a sealed cap, CuTC (2.8 mg 0.015 mmol), ligand 2 9 (3 00 0.05 M in CH 2 Cl 2 0.015 mmol), EtOH ( 75 0 ) and CH 2 Cl 2 ( 2 00 ) were added The mixture was stirred at 30 C for 1.5 h. Other complex solution s with more dilute concentration s w ere prepared from this stock solution. Table 2 6 to Table 2 9 contained the data ready to process for the kinetic study of CuTC and l igand 2 9 c omplex The general procedure for m onitoring reaction conversion vs time with the help of HPLC is as follows. To the complex stock solution,

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66 1 b ) as an internal standard nitromethane (0.27 0 mL, 5 .0 mmol), 100 mg 4 molecular sieves, DIPEA 1M in EtOH, 0.05 mmol) were added. The reaction mixture was stirred at 30 C for 30 min to reduce the temperature influence from a dding substrates Then, 0.5 mmol 4 fluorobenzaldehyde was added. The reaction progress was monitored by the removal of 5 mixture, filtration through silica gel with 10% CH 2 Cl 2 in n h exane as the eluent, and HPLC analysis (Chir alpak IB column, 96.5:3.5 n hexane: isopropanol, 1 .0 mL/min, 215 nm, 1 b romonaphthalene: 4.0 min, 4 fluorobenzaldehyde: 5.5 min) for the first 40 70% of the conversion The slopes of the least square lines for the plots of Ln([SM] t /[SM] 0 ) vs time were det ermined (Figure 2 5) Table 2 6 Kinetic data for 3 mol % l oading of a za B ox c atalyst 2 9 CuTC [9.1 mM] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 10.98 89.02 8.107 0 0 0.5 13.25 86.75 6.5 47 19.2 0.214 1.0 14.82 85.18 5.747 29.1 0.344 1.5 17.85 82.15 4.602 43.2 0.566 2.0 19.61 80.39 4.099 49.4 0.682 2.5 22.87 77.13 3.372 58.3 0.877 3.0 23.35 76.65 3.282 59.5 0.904 3.5 27.31 72.69 2.662 67.1 1.114 Table 2 7 Kinetic data for 1.5 mol % l oading of a za B ox c atalyst 2 9 CuTC [4.5 mM] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 11.04 88.96 8.058 0 0 0.5 11.58 88.42 7.635 5.2 0.054 1.0 12.91 87.09 6.746 16.2 0.176 1.5 13.8 9 86.11 6.199 23.0 0.263 2.0 15.03 84.97 5.653 29.8 0.355 2.5 16.35 83.65 5.116 36.5 0.454 3.0 17.79 82.21 4.621 42.7 0.557 3.5 20.0 80.0 4.0 50.3 0.699 4.0 20.57 79.43 3.86 52.1 0.736 5.0 23.26 76.74 3.299 59 .0 0.894

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67 Table 2 8 Kinetic data for 0.75 mol % l oading of a za B ox c atalyst 2 9 CuTC [2.3 mM] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 10.06 89.94 8.94 0 0 1 10.85 89.15 8.216 8.1 0.084 2 11.71 88.29 7.539 15.6 0.169 3 12. 28 87.62 7.077 21.0 0.234 4 14.06 85.94 6.112 31.6 0.381 5 14.46 85.54 5.92 34.0 0.413 6 15.07 84.93 5.636 37.0 0.462 7 15.92 84.08 5.28 41.0 0.528 Table 2 9 Kinetic data for 0.325 mol% l oading of a za B ox c atalyst 2 9 CuTC [1.1 mM] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 10.94 89.05 8.14 0 0 1 11.43 88.57 7.74 4.9 0.050 2 12.29 87.71 7.136 12.3 0.131 3 12.58 87.42 6.949 14.6 0.158 4 12.79 87.21 6.818 16.2 0.177 5 13.34 86.66 6.4 96 20.1 0.223 6 14.48 85.52 5.906 27.4 0.320 7 14.62 85.38 5.839 28.2 0.332 Based on pseudo first order kinetics hypothesis, d ifferent k obs values (h 1 ) were obtained as the slope of the linear plots of Ln[SM] t /[SM] 0 versus time (h) under the differen t catalyst concentration s ( Table 2 6 Table 2 9 Figure 2 5 ) Figure 2 5 Kinetic s tudy of l igand 2 9 CuTC c omplex

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68 A linear relationship was observed be t ween k obs and precatalyst concentration ( Table 2 10 Figure 2 6 ) This can be explained by that a mo nomeric aza Box CuTC species might be involved in the transition state. Besides, the yields and ees are quite good already. Therefore bimetallic aza Box might not bring significant advantage over the monometallic aza Box based on the first order kinetic be havior. Table 2 10 Kinetic d ata for Figure 2 6 [ C atalyst] ( m M) k obs ( h 1 ) 1 1 0.0472 2 3 0.07 7 4 5 0.188 9 1 0.309 F igure 2 6 Determination of reaction order in aza Box Cu concen tration for the Henry reaction Kinetic Study for T ertiary A mine B a se 2 14 Figure 2 7 Kinetic study of base 2 14 concentration vs rate for the reaction 2 5 e 2 6 e

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69 K inetic experiments were also surveyed to figure out the reaction order versus the tertiary amine base concentration ( Tab le 2 11 to Table 2 15 see experimental section for detail procedure ) 1 B enzyl 4 ethylpiperazine 2 14 was chosen for the kinetic study because the structure in 1 ethylpiperazine possessed some rigidity and can be easily incorporated into the design of cat alyst 2 4a (Figure 2 8 ). A series of different k obs values under different concentration s of base 2 14 were obtained (Table 2 9 Table 2 1 3 Figure 2 8 ) 29 Figure 2 8 Design of bifunctional aza Box ligand 2 4a by tether ing 1 benzyl 4 ethylpipe razine 2 14 to the aza Box core Table 2 11 Kinetic data for 2 mol % l oading of b ase 2 14 [ 0.0095 M] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A(internal standard) B (aldehyde) 0 50.5 49.5 0. 982 0 0 2.7 52.2 47.8 0.916 6.7 0.069 4.0 53.6 46.4 0.865 11.9 0.127 5.1 54.8 45.2 0.826 15.9 0.173 8. 7 58.6 41.4 0.706 28.0 0.328 10. 7 59.6 40.4 0.679 32.9 0.399 12. 4 61.0 39.0 0.639 37.9 0.476 Table 2 1 2 Kinetic data for 5 mol % l oading of b ase 2 14 [ 0 .024 M] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 53.1 46.9 0.884 0 0 1. 1 55.1 44.9 0.815 7.8 0.081 1. 6 55.8 44.2 0.791 10.5 0.111 2.1 57.8 42.2 0.729 17.5 0.194 2.7 58.8 41.2 0.700 20.8 0.234 4. 6 61.8 38.2 0.618 30.1 0.358 5.5 63.6 36.4 0.573 35.1 0.431 6. 4 64.5 35.5 0.550 37.8 0.475

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70 Table 2 1 3 Kinetic data for 10 mol% l oading of b ase 2 14 [ 0.048 M] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standa rd) B (aldehyde) 0 50.8 49.2 0.969 0 0. 0. 7 52.8 47.2 0.893 7.9 0.082 1.2 54.3 45.7 0.841 13.2 0.142 1. 9 56.3 43.7 0.776 19.9 0.223 2. 5 58.0 42.0 0.723 25.3 0.292 3.0 60.8 39.2 0.646 33.3 0.405 3. 7 61.6 38.4 0.624 35.6 0.44 0 4.2 63.6 36.4 0.573 40.9 0.526 5.0 65.9 34.1 0.518 46.5 0.625 Table 2 1 4 Kinetic data for 20 mol % l oading of b ase 2 14 [ 0.096 M] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A(internal standard) B (aldehyde) 0 50.7 49.3 0.971 0 0 0.4 53.3 46.7 0.877 9.6 0.101 0.7 56.1 43.9 0.781 19.6 0.218 1.1 58.9 41.1 0.698 28.1 0.33 2.0 62.2 37.8 0.607 37.6 0.471 2. 6 65.6 34.4 0.525 45.9 0.614 3.0 69.2 30.8 0.446 54.0 0.777 3.6 70.2 29.8 0.424 56.3 0.828 Table 2 1 5 Kinetic data for 30 mol % l oading o f b ase 2 14 [ 0. 144 M] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 51.9 48.1 0.926 0 0 0. 4 54.9 45.1 0.821 11.4 0.121 0. 8 57.8 42.2 0.729 21.2 0.238 1.1 61.4 38.6 0.628 32.1 0.387 2.0 68.3 3 1.7 0.464 49.9 0.693 According to Jrgensen and You an excess amount of base decreased the enantioselectivity in their reported catalytic systems 27 b, 27 d One concern is if the kinetic study of base 2 14 is affected by base promoted racemic reaction To figure this out, all the reactions for kinetic study were worked up after 24 h. It is interesting to see that n o dramatic ee drop was observed for up to 30 mol% loading of base which means the influence coming from racemic react i on is negligible. The lin ear plot of k obs versus concentration of 2 14 indicates that the reaction is first order in tertiary amine concentration ( Table 2 1 6 Figure 2 10 ). 30 This result supported our hypothesis that tertiary amine 2 14 is involved in the rate determining

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71 step T herefore, if the amine is properly tethered to the aza Box ligand the unique dual activation effect might be observed in terms of the reaction rate acceleration or improvement of stereoselectivity. Figure 2 9 Kinetic s tudy of b ase 2 14 Table 2 1 6 Kine tic d ata for Figure 2 10 [ B ase ] ( M) k obs (h 1 ) 0.0095 0.037 0.024 0.076 0.048 0.126 0.096 0.233 0.144 0.344 F igure 2 10 Determination of reaction order in tertiary amine concentration Development of Dual A ctivation C atalyst K inetic results in dicated that k obs [ 2 9 CuTC] and k obs [base 2 14 ] therefore, it might be predicted that covalent ly linked metal / tertiary amine catalysts such as 2 4a

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72 might exhibit better performance due to a proximity effect. Meanwhile, the beneficial effect from a dinuclear aza Box s uch as 2 2 a might not be observed However, it can not completely rule out the possibility that the reaction mechanism might change from the monometallic mode to cooperative bimetallic pathway if the two metal centers are close to each other To test this hypothesis, both dinucleating ligand 2 2 and bifunctional ligand 2 4 a were evaluated in the asymmetric Henry r eaction and compared side by side with unfunctionalized, monomeric aza Box 2 9 ( Table 2 5 and Figure 2 11 ) As discussed in C hapter 1 ( Design and Study of Dual Activation Catalysts ), designing the dual activation catalysts is a hit or miss process. Therefore, to minimize the factors that the dimeric catalysts were inefficient due to the undesired bulky effect from substituent groups on the aza Box, it is still necessary to survey the dimeric aza Box ligands. Following the protocol described in T able 2 2 ( see experimental section for detail ) dimer ic ligands were prepared by alkylation of the center nitrogen in aza B ox with an alkyl dibromide L igand s 2 2(a f) were featured in different linker s and bulky groups. The optimized Henry reaction condition for monomeric ligand in Table 2 5 was used to test eff ectiveness of dimeric ligan ds (Table 2 1 7 ). Compared to the result of monomeric ligand 2 9 only 2 2a and 2 2e gave the similar result s The other dimeric ligands turned out to be less efficient than monomeric catalyst 2 9 It was found that spacer of these dimeric ligands affected the reactivity and enantioselectivity. Both para and ortho disubstituted dimer ic ligands gave slightly Upon consideration of the tedious synthesis towards lig and 2 2e and 2 13 ligand 2 2a was selected for further comparison study.

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73 T able 2 1 7 Screening of d imer ic l igand E n try L igand T ime (h) Y ield (%) E e (%) 1 2 2a 36 95 92 2 2 2b 36 92 84 3 2 2c 36 65 79 4 2 2d 36 81 76 5 2 2e 36 90 94 6 2 2f 36 75 84 Mononuclear vs D inuclear C atalyst for A symmetric Henry R eaction Figure 2 1 1 Mononu cleating ligand 2 9 vs d inucleating ligand 2 2a The paralle l experiments using d inucleating ligand 2 2 a vs m ononucleating ligand 2 9 show virtually no difference in the enantioselective Henry reaction ( Figure 2 11, Tables 2 1 8 ) B oth ligand s 2 9 a nd 2 2a showed very similar reaction rates and stereoselectivities These observations are consistent with the kinetic study conclusion that one metal center is involved in the transition state

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74 T able 2 1 8 Enantioselective Henry r eaction ( m ononuclear vs d inuclear c atalyst) E ntry S ubstrate L igand T ime (h) Y ield (%) E e (%) 1 2 5c 2 9 24 99 94 2 2 2 a 24 99 94 3 2 5d 2 9 36 88 96 4 2 2 a 36 90 95 5 2 5h 2 9 60 85 90 6 2 2 a 60 83 91 B oth mono metallic and bimetallic systems catalyzed the less reactive nitroethane Henry reacti ons with high efficiency at 20 C using 10 equiv of nitroethane (Table 2 1 9 ). No dram atic difference was observed. T able 2 1 9 Diastereoselective Henry r eaction using 10 equiv of nitroethane ( m ononuclear vs d inuclear c atalyst) E ntry S ubstrate EtNO 2 (equiv ) L igand T ime (h) Y ield (%) A nti : s yn E e ( anti ) (%) E e ( syn ) (%) 1 2 5c 10 2 9 48 99 1.9:1 83 66 2 10 2 2a 48 97 2.3:1 91 68 3 2 5e 10 2 9 24 97 1.4:1 94 9 3 4 10 2 2a 24 99 1.4:1 94 9 7 T he us e of nitroethane could be reduced from 10 equivalents to 5 equivalents without the loss of enantioselectivity (Table 2 20 vs Table 2 19 ). No dramatic difference between the reactions catalyzed by these two catalysts was observed.

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75 Table 2 20 Diastereoselective Henry r eaction using 5 equiv of ni troethane (mononuclear vs dinuclear catalyst) E ntry S ubstrate EtNO 2 (equiv.) L igand T ime (h) Y ield (%) A nti : s yn E e ( anti ) (%) E e ( syn ) (%) 1 2 5c 5 2 9 48 94 1.9:1 83 67 2 5 2 2a 48 95 3.1:1 91 68 3 2 5e 5 2 9 24 96 1.6:1 94 95 4 5 2 2a 24 96 1.6:1 94 97 Base T ethered B ifunctional C atalyst for A symmetric Henry R eaction Figure 2 1 2 A mine tethered aza Box ligand 2 4a v s unfunctionalized ligand 2 9 with external base additive 2 14 The parallel reaction s using unfunctionalized ligand 2 9 with external base additive 2 14 and amine tethered aza Box ligand 2 4a w ere monitored for reaction progress by HPLC Interestingly tethered aza Box ligand 2 4a exhibited a rate acceleration (Figure 2 1 3 ). R ate enhancement ( 2.5 times ) was observed for this bi f unctio nal catalyst compared to the unfunctionalized ligand 2 9 with external base additive 2 14 We also found that this Henry reaction p roceeded spot to spot to the product and the active catalytic systems survived for more than 3 days. Further comparison study was conducted using bifunctional aza Box CuTC ( 2 4a CuTC ) and unfunctionalized aza Box CuTC ( ligand 2 9 CuTC with external base ad ditive 2 14 ) side by side (Table 2 21). C ombination of unfunctionalized ligand 2 9 with

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76 base 2 14 gave lower yield under the identical reaction conditions, which is in agreement with aforementioned kinetic study results (Table 2 21 entries 2, 4, 6 vs entr ies 1, 3, 5). However, it should be noted that no matter for the kinetic study Figure 2 12 and the comparison study in Table 2 21, the difference between bifunctional ligand 2 4a and ligand 2 9 with base 2 14 is rather moderate This is due to the fact th at base 2 14 may not be the optimal base additive for this reaction compared with i Pr 2 NEt as shown in Table 2 5. Further substrate scope was surveyed using 2 4a CuTC (Table 2 22 ). Good yield s (80 88 %) and excellent enantioselectivit ies (9 3 9 5 % ee) were ob tained for various benz aldehydes. To the best of our knowledge, t his is the first effective base tethered aza Box for asymmetric Henry reaction. Figure 2 1 3 Kinetic plots of 2 4a versus 2 9 and 2 14

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77 Table 2 21 Enantiose lective Henry r eaction ( b ifunctional 2 4a CuTC vs 2 9 CuTC & 2 14 ) E ntry L igand & b ase S ubstrate T ime (h) Y ield (%) E e (%) 1 2 4a 2 5c 36 81 93 2 2 9 & 2 14 2 5c 36 61 90 3 2 4a 2 5f 24 83 90 4 2 9 & 2 14 2 5f 24 48 91 5 2 4a 2 5e 16 99 92 6 2 9 & 2 14 2 5e 24 78 95 Table 2 22 Brief substrate scope survey using 2 4a CuTC E ntry L igand & b ase S ubstrate T ime (h) Y ield (%) E e (%) 1 2 4a 2 5i Y = 2 F 24 86 93 2 2 4a 2 5d Y = 4 MeO 36 80 95 3 2 4a 2 5j Y = 2 Cl 24 88 95 4 2 4a 2 5g 36 86 93 As we can se e choosing th e base is crucial for this reaction. M ore efficient bifunctional catalyst systems might be constructed if an optimal base is properly

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78 incorporated into the aza Box scaffold. i Pr 2 NEt has been proved to be the best base for this purpose (Table 2 5). Therefore two bifunctional catalysts ( 2 4b and 2 4c ) were prepared ( Figure 2 14) Figure 2 1 4 A mine tethered aza Box ligand 2 4b or 2 4 c v s unfunctionalized ligand 2 9 with external base i Pr 2 NEt Ligand 2 4b turn ed out to be ineffective for asymmetric Henry reaction under current optimized cond i tions, we believe the tether between base and Lewis acid center is not long enough for cooperative dual activation just as the situation mentioned in Hayashi 16 a I t is not to our surprise to see that DIPEA bifunctional catalyst 2 4c gave high yield s (85 99%) and excellent enantioselectivit ies (mostly 90 97% ee). However, compared to the combination of 2 9 CuTC and external base i Pr 2 NEt, bifunctional catalyst 2 4c d oes not show clear advantage as both catalytic systems give very similar results (Table 2 23 entries 1, 3, 5, 7, 9 vs entries 2, 4, 6, 8, 10). Based on these results, it is reasonable to conclude that the optimal linker between the two ac tive centers re quires both desirable length to reach the substrates and some rigid ity to confine cooperation. The linker rigidity resulting from the piperazine ring structure in 2 4a (vs the flexible linker portio n in 2 4c ) might be one of the key elements essential for bifunctional rate acceleration. Although it might be cha llenging to make more rigid tether linking diisopropylamine unit to the aza Box core this would be an interesting topic for the future.

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79 Table 2 23 Enantioselective Henry r eaction ( b ifunctional 2 4c CuTC vs 2 9 CuTC & i Pr 2 NEt) E ntry L igand & b ase S ubstrate T ime (h) Y ield (%) E e (%) 1 2 4c 2 5a 16 99 70 2 2 9 & i Pr 2 NEt 2 5a 16 99 70 3 2 4c 2 5d 36 8 5 9 3 4 2 9 & i Pr 2 NEt 2 5d 36 88 96 5 2 4c 2 5e 16 9 9 97 6 2 9 & i Pr 2 NEt 2 5e 20 95 97 7 2 4c 2 5g 24 9 4 9 2 8 2 9 & i Pr 2 NEt 2 5g 24 91 90 9 2 4c 2 5h 60 8 7 90 1 0 2 9 & i Pr 2 NEt 2 5h 60 85 90 T he unique feature of the new bifunctional aza Box catalyst was observed i n diastereoselective nitro aldol reactions with nitroethane (T able 2 2 4 ). Without the tertiary amine base, t he aza Box Cu catalyst did not catalyze the diastereoselect ive nitro aldol reaction at 20 C (Table 2 2 4 entry 1). Base 2 14 turned out to be pivotal to generate the nitro aldol products in 54% yield, albeit w ith moderate enantioselectivity ( 72 % ) (entry 2). By comparison, t he use of bifunctional aza Box ligand 2 4a resulted in higher yield (81%) and ee (92% ee for anti 97% ee for syn : entry 3).

PAGE 80

80 T ether length play s an important role. In the cases of 2 4b for which the diisopropylamine is tethered to the aza Box by a shorter linker much slower reaction rate (27% yield after 144 h) as well as lower enantioselectivity (80% ee for syn ) were obtained (entry 4). This could be caused by that the diisopropylamine mo iety in 2 4b is not extended enough to direct the substrate close to the metal center for reaction. T ether rigidity is also very crucial. For the ligand 2 4c in which diisopropylamine unit is linked to the aza Box through a longer and more flexible linke r higher yield (99%) and ee (92% ee for anti 96% ee for syn : entry 5) were obtained. However, 2 4c CuTC did not provide much advantage over the combination of 2 9 CuTC with external base i Pr 2 NEt (Table 2 2 4 entry 5 vs entry 6). This m ight be due to the fact that a flexible linker in 2 4c may not be able to effectively hold two reaction centers in close proximity. Table 2 24 Diastereoselective Henry r eactions c atalyzed by b ifunctional c atalyst E ntry L igand A dditive T ime (h) Y ield (%) A nti : S yn E e ( anti ) (%) E e ( syn ) (%) 1 2 9 24 0 2 2 9 2 14 (5 mol%) 24 54 1.3:1 72 96 3 2 4a 24 81 1.3:1 92 97 4 2 4b 144 27 1.4:1 80 92 5 2 4c 24 99 1.5:1 92 96 6 2 9 i Pr 2 NEt (5 mol%) 24 96 1.6:1 94 95

PAGE 81

81 Th e above observ ations suggest that the tertiary amine might be important not only for generating the nitronate anion through deprotonation, but also for the possible stabilization of the resulting nitronate anion for the sub se quent carbon carbon bond formation (Figure 2 1 5 ). In the absence of the optimal linker, this extra stabilization bonus might be negligible Figure 2 15 Plausible transition state model for bifunctional catalyst 2 4 a CuTC Summary and Conclusion In summary dinucl ea ting and base functionalized aza bis(oxazoline) ligands were developed to explore the concept of dual activation in the Cu catalyzed asymmetric Henry reaction. Kinetic study predicted that a base tethered bifunctional aza Box m ight exhi bit unique dual acti vation effect. This was further proved by that t he ethylpiperazine functionalized aza Box copper catalyst ( 2 4a CuTC ) resulted in rate acceleration (2.5 times) as well as improved enantioselectivity (72% ee vs 92% ee) compared to the corresponding unfuncti onalized aza Box copper catalyst with external 1 benzyl 4 ethylpiperazine base ( 2 9 CuTC & 2 14 ) Choosing the optimal tertiary amine base a nd the tether length were also important for good reaction rates and stereoselectivities. Thus, although the diis opropylamine functionalized aza Box copper catalyst featuring a flexible linker ( 2 4c

PAGE 82

82 CuTC ) showed the best performance among three bifunctional catalysts tested in asymmetric nitroethane Henry reactions (99% yield, anti : syn = 1.5 : 1, 92% ee for anti 96% e e for syn ) bifunctional ligand 2 4c does not provide much advantage compared to the combination of unfunctionalized ligand 2 9 with i Pr 2 NEt additive This again is consistent with the tenet of dual activation that a n optimal rigid linker is the key to br ing two active sites close to each other for efficient cooperation Experimental Section All reactions for ligand synthesis 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 po sitive pressure of dry argon by Meyer Solvent Dispensing System prior to use. Unless specified in the table, the Henry reactions were run under air atmosphere. All the chemicals used were purchased from Sigma Aldrich Co., Acros Organics and Strem Chemicals Inc. and were used as received without further purification. NMR spectra were recorded either using a Mercury 300 FT NMR, operating at 300 MHz for 1 H NMR and at 75.4 MHz for 13 C NMR or using a Inova 500 FT NMR, operating at 5 00 MHz for 1 H NMR and at 125 M Hz for 13 C NMR. All chemical shifts for 1 H and 13 C NMR spectroscopy were referenced to residual signals from CDCl 3 ( 1 H) 7.27 ppm and ( 13 C ) 77.23 ppm. High resolution mass spectra were recorded on a Finnigan MAT95Q Hybrid Sector spectrometer or a Agilent 62 10 TOF LC/MS. Enantiomer ic ratios were determined by chiral HPLC analysis (Shimadzu) using Chiralpak IA and IB columns and a ( S S ) Whelk O 1 column. Starting Compounds ( S ) valine ( R ) valine 2 phenylglycine ( S ) tert leucinol (1 S ,2 R ) ( ) cis 1 amino 2 i ndanol were purchased from Sigma Aldrich Co., and Acros Organics and were used as received without further purification. ( S ) Valinol ( R ) Valinol

PAGE 83

83 ( R ) ( ) alpha phenylglycino l and ( S ) 3 amino 2,4 dimethylpentan 2 ol were prepared from the references cited 31 General P rocedure for E nantioselective Henry R eaction To a 3.0 mL vial, CuTC (5.0 mg, 0 2 Cl 2 (0.05 M for ligand 2 9 0.025 M for dimeric ligand 2 2a mixture was stirred at 30 C under air atmosphere for 1.5 h until the solution changed into deep blue. Then, 100 mg of 4 mol ecular sieves and CH 3 NO 2 were added to this mixture. DIPEA or base 2 14 added. Then the mixture was stirred at 30 C for another 30 min. After that, aldehyde 2 5 e (0.5 mmol) was added and the mixtur e was stirred at 30 C for 20 24 h. The reaction mixture was purified by flash column chromatography on silica gel ( n hexane/EtOAc 15:1 then 3:1) to give the nitroaldol adduct 2 6 e as a colorless oil (94 mg, 95% yield, 97% ee). For those 2 4 c Cu catalyzed re actions, the procedure was the same except that no external base was necessary. For those 2 4a Cu catalyzed reactions, the procedure was the same except that no external base was necessary and the reaction te mperature was maintained at 20 C. ( S ) 2 Nitro 1 (4 nitrophenyl)ethanol 2 6a 1 H NMR (300 MHz, CDCl 3 ) : ppm 8.10 8.44 (m, 2 H), 7.62 (d, J = 8.2 Hz, 2 H), 5.53 5.76 (m, 1 H), 4.47 4.71 (m, 2 H), 3.17 3.47 (m, 1 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 148.3, 145.3, 127.2, 124.4, 80.9, 70.2. Enantiomeric excess was determined by HPLC with a Chiralpak I B column (85:15

PAGE 84

84 n hexane:isopropanol, 1 mL/min, 254 nm); minor t r = 13.39 min; major t r = 15.00 min; 87% ee. Configuration assignment: Absolute configuration of major isomer w as determined to be ( S ) by comparison of the retention time with literature data. 32 ( S ) 2 N itro 1 phenylethanol 2 6b. 1 H NMR (300 MHz, CDCl 3 ) : ppm 7.34 7.43 (m, 5H), 5.42 (dd, J = 9.3, 1.8 Hz, 1H), 4.59 (ddd, J = 13.2, 9.6, 0.9 Hz, 1 H), 4.49 (ddd, J = 13.5, 3.0, 0.9 Hz, 1 H), 2.91 (s, 1H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 138.8, 129.7, 129.6, 126.6, 81.9, 71.6; HRMS (DART) calcd for C 8 H 13 N 2 O 3 [M+ N H 4 ] + : 185.0921. Found 185.0918. Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85:15 n hexane: isopropanol, 0.8 mL/min, 215 nm); mino r t r = 8.93 min; major t r = 9.76 min; 92% ee. Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literature data. 32 ( S ) 1 (4 F luorophenyl) 2 nitroethanol 2 6c. 1 H NMR (300 MHz, CDCl 3 ) : ppm 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 ) : ppm 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) calcd for C 8 H 7 FNO 3 [M H] : 184.041 5 Found 184.0413. Enantiomeric excess was determined by HPLC with a Chiralpak IB column

PAGE 85

85 (90:10 n hexane:isopropanol, 1.0 mL/min, 215 nm); minor t r = 9.19 min; major t r = 10.10 min; 94% ee. Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literature data. 32 ( S ) 1 (4 M ethoxyphenyl) 2 nitroethanol 2 6d. 1 H NM R ( 300 MHz, CDCl 3 ) : ppm 7.27 7.36 (m, 2 H) 6.86 6.96 (m, 2 H) 5.40 (d, J = 9.6 Hz, 1 H) 4.60 ( dd J = 12.7, 9. 1 Hz 1 H) 4.47 ( dd J = 13.3, 3.1 Hz 1 H) 3.80 (s, 3 H) 2.80 (d, J = 2.3 Hz, 1 H) ; 13 C NMR (75 MHz, CDCl 3 ) : ppm 160.3, 130.4, 127.5, 11 4.6, 81.5, 70.9, 55.6 ; HRMS (DART) calcd for C 9 H 10 NO 4 [M H ] : 196.061 5 Found 196.0608 Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85:15 n hexane: isopropanol, 0.8 mL/min, 215 nm); minor t r = 12.0 min; major t r = 13.6 min; 96 % e e. Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literature data. 32 ( S ) 1 (2 M ethoxyphenyl) 2 nitroethanol 2 6e. 1 H NMR ( 300 MHz, CDCl 3 ): ppm 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 ): ppm 156.2, 130.0, 127.4, 126.1, 121.4, 110.7, 80.1, 68.0, 55.6 ; HRMS (GC CI) calcd for C 9 H 11 N O 4 [M] + : 197.0688 Found: 197.0688 Enantiomeric excess was determined by

PAGE 86

86 HPLC with a Chiralpak IB column (90:10 n hexane: isopropanol, 1 mL /min, 215 nm); minor t r = 9.9 min; major t r = 10.9 min; 9 7 % ee. Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literature compound 32 ( S ) 1 ( N aphthalen 1 yl) 2 nitroethanol 2 6f. 1H NMR (300 MHz, CDCl3): ppm 8.02 (d, J = 8.5 Hz, 1 H), 7.91 (d, J = 7.6 Hz, 1 H), 7.85 (d, J = 8.2 Hz, 1 H), 7.75 (d, J = 7.3 Hz, 1 H), 7.47 7.63 (m, 3 H), 6.23 (dd, J = 7.5, 4.3 Hz, 1 H), 4.58 4.70 (m, 2 H), 2.98 (s, 1 H); 13C NMR (75 MHz, CDCl3): ppm 133.9, 133.7, 129.7, 12 9.6, 129.5, 127.3, 126.3, 125.7, 124.0, 122.0, 81.0, 68.5; HRMS (DART) calcd for C12H10NO3 [M H] : 216.0666, Found: 216.0658; Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85:15 n hexane: isopropanol, 1.0 mL/min, 215 nm); minor tr = 8.1 min; major tr = 10.3 min; 93% ee. Configuration assignment: Absolute configuration of major isomer was determined to be (S) by comparison of the retention time with literature data. 32 ( S ) 1 ( N aphthalen 2 yl) 2 nitr oethanol 2 6g 1 H NMR (300 MHz, CDCl 3 ): ppm 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 ): ppm 135.6, 13 3.6, 133.4, 129.2, 128.3, 128.0, 126.9, 126.9, 125.5,

PAGE 87

87 123.4, 81.4, 71.4 ; HRMS (DART TOF MS) calcd for C 12 H 10 NO 3 [M H] : 216.066 6 Found 216.0664. Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85:15 n hexane: isopropanol, 0.8 mL/min 215 nm); minor t r = 18.0 min; major t r = 23.3 min; 90% ee. Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literature data. 32 ( S ) 1 Nit ro 4 phenylbutan 2 ol 2 6h. 1 H NMR (300 MHz, CDCl 3 ): ppm 7.07 7.45 (m, 5 H), 4.37 4.43 (m, 2 H), 4.26 4.37 (m, 1 H), 2.69 2.92 (m, 2 H), 2.66 (d, J = 4.7 Hz, 1 H), 1.72 1.95 (m, 2 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 140.8, 128.9, 128.6, 126.5, 80.7, 68.0 35.3, 31.5. Enantiomeric excess was determined by HPLC with a Chiralpak IA column (90:10 n hexane:isopropanol, 1 mL/min, 215 nm); minor t r = 10.53 min; major t r = 12.39 min; 91% ee. Configuration assignment: Absolute configuration of major isomer was det ermined to be ( S ) by comparison of the retention time with literature data 32 ( S ) 1 (2 F luorophenyl) 2 nitroethanol 2 6i. 1 H NMR (300 MHz, CDCl 3 ): 7.54 (td, J = 7.6, 1.8 Hz, 1 H), 7.28 7.42 (m, 1 H), 7.15 7.25 (m, 1 H), 7.01 7.15 (m, 1 H), 5.64 5.79 (m, 1 H), 4.50 4.68 (m, 2 H), 3.26 (br s, 1 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 159.6 (d, J CF = 246.2 Hz), 130.7 (d, J CF = 8.3 Hz), 127.8 (d, J CF = 3.7 Hz), 125.1 (d,

PAGE 88

88 J CF = 3.4 Hz), 116.7 (d, J CF = 21.5 Hz), 116.0 (d, J CF = 21.2 Hz), 80.0 (d, J CF = 2.0 Hz), 65.7 (d, J CF = 2.9 Hz); HRMS (DART) m/z calcd for C 8 H 7 FNO 3 [M H] : 184.0415. Found 184.0411. Enantiomeric excess was determined by HPLC with a ( S, S ) Whelk O1 column (95:5 n hexane:isopropanol, 0.8 mL/min, 215 nm); major t r = 9.3 min; minor t r = 8.6 min; 93% ee. Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison of the retention time with literatur e data. 32 ( S ) 1 (2 C hlorophenyl) 2 nitroethanol 2 6j. 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 (d d, J = 13.6, 2.5 Hz, 1 H), 4.44 (dd, J = 13.3, 9.3 Hz, 1 H), 3.24 (br s, 1 H); 13 C NMR (75 MHz, CDCl 3 ) : CI) m/z calcd for C 8 H 8 ClNO 3 [M] + : 201.0193. Found: 201.0208. Enantiomeric excess was deter mined by HPLC with a ( S,S ) Whelk O1 column (95: 5 n hexane: iso propanol, 1mL/min, 215 nm); minor t r = 11.0 min; major t r = 13.1 min; 95% ee. Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison of the ret ention time with literature data. 32 General P rocedure for Diastereoselective Henry R eaction To a 3.0 mL vial, CuTC 2 Cl 2 (0.05 M for ligand 2 9 0.025 M for dimeric ligand 2 2a mixture was stirred at 2 0 C under air atmosphere for 1.5 h until the solution changed into deep blue. Then, 100 mg 4 molecular sieves and Et NO 2 ( 180 2.5 mmol) were added to this mixture. DIPEA or base 2 14

PAGE 89

89 added. Then the mixture was stirred at 2 0 C for another 30 min. After that, aldehyde 2 5 e (0.5 mmol) was added and the m ixture was stirred at 2 0 C for 2 4 144 h. The reaction mixture was purified by flash column chromatography on silica gel ( n hexane/EtOAc 15:1 then 3:1) to give the nitroaldol adduct 2 15 e as a colorless oil For those 2 4a 2 4b and 2 4c Cu TC catalyzed rea ctions, the procedure was same except that no external base was necessary (1 S ,2 R ) 1 (4 Fluorophenyl) 2 nitropropan 1 ol 2 15c. 1 H NMR (300 MHz, CDCl 3 ): ppm 7.31 7.43 (m, 2 H), 6.98 7.17 (m, 2 H), 5.36 (d, J = 3.7 Hz, 1 H ( anti )), 5.03 (d, J = 9.0 Hz, 1 H ( syn )), 4.68 4.77 (m, 1 H ( syn )), 4.61 4.70 (m, 1 H ( anti )), 2.81 (br. s, 1 H( anti )), 2.72 (br. s, 1 H ( syn )), 1.50 (d, J = 6.8 Hz, 3 H ( anti )), 1. 31 (d, J = 7.1 Hz, 3 H ( syn )); HRMS ( GC NCI MS) c alcd. for C 9 H 10 FNO 3 [M] : 199.0645. Found 199.0642. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 97.5 : 2.5 n hexane:isopropanol, 0.8 mL/min, 2 10 nm); anti : minor t r = 14.0 min; ma jor t r = 14.7 min; 91 % ee ; syn : minor t r = 17.7 min; major t r = 24.0 min ; 68% ee. Configuration assignment: Absolute configuration of major syn isomer was determined to be ( 1 S 2 S ) by comparison with literature compound. 32

PAGE 90

90 (1 S ,2 S ) 1 (2 Methoxyphenyl) 2 nitropropan 1 ol 2 15e ( anti ) 1 H NMR ( 300 MHz, CDCl 3 ) : ppm 7.43 (dd, J = 7. 8 1.56 Hz, 1 H), 7.31 (td, J = 7. 9 1.8 Hz, 1 H), 7.00 (t, J = 7.5 Hz, 1 H), 6.90 (d, J = 7. 4 Hz, 1 H), 5. 54 (dd, J = 5.2, 3.8 Hz, 1 H), 4.90 (qd, J = 6.9, 3. 7 Hz, 1 H), 3.88 (s, 3 H), 3.00 (d, J = 5. 4 Hz, 1 H), 1.49 (d, J = 6. 8 Hz, 3 H); HRMS ( GC CI MS) calcd for C 10 H 13 NO 4 [M] : 211.0845. Found 211.08 20 Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O 1 column ( 95 : 5 n hexane:isopropanol, 0.8 mL/min, 2 10 nm); minor t r = 12.9 min; major t r = 14.0 min; 94 % ee Configuration assignment: Absolute configuration of major anti isomer was determined to be ( 1 S 2 R ) by comparison with literature data. 32

PAGE 91

91 (1 S ,2 S ) 1 (2 Methoxyphenyl) 2 nitropropan 1 ol 2 15e ( anti ). 1 H NMR (300 MHz, CDCl 3 ): ppm 7.26 7.38 (m, 2 H), 6.96 7.03 (m, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 5.10 5.18 (m, 1 H), 5.00 (dd, J = 9.1, 6.79 Hz, 1 H), 3.89 ( s, 3 H), 3.28 (d, 1 H), 1.33 (d, J = 6.8 Hz, 3 H); HRMS ( GC CI MS) calcd for C 10 H 13 NO 4 [M] : 211.0845. Found 211.08 20. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O 1 column ( 95 : 5 n hexane:isopropanol, 0.8 mL/min, 2 10 nm); minor t r = 19. 8 min; major t r = 26. 7 min ; 97%ee. Configuration assignment: Absolute configuration of major syn isomer was determined to be ( 1 S 2 R ) by comparison with literature data. 32

PAGE 92

92 Ligand S ynthesis General P rocedure for t he S ynt hesis of A minooxazoline The method was followed according to the literature procedure. 33 To a solution of bromine (14.8 g, 4.77 mL, 92.8 mmol) in methanol (120 mL), NaCN (4.76 g, 97.1 mmol) was added portionwise ly at 0C during 1 h. T o the resulting soluti on, ( S ) valinol (8.70 g, 84.40 mmol) in methanol (210 mL) was added and the reaction mixture was stirred for 1 h at room temperature The reaction was quenched with a saturated ammonium hydroxide solution (45 mL) After the removal of the solvent, t he resi due was dissolved in NaOH (90 mL of 20 % solution) and was extracted three times with EtOAc (20 mL). The combined organic layers were dried over anhydrous MgSO 4 The product 2 16a (10.0 g, 93%) was obtained as a yellow solid after removing the solvent and was used for the next step without further purification. ( S ) 4 I sopropyl 4,5 dihydrooxazol 2 amine 2 16a. Yellow solid (10.0 g, 93%). 1 H NMR (300 MHz, CDCl 3 ) : ppm 4.67 5.18 (br. s, 2 H), 4.25 (dd, J = 8.8, 7.9 Hz, 1 H), 3.92 (t, J = 7.8 Hz, 1 H), 3.71 (dt, J = 8.8, 7.0 Hz, 1 H), 1.55 1.69 (m, 1 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.83 (d, J = 6.7 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 161.1, 71.4, 70.1, 33.5, 19. 1, 18.5; HRMS ( DART ) calcd for C 6 H 13 N 2 O [M+H] + : 129.1022. Found D 26 48.0 ( c 1.0, CHCl 3 ) 33

PAGE 93

93 ( R ) 4 I sopropyl 4,5 dihydrooxazol 2 amine 2 16b. Yellow solid (2.6 g, 97%). 1 H NMR (300 MHz, CDCl 3 ) : 5.12 (br. s, 2 H), 4.26 (dd, J = 8.8, 7.9 Hz, 1 H),, 3.93 (t, J = 7.6 Hz, 1 H), 3.72 (dt, J = 8.8, 7.0 Hz, 1 H), 1.50 1.70 (m, 1 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.84 (d, J = 6.7 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 161.0, 71.4, 70.1, 33.5, 19.1, 18.5 ; HRMS ( DART ) calcd for C 6 H 13 N 2 O [M+H] + : 129.1022. Found D 26 +47.4 ( c 1.0, CHCl 3 ) ( S ) 4 Isopropyl 5,5 dimethyl 4,5 dihydrooxazol 2 amine 2 16c Off white solid (1.5 g, 80%). 1 H NMR (300 MHz, CDCl 3 ): ppm 5.13 (br. s, 2 H), 3.15 (d, J = 8.5 Hz, 1 H), 1.58 1.80 (m, 1 H), 1.40 (s, 3 H), 1.26 (s, 3 H), 0.97 (d, J = 6.5 Hz, 3 H), 0.87 (d, J = 6.7 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 159.8, 86.9, 77.8, 29.5, 28.7, 21.3, 21.1, 20.7; HRMS ( DART ) calcd for C 8 H 1 7 N 2 O [M+H] + : 157.1335. D 26 15.2 ( c 1.0, CHCl 3 ) ( R ) 4 Phenyl 4,5 dihydrooxazol 2 amine 2 16d Yellow solid (1.6 g, 93%). 1 H NMR (300 MHz, CDCl 3 ) : ppm 7.50 7.10 (m, 5 H), 5.09 (dd, J = 9.2, 7.5 Hz, 1 H), 4.62 (dd, J = 9.3, 7.9 Hz, 1 H), 4.44 (br. s, 2 H), 4.13 3.93 (m, 1 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 161.9, 143.7, 128.8, 127.6, 126.6, 75.6, 67.8; HRMS ( DART ) calcd for C 9 H 1 1 N 2 O [M+H] + : 163.0866. D 26 9.0 ( c 1.0, CHCl 3 ) 33

PAGE 94

94 ( S ) 4 tert Butyl 4,5 dihydrooxazol 2 amine 2 16e White solid (0.91 g, 99%). 1 H NMR (300 MHz, CDCl 3 ) : ppm 4.17 4.23 (m, 1 H), 4.02 4.10 (m, 1 H), 3.90 3.98 (m, 1 H), 3.69 3.76 (m, 1 H), 0.91 (s, 9 H); 13 C NMR (75 MHz, CDC l 3 ) : ppm 160.7, 73.6, 69.7, 34.0, 25.8; HRMS ( DART ) calcd for C 7 H 1 5 N 2 O [M+H] + : 143.1179. Found 143.1180; D 26 41.1 ( c 1.0, CHCl 3 ) 33 General P rocedure for the S ynthesis of O xazolidinone The oxazolidinone was synthesized according to literature proced ure 33 To a two neck round bottom flask, ( S ) valinol (4.0 g, 38.8 mmol), diethyl carbonate ( 14.0 mL 117 mmol) K 2 CO 3 (0.80g, 5.82 mmol) and sodium ethoxide (50 mg, 0.7 mmol) were added under argon atmosphere. The mixture was heated at 129 C for 6 h and dur ing this period, ethanol generated was removed from the system by distillation. T hen the reaction mixture was cooled down to room temperature and concentrated under vacuum. The residue was dissolved in EtOAc (50 mL) and the solution was washed with saturat ed aqueous NH 4 Cl ( 30 mL) solution The aqueous phase was then further extracted with EtOAc (40 mL), the combined organic phases were dried over anhydrous Mg SO 4 and the solvent was evapora ted under reduced pressure. The product 2 17a was purified by re crys tallization using EtOAc and n hexane (4.5 g, 84%) to give a white solid

PAGE 95

95 ( S ) 4 I sopropyloxazolidin 2 one 2 17a. White solid (4.5 g, 84%). 1 H NMR (300 MHz, CDCl 3 ): ppm 6.69 (br. s, 1 H), 4.43 (t, J = 8.7 Hz, 1 H), 4.08 (dd, J = 8.7, 6.3 Hz, 1 H), 3.59 (t, J = 6.3 Hz, 1 H), 1.63 1.78 (m, 1 H), 0.95 (d, J = 6.7 Hz, 3 H), 0.89 (d, J = 6.7 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 160.7, 68.9, 58.6, 32.9, 18.2, 17.9; HRMS ( ESI ) calcd for C 6 H 11 NO 2 Na [M+ Na ] + : 152.0682. D 26 +7.8 ( c 1.0, CHCl 3 ). 33 ( S ) 4 tert B utyloxazolidin 2 one 2 17b. White solid (1.4 g, 95%). 1 H NMR (300 MHz, CDCl 3 ) ppm 7.33 (br. s, 1 H), 4.31 ( t, J = 8.9 Hz, 1 H), 4.13 (dd, J = 9.1, 5.9 Hz, 1 H), 3.55 (ddd, J = 8.9, 5.9, 0.7 Hz, 1 H), 0.85 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 161.0, 66.7, 61.7, 33.4, 24.9; HRMS ( ESI ) calcd for C 7 H 13 NO 2 Na [M+ Na ] + : 166.0838. D 26 +7.3 ( c 1. 0, CHCl 3 ) 33 ( S ) 4 I sopropyl 5,5 dimethyloxazolidin 2 one 2 17c. White solid (1.6 g, 85%). 1 H NMR (300 MHz, CDCl 3 ): ppm 6.79 (br. s, 1 H), 3.20 (d, J = 8.5 Hz, 1 H), 1.71 1.94 (m, 1 H), 1.49 (s, 3 H), 1.39 (s, 3 H), 1.01 (d, J = 6.5 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 159.6, 84.1, 68.6, 28.8, 28.7, 21.5, 20.2, 20.1; H RMS

PAGE 96

96 ( DART ) calcd for C 8 H 1 6 NO 2 [M+H] + : 158.1176. Found 158.1176; [ ] D 26 +15.2 ( c 1.0, CHCl 3 ). 34 (3a R ,8a S ) 3,3a,8,8a T etrahydro 2 H indeno[1,2 d ]oxazol 2 one 2 17d. White solid (5.5 g, 95%). 1 H NMR (300 MHz, CD 3 COCD 3 ) : ppm 7.00 7.78 (m, 4 H), 5.30 5.42 (m, 1 H), 5.19 (d, J = 7.1 Hz, 1 H), 3.32 3.47 (m, 1 H), 3.11 3.31 (m, 1 H), 2.88 (s, 1 H); 13 C NMR (75 MHz, CD 3 COCD 3 ) : ppm 159.7, 141.6, 138.8, 130.3, 128.9, 126.9, 126.4, 81.3, 62.3, 39.9; H RMS ( DART ) calcd for C 10 H 10 NO 2 [M+H] + : 176.0706. Found D 26 +63.3 ( c 2.0, CH 3 COCH 3 ) 35 ( R ) 4 P henyloxazolidi n 2 one 2 17e. White solid (2.2 g, 80%). 1 H NMR (300 MHz, CDCl 3 ppm 7.25 7.49 (m, 5 H), 5.95 (br. s, 1 H), 4.91 5.00(t, J = 6.9 Hz, 1 H), 4.73 (t, J = 8.7 Hz, 1 H), 4.18 (dd, J = 8.7, 6.9 Hz, 1 H); 13 C NMR (75 MHz, CDCl 3 ppm 159.9, 139.7, 129.5, 1 29.1, 126.3, 72.8, 56.6; H RMS ( DART ) calcd for C 9 H 10 NO 2 [M+H] + : 164.0706. D 26 54.9 ( c 1.0, CHCl 3 ) 33 General P rocedure for the S ynthesis of E thoxyoxazoline A solution of ( S ) 4 isopropyloxazolidin 2 one 2 17a (2.00 g, 15.3 mmol) in anh ydrous CH 2 Cl 2 (6.0 mL) was cooled to 0C and Et 3 OBF 4 (2.90 g, 22.5 mmol) in 13 mL of CH 2 Cl 2 was added dropwise ly The solution was stirred at room temperature overnight and was diluted with 100 mL EtOAc and then slowly poured into an ice cold

PAGE 97

97 saturated sod ium bicarbonate solution ( 1 50 mL). The phases were separated and the aqueous phase was extracted with EtOAc twice The combined organic layers were dried over anhydrous MgSO 4 and the solvent was evaporated to give the desired product 2 18a as a colorless o il (2.35 g 98 %). The substance was used for the next step without further purification. ( S ) 2 E thoxy 4 isopropyl 4,5 dihydrooxazole 2 18a Colorless oil (2.35 g, 98%). 1 H NMR (300 MHz, CDCl 3 ) : ppm 4.33 (dd, J = 8.9 8. 4 Hz, 1 H) 4.20 4.29 (m, 2 H) 4.06 (dd, J = 8.2, 7.0 Hz, 1 H) 3.81 (dt, J = 9. 1, 6.6 Hz, 1 H) 1.64 1.78 (m, 1 H) 1.32 (t, J = 7.5 Hz, 3 H) 0.9 2 (d, J = 6.7 Hz, 3 H) 0.85 (d, J = 6 .7 Hz, 3 H) ; 13 C NMR (75 MHz, CDCl 3 ) : ppm 162. 6 71. 1 69. 4 66. 7 33. 2 18.7, 17.8, 14.5 ; H RMS ( DART ) calcd for C 8 H 16 NO 2 [M+H] + : 158.1176. Found 158.1178; [ ] D 26 26.0 ( c 1.0, CHCl 3 ) 33 (3a R ,8a S ) 2 Ethoxy 8,8a dihydro 3a H indeno[1,2 d ]oxazole 2 18b W hite solid (3.2 g, 95%). 1 H NMR ( 300 MHz, CDCl 3 ) : ppm 7.42 7.51 (m, 1 H), 7.22 7.31 ( m, 3 H), 5.42 5.49 (m, 1 H), 5.36 5.43 (m, 1 H), 4.15 4.30 (m, 2 H), 3.35 3.45 (m, 1 H), 3.24 3.34 (m, 1 H), 1.29 (t, J = 7.22 Hz, 3 H) ; 13 C NMR (75 MHz, CDCl 3 ) : ppm 163. 2 142. 9, 139.8, 128.6, 127. 6, 125.6, 125.4, 83.9, 73.8 66. 9, 39.4 14. 5; HRMS (ESI) calcd for C 12 H 14 NO 2 [M+H] + : 204.1019. Found 204.1046; [ ] D 27 +123.2 ( c 2.0, CHCl 3 ).

PAGE 98

98 ( S ) 2 Ethoxy 4 isopropyl 5,5 dimethyl 4,5 dihydrooxazole 2 18c Colorless oil (1.2 g, 90%). 1 H NMR (300 MHz, CDCl 3 ) : ppm 4.21 (dd, J = 6. 9, 2. 5 Hz, 2 H) 3.22 (d, J = 7.9 Hz, 1 H) 1.67 1.80 (m, 1 H) 1.43 (s, 3 H) 1. 3 3 (s, 3 H) 1.24 1.31 (m, 3 H) 1.01 (d, J = 6.7 Hz, 3 H) 0.92 (d, J = 6. 5 Hz, 3 H) ; 13 C NMR (75 MHz, CDCl 3 ) : ppm 160. 6 8 8.0 78.0, 6 6.0 29.6, 29. 3 21.4, 21. 2 20. 4 14.6 ; HRMS (ESI) calcd for C 1 0 H 20 NO 2 [M+H] + : 186.1489 Found 186.1480; [ ] D 27 23.7 ( c 1.0, CHCl 3 ). ( S ) 4 tert B utyl 2 ethoxy 4,5 dihydrooxazole 2 18d Colorles s oil (1.0 g, 99%). 1 H NMR (300 MHz, CDCl 3 ): ppm 4.27 4.32 (m, 1 H), 4.2 2 4.26 ( m 2 H), 4.11 4.19 (m, 1 H), 3.69 3.77 (m, 1 H), 1.32 (t, J = 7.0 Hz, 3 H), 0.86 (s, 9 H) ; 13 C NMR (75 MHz, CDCl 3 ): ppm 162.5, 72.9, 69.7, 66. 7 3 4.0 25.6, 14.6 ; H RMS ( DAR T ) calcd for C 9 H 18 NO 2 [M+H] + : 172.1332. Found 172.1338; [ ] D 26 35.0 ( c 1.0, CHCl 3 ). 33 ( R ) 2 Ethoxy 4 phenyl 4,5 dihydrooxazole 2 18e Colorless oil (1.7 g, 99%). 1 H NMR (300 MHz, CDCl 3 ) : ppm 7.13 7.45 (m, 5 H), 5.14 (dd, J = 9.4, 7.6 Hz, 1 H), 4.68 4.76 (m, 1 H), 4.30 4.44 (m, 2 H), 4.13 4.21 (m, 1 H), 1.36 1.43 (m, 3 H) ; 13 C NMR (75 MHz, CDCl 3 ) : ppm 163. 9 14 3.0 128.8, 127.7, 126.5, 75. 8 67.2, 6 7.0 14.5 ; HRMS

PAGE 99

99 (ESI) calcd for C 1 1 H 14 NO 2 [M+H] + : 192.1019. Found 19 D 26 30.9 ( c 1.0, CHCl 3 ). 33 General P rocedure for the S ynthesis of A za B is(oxazolines) All aza bis(oxazoline ) lig ands were prepared according to literature procedure. 33 Ethoxyoxazoline ( 1 equiv ), aminooxazoline (0.9 equiv), and a catalytic amou nt of p toluenesulfonic acid ( 5 mol% ) were dissolved in toluene ( 0.1 M ) and refluxed for 24 48 h. T he n the solvent was removed by evaporation and the residue was purified by column chromatography on Et 3 N neutralized silica gel using ethyl acetate/ n hexane as an eluent. General P rocedure for A lkylation of A za B ox L igand The method was followed by the literature procedure. 33 To a 10 mL flame dried Schlenk flask, i Pr aza bis(oxazoline) 2 1 ( 1 mL, 0.5 mmol in THF ) was added. Under argon atmosphere, anhydrous THF ( 2.0 mL) was added and the rea ction mixture was cooled to 78 C for 10 min. Then n BuLi ( 220 n h exane, 0.55 mmol) was slowly added into the reaction flask and the r eaction mixture was kept at 78 C for another 10 min. Benzyl bromide (90 0.75 mmol) was slowly added into the reaction flask at 78 C. The cold bath was removed and the flask was warm ed up slowly to room temperature. The r eaction proceeded overnight at this temperature. Loading all reactio n mixture into a short column ( 1.0 cm diameter, 5.0 cm height of basic alumina, 60 325 Mesh) and flushing by n hexane/EtOAc 3:1 gave 2 9 as a yellow oil ( 121 mg, 7 4 %).

PAGE 100

100 ( S ) B is(( S ) 4 isopropyl 4,5 dihydrooxazol 2 yl)amine 2 1 Pink oil (0.80 g, 53%). 1 H NM R (300 MHz CDCl 3 ): ppm 8.13 (s, 1 H), 4.31 (t, J = 8.8 Hz, 2 H), 3.98 (dd, J = 8.4, 7.2 Hz, 2 H), 3.76 (dt, J = 8.8, 7.0 Hz, 2 H), 1.55 1.74 (m, 2 H), 0.92 (d, J = 6.7 Hz, 6 H), 0.81 0.86 (m, 6 H); 13 C NMR (75 MHz, DMSO d 6 ): ppm 165.1, 68.5, 64.4, 32 .2, 18.1, 17.6; HRMS ( DART ) calcd for C 12 H 2 2 N 3 O 2 [M+H] + : 240.1707 Found 240.1709; [ ] D 26 +41.3 ( c 4.0, CHCl 3 ). 33 ( S ) N Benzyl 4 isopropyl N (( S ) 4 isopropyl 4,5 dihydrooxazol 2 yl) 4,5 dihydrooxazol 2 amine 2 9 Colorl ess oil (121 mg, 74%). 1 H NMR (300 MHz, CDCl 3 ): ppm 6.97 7.58 (m, 5 H), 5.01 (q, J = 15.2 Hz, 2 H), 4.32 (dd, J = 9.2, 8.3 Hz, 2 H), 4.06 (dd, J = 8.2, 6.9 Hz, 2 H), 3.83 (dt, J = 9.1, 6.5 Hz, 2 H), 1.56 1.72 (m, 2 H), 0.81 (d, J = 6.7 Hz, 6 H), 0.74 (d, J = 6.7 Hz, 6 H) ; 13 C NMR (75 MHz, CDCl 3 ): ppm 157.3, 137.8, 128.3, 127.9, 127.3, 71.5, 70.0, 53.1, 33.0, 18.7, 17.8; HRMS (ESI) calcd for C 19 H 28 N 3 O 2 [M+H] + : 330.2176. Found 330.2193; [ ] D 27 17.5 ( c 1.0, CHCl 3 ). ( S ) N Benzyl 4 isopropyl N (( S ) 4 isopropyl 5,5 dimethyl 4,5 dihydrooxazol 2 yl) 5,5 dimethyl 4,5 dihydrooxazol 2 amine 2 10 Colorless oil (350 mg, 77%). 1 H

PAGE 101

101 NMR (300 MHz, CDCl 3 ) : ppm 6.88 7.64 (m, 5H), 4.74 5.00 (m, 2 H), 3.20 (d, J = 7.6 Hz, 2 H), 1.59 1. 77 (m, 2 H), 1.33 (s, 6 H), 1.23 (s, 6 H), 0.93 (d, J = 6.5 Hz, 6 H), 0.88 (d, J = 6.5 Hz, 6 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 156.3, 138.4, 128.3, 128.2, 127.2, 87.7, 78.2, 52.4, 29.5, 28.8, 21.1, 21.0, 20.4; HRMS (ESI) calcd for C 23 H 36 N 3 O 2 [M+H] + : 386.2 802. Found 386.2807; [ ] D 26 43.4 ( c 1.0, CHCl 3 ). ( S ) N Benzyl 4 tert butyl N (( S ) 4 tert butyl 4,5 dihydrooxazol 2 yl) 4,5 dihydrooxazol 2 amine 2 11 Colorless oil (550 mg, 74%). 1 H NMR (300 MHz, CDCl 3 ): ppm 7.09 7. 50 (m, 5 H), 4.88 5.20 (m, 2 H), 4.29 (t, J = 9.0 Hz, 2 H), 4.13 4.23 (m, 2 H), 3.76 (dd, J = 9.3, 6.7 Hz, 2 H), 0.76 (s, 18 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 157.4, 138.0, 129.0, 128.3, 127.3, 73.6, 70.3, 53.4, 34.2, 26.1, 25.6; HRMS (DART) calcd for C 2 1 H 3 2 N 3 O 2 [M+H] + : 358.2489. D 26 11.8 ( c 2.0, CHCl 3 ). ( R ) N M ethyl 4 phenyl N (( R ) 4 phenyl 4,5 dihydrooxazol 2 yl) 4,5 dihydrooxazol 2 amine 2 12. Colorless oil (410 mg, 89%). 1 H NMR (300 MHz, CDCl 3 ) : ppm 7.19 7.69 (m, 10 H), 5.33 (dd, J = 9.4, 7.8 Hz, 2 H), 4.93 (dd, J = 9.6, 8.3 Hz, 2 H), 4.38 (t, J = 8.0 Hz, 2 H), 3.65 (s, 3 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 159.1, 142.7, 128.9, 127.8, 126.7, 76.6, 67.7, 37.6. HRMS (ESI) calcd for C 19 H 20 N 3 O 2 [M+H ] + : 3 22 1550. Found 322.1553; [ ] D 26 +42.8 ( c 2.0, CHCl 3 ) 33

PAGE 102

102 (3a R ,8a S ) N Benzyl N (( R ) 4 isopropyl 4,5 dihydrooxazol 2 yl) 8,8a dihydro 3a H indeno[1,2 d]oxazol 2 amine 2 13 Colorless oil (650 mg, 70%). 1 H NMR (300 MHz, CDCl 3 ): ppm 7.41 7.51 (m, 1 H), 7.15 7.34 (m, 8 H), 5.51 5.56 (m, 1 H), 5.39 5.47 (m, 1 H), 4.88 5.10 (m, 2 H), 4.33 (t, J = 8.8 Hz, 1 H), 4.08 (dd, J = 8.2, 6.7 Hz, 1 H), 3.84 (dt, J = 9.3, 6.5 Hz, 1 H), 3.44 3.32 (m, 1 H), 3.30 3.19 (m, 1 H), 1.63 ( dq, J = 13.3, 6.6 Hz, 1 H), 0.82 (d, J = 6.7 Hz, 3 H), 0.75 (d, J = 6.7 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 158.2, 157.0, 142.7, 139.6, 137.6, 128.5, 128.3, 127.8, 127.6, 127.3, 125.8, 125.3, 84.5, 74.5, 71.5, 70.0, 53.1, 39.4, 32.9, 18.6, 17.8; HRMS (ESI) calcd for C 23 H 26 N 3 O 2 [M+H] + : 376.2020. D 28 +30.1 ( c 1.0, CHCl 3 ). (3a R ,8a S ) N (( R ) 4 Isopropyl 4,5 dihydrooxazol 2 yl) 8,8a dihydro 3a H indeno[1,2 d]oxazol 2 amine 2 19 a. Ethoxyoxazoline 2 18b (1 .52 g, 7.5 mmol), aminooxazoline 2 16b (864 mg, 6.8 mmol), and a catalytic amount of p toluenesulfonic acid (65 mg, 0.38 mmol) were dissolved in toluene (75 mL) and refluxed for 48 h. After removal of the solvent, the residue was passed through Et 3 N neutra lized silica gel to give a white solid (775 mg, 40%). 1 H NMR (300 MHz, CDCl 3 ): ppm 7.40 (dd, J = 6.0, 3.4 Hz, 1 H), 7.16 7.31 (m, 3 H), 5.50 (d, J = 7.6 Hz, 1 H), 5.31 (td, J = 7.0, 2.4 Hz, 1 H), 4.39 (t, J = 8.7 Hz, 1 H), 4.12 (dd, J = 8.7, 6.6 Hz, 1 H), 3.76 (dt, J = 8.5, 6.7 Hz, 1 H), 3.35 3 .46 (m, 1 H), 3.25 3.35 (m, 1 H), 1. 80 (dq, J = 13.5, 6.7 Hz, 1 H), 1.01 (d, J = 6.7

PAGE 103

103 Hz, 3 H), 0.93 (d, J = 6.7 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 166.3, 165.7, 143.1, 140.4, 128.5, 127.5, 125.6, 125.3, 81.3, 73.3, 69.5, 62.0, 39.8, 32.7, 18.7, 18.0; HRMS (ESI) calcd for C 16 H 20 N 3 O 2 [M+ H] + : 286.1550. Found 286.1574; [ ] D 29 88.9 ( c 1.0, CHCl 3 ). ( S ) Bis(( S ) 4 isopropyl 5,5 dimethyl 4,5 dihydrooxazol 2 yl)amine 2 19b White solid (496 mg, 42%). 1 H NMR (300 MHz, CDCl 3 ): ppm 3.27 (d, J = 9.3 Hz, 2 H), 1 .72 1.87 (m, 2 H), 1.47 (s, 6 H), 1.31 (s, 6 H), 1.03 (d, J = 6.5 Hz, 6 H), 0.92 (d, J = 6.5 Hz, 6 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 164.6, 84.9, 74.6, 29.0, 28.7, 21.2, 21.1, 20.4; HRMS (ESI) calcd for C 16 H 30 N 3 O 2 [M+H] + : 296.2333. Found 296.2335; [ ] D 28 +18.8 ( c 1.0, CHCl 3 ). ( R ) B is(( R ) 4 phenyl 4,5 dihydrooxazol 2 yl)amine 2 19c. White solid (760 mg, 55%). 1 H NMR (300 MHz, CDCl 3 ) : ppm 7.01 7.51 (m, 10 H), 5.07 (dd, J = 9.1, 7.5 Hz, 2 H), 4.66 (t, J = 8.9 Hz, 2 H), 4 .04 4.21 (m, 2 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 166.6, 141.5, 129.1, 128.4, 126.6, 73.8, 63.5; HRMS (ESI) calcd for C 1 8 H 18 N 3 O 2 [M+H] + 308.1394. Found 308.1389; [ ] D 26 387.1 ( c 1.0, CHCl 3 ) 33

PAGE 104

104 ( S ) B is(( S ) 4 tert butyl 4,5 dihydrooxazol 2 yl)amine 2 19d. White solid (721 mg, 90%). 1 H NMR (300MHz, CDCl 3 ) : ppm 4.29 (t, J = 9.2 Hz, 2 H), 4.13 (dd, J = 8.9, 6.8 Hz, 2 H), 3.77 3.83 (m, 2 H), 0.89 (s, 18 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 166.3, 69.0, 67.6, 33.8, 25.5; HRM S ( DART ) m/z calcd for C 14 H 26 N 3 O 2 [M+H] + 268.2020 D 29 +90.1 ( c 1.0, CHCl 3 ). 33 Synthesis of D imeric A za B ox L igand 2 2 ( a f ) (4 S ,4' S ) N N (1,3 Phenylenebis(methylene))bis(4 isopropyl N (( S ) 4 isoprop yl 4,5 dihydrooxazol 2 yl) 4,5 dihydrooxazol 2 amine) 2 2a To a 10 mL flame dried Schlenk flask, i Pr aza bis(oxazoline) 2 1 ( 4.0 mL, 0.5 M in THF, 2.0 mmol) and KI (5 mg) were added. Under argon atmosphere, anhydrous THF ( 12.0 mL) was added and the react ion mixture was cooled to 78 C for 10 min. Then n BuLi ( 2.5 M in n hexane, 2.2 mmol) was slowly added into the reaction flask and the r eaction mixture was kept at 78 dibromo m xylene ( 253 mg, 0. 96 mmol) in THF ( 4.0 mL) was slowly added into the reaction flask at 78 C. The co ld bath was removed and the flask was warmed slowly up to room temperature. Reaction proceeded for another 14 h at this temperature. Loading all reaction mixture into a short column (1.0 cm diameter, 5.0 cm height of basic alumina, 60 325 Mesh) and flushin g by n hexane/EtOAc 3:1 gave 2 2a as a yellow oil (406 mg, 70 %). 1 H NMR (300 MHz,

PAGE 105

105 CDCl 3 ) ppm 6.96 7.44 (m, 4 H), 4.87 5.07 (m, 4 H), 4.32 (t, J = 8.8 Hz, 4 H), 4.01 4.10 (m, 4 H), 3.82 (dt, J = 9.1, 6.6 Hz, 4 H), 1.57 1.73 (m, 4 H), 0.83 (d, J = 6.5 Hz, 12 H), 0.75 (d, J = 6.8 Hz, 12 H); 13 C NMR (75 MHZ, CDCl 3 ): ppm 157.1, 137.6, 128.2, 12 7.5, 126.6, 71.5, 70.1, 53.0, 33.0, 18.8, 17.9; HRMS (ESI) calcd for C 32 H 48 N 6 O 4 Na [M+Na] + : 603.3629. Found 603.3621; [ ] D 26 25.4 ( c 1.0, CHCl 3 ). (4 S ,4' S ) N N (1,2 Phenylenebis(methylene))bis(4 isopropyl N (( S ) 4 isopr opyl 4,5 dihydrooxazol 2 yl) 4,5 dihydrooxazol 2 amine) 2 2b 1 H NMR (300 MHz, CDCl 3 ): ppm 7.22 7.36 (m, 2 H), 7.09 7.19 (m, 2 H), 5.12 (d, J = 3.7 Hz, 4 H), 4.32 (t, J = 8.6 Hz, 4 H), 4.02 4.10 (m, 4 H), 3.83 (dt, J = 9.1, 6.6 Hz, 4 H), 1.66 (dq, J = 13. 2, 6.6 Hz, 4 H), 0.82 (d, J = 6.8 Hz, 12 H), 0.75 (d, J = 6.8 Hz, 12 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 157.3, 135.3, 127.1, 126.9, 71.4, 70.2, 50.3, 32.9, 18.8, 17.9. HRMS(ESI) calcd for C 32 H 48 N 6 O 4 [M+H] + : 581.3809. Found 581.3829; [ ] D 26 20.1 ( c 2.0, CHCl 3 ). (4 S ,4' S ) N N (4,6 Diisopropyl 1,3 phenylene)bis(methylene)bis(4 isopropyl N (( S ) 4 isopropyl 4,5 dihydrooxazol 2 yl) 4,5 dihydrooxazol 2 amine) 2 2c 1 H NMR (300 MHz, CDCl 3 ) : ppm 7.26 (s, 1 H), 7.11 (s, 1 H), 4.77 5.24 (m, 4 H), 4.31 (t, J

PAGE 106

106 = 8.8 Hz, 4 H), 4.05 (t, J = 7.6 Hz, 4 H), 3.81 (ddd, J = 9.0, 6.9, 6.7 Hz, 4 H), 3.25 (dt, J = 13.7, 6.8 Hz, 2 H), 1.56 1.69 (m, 4 H), 1.19 (dd, J = 14.5, 6.9 Hz, 12 H), 0.81 (d, J = 6.7 Hz, 12 H), 0.71 (d, J = 6.7 Hz, 12 H) ; 13 C NMR (75 MHz, CDCl 3 ) : ppm 157.3, 146.2, 130.8, 128.4, 121.8, 71.3, 70.2, 50.4, 32.9, 28.7, 24.15, 23.8, 18.8, 17.8. HRMS( APC I) calcd for C 38 H 60 N 6 O 4 [M+H] + : 665.4749 Found 665.4759. [ ] D 26 61.6 ( c 1.0, CHCl 3 ). (4 S ,4' S ) N,N' ( D ibenzo[b,d]f uran 4,6 diylbis(methylene))bis(4 isopropyl N (( S ) 4 isopropyl 4,5 dihydrooxazol 2 yl) 4,5 dihydrooxazol 2 amine) 2 2d 1 H NMR (300 MHz, CDCl 3 ) : ppm 7.72 (d, J = 7.6 Hz, 2 H), 7.32 (d, J = 7.6 Hz, 2 H), 7.14 7.26 (m, 2 H), 5.43 (s, 4 H), 4.31 (t, J = 8.8 Hz, 4 H), 4.06 (t, J = 7.6 Hz, 4 H), 3.81 (dt, J = 9.1, 6.5 Hz, 4 H), 1.54 1.67 (m, 4 H), 0.75 (d, J = 6.8 Hz, 12 H), 0.69 (d, J = 6.8 Hz, 12 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 157.4, 153.8, 124.6, 124.2, 122.9, 122.1, 119.3, 71.6, 70.1, 48.1, 32.9, 18.7, 17.8. HRMS(ESI) calcd for C 38 H 50 N 6 O 5 [M+Na] + : 693.3734. Found 693.3775. [ ] D 26 11.7 ( c 2.0, CHCl 3 )

PAGE 107

107 (3a R ,3a' R ,8a S ,8a' S ) N N (1,3 P henylenebis(methylene))bis( N (( R ) 4 isopropyl 4,5 dihydrooxazol 2 yl) 8,8a dihydro 3aH indeno[1,2 d]oxazol 2 amine) 2 2e 1 H NMR (300 MHz, CDCl 3 ) : ppm 7.41 7.50 (m, 2 H), 7.03 7.30 (m, 10 H), 5.47 5.59 (m, 2 H), 5.36 5.47 (m, 2 H), 4.73 5.03 (m, 4 H), 4.25 4.41 (m, 2 H), 3.97 4.16 (m, 2 H), 3.73 3.92 (m, 2 H), 3.14 3.47 (m, 4 H), 1.56 1.71 (m, 2 H), 0.82 (d, J = 6.8 Hz, 6 H), 0.75 (d, J = 6.8 Hz, 6 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 158.1, 157.0, 142.7, 139.6, 137.4, 128.5, 128.2, 127.6, 127.3, 126.4, 125.8, 125.3, 84.5, 74.6, 71.4, 70.0, 52.9, 39.4, 33.0, 18.7, 17.9. HRMS( APC I) calcd f or C 40 H 44 N 6 O 4 [M+H] + : 673.3497. Found 673.3526. [ ] D 26 +125.6 ( c 2.4, CHCl 3 ). (4 S ,4' S ) N N (1,4 phenylenebis(methylene))bis(4 isopropyl N (( S ) 4 isopropyl 4,5 dihydrooxazol 2 yl) 4,5 dihydrooxazol 2 amine) 2 2f 1 H NMR (300 MHz, CDCl 3 ) : ppm 7.31 (s, 4 H), 4.91 5.10 (m, 4 H), 4.34 (t, J = 8.7 Hz, 4 H), 4.01 4.16 (m, 4 H), 3.85 (ddd, J = 9.2, 6.7, 6.6 Hz, 4 H), 1.67 (dq, J = 13.3, 6.6 Hz, 4 H), 0.87 (d, J = 7.0 Hz, 12 H), 0.79 (d, J = 6.8 Hz, 12 H); 13 C NMR (75 MHz, CDC l 3 ) : ppm 157. 4, 136.7, 127.9, 71.5, 70.1, 52.9, 33.0, 18.9, 17.9. HRMS(ESI) calcd for C 32 H 48 N 6 O 4 [M+H] + : 581.3810 Found 581.3803. [ ] D 26 35.5 ( c 2.0, CHCl 3 ).

PAGE 108

108 General P rocedure for S ynthe s is of B ackbone of B ifunctional C atalyst To a round bottom flask , dibromo m xylene (1.0g, 3.8 mmol), CH 2 Cl 2 (15 mL) and 1 ethylpiperazine (0.40 mL, 3.1 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. After evaporation of the majority of CH 2 Cl 2 the residue was passed through Et 3 N ne utralized silica gel to give the desire d product 2 3a as a colorless oil (394 mg, 35%). (note: Compound 2 3a is unstable without the solvent. After purification, dilute stock solution in THF needs to be made right away for the next step) 1 (3 (Bromomethyl)benzyl) 4 ethylpiperazine 2 3a Colorless oil (394 mg, 35%). 1 H NMR (300MHz, CDCl 3 ) : ppm 6.99 7.52 (m, 4 H), 4.48 (s, 2 H), 3.50 (s, 2 H), 2.06 2.86 (m, 10 H), 1.07 (t, J = 7.0 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 139.2, 138.0, 129.9, 129.5, 128.9, 128.0, 63.0, 53.3, 53.0, 52.5, 33.8, 12.2; H RMS ( DART ) calcd for C 14 H 22 NO 2 [M+H] + : 297 .096 1 Found 297.0953. N (3 (Bromomethyl)benzyl) N isopropylpropan 2 amine 2 3b. Compound 2 3b was prepared following the general procedure. Colorless oil (180 mg, 14%). 1 H NMR (300 MHz, CDCl 3 ) : 7.51 (m, 4 H ), 4.51 (s, 2 H), 3.64 (s, 2 H), 2.86 3.15 (m, 2 H), 0.97 1.07 (d, J = 5.4 Hz, 12 H); 13 C NMR (75 MHz, CDCl 3 ) :

PAGE 109

109 128.7, 128.6, 128.2, 127.1, 49.0, 48.1, 34.3, 21.0; HRMS (ESI) calcd for C 14 H 23 BrN [M+H] + : 284.1008. found 284.1021. N (2 (3 ( B romomethyl)benzyloxy)ethyl) N isopropylpropan 2 amine 2 3c To a 25 mL flame dried Schlenk flask, 2 (diisopropylamino) ethanol (0.28 mL, 1.69 mmol in 2.0 mL THF) and KI (5 mg) were added. Under argon atmosphere, the r eaction mixture was cooled to 78 C for 10 min. Then n BuLi ( 1.2 mL 1.6 M in n hexane, 1. 92 mmol) was slowly added into the reaction flask and the reaction mixture was kept at 78 C for another 10 min. D ibromo m xylene ( 600 m g, 2.27 mmol ) in THF (2 mL) was slowly added into the flask under 78 C The cold bath was removed and the flask was slowly heated up to 75 C The reaction proceeded for another 24 h at this temperature. The reaction mixture was purified by column chromatography on silica gel ( c hloroform / MeOH 9:1) followed by another column chromatography on Et 3 N neutralized silica gel using ethyl acetate/ n hexane as an eluent. to give compound 2 3c ( 254 mg, 45 %) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ): ppm 7.26 7.41 (m, 4 H), 4.53 (s, 2 H), 4.51 (s, 2 H), 3.46 (t, J = 7.5 Hz, 2 H), 2.96 3.06 (m, 2 H), 2.67 (t, J = 7.5 Hz, 2 H), 1.02 (d, J = 6.6 Hz, 12 H); 13 C NMR (12 5 MHz, CDCl 3 ): ppm 139.7, 138.1, 129.1, 128.4, 128.3, 127.8, 73.0, 72.5, 49.7, 45.1, 33.7, 21.0; HRMS (ESI) calcd for C 16 H 27 BrNO [M+H] + : 328.1271. Found 328.1278.

PAGE 110

110 1 Benzyl 4 ethylpiperazine 2 14 To a round bottom flask, benzyl bromide (2.47 mL, 20.8 mmol), CH 2 Cl 2 (30 mL) and 1 ethylpiperazine (5.28 mL, 41.6 mmol) were added. The reaction mixture was stirred at room temperature for 4 h. After evaporation of the majority of CH 2 Cl 2 the residue was passed through Et 3 N neutralized silica to give 2 14 as a yellow oil (3.22 g, 75%). 1 H NMR (300 MHz, CDCl 3 ): ppm 7.06 7.43 (m, 5 H), 3.51 (s, 2 H), 2.10 2.72 (m, 10 H), 1.07 (t, J = 7.2 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 138.4, 129.5, 128.4, 127.2, 63.3, 53.3, 53.1, 52.6, 12.2; HRMS (DART) calcd for C 13 H 21 N 2 [M+H] + : 205.1699. Found 205.1699. 36 General P ro cedure for the S ynthe s is of B ifunctional L igands To a 5.0 mL flame dried Schlenk flask, i Pr a za bis(oxazoline) 2 1 (0.65 mmol in 1.3 mL THF) and 3 mg of KI were added. Under argon atmosphere, THF (6.0 mL) was added and the reaction mixture was cooled to 78 C for 10 min. Then n BuLi ( 2.5 M in n hexane, 0.73 mmol) was slowly added into the reaction flask and the r eaction mixture was kept at 78 C for another 10 min. 1 (3 ( B romomethyl)benzyl) 4 ethylpiperazine 2 3 a (265 mg, 0.89 mmol) in THF (2.0 mL) was slowly added into the rea ction flask at 78 C. The cold bath was removed and the flask was slowly warmed to room temperature or 40 C as indicated in the main text, Table 2 2 The r eaction proceeded for another 24 h at this temperature. The r eaction mixture was purified by flash co lumn chromatography on basic alumina ( n hexane/EtOAc 9:1) to give compound 2 4a (192 mg, 65%) as a yellow oil.

PAGE 111

111 ( S ) N (3 ((4 Ethylpiperazin 1 yl)methyl)benzyl) 4 isopropyl N (( S ) 4 isopropyl 4,5 dihydrooxazol 2 yl) 4,5 d ihydrooxazol 2 amine 2 4a Yellow oil (192 mg, 65%). 1 H NMR (300 MHz, CDCl 3 ): ppm 7.06 7.39 (m, 4 H), 4.86 5.15 (m, 2 H), 4.28 4.42 (m, 2 H), 4.09 (t, J = 7.6 Hz, 2 H), 3.85 (dt, J = 9.1, 6. 5 Hz, 2 H), 3.46 (s, 2 H), 2.30 2.60 (m, 10 H), 1.57 1.76 (m, 2 H), 1.06 (t, J = 7.2 Hz, 3 H), 0.85 (d, J = 6.7 Hz, 6 H), 0.77 (d, J = 6.7 Hz, 6 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 157.4, 138.2, 137.7, 128.9, 128.3, 128.2, 126.6, 71.5, 70.1, 63.2, 53.3, 53.1, 53.1, 52.5, 33.0, 18.8, 17.9, 12.2; HRMS (ESI) calcd for C 26 H 4 2 N 5 O 2 [M+H] + : 456.3333. Found 456.3331; [ ] D 26 17.7 ( c 4.0, CHCl 3 ). (S) N (3 ((Diisopropylamino)methyl)benzyl) 4 isopropyl N ((S) 4 isopropyl 4,5 dihydrooxazol 2 yl) 4,5 dihydrooxazol 2 amine 2 4b Yellow oil (120 m g, 67%). 1 H NMR (300 MHz, CDCl 3 ): ppm 7.11 7.41 (m, 4 H), 5.03 (d, J = 12.2 Hz, 2 H), 4.35 (dd, J = 9.2, 8.4 Hz, 2 H), 4.10 (dd, J = 8.2, 6.8 Hz, 2 H), 3.86 (d, J = 8.8 Hz, 2 H), 3.59 (s, 2 H), 2.93 3.05 (m, 2 H), 1.61 1.74 (m, 2 H), 1.00 (d, J = 6.6 Hz, 12 H), 0.85 (d, J = 6.8 Hz, 6 H), 0.78 (d, J = 6.5 Hz, 6 H); 13 C NMR (75 MHz, CDCl 3 ): ppm 157.4, 143.3, 137.4, 128.0, 127.4, 126.9, 125.7, 71.5, 70.1, 53.2, 49.1, 47.9, 33.0, 21.1, 21.0, 18.9, 17.9; HRMS (ESI) calcd for C 26 H 4 3 N 4 O 2 [M+H] + : 443.3381. Foun d 443.3403; [ ] D 26 10.8 ( c 0.5, CHCl 3 ).

PAGE 112

112 (S) N (3 ((2 ( D iisopropylamino)ethoxy)methyl)benzyl) 4 isopropyl N ((S) 4 isopropyl 4,5 dihydrooxazol 2 yl) 4,5 dihydrooxazol 2 amine 2 4c Prepared according to the general proc edure except that after column, pentane was used to precipitate out remained impurities. Colorless oil (199 mg, 76%). 1 H NMR (300 MHz, CDCl 3 ): ppm 7.17 7.45 (m, 4 H), 4.96 5.17 (m, 2 H), 4.50 (s, 2 H), 4.37 (t, J = 8.8 Hz, 2 H), 4.07 4.16 (m, 2 H), 3.85 3 .93 (m, 2 H), 3.43 (t, J = 7.5 Hz, 2 H), 2.95 3.05 (m, 2 H), 2.62 2.70 (m, 2 H), 1.66 1.73 (m, 2 H), 1.01 (d, J = 6.6 Hz, 12 H), 0.88 (d, J = 6.7 Hz, 6 H), 0.81 ppm (d, J = 6.9 Hz, 6 H); 13 C NMR (125 MHz, CDCl 3 ): ppm 157.4, 138.7, 137.9, 128.4, 127.4, 12 7.2, 126.6, 73.4, 72.3, 71.6, 70.1, 53.1, 49.7, 45.1, 33.0, 21.0, 18.8, 17.9; HRMS (ESI) calcd for C 28 H 4 6 N 4 Na O 3 [M+Na] + : 509.3462. Found 509.3446 ; D 21 14.9 ( c 2.05, CHCl 3 ). General Procedure for Kinetic S tudy of B ase 2 14 (Table 2 11 Table 2 15) To a 3 .0 mL vial with a sealed cap ligand 2 9 (2 00 0.05M in CH 2 Cl 2 0.01 mmol ), CuTC ( 1.9 mg 0.01 mmol) and EtOH ( 74 0 ) w ere added. The mixture was stirred for 1 h at room temperature for the formation of the complex Then 2 methoxybenzaldehyde (68 m g 0.5 mmol), nitromethane ( 54 1 .0 mmol) and 1 bromonaphthalene ( ) as an internal standard were added and the reaction mixture was cooled down to 20 C for 10 min. The reaction was triggered by an injection of 10 150 of 1 benzyl 4 ethylpiperaz ine 2 14 (1 .0 M in DCM 0.01 mmol ) accordingly The which was filtered

PAGE 113

113 through silica gel with 10% CH 2 Cl 2 in n h exane as the eluent, and analyzed by HPLC (Chiralpak IB column, 9 5 : 5 n hexane:i sopropanol, 0.8 mL/min, 215 nm, 1 b romonaphthalene: 4. 9 min, 2 methoxybenzaldehyde : 7.9 min) for the first 40 6 0% conversion of the reaction. The slopes of the least square lines for the plots of Ln([SM] t /[SM] 0 ) vs. time were determined All kinetic react ions were quenched after 24 hours and gave 90 94% ee. Kinetic C omparison between B ifunctional C atalyst and N on F unctional C atalyst ( for Figure 2 1 3 ) Figure 2 1 6 Reaction rate comparison bet w een 2 4a vs 2 9 and 2 14 To a 3 .0 mL vial with a sealed cap ligand 2 4a (2 00 0.05M in CH 2 Cl 2 0.01 mmol ), CuTC ( 1.9 mg 0.01 mmol) and EtOH ( 75 0 ) w ere added (Figure 1 12) The mixture was pre mixed for 1 h at room temperature for the complex formation. Then 2 methoxy benzalde hyde (68 mg 0.5 mmol) and 1 bromonaphthalene ( 30 .0 ) as an internal standard were added and the reaction mixture was cooled down to 20 C for 10 min. The reaction was triggered by injection of nitromethane ( 54 1 .0 mmol). The reaction progress was mo which was filtered through silica gel with 10% CH 2 Cl 2 in n h exane as the eluent, and analyzed by HPLC (Chiralpak IB column, 9 5 :5 n hexane:isopropanol, 0.8 mL/min, 215 nm, 1 b romonaphthalene: 4. 9 min, 2 methoxybenzald ehyde : 7.9 min) for the first 40 70% conversion of the reaction. The slopes of the least square lines for the plots of Ln([SM] t /[SM] 0 ) vs time were determined

PAGE 114

114 Table 2 2 5 Kinetic data for 2 mol% l oading of b ifunctional c atalyst 2 4a [ 0.0095 M] Time (h) A rea (%) Parameter ( B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 48.8 51.2 1.049 0 0 0. 6 51.0 49.0 0.961 8.4 0.0877 1.1 53.4 46.6 0.872 16.9 0.187 1.7 55.2 44.8 0.813 22.5 0.255 2. 3 56.9 43.1 0.759 27.6 0.323 2. 8 57.1 42.9 0.750 28.5 0.335 3. 4 58.4 41.6 0.713 32 .0 0.386 3.9 60.0 40.0 0.667 36.4 0.453 4.4 61.8 38.2 0.618 41.1 0.529 5.7 63.3 36.7 0.581 44.6 0.616 6.9 66.7 33.3 0.499 52.4 0.742 7.9 69.2 30.8 0.445 57.6 0.858 8.8 71.3 28.7 0.402 61.7 0.96 0

PAGE 115

115 CHAP TER 3 UREA ( SALEN ) CO BALT BIFUNCTIONAL CATALYST FOR ANTI SELECTIVE ASYMMETRIC HENRY REACTION S Backgrou n d and I ntroduction The asymmetric catal ysis using synergistic dual activation has emerged as a powerful strateg y for highly efficient synthetic transform ations. 37 For the reactions where two metal centers are simultaneously involved in the mechanism, bimetallic catalysts are more capable t han the monometallic catalysts. Similarly, for the reactions wh ich benefit from the transition state through the coopera tive activation the catalysts with two complementary functional groups are expected to work better than the catalysts with mono active site To date, there are excellent examples for b oth highly effective dual activation bimetallic catalysts (Figure 3 1 A ) 4 d 5 a 6 c 7a and bifunctional catalysts (Figure 3 1 B and Figure 3 1 C ). 10a, 10 d, 10 g, 10 h, 11 h, 12 a 12 c, 12 k 12n,12j,13a, 16 c, 38 Figure 3 1. Dual activation catalysts

PAGE 116

116 To design such cooperative catalysts, it is essential to dev ise the scaffold with decent rigid ity and reasonable geometry to facilitate the more selective intramolecular dual activation pathway between two active sites and suppress the less selective intermolecular activation pathway. In order to maintain the high catalytic activity, the two active sites need to be compatible and complementary to each other Currently, bifunctional catalysts usually feature with Lewis acid/base or hydrogen bond donor/base system (Figure 3 1B and Figure 3 1C). However, the strategy o f incorporating Lewis acid/H bond donor in to a single catalyst is not reported to the best of our knowledge 39 Therefore, we envisioned that by tethering H bond donor site to the chiral Lewis acid, due to the proximity, the novel mode of cooperative activa tion would be realized taking advantage of the molecular recognition and activation ability from H bond donors such as ureas or thioureas As a continuation of our research program to explore the cooperative activation catalysts, we previously developed new catalyst designs for asymmetric Henry reactions such as bifunctional, b ase tethered aza bis (oxazoline) Cu catalysts (Chapter 2) 22 a and self assembling ( salen ) Co catalyst s through 2 pyridone/aminopyridine hydrogen bonding 8 a Recently, modification o f such self assembling (salen) Co catalyst with urea urea hydrogen bonding resulted in significant rate acceleration (up to 13 times) in the hydrolytic kinetic resolution of epoxides, probably through facilitating bimetallic pathway (Figure 3 2 A ) 22 b Howev er, as can be seen in many organocatalysts, the (thio)urea functional groups are able to activate carbonyl groups or recognize nitronate anions through double hydrogen bonds. 40 41 Thus, we were intrigued by the idea that this bis urea salen scaffold could o ffer a cooperative activation of both a nitronate and

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117 an aldehyde through urea hydrogen bonding and metal coordination for the anti selectivity (Figure 3 2 B). 42 Figure 3 2 Dual activation catalyst developed for h ydrolyti c k inetic r esolution of e poxides and asymmetric Henry reaction s R esults and D iscussion Ligand S tructure S urvey Based on our previous work 22 a, 22 b and our hypothesis that the catalyst geometry and urea nature may affect the catalytic activity, a group of ur ea (salen) Co catalysts bearing different linkers and ureas were prepared for the asymmetric Henry reaction study (Table 3 1). The urea moieties turned out to be crucial for improving the yield and enantioselectivity. Without urea functionality, s imple (s alen) Co 3 3 a gave 12% yield and 57% ee for this reaction (entry 1), whereas the mono urea (salen) Co 3 3 b catalyzed this reaction with 99% yield and 65% ee (entry 2), and the corresponding bis urea catalyst 3 3c gave 99% yield and 76% ee (entry 3). The ef fects from the substituent groups on the urea aromatic rings are also significant (entries 3 6). Compared with electron neutral phenyl urea (entry 4), both 4 MeO and 4 Cl phenyl urea 6). 3,5 B is(trifluoromethyl)pheny l urea gave the highest yield and enantioselectivity (entry 3) and therefore was attached to more rigid or

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118 extended linkers to test geometry effect s (entries 7 9). However, none of these structure modifications gave better results (entries 7 9 vs entry 3). Table 3 1. Screening of u rea m oieties and l inkers a All reactions were performed on a 0.25 mmol scale of aldehyde using 2 mol% of cobalt catalyst, 2 mol% of i Pr 2 NEt, and 10 equiv of nit romethane in 1.0 mL of CH 2 Cl 2 at 30 C for 90 h. b Isolated yield. c Determined by HPLC using a Chiralpak IB column. d The S chirality of product was determined by comparison of the retention time with the literature data (See experimental section). A low er temperature general ly improve s the stereoselectivity u nless mechanism changes or there are solubility issues O ur previous study showed that addition of more base increase d the rate of the Henry reaction. 22 a Therefore, the reaction temperature was decre 50 C and 1 equiv of i Pr 2 NEt was used for further screening (Table 3 2). In the absence of urea, simple (salen) Co 3 3 a gave 24% yield and 20% ee under

PAGE 119

119 this condition (entry 1) while mono urea (salen)Co 3 3 b gave a high yield of 99% and a high ee of 89% (entry 2). B is urea catalyst 3 3 c gave 90% ee and showed a faster reaction rate than mono urea (salen) Co 3 3 b (entry 4). The reaction was completed within 6 hours using bis urea catalyst 3 3 c whereas there was still unreacted aldehyde 3 1a remainin g even after 16 hours using mon o urea catalyst 3 3b Table 3 2. Catalyst s urvey under f urther o ptimized r eaction c onditions a All reactions were performed on a 0.25 mmol scale of aldehyde using 2 mol % of cobalt catalyst, 1 equiv of i Pr 2 NEt, and 10 equiv of nitromethane in 0.25 mL of CH 2 Cl 2 at 50 C for 24 h. b Isolated yield. c Determined by HPLC using a Chiralpak IB column. d Reaction finished within 6 hours by HPLC monitor. In the absence of (salen) Co, urea 3 4 alone a lso promoted the reaction in 88% yield at 50 C ( Table 3 2, entry 3) To figure out if the cobalt metal center is involved in the catalysis, the metal free bis urea salen 3 3 j was test ed. In this case, 18% ee and

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120 99% yield w ere obtained (entry 5), suggesting an important role of cobalt center F ro m the catalyst geometry survey, the methylene linker proved to be the best in terms of yield and enantioselectivity (entry 4 vs entries 6 8). Therefore, catalyst 3 3 c was chosen for further study. Diastereoselective Henry R eaction Our next goal is to explo re the diastereoselective Henry reactions using catalyst 3 3c A lthough the asymmetric Henry reactions using nitroalkanes other than nitromethane are highly valuable, examples of high ly di a stereoselective nitroaldol reactions were relatively rare 43 Particu larly, d evelopment of catalytic systems showing good anti selectiv ity is very challenging 44 The difficulty can be attributed to the fact that a close d chelation model generally prefers syn diastereoselectivity (Figure 3 3 A) 19 g A strategy involving an ope n transition state using silyl nitronates was first introduced by Seebach group for highly anti selective racemic Henry reactions. 44 a Maruoka and Jrgensen groups then applied these silyl nitronates to catalytic asymmetric Henry reactions with good anti di astereoselectivity. 44 b c Later, the research groups of Shibasaki and Ooi independently developed highly anti selective asymmetric Henry reactions using nitroalkane directly Figure 3 3B shows their strategies to stabilize the desired anti periplanar open t ransition state using a heterobimetallic catalyst (Shibasaki) 19 g or a double hydrogen bonding organocatalyst (Ooi). 44 d We envisioned that this bis urea functionalized ( salen )Co 3 3c could facilitate a bimetallic pathway just as it promoted HKR (Figure 3 3 c, S1 ) 22 b or an intramolecular dual activation pathway involving a urea and a Lewis acid Figure 3 3 C S2 ).

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121 Figure 3 3 Strategies for syn or anti diastereoselective Henry reaction Cat alyst 3 3c was evaluated for the diastereoselective Henry reaction between 2 methoxy benzaldehyde 3 1a and nitroethane under the condition s optimized in T able 3 2 (2 mol% of 3 3c 1 equiv of i Pr 2 NEt at 50 C). A promising dr of 4.5 : 1 ( anti : syn ) was obtained, albeit with frustrating % ee o f 34/32 ( anti / syn ). B y lowering the temperature 70 C and using 5 mol% of catalyst, t he ee of anti product was improved to 53% (Table 3 3, entry 1). Cobalt metal o xidation state proved to be pivotal, and Co(III) catalyst (X= OTs) significantly improved the reaction yield, an anti : syn diastereomeric ratio, and the enantioselectivity (entry 2 vs entry 1 ). The reaction conditions were then further optimized in terms of solvent, and base. Better anti selectivity was observed in

PAGE 122

122 MTBE (methyl t butyl ether) than in CH 2 Cl 2 (entries 3,5,7 vs entries 2,4,6). N Ethylpiperidine (EtPip) was more effective than other tertiary amines, giving higher anti selectivity (entries 6 7 v s entries 2 4). Table 3 3. Base, s olvent and c ounter i on s urvey for the d iastereoselective Henry r eaction E ntry a X B ase S olvent Y ield b (%) D r c ( a nti : syn ) % E e d ( anti / syn ) 1 i Pr 2 NEt CH 2 Cl 2 49 4 : 1 53/18 2 TsO i Pr 2 NEt CH 2 Cl 2 71 8: 1 92/59 3 TsO i Pr 2 NEt MTBE 68 11: 1 87/58 4 TsO Et 3 N CH 2 Cl 2 88 13: 1 90/59 5 TsO Et 3 N MTBE 82 18: 1 93/73 6 TsO EtPip CH 2 Cl 2 83 24: 1 95/82 7 TsO EtPip MTBE 81 >50: 1 93/ND a All reactions were performed on a 0.25 mmol scale of aldeh yde using 5 mol % of 3 3cX and 10 equiv of nitroethane in 0.1 mL of solvent at 70 C. b Isolated yields. c Determined by 1 H NMR analysis. d The w ere determined by chiral HPLC analysis using ( S S ) Whelk O1 column. MTBE: Methyl t butyl ether. EtPip: N Ethylpiperidine. The counter ion was also optimized Although the tosylate anion gave excellent diastereoselectivity for 2 methoxy benzaldehyde 3 1a (Table 3 3, entry 7), it only gave 2 : 1 dr for the reaction of 4 fluorobenzaldehyde 3 1b (Table 3 4, entry 1). The counter ions affected both the yield and stereoselectivity ( Table 3 4, entries 1 6). 3,5 B is(trifluoromethyl)benzoate (Ar F CO 2 ) wa s chosen as the optimal counter ion [ 98% ee for anti 2.5 : 1 ( anti : syn ), entry 5] This was further justified by the rea ction of 2 methoxy benzaldehyde 3 1a in the presence of 3 3cO 2 CAr F which gave an excellent dr of 48 : 1 ( anti : syn ) and 96% ee for anti product ( Table 3 4, entry 6).

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123 Table 3 4. Counter i on o ptimization for d iastereoselective Henry r eactions E ntry a 3 1 X T (h) Y ield b (%) D r c ( a nti : syn ) % E e d ( anti / syn ) 1 3 1b T s O 24 87 2 : 1 95/79 2 3 1b DNB 16 92 1.9 : 1 97/87 3 3 1b C 6 F 5 CO 2 18 86 2.2 : 1 97/82 4 3 1b CF 3 COO 18 68 1.9: 1 97/84 5 3 1b Ar F CO 2 18 87 2.5: 1 98/85 6 3 1a Ar F CO 2 24 84 48: 1 96/ND a All reactions were performed on a 0.25 mmol scale of aldehyde using 5 mol % of 3 3cX and 10 equiv of nitroeth ane in 0.1 mL of solvent at 70 C. b Isolated yields. c Determined by 1 H NMR analysis. d were determined by chiral HPLC analysis using ( S S ) Whelk O1 column. DNB: 3,5 dinitrobenzoate. MTBE: methyl t butyl ether. EtPip: N Ethylpiperidine. Ar F : 3,5 bis(trifluoromethyl) phenyl. Ligand S tructure S urvey under F inal O ptimized C onditions Various catalyst analogues featuring different linker geometry and urea electronic nature were evaluated once again under the newly optimized Co(III) conditions. Changing the linker geometry led to the different yields and stereoselectivities ( Table 3 5, entries 2 4). 1,2 D isubstituted ben zene spacer gave a good yield ( 75% ) and high dr (16: 1 anti : syn ) albeit with a poor ee ( 26% ee for anti ) (entry 4). 1,3 D isubstituted benzene spacer gave a good ee ( 90% ) a moderate dr of (6: 1 ) and a poor yield ( 35% ) (entry 3). The methylene spacer brings not only the best yield but also the best stereosele c tivity (entry 1). Substituent effects on the urea aromatic ring were studied (Table 3 5) P entafluoro phenyl catalyst 3 3p O 2 Ar F failed to promote this reaction, which is probably caused by the poor sol ubility (entry 8). Both electron rich and electron deficient rings worked better than electron neutral ring s in terms of yield and stereoselectivity (entries 5 6 vs entry 7). 4 ( T rifluoromethyl) phenyl showed the second best result in terms of yield, dr and ee (entry 6). Overall, the trend in Table 3 5 was similar to that in Table 3 1.

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124 Table 3 5. C atalyst s tructure s urvey under the f inal o ptimized c ondition s a All reactions were performed on a 0.25 mmol scale of aldehyde usi ng 5 mol % of cobalt catalyst and 10 equiv of nitroethane in 0.1 mL of MTBE at 70 C. b Isolated yields. c Determined by 1 H NMR analysis. d w ere determined by chiral HPLC analysis using ( S S ) Whelk O1 Enantioselective Henry R eaction Under the o ptimized conditions, n itr omethane Henry reactions exhibited very high enantioselectivity (91 97% ee) over a wide range of aldehyde substrates (Table 3 6 ). Excellent ee values (94 97% ee) were observed with variously substituted benzaldehydes, including ort ho (compounds 3 1 a 3 1 c 3 1 d 3 1 e 3 1 f ), meta ( 3 1 g ), para substituted ( 3 1 b 3 1 h 3 1 i 3 1 j ) and unsubstituted benzaldehyde ( 3 1 k ). It is worth mentioning that the electron rich benzaldehyde s such as 3 1 a 3 1 c and 3 1 j reacted smoothly with nitr omethane under the current condition s Furthermore, high

PAGE 125

125 enantioselectivity (91 92% ee) and good yield (88 90%) were also observed with linear aliphatic aldehydes ( 3 1 l 3 1 m unsaturated aldehyde ( 3 1 n ). Table 3 6. Enantioselective Henry r eact ions ( r eaction s cope)

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126 Table 3 6. C ontinued a All reactions were performed on a 0.25 mmol scale of aldehyde using 5 mol % of 3 3cO 2 CAr F and 10 equiv o f nitromethane in 0.3 mL of CH 2 Cl 2 C. Diastereoselective Henry R eaction Substrate scope was s tudied for diastereoselective Henry reactions (Table 3 7 ). High enantioselectivity w as observed in all cases (90 98% ee for anti ). However, the anti diastereoselectivity varies depending on the substrates Good to excellent anti selectivities were obtained with benza ldehydes with an ortho substitu ent such as methoxy (compounds 3 5aa 3 5ab ), benzyloxy ( 3 5oa ), allyloxy ( 3 5ra ) and halide functionality (compounds 3 5ea 3 5fa ). The reactio n with TBSO substituted nitroethane ( 3 6 b ) proceeded well with excellent stereoselectivit y, albeit the slower rate in some cases (compounds 3 5ab 3 5sb and 3 5tb ). High anti selectivities (> 8 : 1) were also observed with o,p or o,m disubstituted benzaldeh ydes ( compounds 3 5pa 3 5qa 3

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127 5ra 3 5sa 3 5ca 3 5ta ). However, anti selectivity significantly decreases with benzaldehydes lacking ortho substitution (~2 : 1 dr, compounds 3 5ka 3 5ba ). It is interesting to note that bulky aliphatic aldehyde, 3 methyl 2 butenal gave 9 : 1 ( anti : syn ) selectivity ( 3 5va ) while linear aliphatic aldehyde 3 1l generated an almost equal mixture of diastereomers ( 3 5la ). Current method works for highly electron rich aldehydes as well. For example, reaction with 2,5 dimethoxybenz aldehyde gave 99% yield and 96% ee for anti with 24 : 1 ( anti : syn ) selectivity after 16 hours ( 3 5ta 1 ). Bulky and electron rich 2 methoxy 1 naphthaldehyde also gave excellent result (97% ee for anti 17 : 1 ( anti : syn ) 3 5ua ). Table 3 7. Diastereoselective H enry r eactions ( r eaction s cope)

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128 Table 3 7. C ontinued

PAGE 129

129 Table 3 7. C ontinued a For the reaction involving nitroethane 3 6a : All reactions were performed on a 0.25 mmol scale of aldehyde using 5 mol % of 3 3cO 2 CAr F and 10 equiv of nitroethane in 0.1 mL of MTBE. b For the reaction involving 3 6b (TBSOCH 2 CH 2 NO 2 ): 5 equiv of 3 6b and 0.5 mL of MTBE were used. c Isolated yields. d Determined by 1 H NMR analysis. e S S ) Whelk O1 column. f The absolute configuration of the product was determined by comparison with the literature data (See experimental section) Ar F : 3,5 bis(trifluoromethyl)phenyl, TBS: t butyl dimethylsilyl. To demonstrate the synthetic utility, this catalyst was applied to the efficient synthesis of L erythro methoxamine h ydrochloride 1 adrenergic receptor agonist 45 Following the standard procedure, 2,5 d imethoxybenzaldehyde reacted with nitroethane in the present of 5 mol% ent 3 3cO 2 Ar F the ( S S ) enantiomer of catalyst 3 3cO 2 Ar F at 50 C (Scheme 3 1). After 1 6 hours, this reaction gave 99% conversion. A purification by chromatography on silica gel to get rid of syn isomer gave 91% is olated yield for the anti isomer in 94% ee. Treatment of this nitro alcohol 3 5ta 2 with 10 w% Pd/C and H 2

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130 followed by treatment with HCl gave ( 1 R 2 S ) methoxamine hydrochloride 3 7ta 2 (82% yield and 98% ee for 2 steps after rec r ystallizat i on). Orth o substituent groups such as methoxy are important to achieve high anti diastereoselectivity. Application of this type of substrates was demonstrated by the synthesis of methoxamine. The next goal is to explore the possibility of removing methoxy group by nickel catalysts Methoxy group s are generally inert for transition metal cataly zed oxidative addition process. R ecently, nickel catalyzed demethoxylations were reported by the research groups of Tobisu 46 a Martin 46 b and Hartwig 46 c However, the limitation is obvious: i n the cases reported by Tobisu and Martin, the directing groups such as pyridine, oxazolines, pyrazoles or ester are essential for successfully removing the methoxy group from carbene (SIPr) compl ex, except aryl or alkyl ethers, no other functional groups are present in the reported substrates Therefore, it is worthw h ile to test the feasibility of these methodologies in the presence of more complicated substrates without directing groups. Carbamat e 3 7aa 1 oxazolidine 3 7aa 3 were synthesized and tested under the desired demethoxylation product (Scheme 3 2). Study towards this goal will be an interesting topic in the fu ture Scheme 3 1 Expedited s ynthesis of m ethoxamine

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13 1 Scheme 3 2 Attempted cleavage of methoxy group on aromatic ring through nickel chemistry Mechanism S tudy Discussion on M on ometallic vs B imetallic P athway Based on our hypothesis this bis urea (salen) Co is able to promote the Henry reaction through either a bimetallic pathway (Figure 3 3 S1 ) or an intramolecular bifunctional pathway (Figure 3 3 S2 ). From the facts that both mon o urea and bis urea (salen) Co worked better than unfunctionalized (salen) Co (Table 3 1, entries 2 3 vs entry 1; Table 3 2, entries 2, 4 vs entry 1), th e bis urea catalyst worked more efficient ly than the mon o urea catalyst (Table 3 1, entry 3 vs entry 2; Table 3 2, entry 4 vs entry 2), and the electronic properties of the urea affected the yields and stereoselectivities (Table 3 1, entries 2 6) U rea arms definitely play a crucial role in the mechanism. However, this information only is not enough to an swer our question: Do the urea moieties act as the simple hydrogen bond scaffold which enables the catalysts to self assemble into the more active dimeric species or as an additional activating group for the reaction partner? Nonlinear E ffect To gain insi ghts into the mechanism of this urea (salen)Co catalyst, a nonlinear effect study was conducted. The catalyst 3 3c O 2 Ar F enantiomeric excess vs the

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132 product enantiomeric excess w as plotted. A linear relationship was observed (Figure 3 4), which suggested a monomeric catalyst model. Figure 3 4. Nonlinear effect study Kinetic S tud ies To further elucidate the mechanism, kinetic studies were conducted The rate of the reaction 3 1 a 3 2 a was found to be first order with resp ect to [catalyst] (rate [ 3 3c O 2 CAr F ]). This is different from the hydrolytic kinetic resolution of epoxides, where the rate is second order dependent on [catalyst] (rate [ bis urea salen( C o) ] 2 ). 22 b Therefore, the first order kinetic s observed may sugge st the mechanis tic scenario 2 where monomeric catalyst is involved in the transition state (Figure 3 3 S2 ). However, the se observations still cannot rule out possible bimetallic mechanisms: 1) The self assembly of dimeric catalyst prevails and never diss ociates, which w ould display a first order kinetic on catalyst concentration ; 2) if the reaction is promoted by tightly bo und dim er catalyst, and the hetero dimer ( R R ) + ( S S ) showed similar catalytic activity as homo dimer ( S S ) + ( S S ) or ( R R ) + ( R R ), an absence of NLE w ould be observed One direct way to address this concern is to figure out the s elf association strength of bis urea salen catalyst. The attempts for this were unsuccessful due to solubility and

PAGE 133

133 paramagnetic impurity issues Alternativel y, this question can be addressed by studying the effect of urea additives Figure 3 5. Kinetic study Control E xperiment s The control experiment began with the study of unfunctionalized (salen) Co 3 3a O 2 CAr F which gave a poor yield ( 30% ) and a poor dr (3: 1 anti : syn ) with 78% ee (Table 3 8, entry 1). Addition of 10 mol% urea 3 4 improved the yield from 30% to 75% and the dr from 3 : 1 to 5 : 1 with slight decrease in enantioselectivity (entry 3 vs entry 1 ). A further yield improvement was obtained when using 50 mol% of urea (entry 4). These observations together with the results in T able 2 entries 1 and 3 suggested a urea cobalt cooperative activation based on the following reasoning: 1) If the urea worke d only as the linker for the formation of more active dimeric catalyst, the addition of exogenous urea would lead to either no difference in conversion of Henry reaction product or a reduced rate by inhibit ing t he reactive dim er formation Alternatively, u rea may compete with substrates for binding to the metal center. 2) Instead of simply promoting the undesired background racemic reaction, urea 3 4 maybe cooperate with 3 3a O 2 CAr F for the catalysis because the yield was doubled (from 30% to 75%) without dramatic loss of ee. More interestingly, mon o urea (salen)Co 3 3b O 2 CAr F

PAGE 134

134 gave 73% yield and 8 : 1 dr with 82% ee ( anti ) and was less efficient than bis urea (salen)Co 3 3 c O 2 CAr F (entry 2 vs entry 5). This could be explained by the bimetallic mechanism in w hich case mono urea (salen)Co did not self assemble as efficiently as bis urea(salen)Co. Another possibility for the low stereoselectivity by 3 3b O 2 CAr F is that the undesi red interaction between counter ion (Ar F CO 2 ) and mono urea decrease the availability of urea with free hydrog en bonds and therefore reduce the catalytic activity of urea for the urea cobalt cooperative mechanism However, this might require further evidence to prove it Table 3 8. Control e xperiments ( h ydrogen b ond e ffect) a All reactions were performed on a 0.25 mmol scale of aldehyde using 5 mol % of cobalt catalyst and 10 equiv of nitro ethane in 0.1 mL of MTBE at 70 C. b Isolated yields. c Determined by 1 H NMR analysis. d chiral HPLC analysis using ( S S ) Whelk O1

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135 The urea N H moiety proved to be crucial for both reaction rate and stereoselectivity, as the N methyl catalyst ( 3 3 q O 2 CAr F ) gave nitroaldol product 3 5aa in much lower yield and stereoselectivity (Table 3 8, en try 6) compared to N H urea catalyst 3 3 2 CAr F (entry 5). These results suggested the importance of urea hydrogen bond functionality. Proposed T ransition S tate Based on our control experiment s nonlinear effect study and kinetic stud ies a urea cobalt cooperative model is proposed as follows ( Figure 3 6 ) According to this model, this bis urea (salen)Co catalyst possessed two active sites for asymmetric Henry reaction. Cobalt (III) center is believed to activate carbonyl group which brings excellent ee for generated alcohol chiral center. Urea moieties are able to: 1) activate the incoming nitroethane for base deprotonation, 2) stabilize the nitronate ion, and direct nitronate to the position for the best enantio and diastereosele c tivity Meanwhile, the interaction mode between the substrates and active sites might be different from the a forementioned scenario, i.e. the urea moiety interacts with carbonyl group and the cobalt center stabilizes the nitronate ion. Figure 3 6. Dual a ctivation w orking m odel

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136 Conclusion I n conc l usion, novel urea (salen)cobalt bifunctional catalyst has been developed for highly enantioselective and anti diastereoselective Henry reactions. Applying urea salen ligands to other asymmetric catalysi s to explore the concept of cooperative activation by Lewis acid and hydrogen bonds is an int eresting topic in the future Experimental Section General R emarks All the reactions for ligand synthesis were conducted in flame dried glassware under an inert at mosphere of dry argon. THF, CH 2 Cl 2 and Et 2 O were passed through two packed columns of neutral alumina under positive pressure prior to use. T he Henry reactions were run under air atmosphere. NMR spectra were recorded using a FT NMR machine operating at 5 00 MHz or 300 MHz for 1 H NMR and at 126 MHz or 75 MHz for 13 C NMR. All chemical shifts for 1 H and 13 C NMR spectroscopy were referenced to residual signals from CDCl 3 ( 1 H) 7.26 ppm and ( 13 C) 77.23 ppm or DMSO d 6 ( 1 H) 2.50 ppm and ( 13 C) 39.5 ppm. High resolu tion mass spectra were recorded on a MALDI TOF spectrometer an APCI TOF spectrometer, a DART spectrometer or an ESI TOF spectrometer Enantiomer ic excesses were determined by chiral HPLC analysis (Shimadzu) using Chiralpak IB and I A columns and a ( S S ) Wh elk O 1 column. Unless specified, all starting materials were purchased from Sigma Aldrich Co ., and Acros Organics and were used as received without further purification. 3 tert Butyl 2 hydroxy 5 iodobenzaldehyde 47 a 4 b romo 2 tert butyl pheno l, 47 b and 5 (az idomethyl) 3 tert butyl 2 hydro xybenzaldehyde 22 b were prepared according to the literature procedure. For the detailed synthesis procedure and characterization for the following known catalyst s, please see our recent report (Figure 3 7) 22 b

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137 Ligand and C at alyst P reparation Figure 3 7. Known ligand s reported by our previous study 1 (3,5 B is(trifluoromethyl)phenyl) 3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea 3 8c. This reaction was carri ed out according to our previous report 22 b To a solution of 5 (azidomethyl) 3 tert butyl 2 hydroxybenzaldehyde (2.50 g, 10.70 mmol) in ethyl acetate (50 mL), 3,5 b is(trifluoromethyl)phenyl isocyanate (1.2 mL, 10.70 mmol, 1.05 equiv) was added. After addit ion of Pd C (10 wt %, ~250 mg), the mixture was allowed to stir overnight under 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 pu rified by column chromatography on silica gel ( n hexane:EtOAc 2:1) to give 1 (3,5 b is(trifluoromethyl)phenyl) 3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea 3 8c (3.20 g, 65%) as a white powder. 1 H NMR ( 500 MHz, DMSO d 6 ): ppm 11. 75 (s, 1 H) 9.96 (s, 1 H) 9.36 (s, 1 H), 8.09 (s, 2 H), 7.5 3 7.5 4 (m, 3 H), 7.03 (t, J = 5.7 Hz, 1 H), 4.29 (d, J = 5.9 Hz, 2 H), 1.36 (s, 9 H); 13 C NMR ( 126 MHz, DMSO d 6 ): ppm 199.3, 159.6, 155.5, 143.3, 137.9, 134.1, 131.9, 131.7,

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138 131.3 (q, J = 32 Hz), 131.2, 124.1 (q, J = 271 Hz), 121.1, 118.1, 42.9, 35.1, 29.7; HRMS (ESI TOF) Calcd. for C 21 H 2 4 F 6 N 3 O 3 [M +NH 4 ] + : 480.1716 Found: 480.1743. 1 (3,5 B is(trifluoromethyl)phenyl) 3 (3' tert butyl 5' formyl 4' hydr oxybiphenyl 4 yl)urea 3 8g. A stirred mixture of urea functionalized boronic acid pinacol ester 3 12g (253 mg, 0.53 mmol), 3 tert butyl 2 hydroxy 5 iodobenzaldehyde (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 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 reduce d pressure, then the residue was purified by column chromatography on silica gel (10%, then 33% ethyl acetate in n hexane) to give the resulting salicylaldehydes 3 8g as a yellow solid (169 mg, 60%). 1 H NMR (300 MHz, DMSO d 6 ): ppm 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 ): ppm 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) Calcd. for C 26 H 2 3 F 6 N 2 O 3 [M +H ] + : 525.1607 Found: 525.1613.

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139 1 (3,5 Bis(trifluoromethyl)phenyl) 3 (4 ((3 tert butyl 5 formyl 4 hydroxyphenyl) ethynyl)phenyl)urea 3 8h. To a 10 mL flame dried Schlenk flask, 1 (3,5 bis(trifluoro methyl)phenyl) 3 (4 ethynylphenyl)urea 3 12h (400 mg, 1.08 mmol), 3 tert butyl 2 hydroxy 5 iodobenzaldehyde (386 mg, 1.08 mmol ), PdCl 2 (PPh 3 ) 2 (15 mg, 0.02 mmol), and CuI (8 mg, 0.04 mmol) were added. The mixture was degassed and backfilled with argon three times. Then 2 mL THF was added. The reaction was triggered by the addition of triethylamine (0.74 mL). The reaction mixture was stirred at room temperature for 24 h. Then the solvent was removed and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 9:1) to give the desired product 3 8h as a yellow powder (472 mg, 80%). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 11.97 (s, 1 H), 10.00 (s, 1 H), 9.47 (s, 1 H), 9.23 (s, 1 H), 8.15 (s, 2 H), 7.90 (d, J = 2.2 Hz, 1 H), 7.66 (s, 1 H), 7.63 (d, J = 2.2 Hz, 1 H ), 7.55 7.58 (m, 2 H), 7.49 7.52 (m, 2 H), 1.41 (s, 9 H); 13 C NMR (126 MHz, DMSO d 6 ): ppm 199.0, 160.6, 1 53.0, 142.4, 140.2, 138.8, 136.7, 136.0, 132.8, 131.4 (q, J = 32.8 Hz), 124.0 (q, J = 272.2 Hz), 121.6, 119.4, 118.8, 116.6, 115.3, 114.4, 89.1, 88.3, 35.3, 29.6; HRMS ( ESI ) Calcd. for C 28 H 22 F 6 N 2 O 3 Na [M + Na] + : 571.1427, Found: 571.1448

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140 1 (3,5 B is(trifluoromethyl)phenyl) 3 (4 (3 tert butyl 5 formyl 4 hydroxyphene thyl)phenyl)urea 3 8i The procedure was followed by the literature. 48 A solution of 1 (3,5 bis(trifluoromethyl)phenyl) 3 (4 ((3 tert butyl 5 formyl 4 hydroxypheny l)ethynyl)phenyl)urea 3 8h (465 mg, 0.85 mmol) in MeOH (14 mL) and EtOAc (14 mL) was degassed by bubbling argon through it for 5 min. Pd C (10 wt %, 47 mg) was added to the mixture. A balloon filled with hydrogen was attached and the mixture was briefly de gassed and backfilled with hydrogen three times. The reaction was stirred at room temperature for overnight. The mixture was filtered through Celite, and washed with CH 2 Cl 2 The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc) to g ive the desired product 3 8i as a white powder (422 mg 93%). 1 H NMR (300 MHz, DMSO d 6 ) : ppm 11.65 (s, 1 H), 9.91 (s, 1 H), 9.33 (s, 1 H), 8.86 (s, 1 H), 8.10 (s, 2 H), 7.59 (s, 1 H), 7.47 (d, J = 2.1 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 2 H), 7.26 (d, J = 2.1 Hz, 1 H), 7.11 (d, J = 8.5 Hz, 2 H), 2.82 (s, 4 H), 1.31 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) : ppm 199.2, 158.9, 153.1, 142.6, 137.6, 137.4, 136.1, 135.4, 133.0, 132.0, 131.4 (q, J = 32.3 Hz), 1 29.5, 124.0 (q, J = 272.3Hz), 121.1, 120.0, 118.6, 114.9, 37.1, 37.0, 35.0, 29.7; HRMS (ESI) Calcd. for C 28 H 2 6 F 6 N 2 O 3 Na [M + Na] + : 575.1740 Found: 575.1735

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141 1 (3,5 B is(trifluoromethyl)phenyl) 3 (3 (3 tert but yl 5 formyl 4 hydroxyphenyl)pro pyl)urea 3 8k To a solution of 5 (3 a zidopropyl) 3 tert butyl 2 hydroxybenzal dehyde 3 19k (100 mg, 0.68 mmol) in ethyl acetate (5 mL), 3,5 bis(trifluoromethyl) phenyl isocyanate (70 L 0.68 mmol) was added. Pd C (10 wt %, 10 mg), was added and the mixture was stirred overnight under hydrogen atmosphere. Then the reaction mixture was filtered through celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pr essure, and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 3/1) to give the resulting salicylaldehyde 3 8k as a white solid (293 mg, 88%). 1 H NMR (500 MHz, CD 3 OD d 4 ): ppm 9.86 (s, 1 H), 8.01 (s, 2 H), 7.46 7.50 (m, 1 H), 7 .44 (s, 1 H), 7.35 7.39 (m, 1 H), 3.2 5 3.28 ( m 2 H), 2.66 2.72 (m, 2 H), 1.84 1.92 (m, 2 H), 1.41 (s, 9 H) ; 13 C NMR (126 MHz CD 3 OD d 4 ): ppm 199.3, 160.4, 157.5, 143.6, 139.1, 135.9, 134.0, 133.3 (q, J = 32.8 Hz) 132.6, 125.0 (q, J = 273.4 Hz) 122.1, 119.1, 115.6, 40.5, 35.8, 33.3, 32.9, 29.9; HRMS (ESI) Calcd. for C 2 3 H 2 4 F 6 N 2 O 3 Na [M + Na ] + : 513.1583 Found: 513.1608 1 (3,5 B is(trifluoromethyl)phenyl) 3 (3' tert butyl 5' formyl 4' hydroxybiphenyl 3 yl)urea 3 8l. To a 25 mL Schlenk flask, 1 (3,5 bis(trifluoromethyl) phenyl) 3 (2 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)phenyl)urea 3 12l (500 mg,

PAGE 142

142 1.05 mmol), Pd(dppf)Cl 2 (40 mg, 0.05 mmol), Na 2 CO 3 (333 mg, 3.14 mmol) and 3 tert butyl 2 hydroxy 5 iodobenzaldehyde (320 mg, 1.05 mmol) were added under argon atmosphere. Then dimethoxyethane (2 mL), H 2 O (0.7 mL) were added. The reaction mixture was heated at reflux overnight. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (80 mL) three times. The combined organic layer was washed with saturated aq. Na 2 SO 3 solution and dried over anhydrous Na 2 SO 4 The solvent was removed and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 9/1) to give 3 8l as a white powder (313 mg, 60%). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 11.87 (s, 1 H), 10.09 (s, 1 H), 9.45 (s, 1 H), 9.09 (s, 1 H), 8.15 (s, 2 H), 7.93 (d, J = 2.1 Hz, 1 H), 7.77 (s, 2 H), 7.64 (s, 1 H), 7.31 7.50 (m, 3 H), 1.45 ppm (s, 9 H); 13 C NMR (126 MHz, DMSO d 6 ) : ppm 199.7, 160.2, 153.2, 142.6, 140.6, 140.4, 138.5, 132.2, 131.4 (q, J = 32.8 Hz), 131.0, 130.2, 124.0 (q, J = 273.4 Hz), 121.6, 121.4, 118.73, 118.71, 118.6, 117.5, 115.1, 35.3, 29.7; HRMS (ESI) Calcd. for C 26 H 22 F 6 N 2 O 3 Na [M+Na] + : 547.1427, Found: 54 7.1450. 1 (3,5 B is(trifluoromethyl)phenyl) 3 (3' tert butyl 5' formyl 4' hydroxybiphenyl 2 yl)urea 3 8m. To a 25 mL Schlenk flask, 1 (3,5 bis(trifluoromethyl)phenyl) 3 (2 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)phe nyl)urea 3 12m (500 mg, 1.05 mmol), Pd(dppf)Cl 2 (40 mg, 0.05 mmol), Na 2 CO 3 (333 mg, 3.14 mmol) and 3 tert butyl 2 hydroxy 5 iodobenzal dehyde (320 mg, 1.05

PAGE 143

143 mmol) were added under argon atmosphere. Then dimethoxyethane (2 mL), H 2 O (0.7 mL) were added. The reaction mixture was refluxed overnight. Then reaction mixture was poured into water (100 mL), extracted with methylene chloride (80 mL) three times. The combined organic layer was washed saturated aq. Na 2 SO 3 solution and dried over anhydrous Na 2 SO 4 The s olvent was removed and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 9/1) to give 3 8m as a white powder (392 mg, 75%). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 11.88 (s, 1 H), 10.04 (s, 1 H), 9.52 (s, 1 H), 8.03 8.07 (m, 1 H), 8.01 (s, 2 H), 7.76 (d, J = 2.3 Hz, 2 H), 7.56 (d, J = 2.2 Hz, 2 H), 7.35 7.41 (m, 2 H), 7.24 7.30 (m, 1 H), 1.34 (s, 9 H); 13 C NMR (75 MHz, DMSO d 6 ) : ppm 199.5, 160.1, 153.7, 142.6 138.0, 135.7, 135.4, 134.6, 133.3, 131.3 (q, J = 32.3 Hz), 130.9, 130.3, 128.7, 125.7(4), 125.7(0), 124.0 (q, J = 273.5 Hz), 121.5, 118.4, 115.0, 35.2, 29.5; HRMS (ESI) Calcd. for C 26 H 2 2 F 6 N 2 O 3 Na [M + Na] + : 547.1427 Found: 547.1405 1 (3 tert Butyl 5 formyl 4 hydroxybenzyl) 3 (perfluorophenyl)urea 3 8p. To a solution of 4 (aminomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol 3 20p (402 mg, 1.52 mmol) in CH 2 Cl 2 (10 mL) at rt, pentafluorophenyl isocyanate (0.2 mL, 1.52 mmol) was added and stirred for 2 h. Then the solvent was removed under reduced pressure. The residue was dissolved in THF (5 mL). 10 wt% aq. HCl (0.5 mL) was added to this solution. The mixture was stirred for 2 h at room temperature. Then the solvent was remo ved under reduced pressure. The residue was dissolved in EtOAc (10 mL), and

PAGE 144

144 washed with water and saturated aq. NaHCO 3 The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column c hromatography on silica gel ( n hexane:EtOAc 9:1) to give the resulting salicylaldehyde 3 8p as a white powder (450 mg, 71%). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 11.74 (s, 1 H), 9.95 (s, 1 H), 8.42 (s, 1 H), 7.52 (d, J = 4.3 Hz, 2 H), 6.97 7.17 (m, 1 H), 4.26 (d, J = 5.9 Hz, 2 H), 1.37 (s, 9 H); 13 C NMR (126 MHz, DMSO d 6 ) : ppm 199. 1 159.6, 155.3, 128.7 (mult.), 139.4 (mult.), 137.9, 136.8 (mult.), 134.0, 131.7, 131.1, 121.0, 115.3 (mult.), 43.2, 35.1, 29.7; HRMS ( ESI ) Calcd. for C 19 H 17 F 5 N 2 O 3 Na [M + Na] + : 439.1 052 Found: 439.1070. 1 (3,5 B is(trifluoromethyl)phenyl) 3 (3 tert butyl 5 formyl 4 hydroxybenzyl) 1,3 dimethylurea 3 8q To a solution of 1 (4 (benzyloxy) 3 tert butyl 5 formylbenzyl) 3 (3,5 bis (trifluoromethyl)pheny l) 1,3 dimethylurea 3 10 (112 mg, 0.19 mmol) in ethyl acetate (10 mL), Pd C (10 wt %, 10 mg) was added. The mixture was then allowed to stir overnight under a hydrogen balloon. This reaction mixture was filtered through Celite, and washed with ethyl acetat e. The filtrate was concentrated under reduced pressure, and then the residue was purified by column chromatography on silica gel (n hexane:EtOAc 10:1 then 5:1) to give product 3 8q (92 mg, 99%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ) : ppm 11.79 (d, J = 0.6 Hz, 1 H), 9.85 (d, J = 1.1 Hz, 1 H), 7.51 (s, 1 H), 7.41 (s, 3 H), 7.31 (s, 1 H), 4.43 (s, 2 H), 3.32 (d, J = 1.1 Hz, 3 H), 2.63 (s,

PAGE 145

145 3 H), 1.40 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 197.2, 161.0, 160.9, 147.7, 139.3, 134.4, 133.0 (q, J = 33.0 Hz ), 131.4, 127.5, 123.2 (q, J = 271.5 Hz), 121.3, 120.7, 116.8, 53.1, 38.8, 36.4, 35.1, 29.3; HRMS (DART) Calcd. for C 23 H 25 F 6 N 2 O 3 [M+H] + : 491.1764, Found: 491.1768. 1 (4 ( B enzyloxy) 3 tert butyl 5 formylbenzyl) 3 (3,5 bis (trifluoromethyl)phenyl) urea 3 9. 1 (3,5 B is(trifluoromethyl)phenyl) 3 (3 tert butyl 5 formyl 4 hydroxybenzyl) urea 3 8c (203 mg, 0.44 mmol) was dissolved in dry DMF (3.0 mL) and anhydrous K 2 CO 3 (73 mg, 0.53 mmol) was added at room temperature under argo n. After addition of benzyl bromide (68 L, 0.57 mmol), the mixture was then allowed to stir for 2 days. 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 product 3 9 (193 mg, 80%) as a white solid. 1 H NMR (500 MHz, CDCl 3 ): ppm 10.20 (s, 1 H), 7.79 (s, 2 H), 7.59 7.62 (m, 1 H), 7.58 (s, 1 H), 7.41 7.52 (m, 6 H), 7.37 7.41 (m, 1 H), 5.70 5.74 (m, 1 H), 5.01 (s, 2 H), 4.45 (d, J = 5.8 Hz, 2 H), 1.43 (s, 9 H); 13 C NMR ( 126 MHz, CDCl 3 ): ppm 191.3 161.4, 155.1, 145.1, 140.7, 136.2, 134.6, 133.5, 132.4 (q, J = 32 .7 Hz), 130.2, 129.0, 128.7, 127.4, 126.0, 122.9 ( q, J = 273.4 Hz ), 118.7, 116.2, 80.8, 43.8, 35.5, 31.0; HRMS ( ESI ) Calcd. for C 28 H 26 F 6 N 2 O 3 Na [M + Na] + : 575.1740, Found: 575.1764

PAGE 146

146 1 (4 ( B enzyloxy) 3 tert butyl 5 formylbenzyl) 3 (3,5 bis(trifluoromethy l)phenyl) 1,3 dimethylurea 3 10. 1 (4 (Benzyloxy) 3 tert butyl 5 formylbenzyl) 3 (3,5 bis(trifluoro methyl) phenyl)urea 3 9 (140 mg, 0.25 mmol) was dissolved in dry DMF (3.0 mL) and 60% NaH (2 5 mg, 0.63 mmol) was added at 0 C under argon. After stirring f 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 ove r 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 product 3 10 (112 mg, 76%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3 ) : ppm 10.32 (s, 1 H), 7.60 (d, J = 7.4 Hz, 2 H), 7.47 7.54 (m, 3 H), 7.34 7.46 (m, 5 H), 5.06 (s, 2 H), 4.49 (s, 2 H), 3.34 (s, 3 H), 2.67 (s, 3 H), 1.45 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 190.2, 161.7, 160.8, 147.6, 145.1, 136.5, 133.6, 133.0 (q, J = 33.0 Hz), 132. 5, 130.4, 128.9, 128.5, 127.3, 127.1, 123.2 (q, J = 272.3 Hz), 121.0, 116.6, 80.8, 53.2, 38.8, 36.6, 35.5, 31.0; HRMS (DART) Calcd. for C 30 H 31 F 6 N 2 O 3 [M+H] + : 581.2233, Found: 581.2237.

PAGE 147

147 1 (3,5 B is(trifluoromethyl)phenyl) 3 (3 tert butyl 5 (( E ) ((2 R ) 2 (( E ) 3,5 di tert butyl 2 hydroxybenzylideneamino)cyclohexylimino)methyl) 4 hydroxybenzyl)urea 3 11b. The procedure was followed by our recent report. 22 b 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) was 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 an additional 3 h at this temperature, followed by the addition of 1 (3,5 bis(trifluoromethyl)phenyl) 3 (3 tert butyl 5 formyl 4 hydroxybenzyl)urea 3 8c (190 mg, 0.48 mmol, 1.0 eq uiv) in EtOH (5 mL) and triethylamine (0.13 mL, 0.96 mmol, 2 equiv). The reaction mixture was allowed to stir at room temperature overnight. The solution was concentrated under reduced pressure and the residue was purified by column chromatography on silic a gel ( n hexane:EtOAc 5:1 then 2:1) to give the resulting mono urea salen 3 11b as a yellow solid (221 mg, 59%). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 14.13 (s, 1 H), 13.87 (s, 1 H), 9.22 (s, 1 H), 8.47 (d, J = 6. 0 Hz, 2 H), 8.07 (s, 2 H), 7.52 7.55 (m, 1 H), 7.20 (t, J = 2.4 Hz, 2 H), 7.10 (d, J = 2.3 Hz, 2 H), 6.82 6.88 (m, 1 H), 4.12 4.19 (m, 2 H), 3.37 3.46 (m, 2 H), 1.86 1.95 (m, 2 H), 1.74 1. 85 (m, 2 H), 1.58 1.69 (m, 2 H), 1.40 1.51 (m, 2 H), 1.32 (s, 9 H), 1.27 (s, 9 H), 1.17 (s, 9 H); 13 C NMR (DMSO d 6 126 MHz): ppm 167.1, 166.6, 159.6,

PAGE 148

148 158.1, 155.3, 143.3, 140.2, 136.9, 136.1, 131.3 (q, J = 3 1.5 Hz), 129.6, 129.5, 129.3, 126.8, 124.1 (q, J = 273.4 Hz), 119.4, 118.6, 118.2, 117.9, 114.1, 71.9, 71.6, 64.2, 60.4, 56.7, 52.5, 43.2, 35.1, 34.4, 33.3, 31.8, 29.8, 24.5; HRMS ( ESI ) calcd for C 42 H 52 F 6 N 4 Na O 3 [M+N a ] + : 797.3836 Found 797.3872. 1,1' (5',5'' (1 E ,1' E ) (1 R ,2 R ) C yclohexane 1,2 diylbis(azan 1 yl 1 ylidene)bis(methan 1 yl 1 ylidene)bis(3' tert butyl 4' hydroxybiphenyl 5',4 diyl))bis(3 (3,5 bis(trifluoro methyl)phenyl)urea) 3 11 g To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine (16 mg, 0.14 mmol) in THF (8 mL), urea functionalized salicylaldehyde 3 8g (142 mg, 0.27 mmol) 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 g el (ethyl acetate) to give the resulting salen 3 1 1 g as a yellow solid(133 mg, 86%). 1 H NMR (300 MHz, DMSO d 6 ) : ppm 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 ) : ppm 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) Calcd. for C 58 H 5 5 F 12 N 6 O 4 [M +H ] + : 1127.4088 Foun d: 1127.4098.

PAGE 149

149 1,1' (4,4' (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 butyl 4 hydroxy 5,1 phenylene)bis(ethyne 2,1 diyl))bis(4,1 phenylene))bis(3 (3,5 bis(triflu oromethyl)phenyl)urea) 3 11h. To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine (1 1 mg, 0.10 mmol) in THF ( 2 .0 mL), salicylaldehyde 3 8h (100 mg, 0.20 mmol, 2.0 equiv) was added at room temperature, and then allowed to stir overnight. The solution was conc entrated under reduced pressure, and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 5:1 then 2:1) to give product 3 11h as a yellow solid ( 85 mg, 73 %). 1 H NMR (300 MHz, DMSO d 6 ) : ppm 14.58 (s, 2 H), 9.45 (s, 2 H), 9.18 (s 2 H), 8.50 (s, 2 H), 8.14 (s, 4 H), 7.62 7.68 (m, 2 H), 7.39 7.57 (m, 8 H), 7.33 (dd, J = 19.5, 1.9 Hz, 4 H), 3.43 3.54 (m, 2 H), 1.41 2.05 (m, 8 H), 1.35 (s, 18 H); 13 C NMR (126 MHz, DMSO d 6 ) : ppm 166.5, 162.0, 153.0, 142.4, 140.0, 138.1, 133.9, 132.6 132.5, 131.4 (q, J = 32.3 Hz), 127.5, 124.0 (q, J = 270.8Hz), 119.4, 118.7, 117.0, 115.2, 112.1, 89.2, 88.1, 70.9, 35.2, 32.7, 29.6, 24.4; HRMS (ESI) Calcd. for C 62 H 54 F 12 N 6 O 4 Na [M + Na] + : 1197.3907 Found: 1197.3924

PAGE 150

150 1,1' (3,3' (2,2' (5,5' (1 E ,1' E ) (1 R) C yclohexane 1,2 diylbis(azan 1 yl 1 ylidene) bis(methan 1 yl 1 ylidene)bis(3 tert butyl 4 hydroxy 5,1 phenylene))bis(ethane 2,1 diyl))bis(3,1 phenylene))bis(3 (3,5 bis(trifluoromethyl)phenyl)urea) 3 11i. To a solution of (1 R ,2 R ) cyclo hexane 1,2 diamine (8.2 mg, 0.072 mmol) in THF (3.0 mL), salicylaldehyde 3 8i (77 mg, 0.14 mmol, 2.0 equiv) was added and then stirred overnight at room temperature. The solution was concentrated under reduced pressure, and the residue w as purified by column chromatography on silica gel ( n hexane:EtOAc 5:1 then 2:1) to give product 3 11i as a yellow powder (75 mg, 88%). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 13.89 (s, 2 H), 9.33 (s, 2 H), 8.85 (s, 2 H), 8.41 (s, 2 H), 8.1 3 (s, 4 H), 7.61 (s, 2 H), 7.31 7.40 (m, 4 H), 7.07 (d, J = 8. 5 Hz, 4 H), 6.98 (s, 4 H), 3.37 3.43 (m, 2 H), 2.69 (s, 8 H), 1.40 1.98 (m, 8 H), 1.23 1.36 (m, 18 H); 13 C NMR (126 MHz DMS O d 6 ): ppm 166.9, 158.5, 153.1, 142.7, 137.5, 136.5, 136.4, 131.4 (q, J = 30.2 Hz), 131.0, 130.4, 129.8, 129.3, 124.0 (q, J = 273.4 Hz), 119.6, 118.7, 118.6, 114.9, 71.7, 37.4, 37.3, 35.0, 33.2, 29.8, 24.5; HRMS (ESI) Calcd. for C 62 H 62 F 12 N 6 O 4 Na [M + Na ] + : 1205.4533 Found: 1205.4593

PAGE 151

151 1,1' (3,3' (5,5' (1 E ,1' E ) (1 R ) C yclohexane 1,2 diylbis(azan 1 yl 1 ylidene)bis(me than 1 yl 1 ylidene)bis(3 tert butyl 4 hydroxy 5,1 phenylene))bis(propane 3,1 diyl))bis(3 (3,5 bis(triflu oromethyl)phenyl)urea) 3 11k. To a solution of (1 R ,2 R ) cyclo hexane 1,2 diamine (12.8 mg, 0.11 mmol) in THF (3.0 mL), salicylaldehyde 3 8k (107 mg, 0.22 mmol, 2.0 equiv) was added and then stirred overnight at room temperature. The solution was concentrat ed under reduced pressure, and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 5:1 then 2:1) to give product 3 11k as a yellow powder (107 mg, 90%). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 13.83 (s, 2 H), 9.18 (s, 2 H), 8.37 (s, 2 H), 8.07 (s, 4 H), 7.49 (s, 2 H), 6.97 7.03 (m, 2 H), 6.89 6.95 (m, 2 H), 6.44 6.49 (m, 2 H), 3.30 3.36 (m, 2 H), 3.02 3.09 (m, 4 H), 2.39 2.45 (m, 4 H), 1.84 1.92 (m, 2 H), 1.69 1.81 (m, 4 H), 1.55 1.67 (m, 4 H), 1.38 1.47 (m, 2 H), 1.25 (s, 18 H); 13 C NMR (126 MHz DMSO d 6 ): ppm 166.2, 157.8, 154.9, 142.8, 136.1, 130.7 (q, J = 31.5 Hz) 130.6, 129.6, 129.1, 123.5 (q, J = 27 2.2 Hz) 118.1, 117.3, 113.4, 71.2, 38.9, 34.3, 32.6, 31.8, 31.6, 29.2, 23.9; HRMS (ESI) Calcd. for C 52 H 58 F 12 N 6 O 4 Na [M + Na ] + : 1081.4220 Found: 1081.4250

PAGE 152

152 1,1' (5',5'' (1 E ,1' E ) (1 R ,2 R ) C yclohexane 1,2 diylbis(azan 1 yl 1 ylidene)bis(methan 1 yl 1 ylidene)bis(3' tert butyl 4' hydroxybiphenyl 5',3 diyl))bis(3 (3,5 bis(trifluoro methyl)phenyl)urea) 3 11l. To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine (33 mg, 0.29 mmol) in THF (5 mL), salicylaldehyde 3 8l (299 mg, 0.57 mmol) was added and then stirred for 16 h at room temperature. The solution was concentrated under reduced pressure and the residue was purified by column chr omatography on silica gel ( n hexane:EtOAc 5:1) to give the resulting bis urea salen 3 11l as a yellow powder (209 mg, 65%). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 14.32 (s, 2 H), 9.40 (s, 2 H), 9.00 (s, 2 H), 8.58 (s, 2 H), 8.12 (s, 4 H), 7.62 (br. s., 4 H), 7.4 0 (d, J = 4.7 Hz, 6 H), 7.29 7.36 (m, 2 H), 7.08 7.17 (m, 2 H), 3.42 3.52 (m, 2 H), 1.40 2.02 (m, 8 H), 1.34 (s, 18 H); 13 C NMR (126 MHz DMSO d 6 ) : ppm 167.1, 160.5, 153.2, 142.6, 141.4, 140.2, 137.6, 131.4 (q, J = 32.8 Hz), 130.4, 130.0, 128.6, 128.3, 1 24.0 (q, J = 272.1 Hz), 121.2, 119.1, 118.7, 118.0, 117.4, 115.0, 71.6, 35.2, 33.1, 29.7, 24.5; HRMS (ESI) Calcd. for C 58 H 55 F 12 N 6 O 4 [M + H ] + : 1127.4088 Found: 1127.4111

PAGE 153

153 1,1' (5',5'' (1 E ,1' E ) (1 R ,2 R ) C yclohexane 1,2 diylb is(azan 1 yl 1 ylidene)bis (methan 1 yl 1 ylidene)bis(3' tert butyl 4' hydroxybiphenyl 5',2 diyl))bis(3 (3,5 bis(trifluoromethyl)phenyl)urea) 3 11m. To a solution of (1 R ,2 R ) cyclohexane 1,2 di amine (22 mg, 0.19 mmol) in THF (5 mL), salicylaldehyde 3 8m (1 99 mg, 0.38 mmol) was added at room temperature, and then allowed to stir for 16 h. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 5:1) to give the resulting bis ure a salen 3 11m as a yellow powder (182 mg, 85 %). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 14.33 (s, 2 H), 9.52 (s, 2 H), 8.61 (s, 2 H), 7.99 (s, 4 H), 7.82 (s, 2 H), 7.75 (d, J = 8. 0 Hz, 2 H), 7.59 (s, 2 H), 7.29 7.36 (m, 2 H), 7.28 (d, J = 2.1 Hz, 2 H), 7.23 (d, J = 2.1 Hz, 2 H), 7.12 7.20 (m, 4 H), 3.45 3.56 (m, 2 H), 2.00 1.34 (m, 8 H) 1.27 (s, 18 H); 13 C NMR (126 MHz DMSO d 6 ): ppm 166.2, 159.6, 153.0, 141.9, 136.6, 134.9, 134.0, 132.7, 130.7 (q, J = 32.7 Hz), 130.3, 130.2, 130.0, 127.7, 127.5, 124.3, 123.3 (q, J = 294.8 Hz), 118.4, 117.6, 114.2, 70.7, 34.4, 32.7, 28.9, 23.7; HRMS ( ESI) Calcd. for C 58 H 54 F 12 N 6 O 4 Na [M + Na ] + : 1149.3907 Found: 1149.3905

PAGE 154

154 1,1' (5,5' (1 E ,1' E ) (1 R ) C yclohexane 1,2 diylbis(azan 1 yl 1 ylidene)bis(methan 1 yl 1 ylidene)bis(3 tert butyl 4 hydroxy 5,1 phenylene)bis(methylene) )bis(3 (perfluorophenyl)urea) 3 11p. To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine (21 mg, 0.18 mmol) in THF (2 mL), salicylaldehyde 3 8p (150 mg, 0.36 mmol was added and stirred for 16 h. at room temperature. Then the solution was concentrated under r educed pressure. The residue was purified by column chromatogra phy on silica gel ( n hexane:EtOAc 5:1) to give 3 11p as a yellow powder (144 mg, 87%). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 14.10 (s, 2 H), 8.47 (s, 2 H), 8.29 (s, 2 H), 7.20 (d, J = 1.6 Hz, 2 H), 7.05 (d, J = 1.8 Hz, 2 H), 6.90 (t, J = 5.0 Hz, 2 H), 4.13 (t, J = 5.1 Hz, 4 H), 3.41 3.51 (m, 2 H), 1.43 1.98 (m, 8 H), 1.26 1.37 (m, 18 H); 13 C NMR ( 126 MHz, DMSO d 6 ): ppm 166.6, 159.6, 155.1, 143.6 (mult.), 138.8 (mult.), 137.0, 136.9 (mult.), 129.6, 129.3, 129.2, 118.5, 115.4 (mult.), 71.7, 43.5, 35.0, 33.2, 29.8, 24.5; HRMS ( ESI ) Calcd. for C 4 4 H 44 F 10 N 6 O 4 Na [M + Na ] + : 933.3157 Found: 933.3120

PAGE 155

155 1,1' (5,5' (1 E ,1' E ) (1 R ) Cyclohexane 1,2 diylbis(azan 1 yl 1 ylidene)bis(m ethan 1 yl 1 ylidene)bis(3 tert butyl 4 hydroxy 5,1 phenylene)bis(methylene))bis(3 (3,5 bis(trifluoromethyl)phenyl) 1,3 dimethylurea) 3 1 1q To a solution of (1 R ,2 R ) cyclohexane 1,2 diamine (12 mg, 0.10 mmol) in THF (3.0 mL), salicylaldehyde 3 8q (100 mg, 0.20 mmol, 2.0 equiv) was added at room temperature, and then allowed to stir overnight. 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 produc t 3 11q as a yellow oil (90 mg, 84%). 1 H NMR ( 300 MHz, CDCl 3 ): ppm 13.71 13.94 (m, 2 H), 8.28 (s, 2 H), 7.48 (br. s., 2 H), 7.39 (s, 4 H), 7.10 (d, J = 2.3 Hz, 2 H), 6.90 (d, J = 2.3 Hz, 2 H), 4.28 (d, J = 5.4 Hz, 4 H), 3.32 3.41 (m, 2 H), 3.23 3.31 (m, 6 H), 2.51 2.61 (m, 6 H), 1.44 2.07 (m, 8 H), 1.36 (s, 18 H); 1 3 C NMR (75 MHz, CDCl 3 ): ppm 165.3, 160.8, 160.2, 147.7, 138.0, 132.9 (q, J = 33.0 Hz), 129.4, 129.3, 125.5, 123.3 (q, J = 271.5 Hz), 120.8, 118.7, 116.4, 72.6, 53.3, 38.6, 35.9, 35.0, 33.3, 29.4, 24.5; HRMS (DART) Calcd. for C 52 H 59 F 12 N 6 O 4 [M+H] + : 1059.44 01, Found: 1059.4393

PAGE 156

156 1 (3,5 B is(trifluoromethyl)phenyl) 3 (4 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)phenyl)urea 3 12g To a solution of 4 aminophenylboronic acid pinacol ester (198 mg, 0.90 mmol) in CH 2 Cl 2 (4 mL), 3,5 bis(trifluoromethyl) phenyl isocyanate (230 mg, 0.90 mmol) was added at room temperature, and then allowed to stir for 3 h. The reaction mixture was diluted with n hexane (5 mL), then precipitate was collected by filtration, washed with n hexane to gi ve 3 13a as a white solid (387 mg, 90%) 1 H NMR (300 MHz, DMSO d 6 ): ppm 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); 13C NMR (75 MHz, DMSO d 6 ): ppm 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) Calcd. for C 21 H 22 BF 6 N 2 O 3 [M+H] + : 475.1626, Found: 475.1639. 1 (3,5 B is(trifluoromethyl)phenyl) 3 (4 ethynylphenyl)ur ea 3 12h. To a solution of 3,5 bis(trifluoromethyl)phenyl isocyanate (0.75 mL, 4.34 mmol) in 2 mL CH 2 Cl 2 4 ethynylaniline (0.50 g, 4.27 mmol) was added. ( The reaction mixture was stirred for 15 min until no further suspension was formed. ) T he precipitate was collected by filtration and washed by n hexane to give 3 12h as a w hite powder (1.43 g, 91%). 1 H NMR (500

PAGE 157

157 MHz, DMSO d 6 ) : ppm 9.44 (s, 1 H), 9.19 (s, 1 H), 8.13 (s, 2 H), 7.64 (s, 1 H), 7.47 7.56 (m, 2 H), 7.35 7.46 (m, 2 H), 4.05 (s, 1 H); 13 C NMR (1 26 MHz, DMSO d 6 ): ppm 153.0, 142.4, 140.4, 133.1, 131.4 (q, J = 32.8 Hz), 124.0 (q, J = 273.4 Hz), 119.3, 118.8, 116.0, 115.2, 84.3, 80.3; HRMS ( ESI ) Calcd. for C 17 H 10 F 6 N 2 ONa [M + Na] + : 395.0590, Found: 395.0576 1 (3,5 B is(trifluoromethyl)phenyl) 3 (3 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl) phenyl)urea 3 12l. To a solution of 3,5 bis(trifluoromethyl)phenyl isocyanate (0. 3 5 mL, 2.0 mmol) in 5 mL CH 2 Cl 2 3 a minophenylboronic acid pinacol ester ( 40 0 m g, 1.83 mmol) was added. The reaction mixture was stirred for 15 min T he precipitate was collected by fi ltration and washed with hexanes to give 3 12l as a w hite powde r ( 780 mg, 90 % ) 1 H NMR ( 300 MHz DMSO d 6 ): ppm 9.32 (br. s 1 H), 8.96 (b r. s 1 H), 8.12 (s, 2 H), 7.80 7.93 (m, 1 H), 7.56 7.65 (m, 1 H), 7.46 7.52 (m, 1 H), 7.31 (s, 2 H), 1.28 (s, 12 H); 13 C NMR (126 MHz DMSO d 6 ): ppm 153.2, 142.6, 131.4 (q, J = 32.9 Hz), 129.3, 129.1, 125.4, 124.0 (q, J = 273.4 Hz), 122.7, 118.7, 115.0, 84.4, 25.4; HRMS (ESI) Calcd. for C 2 1 H 2 1 BF 6 N 2 O 3 Na [M + Na ] + : 497.1446 Found: 497.1447

PAGE 158

158 1 (3,5 B is(trifluoromethyl)phenyl) 3 (2 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)phenyl)urea 3 12m. To a solution of 3,5 bis(trifluoromethyl)phenyl isocyanate (0. 3 5 mL, 2.0 mmol) in 5 mL CH 2 Cl 2 2 a minophenylboronic acid pinacol ester ( 40 0 m g, 1.83 mmol) was added. The reaction mixture was stirred for 15 min T he precipitate was collected by filtra tion and washed with hexanes to give 3 12m as a w hite powde r ( 798 mg, 92 % ) 1 H NMR (500 MHz DMSO d 6 ) : ppm 9.94 (s, 1 H), 9.12 9.24 (m, 1 H), 8.17 (s, 2 H), 7.68 (s, 1 H), 7.51 7.54 (m, 1 H), 7.41 7.44 (m, 1 H), 7.34 7.39 (m, 1 H), 7.04 7.08 (m, 1 H), 1 .25 (s, 12 H); 13 C NMR (126 MHz, DMSO d 6 ) : ppm 154.2, 142.5, 142.0, 134.9, 131.4 (q, J = 32.8 Hz), 131.0, 124.0 (q, J = 276.0 Hz), 123.6, 120.0, 119.6, 115.7, 83.2, 25.7; HRMS (ESI) Calcd. for C 21 H 2 1 BF 6 N 2 O 3 Na [M + Na] + : 497.1446 Found: 497.1429 5 B romo 3 tert butyl 2 hydroxybenzaldehyde 3 13h. This compound was prepared according to the literature procedure 49 (Yellow solid, 5.5 g, 95% ) 1 H NMR (500 MHz, CDCl 3 ) ppm 11.74 (s, 1 H), 9.82 (s, 1 H), 7.58 7.60 (m, 1 H), 7.53 (d, J = 2.5 H z, 1 H), 1.42 (s, 9 H); 13 C NMR (126 MHz, CDCl 3 ) ppm 196.3, 160.4, 141.4,

PAGE 159

159 137.2, 133.8, 121.9, 111.4, 35.4, 29.2; HRMS ( DART ) Calcd. for C 1 1 H 13 Br O 2 [M] + : 256.0099, Found: 25 6.0097. 4 Bromo 2 tert butylphen ol 3 13k. The compound was prepared according to the literature. 47 b (Colorless oil 99% ) 1 H NMR (500 MHz, CDCl 3 ) : ppm 7.38 (s, 1 H), 7.15 7.22 (m, 1 H), 6.58 (d, J = 8.4 Hz, 1 H), 1.42 (s, 9 H); 13 C NMR (126 MHz, CDCl 3 ) : ppm 153.6, 138.8, 130.4, 130.0 118.4, 113.2, 35.0, 29.6 ( E ) Methyl 3 (3 tert butyl 4 hydroxyphenyl)acrylate 3 14k To a 25 mL flame dried Schlenk flask, 4 bromo 2 tert butylphenol 3 13k (8.0 g, 34.9 mmol), Pd(OAc) 2 (157 mg, 0.70 mmol), P( O Tol) 3 ( 849 mg, 2.79 mmol) were added under argon atmosphere. Then methyl acrylate (6.28 mL, 69.8 mmol) and triethylamine (30 mL) were added. The reaction mixture was refluxed overnight and then poured into 1 M aq. HCl (100 mL), and extracted with EtOAc (80 mL) th ree times. The combined organic layer was dried over anhydrous Na 2 SO 4 Then the solvent was removed and the residue was purified by column chromatography on silica gel to give the desired product 3 14k as a white solid (6.13 g, 75%). 1 H NMR (500 MHz, DMSO d 6 ): ppm 9.97 (s, 1 H), 7.56 (d, J = 15.9 Hz, 1 H), 7.35 7.44 (m, 2 H), 6.81 (d, J = 8.4 Hz, 1 H), 6.34 (d, J = 15.9 Hz, 1 H), 3.67 (s, 3 H), 1.33 (s, 9 H); 13 C NMR (126 MHz, DMSO d 6 ): ppm 167.7, 159.2, 146.1,

PAGE 160

160 136.4, 128.3, 128.0, 125.4, 117.4, 114.1, 51.8, 35.0, 29.9; HRMS (DART) Calcd. for C 14 H 22 NO 3 [M +NH 4 ] + : 252.1594 Found: 252.1585. Methyl 3 (3 tert butyl 4 hydroxyphenyl)propanoate 3 15k. A solution of ( E ) m ethyl 3 (3 tert butyl 4 hydroxyphenyl)acrylate 3 14k (5.9 0 g, 25.2 mmol) in EtOH (75 mL) was degassed by bubbling argon through it for 5 min. Pd C (10 wt %, 0.59 g) was added to the mixture. A balloon filled with hydrogen was attached and the mixture was briefly degassed and backfilled with hydrogen three times. The reaction was stirred overnight at room temperature. The mixture was filtered through Celite and washed with CH 2 Cl 2 The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give 3 15k as a w hite solid ( 5.65 g, 95%). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.10 (d, J = 2.1 Hz, 1 H), 6.86 6.93 (m, 1 H), 6.62 (d, J = 8.0 Hz, 1 H), 5.44 (s, 1 H), 3.72 (s, 3 H), 2.90 (d, J = 8.1 Hz, 2 H), 2.64 (t, J = 7.9 Hz, 2 H), 1.42 (s, 9 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 174.3, 153.2, 136.4, 132.2, 127.3, 126.7, 116 .8, 52.0, 36.5, 34.8, 30.8, 29.8; HRMS ( DART ) Calcd. for C 14 H 2 4 NO 3 [M + NH 4 ] + : 254.1751 Found: 254.1742 2 tert Butyl 4 (3 hydroxypropyl)phenol 3 16k. To a 250 mL flame dried round bottom flask, methyl 3 (3 tert butyl 4 hydroxyl phenyl)propanoate 3 15k (5.40 g, 22.9

PAGE 161

161 mmol) in ether (8 0 mL) was added and cooled to 0 C. Lithium aluminum hydride pellets (1.70 g, 45.4 mmol) was added during 5 minutes. The reaction mixture was slowly warmed up to room temperature and the gas ge nerated was ventilated through an oil bubbler. The reaction mixture was stirred overnight at room tem perature and then cooled down 0 C. Water (1.7 mL) was added during 5 minutes. Then 20 wt% aq. sodium hydroxide (1.7 mL) was added slowly during 10 minutes. Then water (5.1 mL) was added slowly. The reaction mixture was stirred for 30 minutes until all lithium aluminum hydride was quenched by water. This mixture was filtered through Celite, and washed with THF. The filtrate was concentrated and the residue wa s purified by column chromatography on silica gel ( n hexane:EtOAc 3/1) to give 3 16k as a colorless oil (5.24 g, 97%). 1 H NMR (500 MHz, CDCl 3 ) : ppm 7.09 (d, J = 1.9 Hz, 1 H), 6.86 6.92 (m, 1 H), 6.61 (d, J = 8.0 Hz, 1 H), 5.48 (s, 1 H), 3.72 (t, J = 5.0 Hz, 2 H), 2.59 2.70 (m, 2 H), 1.94 1.87 (m, 2 H), 1.42 (s, 9 H); 13 C NMR (126 MHz CDCl 3 ) : ppm 153.1, 136.4, 133.3, 127.3, 126.7, 116.7, 62.8, 34.8, 34.6, 31.8, 29.9; HRMS ( DART ) Calcd. for C 13 H 2 1 O 2 [M + H] + : 209.1536 Found: 209.1533 50 3 tert B utyl 2 hydroxy 5 (3 hydroxypropyl)benzaldehyde 3 17k. To a 50 mL two neck round bottom flask attached with a condenser, 2 tert butyl 4 (3 hydroxypropyl)phenol 3 16k (2.0 g, 9.6 mmol), paraform aldehyde (0.63 g, 21.2 mmol), and anh ydrous MgCl 2 (1.8 g, 19.2 mmol) were added. The reaction mixture was briefly degassed by bubbling argon through it for 5 minutes. THF (15 mL) and triethylamine

PAGE 162

162 (2.7 mL, 19.2 mmol) were added. The reaction mixture was refluxed for 16 hours, then cooled down and poured into 1M aq. HCl (40 mL), extracted with EtOAc (50 mL) three times. The combined organic layer was dried over anhydrous Na 2 SO 4 The solvent was removed and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 3/1) to g ive 3 17k as a colorless oil (1.38 g, 61%). 1 H NMR (500 MHz, CDCl 3 ): ppm 11.64 (s, 1 H), 9.85 (s, 1 H), 7.36 (d, J = 1.4 Hz, 1 H), 7.21 (d, J = 1.4 Hz, 1 H), 3.70 (t, J = 6.3 Hz, 2 H), 2.70 (t, J = 7.8 Hz, 2 H), 1.86 1.92 (m, 2 H), 1.42 (s, 9 H); 13 C NMR (126 MHz CDCl 3 ): ppm 197.3, 159.7, 138.5, 135.0, 132.5, 131.1, 12 0.6, 62.3, 35.0, 34.4, 31.4, 29.5; HRMS ( DART ) Calcd. for C 14 H 2 4 NO 3 [M + NH 4 ] + : 254.1751 Found: 254.1761 51 3 (3 tert B utyl 5 formyl 4 hydroxyphenyl)propyl 4 methylbenzenesulfonate 3 18k. To a 20 mL vial, 3 tert butyl 2 hy droxy 5 (3 hydroxypropyl) benzalde hyde 3 17k (544 mg, 2.3 0 mmol), and TsCl (438 mg, 2.30 mmol) were added. Then CH 2 Cl 2 (2.5 mL) and triethylamine (0.97 mL, 6.90 mmol) were added and stirred overnight at room temperature. Then the solvent was removed and th e residue was purified by column chromatography on silica gel ( n hexane:EtOAc 9/1) to give 3 18k as a yellow oil (764 mg, 85%). 1 H NMR (500 MHz, CDCl 3 ) : ppm 11.65 (s, 1 H), 9.79 (s, 1 H), 7.79 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 1.9 Hz, 1 H), 7.11 (d, J = 2.1 Hz, 1 H), 4.05 (t, J = 6.1 Hz, 2 H), 2.64 2.67 (m 2 H), 2.46 (s, 3 H), 1.91 2.01 (m, 2 H), 1.40 (s, 9 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 197.2, 159.9, 145.1, 138.7, 134.8, 133.3, 131.3,

PAGE 163

163 131.1, 130.1, 128.1, 120.6, 69.6, 35 .1, 30.9, 30.7, 29.4, 21.9; HRMS ( DART ) Calcd. for C 21 H 30 NO 5 S [M + NH 4 ] + : 408.1839 Found: 408.1856 5 (3 A zidopropyl) 3 tert butyl 2 hydroxybenzaldehyde 3 19k. To a 20 mL vial, 3 (3 tert b utyl 5 formyl 4 hydroxyphenyl)pr opyl 4 methyl benzenesulfonate 3 18k (325 mg, 0.83 mmol) and DMF (1 mL) were added. Then s odium azide (57 mg, 0.88 mmol) was added. The reaction mixture was stirred overnight at room temperature. Then the reaction was poured into water (20 mL) and extracte d with EtOAc (50 mL) three times. The organic layer was concentrated and the residue was purified by column chromato graphy on silica gel ( n hexane:EtOAc 24/1) to g ive 3 19k as a yellow oil (184 mg, 85%). 1 H NMR (500 MHz CDCl 3 ) : ppm 11.67 (s, 1 H), 9.86 (s, 1 H), 7.35 (d, J = 1.9 Hz, 1 H), 7.21 (d, J = 2.1 Hz, 1 H), 3.33 (t, J = 7.5 Hz, 2 H), 2.69 (t, J = 7.5 Hz, Hz, 2 H), 1.90 1.93 (m, 2 H), 1.38 1.48 (m, 9 H); 13 C NMR (126 MHz, CDCl 3 ) : ppm 197.3, 159.9, 138.7, 134.9, 131.5, 131.2, 120.7, 50.8, 35.1, 3 2.2, 30.7, 29.5; HRMS (ESI) Calcd. for C 14 H 19 N 3 O 2 Na [M + Na] + : 284.1369 Found: 284.1372 4 ( A zidomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol 3 19p. This reaction was carried out according to the literature procedure. 52 To a mixture of 5 (azidomethyl) 3

PAGE 164

164 tert butyl 2 hydroxybenzaldehyde (1.82 g, 7.81 mmol), triethyl orthoformate (1.4 mL, 8.42 mmol) and 1,3 propane diol (3.3 mL, 46.86 mmol), a catalytic amount of tetra n butylammonium tribromide (370 mg, 0.77 mmol) was adde d. The reaction mixture was stirred at room temperature for 72 h and then quenched by saturated aq. NaHCO 3 solution. The mixture was extracted twice with EtOAc. The combined organic layer was washed with brine and dried over anhydrous Na 2 SO 4 Then the solv ent was removed under reduced pressure. The residue was purified by column chromatography on silica gel ( n hexane:EtOAc 5:1) to give 4 (aminomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol 3 19p as an off white solid (1.70 g, 75%). 1 H NMR (300 MHz, CDCl 3 ) : ppm 8.19 (s, 1 H), 7.17 (d, J = 2.0 Hz, 1 H), 7.02 (d, J = 2.3 Hz, 1 H), 5.62 (s, 1 H), 4.28 4.34 (m, 2 H), 4.22 (s, 2 H), 3.96 4.05 (m, 2 H), 2.21 2.33 (m, 1 H), 1.47 1.54 (m, 1 H), 1.41 (s, 9 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 154.7, 138.2, 128.2, 126. 0, 125.8, 123.0, 103.5, 67.8, 55.1, 35.2, 29.7, 25.9; HRMS (ESI TOF) Calcd. for C 15 H 22 N 3 O 3 [M+H] + : 292.1656, Found: 292.1656. 4 ( A minomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol 3 20p To a solution of 4 (azidomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl)phenol 3 19p (1.40 g, 4.85 mmol) in ethyl acetate (20 mL), Pd C (10 wt %, 140 mg) was added. The mixture was then allowed to stir overnight under hydrogen atmosphere. This reaction mixture was filtered through Celite, and w ashed with ethyl acetate. The filtrate was concentrated under reduced

PAGE 165

165 pressure to give 4 (aminomethyl) 2 tert butyl 6 (1,3 dioxan 2 yl) phenol 3 20p as an off white solid (1.03 g, 80%). This crude compound was used for the next step without further purifi cation. 1 H NMR (300 MHz, CDCl 3 ) : ppm 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), 4.29 4.35 (m, 2 H), 4.01 (t, J = 12.2 Hz, 2 H), 3.75 (s, 2 H), 2.22 2.32 (m, 1 H), 1.47 1.54 (m, 1 H), 1.40 (s, 9H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 154.6, 138.2, 128. 9, 126.8, 126.5, 122.8, 103.8, 67.7, 67.7, 35.2, 29.8, 25.8 ( (3,5 B is(trifluoromethyl) ureido) (salen)cobalt 3 3b To a suspension of salen ligand 3 11b ( 110 mg, 0. 14 mmol) in EtOH ( 3 mL), Co(OAc) 2 4H 2 O ( 35 mg, 0. 14 mmo l) was added and heated at reflux for 3 h under argon. The precipitate was collected by filtration, washed with EtOH, and then dried under vacuum for 24 h to give a (salen)cobalt 3 3b as a red solid (52 mg, 44%). HRMS ( ESI ) calcd for C 42 H 5 0 CoF 6 N 4 O 3 [M] + : 831.3114 Found 831.3107.

PAGE 166

166 Bis((3,5 bis(trifluoromethyl)phenyl)ureido) (salen)cobalt 3 3c To a solution of salen ligand 3 3j (500 mg, 0.50 mmol) in i PrOH (14 mL), Co(OAc) 2 4H 2 O (125 mg, 0.50 mmol, 1.0 equiv) was ad ded and heated at reflux for 3 h under argon. Precipitate was collected by filtration, washed by i PrOH, and then dried under vacuum for 24 h to give a (salen)cobalt complex 3 3c as a red solid ( 480 mg, 91 %) HRMS (ESI TOF) Calcd. for C 48 H 48 CoF 12 N 6 O 4 [M] + ; 1059.287 2 Found: 1059.2975. 22 b Bis(3,5 bistrifluoromethylphenylurea) cobalt salen 3 3g To a solution of salen 3 11g (47 mg, 0.042 mmol) in i PrOH (3.0 mL), Co(OAc) 2 2 O (10 mg, 0.042 mmol) was added, and heated at reflux for 5 h under argon. Precipitate was collected by filtration, washed by EtOH, and then dried under vacuum for 24 h to give 3 3g as a reddish brown solid (40 mg, 81%). HRMS (APCI TOF) Calcd. for C 58 H 52 CoF 12 N 6 O 4 [M] + : 1183.3190, Found: 1183.3168.

PAGE 167

167 Bis(3,5 bistrifluoromethyl ethynyl phenylurea) cobalt salen 3 3h HRMS ( APCI ) Calcd. for C 62 H 53 CoF 12 N 6 O 4 [M + H] + : 1232.3263 Found: 11232.3247 Bis(3,5 bistrifluoromethyl ethyl phenylurea) cobalt salen 3 3i To a solution of salen 3 11i (51 mg, 0.043 mmol) in i PrOH (2.0 mL), Co(OAc) 2 4H 2 O (10.6 mg, 0.043 mmol) was added and heated at reflux for 5 h under argon. The precipitate was collected by filtration, washed by Et OH, and then dried under vacuum for 24 h to give 3 3i as a red solid ( 43 mg, 8 0 %). HRMS ( ESI ) calcd for C 62 H 60 CoF 12 N 6 O 4 [M] + : 1239.3811. Found 1239.3843. 1,1' (5,5' (1 E ,1' E ) (1 R ,2 R ) C yclohexane 1,2 diylbis(azan 1 yl 1 ylidene)bis(methan 1 yl 1 ylidene)bis(3 tert butyl 4 hydroxy 5,1 phenylene)bis(methylene))bis(3 (3,5 bis(trifluoromethyl )phenyl)urea) 3 3j To a

PAGE 168

168 solution of (1 R ,2 R ) cyclohexane 1,2 diamine (64 mg, 0.57 mmol) in THF (5 mL), salicylaldehyde 3 8c (522 mg, 1.13 mmol, 2.0 equiv) was added at room temperature, and then allowed to stir under reflux for 16 h. The solution was con centrated under reduced pressure, and the residue was purified by column chromatography on silica gel ( n hexane:EtOAc 5:1) to give the resulting bis urea salen 3 3j as a yellow solid (510 mg, 91%). 1 H NMR (500 MHz, DMSO d 6 ) : ppm 14.09 (s, 2 H), 9.21 (s, 2 H), 8.45 (s, 2 H), 8.05 (s, 4 H), 7.52 (s, 2 H), 7.15 (d, J = 2.0 Hz, 2 H), 7.04 (d, J = 1.7 Hz, 2 H), 6.86 (t, J = 5.9 Hz, 2 H), 4.13 (d, J = 6.2 Hz, 4 H), 3.38 3.45 (m, 2 H), 1.83 1.93 (m, 2 H), 1.74 1.83 (m, 2 H), 1.56 1.69 (m, 2 H), 1.38 1.49 (m, 2 H ), 1.24 (s, 18 H); 13 C NMR (126 MHz, DMSO d 6 ) : ppm 166.5, 159.5, 155.3, 143.2, 136.9, 131.2 (q, J = 32.0 Hz), 129.6, 129.3, 129.1, 124.0 (q, J = 271.0 Hz), 118.5, 117.9, 114.1, 71.8, 43.1, 34.9, 33.2, 29.7, 24.5; HRMS (APCI TOF) Calcd. for C 48 H 51 F 12 N 6 O 4 [M+H] + : 1003.3775, Found: 1003.3801. 22 b Bis(3,5 bistrifluoromethyl n prop ylurea) cobalt salen 3 3k To a solution of salen 3 11k (54 mg, 0.052 mmol) in i PrOH (2.0 mL), Co(OAc) 2 4 H 2 O (12.9 mg, 0.052 mmol) was added and heated at reflux for 5 h under argon. The prec ipitate was collected by filtration, washed with Et OH, and then dried under vacuum for 24 h to give 3 3k as a red solid ( 50 mg, 8 7 %). HRMS ( ESI ) calcd for C 52 H 56 CoF 12 N 6 O 4 [M] + : 1115.3498. Found 1115.3516.

PAGE 169

169 ( S alen) c obalt 3 3l To a suspension of salen ligand 3 11l (90 mg, 0.08 mmol) in EtOH (2 mL), Co(OAc) 2 4H 2 O (19 mg, 0.08 mmol) was added and heated at reflux for 3 h under argon. The precipitate was collected by filtration, washed with EtOH, and then dried under vacuum for 24 h to give a (salen)cobalt 3 3l as a red solid ( 70 mg, 75 %). HRMS ( ESI ) calcd for C 58 H 52 CoF 12 N 6 O 4 [M] + : 1183.3185. Found 1183.3185. ( S alen) c obalt 3 3m To a suspension of salen ligand 3 11m (146 mg, 0.13 mmol) in EtOH (5 mL), Co(OAc) 2 4H 2 O (32 mg, 0.13 mmol) was added and heated at reflux for 3 h under argon atmosphere. The precipitate was collected by filtration, washed by EtOH, and then dried under vacuum for 24 h to give a (salen)cobalt 3 3m as a red solid ( 138 mg, 90 %). HRMS ( ESI ) calcd for C 58 H 52 CoF 12 N 6 O 4 [M] + : 1183.3185. Found 1183.3209.

PAGE 170

170 Bis( 1,2,3,4,5 pentafluoro phenylureido) (salen)cobalt 3 3p. To a suspension of salen ligand 3 11p (89 mg, 0.10 mmol) in i PrOH (2 mL), Co(OAc) 2 4H 2 O (25 mg, 0.10 mmol) was added and heated at reflux for 3 h under argon. The precipitate was collected by filtration, washed with EtOH, and then dried under vacuum for 24 h to give a (salen)cobalt 3 3p as a red solid ( 8 2 mg, 85%). HRMS ( ESI ) calcd for C 44 H 42 CoF 10 N 6 O 4 [M] + : 967.2434. Found 967.2407. Bis( N N dimethyl ureido) (salen)cobalt 3 3q. To a solution of salen 3 11q (40 mg, 0.037 mmol) in i PrOH (2.0 mL), Co(OAc) 2 4H 2 O (9 mg, 0.037 mmol) was added and heated at reflux for 5 h under argon. Precipitate was collected by filtration, washed by Et OH, and then dried under vacuum for 24 h to give 3 3q (17 mg, 41%) as a brown solid HRMS ( ESI ) Calcd. for C 52 H 5 6 Co F 12 N 6 O 4 [M] + : 1115.3498 Found: 1115.3527 General P roce dure for E nantioselective Henry R eaction To a 3.0 mL vial, cobalt complex 3 3c ( 13.3 mg, 0.0 125 mmol), 3,5 b is(trifluoromethyl) benzo ic acid (3.2 mg, 0.0125 mmol ) and THF ( 0.5 mL ) were added. The mixture was stirred at room temperature under air for 40 min until the solution

PAGE 171

171 changed into deep brown THF was removed under the reduced pressure to g ive a black solid. Then CH 2 Cl 2 (0.3 mL), aldehyde 3 1a (34 mg, 0.25 mmol), and N ethylpiperidine ( 17 0. 125 mmol) were added to this vial. T he reaction mixture w as cooled down to 70 C then CH 3 NO 2 ( 0. 13 mL, 2. 5 mmol) w as added T he mixture was stirred at 7 0 C for 2 0 h. The reaction mixture was purified by flash column chromatography on silica gel ( n hexane/EtOAc) to give the nitroaldol adduct 3 2a as a colorless oil (49 mg, 99%). The absolute configurations of compounds 3 2a 3 2b 3 2d 3 2e 3 2f 3 2h 3 2i 3 2j 3 2k 3 2l 3 2m 3 2n were determined by comparing optical rotation and retention times in HPLC analysis with reported data. The absolute configur ations of the new compounds 3 2 c 3 2g were determined by analogy. ( S ) 1 (2 M ethoxyphenyl) 2 nitroethanol 3 2a (Colorless oil, 99%). 1 H NMR (5 00 MHz, CDCl 3 ): ppm 7.45 7.51 (m, 1 H), 7.34 7.39 (m, 1 H), 7.02 7.08 (m, 1 H), 6.95 (d, J = 8.2 Hz, 1 H), 5.63 5.70 (m, 1 H), 4.58 4.71 (m, 2 H), 3.92 (s, 3 H), 3.16 (d, J = 6.2 Hz, 1 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 156. 3 130. 1 127. 5 126. 2 121. 5 110. 8 80.1, 68. 1 55. 7; Enantiomeric excess was determined by HPLC with a C hiralpak IB column (90:10 n hexane: isopropanol, 1 mL/min, 215 nm); minor t r = 8.35 min; major t r = 9.03 min; 9 7 % ee ; [ ] D 2 6 + 57.8 ( c 4.6 CH 2 Cl 2 ). Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison with literature compound 53

PAGE 172

172 ( S ) 1 (4 F luorophenyl) 2 nitroethanol 3 2 b (Colorless oil, 85%). 1 H NMR ( 5 00 MHz, CDCl 3 ): ppm 7.36 7.49 (m, 2 H), 7.07 7.18 (m, 2 H), 5.49 (dt, J = 9.5, 3.3 Hz, 1 H), 4.48 4.66 (m, 2 H), 2.86 (d, J = 3.7 Hz, 1 H) ; 13 C NMR ( 126 MHz, CDCl 3 ): ppm 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; Enantiomeric excess was determined by HPLC with a Chiralpak IB column (90:10 n hexane:isopropanol, 1.0 m L/min, 215 nm); minor t r = 9.08 min; major t r = 10.04 min; 9 4 % ee ; [ ] D 2 6 + 55.0 ( c 3.4 CH 2 Cl 2 ) Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison with literature data. 53 ( S ) 1 ( B enzo[ d ][1,3]dioxol 4 yl) 2 nitroethanol 3 2c ( White powder, 86%). 1 H NMR (500 MHz, CDCl 3 ) : ppm 6.94 6.98 (m, 1 H), 6.91 (t, J = 7.8 Hz, 1 H), 6.84 6.87 (m, 1 H), 6.03 (dd, J = 13.3, 1.4 Hz, 2 H), 5.57 (dt, J = 8.6, 4.2 Hz, 1 H), 4.63 4. 77 (m, 2 H), 2.96 (d, J = 4.9 Hz, 1 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 147.9, 144.3, 122.6, 119.7, 119.6, 109.4, 101.6, 79.5, 67.2; HRMS ( DART ) Calcd. for C 9 H 13 N 2 O 5 [M + NH 4 ] + : 229.0819 Found: 229.0810; Enantiomeric excess was determined by HPLC with a Chira lpak IB column (85:15 n hexane: isopropanol, 1.0 mL/min, 215 nm); minor t r = 8.73 min; major t r = 11.38 min; 9 5 % ee ; [ ] D 2 6 +41.5 ( c 4.6, CH 2 Cl 2 ). Configuration

PAGE 173

173 assignment: Absolute configuration of major isomer was determined to be ( S ) by analog y ( S ) 1 ( N aphthalen 1 yl) 2 nitroethanol 3 2d (Colorless oil, 99%). 1 H NMR (500 MHz, CDCl 3 ): ppm 8.04 8.10 (m, 1 H), 7.92 7.97 (m, 1 H), 7.89 (d, J = 8.2 Hz, 1 H), 7.75 7.82 (m, 1 H), 7.61 7.66 (m, 1 H), 7.51 7.60 (m, 2 H), 6.23 6.32 (m, 1 H), 4.62 4.76 (m, 2 H), 3.01 (dd, J = 3.8, 0.6 Hz, 1 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 133.9, 133.7, 129.7, 129.6, 129.5, 127.3, 126.3, 125.7, 124.0, 122.0, 81.0, 68.5; Enantiomeric excess was determined by HPLC with a Chiralpak IB colum n (85:15 n hexane: isopropanol, 1.0 mL/min, 215 nm); minor t r = 8.11 min; major t r = 10.11 min; 97% ee; [ ] D 26 +47.1 ( c 4.8, CH 2 Cl 2 ). Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison with literature d ata. 53 ( S ) 1 (2 C hlorophenyl) 2 nitroethanol 3 2e (Colorless oil, 94%). 1 H NMR ( 5 00 MHz, CDCl 3 ) : ppm 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 ( 126 MHz, CDCl 3 ) : ppm 135.8, 131.7, 130.2, 129.9, 127.8, 79.6, 68.1; Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O 1 column ( 95: 5 n hexane: iso propanol, 1 .0 mL/min, 215 nm); m inor t r = 8.57 min; major t r = 9.45 min; 9 5 %

PAGE 174

174 ee ; [ ] D 2 6 + 66.2 ( c 4.1, CH 2 Cl 2 ). Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison with literature data. 53 ( S ) 1 (2 F luorophenyl) 2 nitroethanol 3 2f (Colorless oil, 99%). 1 H NMR ( 5 00 MHz, CDCl 3 ) : ppm 7.54 7.66 (m, 1 H), 7.39 (tdd, J = 7.8, 5.5, 1.6 Hz, 1 H), 7.23 7.28 (m, 1 H), 7.12 (ddd, J = 10.5, 8.3, 1.1 Hz, 1 H), 5.79 (dt, J = 8.7, 4.1 Hz, 1 H), 4.50 4.76 (m, 2 H), 2.96 (d, J = 4.8 Hz, 1 H) ; 13 C NMR ( 126 MHz, CDCl 3 ) : ppm 159.6 (d, J CF = 246.2 Hz), 130.7 (d, J CF = 8.3 Hz), 127.8 (d, J CF = 3.7 Hz), 125.1 (d, J CF = 3.4 Hz), 116.7 (d, J CF = 21.5 Hz), 116.0 (d, J CF = 21.2 Hz), 80.0 (d, J CF = 2.0 Hz), 65.7 (d, J CF = 2.9 Hz) ; Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column (95:5 n hexane:isopropanol, 0.8 mL/min, 215 nm); minor t r = 10.67 min; major t r = 11.59 min; 9 6 % ee ; [ ] D 2 6 + 35.0 ( c 3.3, CH 2 Cl 2 ). Configuration assignment: Absolute configur ation of major isomer was determined to be ( S ) by comparison with literature data. 53 ( S ) 1 (3 F luorophenyl) 2 nitroethanol 3 2g ( C olorless oil 88% ). 1 H NMR (300 MHz, CDCl 3 ) : ppm 7.29 7.45 (m, 1 H), 7.10 7.21 (m, 2 H), 7.04 (td, J = 8.4, 2.5 Hz, 1 H), 5.46 (dd, J = 8.8, 3.4 Hz, 1 H), 4.43 4.64 (m, 2 H), 3.11 (s, 1 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 163.3 ( d, J CF = 246. 0 Hz ), 140.8 ( d, J CF = 6.8 Hz ), 130.9 ( d, J CF = 8.3 Hz ),

PAGE 175

175 121.7 ( d, J CF = 3.0 Hz ), 116.1 ( d, J CF = 2 1.0 Hz ), 113.3 ( d, J CF = 22.5 Hz ), 81.2, 70.5 ( d, J CF = 1.5 Hz ); HRMS ( DART ) Calcd. for C 8 H 2 6 FN 2 O 3 [M + NH 4 ] + : 203.0826 Found: 203.0809; Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85:15 n hexane: isopropanol, 1.0 mL/min, 215 nm); minor t r = 6.76 min; major t r = 7.29 min; 9 5 % ee ; [ ] D 2 6 + 85.3 ( c 3.6, CH 2 Cl 2 ). Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by analog y ( S ) 1 (4 C hlorophenyl) 2 nitroethanol 3 2h ( Colorless oil, 87% ). 1 H NMR ( 3 00 MHz, CD Cl 3 ): ppm 7.27 7.47 (m, 4 H), 5.44 (dd, J = 9.1, 3.5 Hz, 1 H), 4.42 4.67 (m, 2 H), 2.99 (s, 1 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 136.8, 135.1, 129.5, 127.6, 81.2, 70.5; HRMS ( DART ) Calcd. for C 8 H 1 2 Cl N 2 O 3 [M + NH 4 ] + : 219.0531 Found: 219.0527 ; Enantiomeric e xcess was determined by HPLC with a Chiralpak IB column (85:15 n hexane: isopropanol, 1.0 mL/min, 215 nm); minor t r = 7.25 min; major t r = 8.17 min; 9 5 % ee ; [ ] D 2 6 + 42.9 ( c 3.9, CH 2 Cl 2 ). Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by with literature data 53 ( S ) 1 ( B iphenyl 4 yl) 2 nitroethanol 3 2i (White powder, 95%). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.57 7.69 (m, 4 H), 7.44 7.55 (m, 4 H), 7.38 7.42 (m, 1 H), 5.55 (d, J = 9 .5 Hz, 1 H), 4.52 4.75 (m, 2 H), 2.86 (br s, 1 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm

PAGE 176

176 142.3, 140.5, 137.2, 129.1, 128.0, 127.9, 127.4, 126.7, 81.4, 71.1; HRMS ( DART ) Calcd. for C 14 H 17 N 2 O 3 [M + NH 4 ] + : 261.1234 Found: 261.1225 ; Enantiomeric excess was determined b y HPLC with a ( S,S ) Whelk O 1 column (85:15 n hexane: isopropanol, 1.0 mL/min, 215 nm); minor t r = 8.52 min; major t r = 10.47 min; 9 6 % ee ; [ ] D 2 6 + 34.4 ( c 4.8, CH 2 Cl 2 ). Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison with literature data. 53 ( S ) 1 (4 M ethoxyphenyl) 2 nitroethanol 3 2j (Colorless oil, 82%). 1 H NMR (500 MHz, CDCl 3 ) : ppm 7.31 7.39 (m, 2 H), 6.91 6.98 (m, 2 H), 5.39 5.47 (m, 1 H), 4.63 (dd, J = 13. 2, 9.6 Hz, 1 H), 4.47 4.54 (m, 1 H), 3.84 (s, 3 H), 2.80 (d, J = 3.6 Hz, 1 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 160.3, 130.5 127.6, 114.7, 81.5, 70.9, 55.6; Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85:15 n hexane: isopropanol, 0.8 mL/min, 215 nm); minor t r = 11.68 min; major t r = 13.36 min; D 26 +45.2.0 ( c 3.3, CH 2 Cl 2 ). Configuration assignment: Absolute configuration of major isomer was determined to be ( S ) by comparison with literature data. 53 ( S ) 2 N itro 1 phenylethanol 3 2k (Colorless oil, 85%). 1 H NMR ( 5 00 MHz, CDCl 3 ) : ppm 7.34 7.53 (m, 5 H), 5.48 (d, J = 9.6 Hz, 1 H), 4.58 4.70 (m, 1 H), 4.45

PAGE 177

177 4.58 (m, 1 H), 2.96 (br. s., 1 H); 13 C NMR ( 126 MHz, CDCl 3 ) : ppm 138. 4 129. 3 1 29. 2 126. 2 81. 5 71. 3 ; Enantiomeric excess was determined by HPLC with a Chiralpak IB column (85:15 n hexane: isopropanol, 0.8 mL/min, 215 nm); minor t r = 8.83 min; major t r = 9. 68 min; 9 7 % ee ; [ ] D 2 6 + 58.0 ( c 3.1 CH 2 Cl 2 ) Configuration assignment: Ab solute configuration of major isomer was determined to be ( S ) by comparison with literature data. 53 ( S ) 4 (Benzyloxy) 1 nitrobutan 2 ol 3 2l (Colorless oil, 90%). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.23 7.51 (m, 4 H), 4.5 3 4.62 (m, 3 H), 4.47 (d, J = 6.0 Hz, 2 H), 3.69 3.79 (m, 2 H), 3.38 (br. s., 1 H), 1.73 1.98 (m, 2 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 137.7, 128.8, 128.3, 128.0, 80.7, 73.7, 68.2, 67.5, 33.6; HRMS (DART) calcd for C 11 H 19 N 2 O 4 [M+NH 4 ] + : 243.1339. Found 243 .1340. Enantiomeric excess was determined by HPLC with a Chiralpak IA column (95:5 n hexane: isopropanol, 1.0 mL/min, 215 nm); minor t r = 20.34 min; major t r = 23.40 min; 92% ee; [ ] D 26 +40.8 ( c 3.3, CH 2 Cl 2 ). Configuration assignment: Absolute configurat ion of major isomer was determined to be ( S ) by comparison with literature data. 53 ( S ) 1 N itro 4 phenylbutan 2 ol 3 2m (White powder, 89%). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.08 7.48 (m, 4 H), 4.40 4.49 (m, 2 H), 4.30 4. 39 (m, 1 H), 2.85 2.95 (m,

PAGE 178

178 1 H), 2.79 (dt, J = 13.8, 8.1 Hz, 1 H), 2.64 (dd, J = 4.9, 0.8 Hz, 1 H), 1.86 1.96 (m, 1 H), 1.79 1.86 (m, 1 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 140.8, 128.9, 128.7, 126.6, 80.8, 68.0, 35.4, 31.6; HRMS ( DART ) calcd for C 10 H 17 N 2 O 3 [M+NH 4 ] + : 213.1234. Found 213.1238. Enantiomeric excess was determined by HPLC with a Chiralpak IB column (92:8 n hexane: isopropanol, 1.0 mL/min, 215 nm); minor t r = 17.05 min; major t r = 16.47 min; 9 1 % ee; [ ] D 2 6 19.7 ( c 1.1, CH 2 Cl 2 ). Configuration a ssignment: Absolute configuration of major isomer was determined to be ( S ) by comparison with literature data. 53 ( S E ) 1 Nitro 4 phenylbut 3 en 2 ol 3 2n (White solid, 88%) 1 H NMR (500 MHz, CDCl 3 ): ppm 7.25 7.47 (m, 5 H), 6.83 (d, J = 15.9 Hz, 1 H), 6.13 6.22 (m, 1 H), 5.04 5.15 (m, 1 H), 4.50 4.62 (m, 2 H), 2.65 (d, J = 4.5 Hz, 1 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 135.8, 134.0, 129.0, 128.8, 127.0, 125.1, 80.1, 69.9; HRMS ( DART ) calcd for C 10 H 15 N 2 O 3 [M+NH 4 ] + : 211.1 077. Found 211.1077. Enantiomeric excess was determined by HPLC with a Chiralpak IB column ( 85 :1 5 n hexane:isopropanol, 0.8 mL/min, 215 nm); minor t r = 18.00 min; major t r = 17.07 min; 9 2 % ee ; [ ] D 2 6 +17.2.0 ( c 1.9, CH 2 Cl 2 ). Configuration assignment: Abso lute configuration of major isomer was determined to be ( S ) by comparison with literature data. 53 General P rocedure for D iastereoselective Henry R eact ion To a 3.0 mL vial, cobalt complex 3 3c ( 13.0 mg, 0.0 125 mmol), 3,5 b is(trifluoro methyl)benzo ic acid ( 3.2 mg, 0.0125 mmol ) and THF ( 0.5 mL ) were added. The mixture

PAGE 179

179 was stirred at rt under air for 40 min until the solution changed into deep brown THF was removed under the reduced pressure to g ive a black solid. Then MTBE (0.1 mL), aldehyde 3 1a (34 mg, 0.2 5 mmol), and N ethylpiperidine ( 17 0. 125 mmol) were added. T he reaction mixture was cooled down to 70 C then Et NO 2 ( 0. 20 mL, 2. 5 mmol) w as added T he mixture was stirred at 7 0 C for 24 h. The reaction mixture was purified by flash column chromatogra phy on silica gel ( n hexane/EtOAc) to give the nitroaldol adduct 3 5aa (45 mg, 84%) as a colorless oil. Compounds 3 5aa 3 5ba 3 5da 3 5ea 3 5fa 3 5ka are reported compounds. Relative and absolute configurations of these nitroaldol products were determ ined by comparing chemical shifts in 1 H NMR and retention times in HPLC analysis with reported data. The absolute configuration of compound 3 5ta 2 was determined by derivatization into the corresponding methoxamine hydrochloride 3 7ta 2 which is consiste nt with the literature optical rotation. The anti configuration of 3 5ta 2 was confirmed by NOE experiment by derivatization into the corresponding oxazolidinone 3 7ta 3 The absolute configurations of new compounds were determined by analogy. 54 (1 S ,2 R ) 1 (2 Methoxyphenyl) 2 nitropropan 1 ol 3 5aa ( C olorless oil, 84% 48/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.42 7.49 (m, 1 H), 7.32 7.37 (m, 1 H), 7.03 (t, J = 7.5 Hz, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 5.57 (dd, J = 4.9, 4.3 Hz, 1 H), 4.90 4.99 (m, 1 H), 3.91 (s, 3 H), 3.10 (br. s., 1 H), 1.52 (dd, J = 6.9, 1.2 Hz, 3 H) ; 13 C NMR (126 MHz, CDCl 3 ) : ppm 15 6.0, 129.7, 127.9, 126.5, 121.2, 110.6, 85.3, 71.0, 55.7,

PAGE 180

180 12.9; HRMS ( GC CI MS) calcd for C 10 H 13 NO 4 [M] : 211.0845. Found 211.08 20. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O 1 column ( 95 : 5 n hexane:isopropanol, 0.8 mL/min, 2 1 5 nm); mi nor t r = 13.29 min; major t r = 14.38 min ; 9 6 % ee. Configuration assignment: Absolute configuration of major anti isomer was determined to be ( 1 S 2 R ) by comparison with literature data. 54 (1 S ,2 R ) 3 ( tert Butyldimethylsilyloxy) 1 (2 methoxyphenyl) 2 nitropropan 1 ol 3 5ab (White solid, 88% > 50/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.32 7.38 (m, 2 H), 6.99 7.03 (m, 1 H), 6.92 6.95 (m, 1 H), 5.31 5.41 (m, 1 H), 5.00 5.04 (m, 1 H), 4 .21 4.26 (m, 1 H), 4.14 4.19 (m, 1 H), 3.92 (s, 3 H), 3.64 3.68 (m, 1 H), 0.84 0.92 (m, 9 H), 0.06 (d, J = 1.6 Hz, 6 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 156.4, 130.0,

PAGE 181

181 128.3, 126.2, 121.3, 110.9, 91.0, 71.3, 61.8, 55.7, 25.9, 18.4, 5.4, 5.5; HRMS ( APCI TO F ) calcd for C 16 H 27 N Na O 5 Si [M+Na] + : 364.1551. Found 364.1559. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O 1 column ( 9 8 : 2 n hexane:isopropanol, 1.0 mL/min, 2 1 5 nm); minor t r = 10.98 min; major t r = 12.61 min ; 9 4 % ee. Configuration assign ment: Absolute configuration of major anti isomer was determined to be ( 1 S 2 R ) by analogy. (1 S ,2 R ) 1 (4 F luorophenyl) 2 nitropropan 1 ol 3 5ba. (Colorless oil, 87% 2.5/1 anti / syn ) 1 H NMR (500 MHz, CDCl 3 ): ppm 7.33 7.44 (m, 2 H), 7.05 7.15 (m, 2 H), 5.39 (d, J = 2.7 Hz, 1 H), 4.65 4.71 (m, 1 H), 2.77 (br. s., 1 H), 1.53 (dd, J = 6.8, 1.6 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 162.9 ( d, J CF = 248.2 Hz), 134.4, 128.0 (d, J CF

PAGE 182

182 = 8.8 Hz), 116.0 ( d, J CF = 22.7 Hz), 87.6, 73.6, 12.5; Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 97.5 : 2.5 n hexane:isopropanol, 0.8 mL/min, 2 15 nm); anti isomer: minor t r = 14.49 min; major t r = 15.33 min ; 98% ee; syn isomer: minor t r = 18.27 min; major t r = 24.92 min ; 85% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S, 2 R ) by comparison with literature data. 5 4 (1 S ,2 R ) 1 (Benzo[ d ][1,3]dioxol 4 yl) 2 nitropropan 1 ol 3 5ca. (White solid, 96% 8/1 anti / syn ). 1 H NMR (500MHz, CDCl 3 ) : ppm 6.95 6.98 (m, 1 H), 6.87 6.91 (m, 1 H), 6.82 6.84 (m, 1 H), 6.02 6.05 (m, 1 H) 5.98 (d, J = 1.5 Hz, 1 H) 5.51 (t, J = 3. 6 Hz,

PAGE 183

183 1 H) 4.88 (dd, J = 6. 9, 3.7 Hz, 1 H) 2.91 (d, J = 4. 4 Hz, 1 H) 1.55 (d, J = 6. 9 Hz, 3 H) ; 13 C NMR (126 MHz, CDCl 3 ) : ppm 147.6, 143.9, 122.4, 120.4, 119.6, 108.9, 101.5, 85.4, 70.3, 12.7; HRMS ( DART ) calcd for C 1 0 H 15 N 2 O 5 [M +NH 4 ] + : 243.0975 Found 243.0975. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 95 : 5 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 12.09 min; major t r = 13.09 min ; 96% ee; syn isomer: minor t r = 15.79 min; major t r = 21.94 min ; 80% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S, 2 R ) by analogy.

PAGE 184

184 (1 S ,2 R ) 1 (Naphthalen 1 yl) 2 nitropropan 1 ol 3 5da. (Colorless oil, 87%). 1 H NMR (500 MHz, CDCl 3 ) : ppm 8.02 (d, J = 8.2 Hz, 1 H) 7.76 7.96 (m, 3 H) 7.49 7.67 (m, 3 H) 6.30 (t, J = 2.7 Hz, 1 H) 4.87 5.00 (m, 1 H) 2.68 (d, J = 3.4 Hz, 1 H) 1.45 (d, J = 6.8 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ) : ppm 134.0, 133.9, 129.6 129.5, 129.3, 127.3, 126.2, 125.6, 124.2, 122.0, 85.8, 71.1, 11.3; HRMS ( DART ) calcd for C 13 H 17 N 2 O 3 [M+NH 4 ] + : 249.1234. Found 249.1231. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 96 : 4 n hexane:isopropanol, 0.8 mL/min, 2 15 n m); anti isomer: minor t r = 17.18 min; major t r = 20.93 min ; 97% ee; syn isomer: minor t r = 26.49 min; major t r = 51.33 min ; 84% ee Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S, 2 R ) by comparison with litera ture data. 54

PAGE 185

185 (1 S ,2 R ) 1 (2 Chlorophenyl) 2 nitropropan 1 ol 3 5ea (Colorless oil, 89% yield 10/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.60 7.69 (m, 1 H), 7.35 7.41 (m, 2 H), 7.29 7.34 (m, 1 H), 5.86 (t, J = 2.7 Hz, 1 H), 4.86 4.94 (m, 1 H), 2.93 (d, J = 3.7 Hz, 1 H), 1.42 1.52 (m, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 136.0, 131.7, 129.9, 129.8, 128.4, 127.5, 84.3, 70.7, 11.5; HRMS ( ESI ) calcd for C 9 H 9 Cl NO 3 [M H] : 214.0276. Found 214.0278. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 98 : 2 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 10.33 min; major t r = 11.08 min ; 90% ee; syn isome r: minor t r = 14.61 min; major t r = 20.67 min ; 74% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S, 2 R ) by comparison with literature data. 54

PAGE 186

186 (1 S ,2 R ) 1 (2 F luorophenyl) 2 nitropropan 1 ol 3 5fa ( C olorless oil, 90% 8/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.54 7.59 (m, 1 H), 7.31 7.37 (m, 1 H), 7.22 (td, J = 7.6, 1.2 Hz, 1 H), 7.07 (ddd, J = 10.6, 8.2, 1.1 Hz, 1 H), 5.73 (t, J = 3 .6 Hz, 1 H), 4.81 (qd, J = 6.9, 3.2 Hz, 1 H), 2.96 (d, J = 4.3 Hz, 1 H), 1.48 (d, J = 7.0 Hz, 3 H) ; 13 C NMR (126 MHz, CDCl 3 ): ppm 159.4 ( d, J CF = 246.9 Hz), 130.4 (d, J CF = 5.2 Hz), 128.1 (d, J CF = 3.7 Hz), 125.7 (d, J CF = 12.9 Hz), 124.9 (d, J CF = 3.3 H z), 115.7 (d, J CF = 21.3 Hz), 85.4, 68.6, 12.2; HRMS ( DART ) calcd for C 9 H 14 F N 2 O 3 [M+NH 4 ] + : 217.0983. Found 217.0984. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 99 : 1 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: mino r t r = 14.71 min; major t r = 15.58 min ; 94% ee; syn isomer: minor t r = 23.17 min; major t r = 30.76 min ; 82% ee Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S, 2 R ) by comparison with literature data. 54

PAGE 187

187 (1 S ,2 R ) 2 Nitro 1 phenylpropan 1 ol 3 5ka (Colorless oil, 94% 1.6/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.36 7.45 (m, 5 H), 5.48 5.40 (m, 1 H), 4.73 (ddd, J = 6.9, 3.6, 0.8 Hz, 1 H), 2.71 (br. s., 1 H) 1.54 (dd, J = 6.8, 1.3 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 138.6, 129.3, 129.0, 126.2, 87.7, 74.1, 12.4; HRMS ( DART ) calcd for C 9 H 15 N 2 O 3 [M+NH 4 ] + : 199.1077. Found 199.1080. Enantiomeric excess was determined by HPLC with a ( S,S ) W helk O1 column ( 97 : 3 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 10.23 min; major t r = 10.94 min ; 97% ee; syn isomer: minor t r = 13.27 min; major t r = 18.76 min ; 82% ee Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S, 2 R ) by comparison with literature data. 54

PAGE 188

188 (3 S ,4 R ) 1 (Benzyloxy) 4 nitropentan 3 ol 3 5la (Colorless oil, 89% 1.1/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ) : ppm 7.29 7.43 (m, 10 H ( anti + syn )), 4.57 4.63 (m, 1 H ( anti )), 4.53 4.57 (m, 1H ( syn )), 4.54 4.56 (s, 4 H ( anti + syn )), 4.35 (dt, J = 8.3, 4.2 Hz, 1H ( syn )), 4.21 (d, J = 1.1 Hz, 1 H ( anti )), 3.74 3.82 (m, 2 H ( anti )), 3.66 3.74 (m, 2 H ( syn )), 3.30 3.44 (br. s., 2 H ( anti + syn )), 1.75 1.90 (m, 4 H ( anti + syn )), 1.59 (d, J = 6.9 Hz, 3 H ( anti )), 1.55 (d, J = 6.9 Hz, 3 H ( syn )); 13 C NMR (126 MHz, CDCl 3 ): ppm 137.7, 128.8, 128.2, 128.0, 87.6, 86.5, 73.7, 73.6, 72.5, 72.0, 68.3, 68.0, 32.8, 32.4 16.0, 13.7; HRMS (ESI) calcd for C 12 H 17 Na NO 4 [M+Na] + : 262.1050. Found 262.1058. Enantiomeric excess was determined by HPLC with a IA column ( 98.5 : 1.5 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 35.40 min; major t r = 37.47 min ; 96% ee; syn isomer: minor t r = 47.16 min; major t r = 52.83 min ; 90% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be ( 3 S, 4 R ) by analogy.

PAGE 189

189 (1 S ,2 R ) 1 (2 ( B enzyloxy)phenyl) 2 nitropropan 1 ol 3 5oa ( White powder 8 5 %, 11/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.49 (dd, J = 7.5, 1.2 Hz, 1 H), 7.35 7.48 (m, 5 H), 7.33 (td, J = 7.8, 1.8 Hz, 1 H), 7.05 (td, J = 7.5, 1.0 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 5.66 (br. s, 1 H), 5.11 5.21 (m, 2 H), 4.98 (dd, J = 6.9, 3.6 Hz, 1 H), 3.01 (br. s, 1 H), 1.50 (d, J = 6.9 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 155.1, 136.5, 129.7, 129.1, 128.5, 128.0, 127.4, 126.9, 121.6, 112.0, 85.3, 71.0, 70.4, 12.7; HR MS ( DART ) calcd for C 16 H 21 N 2 O 4 [M+NH 4 ] + : 305.1496. Found 305.1487. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 96 : 4 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 13.20 min; major t r = 14.65 min ; 9 6 % ee; sy n isomer: minor t r = 20.97 min; major t r = 26.11 min ; 76% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S 2 R ) by analogy.

PAGE 190

190 (1 S ,2 R ) 1 (2,4 Dimethoxyphenyl) 2 nitropropan 1 ol 3 5pa (Yellow solid, 81% > 50/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.33 (dd, J = 8.4, 0.6 Hz, 1 H), 6.54 (dd, J = 8.4, 2.4 Hz, 1 H), 6.49 (d, J = 2.3 Hz, 1 H), 5.42 5.44 (m, 1 H), 4.90 (dd, J = 6.9, 4.3 Hz, 1 H), 3.88 (s, 3 H), 3.84 (s, 3 H), 2.97 3.05 (m, 1 H), 1.54 (d, J = 6.9 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 161.2 157.2 131.1 128.8, 118.9, 104.7, 98.9, 85.7, 71.3, 55.7, 13.2; HRMS (ESI) calcd for C 11 H 15 Na NO 5 [M+Na] + : 264.0842. Found 264.0855. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 92 : 8 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 13.02 min; major t r = 15.06 min ; 90% ee; syn isomer: t r = 20.36 min; t r = 32.08 min ; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S, 2 R ) by analogy.

PAGE 191

191 (1 S ,2 R ) 1 (4 Bromo 2 methoxyphenyl) 2 nitropropan 1 ol 3 5qa (White solid, 94% 15/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.34 (dd, J = 8.1, 0.7 Hz, 1 H), 7.16 (dd, J = 8.2, 1.8 Hz, 1 H), 7.04 (d, J = 1.8 Hz, 1 H), 5.54 (d, J = 4.1 Hz, 1 H), 4.85 (dd, J = 6.9, 3.4 Hz, 1 H), 3.88 (s, 3 H), 3.04 (d, J = 5.1 Hz, 1 H), 1.46 (d, J = 6.9 Hz, 3 H); 13 C N MR (126 MHz, CDCl 3 ): ppm 156.4, 129.1, 125.8, 124.3, 123.1, 114.3, 84.8, 70.0, 56.1, 12.5; HRMS ( DART ) calcd for C 10 H 16 Br N 2 O 4 [M+NH 4 ] + : 307.0288. Found 307.0288. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 96 : 4 n hexane:isop ropanol, 0.8 mL/min, 2 15 nm); anti isomer: minor t r = 14.58 min; major t r = 15.56 min ; 95% ee; syn isomer: minor t r = 21.68 min; major t r = 31.19 min ; 96% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S, 2 R ) by analogy

PAGE 192

192 (1 S ,2 R ) 1 (2 ( A llyloxy) 5 methylphenyl) 2 nitropropan 1 ol 3 5ra ( Yellow oil 9 6 % 9/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ) : ppm 7.24 (d, J = 2.2 Hz, 1 H), 7.08 (dd, J = 8.4, 2.2 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.05 (dd, J = 17.2, 10.6 Hz, 1 H), 5.54 (dd, J = 5.4, 4.0 Hz, 1 H), 5.44 (dd, J = 17.3, 1.5 Hz, 1 H), 5.32 (dd, J = 10.6, 1.4 Hz, 1 H), 4.95 (dd, J = 6.9, 3.8 Hz, 1 H), 4.58 (ddt, J = 6.9, 5.1, 1.6, 1.6 Hz, 2 H), 3.04 (d, J = 5.6 Hz, 1 H), 2.31 (s, 3 H), 1.51 (d, J = 6.9 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ) : ppm 152.9, 132.9, 130.7, 129.9, 128.5, 126.3, 117.9, 111.8, 85.4, 71.3, 69.1, 20.8, 12.9; HRMS ( DART ) calcd f or C 13 H 21 N 2 O 4 [M +NH 4 ] + : 269.1496 Found 269.1498 Enantiomeric excess was determined by HPLC with a Chiralpak IB column ( 9 9 : 1 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: major t r = 19.88 min ; minor t r = 22.12 min; 9 4 % ee; syn isomer: major t r = 37.30 min ; minor t r = 38.28 min; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S 2 R ) by analogy

PAGE 193

193 (1 S ,2 R ) 1 (5 F luoro 2 methoxyphenyl) 2 nitropropan 1 ol 3 5sa (Off white powder, 92%, 26/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.22 7.26 (m, 1 H), 6.98 7.04 (m, 1 H), 6.84 (dd, J = 9.0, 4.2 Hz, 1 H), 5.61 (d, J = 2.9 Hz, 1 H), 4.90 (dd, J = 6.9, 3.1 Hz, 1 H), 3.87 (s, 3 H), 3.00 (br. s, 1 H), 1.48 (d, J = 6.9 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 157.5 ( d, J CF = 239.9 Hz), 151.9 ( d, J CF = 2.5 Hz), 128.3 ( d, J CF = 7.6 Hz), 115.5 (d, J CF = 23.9 Hz), 114.9 (d, J CF = 25.2 Hz), 111.4 (d, J CF = 8.8 Hz), 84.7, 69.8, 56.1, 12.4; HRMS ( DART ) calcd for C 10 H 16 F N 2 O 4 [M+NH 4 ] + : 247.1089. Found 247.1092. Enantiomeric excess was determined by HPLC with a Chiralpak IA column ( 9 9: 1 n hexane:isopropanol, 1. 2 mL/min, 2 15 nm); anti isomer: minor t r = 62.92 min; major t r = 70.19 min ; 9 6 % ee; syn isomer: minor t r = 131.24 min; major t r = 103.07 min ; 86% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S 2 R ) by analogy.

PAGE 194

194 (1 S ,2 R ) 3 ( tert B ut yldimethylsilyloxy) 1 (5 fluoro 2 methoxyphenyl) 2 nitropropan 1 ol 3 5sb (Colorless oil, 99% 8 /1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ) : ppm 7.16 7.20 (m, 1 H), 7.00 7.05 (m, 1 H), 6.83 6.88 (m, 1 H), 5.44 5.49 (m, 1 H), 4.95 4.99 (m, 1 H), 4.11 4.21 (m, 2 H), 3.87 3.91 (m, 3 H), 3.74 (d, J = 7.0 Hz, 1 H), 0.88 (s, 9 H), 0.07 (s, 6 H); 13 C NMR (126 MHz, CDCl 3 ) : ppm 157.4 ( d, J CF = 240.6 Hz), 152.2, 128.2 (d, J CF = 6.3 Hz), 115.8 (multi), 115.1 (multi), 111.7, 89.9 (d, J CF = 21.4 Hz), 70.3 (d, J CF = 5.0 H z), 61.3 (t, J CF = 12.6 Hz), 56.2 (q, J CF = 16.4 Hz), 25.9 (d, J CF = 5.0 Hz), 5.47 (t, J CF = 7.5 Hz); HRMS ( ESI ) calcd for C 16 H 26 F N Na O 5 Si [M+Na] + : 382.1457. Found 382.1474. Enantiomeric excess was determined by HPLC with a Chiralpak IA column ( 9 9 .5 : 0.5 n hexane:isopropanol, 1.1 mL/min, 2 15 nm); anti isomer: major t r = 35.86 min ; minor t r = 43.28 min; 93% ee; syn isomer: major t r = 72.16 min ; minor t r = 83.49 min; 75 % ee; Configuration assignment: Absolute configuration of major anti isomer was determined t o be (1 S 2 R ) by analogy.

PAGE 195

195 (1 S ,2 R ) 1 (2,5 D imethoxyphenyl) 2 nitropropan 1 ol 3 5ta 1 ( Colorless oil 99 %, 2 4 /1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ) : ppm 7.02 7.06 (m, 1 H), 6.82 6.85 (m, 2 H), 5.54 (dd, J = 5.4, 3.7 Hz, 1 H), 4.92 (dd, J = 6.9, 3.7 Hz, 1 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 3.07 (d, J = 5.4 Hz, 1 H), 1.50 (d, J = 6.9 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ) : ppm 154.1, 150.1, 127.4, 114.1, 114.0, 111.5, 85.2, 70.9, 56.0 (3), 56.0 ( 1 ), 12.8; HRMS ( DART ) calcd for C 11 H 19 N 2 O 5 [M+NH 4 ] + : 259.1288. Found 259.1284. Enantiomeric excess was determined by HPLC with a Chiralpak IB column ( 97 : 3 n hexane: isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 15.74 min; major t r = 16.1 8 min ; 96% ee; syn isomer: minor t r = 26.39 min; major t r = 28.45 min ; 76% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S 2 R ) by analogy

PAGE 196

196 (1 R ,2 S ) 1 (2,5 D imethoxyphenyl) 2 nitropropan 1 ol 3 5ta 2 ( Colorless oil 99 %, 24/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.02 7.06 (m, 1 H), 6.82 6.85 (m, 2 H), 5.54 (dd, J = 5.4, 3.7 Hz, 1 H), 4.92 (dd, J = 6.9, 3.7 Hz, 1 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 3.07 (d, J = 5.4 Hz, 1 H), 1.50 (d, J = 6.9 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 154.1, 150.1, 127.4, 114.1, 114.0, 111.5, 85.2, 70.9, 56.0 (3), 56.0 (1), 12.8; Enantiomeric excess was determined by HPLC with a Chiralpak IB column ( 97 : 3 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: major t r = 15. 35 min ; minor t r = 16. 57 min; 9 4 % ee; syn isomer: major t r = 2 5.87 min ; minor t r = 28.37 min; 76% ee; Configuration assignment: Absolute configuration of major anti isomer was determi ned to be (1 R 2 S ) by derivatizing to the known drug ( 1 R ,2 S Methoxamine hydrochloride )

PAGE 197

197 (1 S ,2 R ) 3 ( tert B utyldimethylsilyloxy) 1 (2,5 dimethoxyphenyl) 2 nitropropan 1 ol 3 5tb (Yell ow oil, 97% 7/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 6.96 (s, 1 H), 6.82 6.89 (m, 2 H), 5.31 5.37 (m, 1 H), 4.98 5.04 (m, 1 H), 4.13 4.26 (m, 2 H), 3.87 (s, 3 H), 3.79 (s, 3 H), 0.88 (s, 9 H), 0.07 (d, J = 1.4 Hz, 6 H); 13 C NMR (126 MHz, CDCl 3 ): pp m 154.1, 150.4, 127.2, 114.4, 114.2, 111.8, 90.8, 71.2, 61.7, 56.0, 25.9, 18.4, 5.4, 5.5; HRMS ( DRAT ) calcd for C 17 H 33 N 2 O 6 Si [M+NH 4 ] + : 389.2102. Found 389.2104. Enantiomeric excess was determined by HPLC with a Chiralpak IB column ( 97 : 3 n hexane:isoprop anol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 9.43 min; major t r = 10.23 min ; 91% ee; syn isomer: minor t r = 14.65 min; major t r = 17.53 min ; 76% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S, 2 R ) by analogy.

PAGE 198

198 (1 S ,2 R ) 1 (2 Methoxynaphthalen 1 yl) 2 nitropropan 1 ol 3 5ua (Colorless oil, 95% 17/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 8.12 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 9. 1 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.58 (dd, J = 8.4, 7.1 Hz, 1 H), 7.43 (d, J = 7.1 Hz, 1 H), 7.33 (d, J = 9.1 Hz, 1 H), 6.06 (dd, J = 10.5, 6.1 Hz, 1 H), 5.11 (t, J = 6.5 Hz, 1 H), 4.59 (d, J = 10.4 Hz, 1 H), 4.08 (s, 3 H), 1.75 (d, J = 6.7 Hz, 3 H) ; 13 C NMR (126 MHz, CDCl 3 ): ppm 155.5, 132.0, 131.4, 129.6, 129.0, 128.0, 124.5, 122.5, 118.5, 112.9, 86.4, 72.4, 56.6, 14.7; HRMS ( DART ) calcd for C 14 H 19 N 2 O 4 [M+NH 4 ] + : 279.1339. Found 279.1335 Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 9 6 : 4 n hexane :isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 67.32 min; major t r = 38.69 min ; 9 7 % ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be ( 1 S 2 R ) by analogy.

PAGE 199

199 (2 R ,3 S ) 5 M ethyl 2 nitrohex 4 en 3 ol 3 5va. (Yellow oil, 80% 9/1 anti / syn ). 1 H NMR (500 MHz, CDCl 3 ): ppm 5.17 (dt, J = 8.6, 1.4 Hz, 1 H), 4.86 (dd, J = 8.6, 4.3 Hz, 1 H), 4.52 (dd, J = 6.7, 4.4 Hz, 1 H), 2.17 (br. s., 1 H), 1.78 (d, J = 1.2 Hz, 3 H), 1.74 (d, J = 1.2 Hz, 3 H), 1.59 (d, J = 6.7 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 140.0, 121.7, 86.6 69.9, 26.1, 18.7, 13.8; HRMS ( DART ) calcd for C 7 H 17 N 2 O 3 [M+NH 4 ] + : 177.1234. Found 177.1235 Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 9 9 : 1 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 16. 60 min; major t r = 17. 14 min ; 9 8 % ee; syn isomer: minor t r = 24.4 9 min; major t r = 32. 44 min ; 65 % ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be ( 2 R, 3 S ) by analogy.

PAGE 200

200 (1 S ,2 R ) 2 N itro 1 o tolylpropan 1 o l 3 5wa (Colorless oil, 88 %). 1 H NMR (500 MHz, CDCl 3 ) : ppm 7.58 (d, J = 7.3 Hz, 1 H), 7.26 7.33 (m, 2 H), 7.19 7.23 (m, 1 H), 5.67 (d, J = 2.7 Hz, 1 H), 4.68 (dd, J = 6.7, 3.0 Hz, 1 H), 2.52 2.58 (m, 1 H), 2.41 (s, 3 H), 1.56 (d, J = 6.9 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ) : ppm 136.8, 134.6, 131.0, 128.6, 126.8, 126.3, 85.6, 71.1, 19.1, 11.9; HRMS ( DART ) calcd for C 10 H 1 7 N 2 O 3 [M+NH 4 ] + : 213.1234 Found 213.1237. Enantiomeric excess was determined by HPL C with a ( S,S ) Whelk O1 column ( 98 : 2 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 12.40 min; major t r = 13.96 min ; 90 %ee; syn isomer: minor t r = 15.23 min; major t r = 25.73 min ; 87 %ee Configuration assignment: Absolute configuratio n of major anti isomer was determined to be (1 S, 2 R ) by comparison with literature data. 54

PAGE 201

201 (2 R ,3 S E ) 2 Nitro 5 phenylhex 4 e n 3 ol 3 5xa ( Colorless oil 82 %). 1 H NMR (500 MHz, CDCl 3 ) : ppm 7.30 7.44 (m, 5 H), 5.72 (dd, J = 8.5, 1.2 Hz, 1 H), 5.05 5.12 (m, 1 H), 4.61 4.69 (m, 1 H), 2.36 (br. s 1 H), 2.17 (d, J = 1.2 Hz, 3 H), 1.66 (d, J = 6.9 Hz, 3 H) ; 13 C NMR (126 MHz, CDCl 3 ) : ppm 142.3, 141.5, 128.7, 128.2, 126.2, 124.2, 86.4, 70. 2, 17.0, 13.7; HRMS ( DART ) calcd for C 12 H 1 9 N 2 O 3 [M +NH 4 ] + : 239.1390 Found 239.1385. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 98 : 2 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 18.58 min; major t r = 19.5 9 min ; 97% ee; syn isomer: minor t r = 23.87 min; major t r = 33.73 min ; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S 2 R ) by analogy.

PAGE 202

202 ( 1 S ,2 R ) 1 (3 F luorophenyl) 2 nitropropan 1 ol 3 5ya (Colorless oil, 82%). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.35 7.45 (m, 1 H), 7.14 7.20 (m, 2 H), 7.02 7.14 (m, 1 H), 5.45 (d, J = 3.2 Hz, 1 H), 4.71 (dd, J = 6.8, 3.4 Hz, 1 H), 2.78 (br. s., 1 H), 1.52 (d, J = 6.9 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 163.3 ( d, J CF = 249.5 Hz), 141.2 ( d, J CF = 6.3 Hz), 130.6 ( d, J CF = 7.6 Hz), 121.7 ( d, J CF = 3.8 Hz), 115.7 ( d, J CF = 21.4 Hz), 113.4 ( d, J CF = 22.7 Hz), 87.4, 73.3, 12.2; HRMS ( DART ) calcd for C 9 H 14 F N 2 O 3 [M+ NH 4 ] + : 217.0983. Found 217.0987. Enantiomeric excess was determined by HPLC with a Chiralpak IB column ( 95 : 5 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 9.80 min; major t r = 12.35 min ; 95% ee; syn isomer: minor t r = 11.70 min; major t r = 13.31 min ; 8 5 % ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S 2 R ) by analogy.

PAGE 203

203 (1 S ,2 R ) 1 ( B iphenyl 4 yl) 2 nitropropan 1 ol 3 5z a (Off white powder, 86%). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.57 7.69 (m, 4 H), 7.43 7.53 (m, 4 H), 7.35 7.43 (m, 1 H), 5.48 (d, J = 3.6 Hz, 1 H), 4.77 (dd, J = 6.9, 3.6 Hz, 1 H), 2.63 2.78 (m, 1 H), 1.58 (d, J = 6.9 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ): pp m 141.8, 140.6, 137.6, 129.1, 128.0, 127.7, 126.7, 87.7, 74.0, 12.5; HRMS ( DART ) calcd for C 15 H 19 N 2 O 3 [M+NH 4 ] + : 275.1390. Found 275.1385. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 96 : 4 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 14.57 min; major t r = 16.18 min ; 97% ee; syn isomer: minor t r = 18.10 min; major t r = 30.21 min ; 86% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be (1 S 2 R ) by analogy.

PAGE 204

204 (1 S ,2 R ) 1 (3 M ethoxyphenyl) 2 nitropropan 1 ol 3 5zaa (Colorless oil, 95% 2/1 anti / syn ) 1 H NMR (500 MHz, CDCl 3 ) : ppm 7.29 7.36 (m, 1 H), 6.93 6.99 (m, 2 H), 6.88 (dd, J = 8.3, 1.4 Hz, 1 H), 5 .41 (d, J = 2.5 Hz, 1 H), 4.71 (dd, J = 6.8, 3.5 Hz, 1 H), 3.84 (s, 3 H), 2.68 (br. s ., 1 H), 1.46 1.58 (m, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 160.2, 140.3, 130.1, 118.4, 114.1, 111.9, 87.6, 74.0, 55.6, 12.3; HRMS ( DART ) calcd for C 10 H 17 N 2 O 4 [M+NH 4 ] + : 2 29.1183. Found 229.1184. Enantiomeric excess was determined by HPLC with a ( S,S ) Whelk O1 column ( 9 9: 1 n hexane:isopropanol, 1.0 mL/min, 2 15 nm); anti isomer: minor t r = 32.85 min; major t r = 36.62 min ; 99% ee; syn isomer: minor t r = 55.66 min; major t r = 75.76 min ; 86% ee; Configuration assignment: Absolute configuration of major anti isomer was determined to be ( 2 R, 3 S ) by analogy.

PAGE 205

205 1 R ,2 S Methoxamine hydrochloride 3 7ta 2 In a round b ottom flask, EtOH (10 mL) was added to a mixture of Pd C (10 wt %, 10 mg) and (1 R ,2 S ) 1 (2,5 dimethoxyphenyl) 2 nitropropan 1 ol (55 mg). The reaction mixture was then allowed to stir vigorously under a hydrogen atmosphere for 9 h. Then, this reaction mixt ure was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the corresponding amino alcohol as a colorless oil. This amino alcohol was then dissolved in eth er (10 mL) and cooled down to 0 C. 4 M HCl in dioxane ( 58 L 0.23 mmol, 1.0 equiv) was added slowly into this solution. The yellow precipitate was formed immediately. The solvent was removed by decanting and this solid was washed with ether (5 mL). Then the liquid was removed by decanting a gain. This was repeated 5 times. Then the remaining solid was collected by filtration and then recrystalized in hexanes and chloroform to give 3 7ta 2 as a white solid (46 mg, 82%). 1 H NMR (500 MHz, DMSO d 6 ): ppm 8.14 (br. s., 3 H), 7.01 (d, J = 3.2 Hz, 1 H), 6.93 (d, J = 8.9 Hz, 1 H), 6.84 (dd, J = 8.9, 3.2 Hz, 1 H), 5.92 (d, J = 4.4 Hz, 1 H), 5.12 (br. s., 1 H), 3.76 (s, 3 H), 3.72 (s, 3 H), 3.35 (s, 1 H), 0.91 (d, J = 6.7 Hz, 3 H); 13 C NMR (126 MHz, DMSO d 6 ): p pm 153.8, 150.2, 130.8, 114.0, 113.2, 112.3, 67.3, 56.5, 56.1, 50.0, 12.3; HRMS ( ESI ) calcd for C 11 H 18 NO 3 [M Cl] + : 212.1281. Found 212.1278. The ee was determined to be 98% by analyzing the ee of corresponding o xazoli din one 3 7ta 3 Configuration as signment: Absolute configuration of major anti isomer was determined to be (1 R 2 S ) by comparison with the literature optical rotation: optical

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206 rotation observed: D 25 27 .0 ( c 3.1, H 2 O ) [lit. [ ] D 25 27 .9 (c 3.1, H 2 O ] (Fujita, M.; Hiyama, T. J. Org. Chem 1988 53 5415 5421 ).

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207 (4 S ,5 R ) 5 (2,5 Dimethoxyphenyl) 4 methyloxazolidin 2 one 3 7ta 3 The method was followed by literature procedure. 55 A s olution of triphosgene (8 mg, 0.027 mmol) in dry CH 2 Cl 2 (0.8 mL) was added slowly to a suspension of (1 R ,2 S ) 2 a mino 1 (2,5 dimethoxyphenyl)propan 1 ol hydrochloride (20 mg, 0.081 mmol) and triethylamine (35 0.25 mmol) in dry CH 2 Cl 2 (1.5 mL) at 0 C. The reaction mixture was stirred at this temperature for 15 min and then warmed up to room temperature for 1 h. Saturated NH 4 Cl solution (3 mL) and ethyl acetate (20 mL) were added to the reaction mixture and a fter stirring for 20 min, the mixture was washed with water. The organic layer was separated and dried 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) t o give the product as a w hite solid ( 17 mg 88%). 1 H NMR (500 MHz, CDCl 3 ): ppm 7.09 (d, J = 2.9 Hz, 1 H), 6.85 (d, J = 3.0 Hz, 1 H), 6.81 6.83 (m, 1 H), 5.91 (d, J = 7.7 Hz, 1 H), 5.45 5.52 (m, 1 H), 4.24 4.35 (m, 1 H), 3.81 (s, 3 H), 3.81 (s. 3 H), 0.81 (d, J = 6.5 Hz, 3 H); 13 C NMR (126 MHz, CDCl 3 ): ppm 159.1, 154.1, 149.9, 124.9, 114.4, 112.2, 111.1, 77.8, 56.1, 56.0, 51.7, 17.7; HRMS ( ESI ) calcd for C 12 H 15 N Na O 4 [M+Na] + : 260.0839. Found 260.0883. Enantiomeric excess was determined by HPLC with a Chiralpak I A column ( 95 : 5 n hexane: isopropanol, 1.0 mL/min, 215 nm); minor t r = 27.48 min; major t r = 22.23 min; 9 8 % ee

PAGE 208

208

PAGE 209

209 Mechanism S tudy General P rocedure for K inetic S tudy To a 3.0 mL vi al, cobalt complex 3 3c ( 6.6 mg 0.0 0625 mmol ), 3,5 b is(trifluoromethyl) benzoic acid (1.6 mg, 0.0 0625 mmol) and THF ( 0.5 mL ) were added. The mixture was stirred at room temperature under air for 40 min until the solution changed into deep brown color The n THF was removed under the reduced pressure to

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210 give a black solid. CH 2 Cl 2 (1.2 mL), 2 methoxybenzaldehyde 3 1a (136 mg, 1 mmol) 1 b romonaphthalene (60 internal standard), and N ethylpiperidine (68 0.5 mmol) were added to this mixture. T he reaction mixture was cooled down to 70 C then CH 3 NO 2 ( 0.52 mL, 10 mmol ) w as added The reaction progress was monitored by the e reaction mixture, filtration through silica gel with 10% isopropanol in n h exane as the eluent, and HPLC an alysis (Chiralpak IB column, 96 : 4 n hexane: isopropanol, 0.8 mL/min, 2 54 nm, 1 b romonaphthalene (internal standard) : 5 .0 4 min, 2 methoxybenzaldehyd e : 8.2 8 min). The first integration ratio ( area (%) of (aldehyde/internal standard) for 0 min) was determined twice before the reaction was triggered by the addition of 1 ethylpiperidine ( 68 0.5 mmol ) and the value was averaged. The slopes of the least square lines for the plots of Ln([SM] t /[SM] 0 ) vs. time were determined. Table 3 9 Kinetic data for 5 mol % l oading of 3 3c O 2 CAr F [ 27.0 mM] Time (h) Area (%) Parameter (B/A) Conversion (% ) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 13.39 86.61 6.468 0 0 0. 42 23.41 76.59 3.271 49.5 0.683 0.88 35.62 64.38 1.807 72.0 1.270 1.32 41.54 58.46 1.407 78.2 1.523 1.75 52.79 47.21 0.8942 86.2 1.980 2.18 66.82 33.18 0.4965 92.3 2.567 2.62 78.32 21.68 0.2768 95.7 3.151 Table 3 10 Kinetic data for 2.5 mol % l oading of 3 3c O 2 CAr F [ 13.5 mM] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 10.94 89.06 8.142 0 0 0.3 3 14.98 85.02 5.668 30.3 0.361 0.77 19.09 80.91 4.238 47.9 0.652 1.20 21.27 78.73 3.700 54.5 0.787 1.65 25.70 74.29 2.890 64.5 1.036 2.08 29.73 70.27 2.360 70.9 1.234 2.51 34.29 65.71 1.916 76.5 1.448 2.94 38.99 61.07 1.565 81.4 1.683

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211 Table 3 11 Kinetic data for 1.25 mol % l oading of 3 3c O 2 CAr F [ 6.75 mM] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 11.42 88.58 7.75 0 0 0.38 13.74 86.26 6.278 18.9 0.211 0.82 15.16 84.83 5.594 28.3 0.327 1.25 16.81 83.19 4.949 36.5 0.447 1.68 20.00 80.00 4.00 48.7 0.661 2.12 21.05 78.95 3.751 51.6 0.722 2.55 22.93 77.07 3.360 56.6 0.836 2.98 24.73 75.27 3.043 60.7 0.934 3.46 27.12 72.88 2.687 65.3 1.06 3.94 29.80 70.20 2.356 69.6 1.19 Table 3 12 Kinetic data for 0.625 mol % l oading of 3 3c O 2 CAr F [ 3.375 mM] Time (h) Area (%) Parameter (B/A) Conversion (%) Ln[SM] t /[SM] 0 A (internal standard) B (aldehyde) 0 11.23 88.77 7.900 0 0 0.55 12.46 87.54 7.026 11.1 0.117 1.00 13.21 86.79 6. 570 16.8 0.184 1.45 13.96 86.04 6.160 21.9 0.247 2.03 14.87 85.13 5.724 27.5 0.322 2.60 15.66 84.34 5.386 31.8 0.383 3.18 16.51 83.49 5.057 36.0 0.446 3.63 17.58 82.42 4.688 40.7 0.522 Table 3 13 Kinetic d ata for F igure 3 5 [ C atalyst] ( m M) k obs ( h 1 ) 3.375 0.135 6.75 0.289 13.5 0.534 27.0 1.137 Figure 3 8 Kinetic s tudy of l igand 3 3c O 2 CAr F c omplex

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212 General P rocedure for N onl inear E ffect S tudy To a 3.0 mL vial, cobalt complex 3 3c ( 26.5 mg, 0.025 mmol the mixture of cobalt complexes ( R R ) 3 3c and ( S S ) 3 3c ), 3,5 b is(trifluoromethyl)ben zoic acid (6.4 mg, 0.025 mmol) and THF ( 0.5 mL ) were added. The reaction mixture was stirred at room temperature under air for 40 min until the solution changed into deep brown color Then THF was removed un der the reduced pressure to g ive a black solid. Then CH 2 Cl 2 (0.6 mL), 2 methoxybenzaldehyde 3 1a (68 mg, 0.5 mmol) and N ethylpiperidine ( 34 0. 2 5 mmol) were added to this mixture. T he reaction mixture was c ool ed down to 70 C then CH 3 NO 2 ( 0.26 mL, 5 mmol) w as added T he mixture was stirred at 7 0 C for 18 h. The reaction mixture was purified by flash column chromatography on silica gel ( n hexane/EtOAc 15:1 then 3:1) to give the nitro aldol adduct as a colorless oil. Enantiomeric excess was determined by HPLC with a Chiralpak IB column (90:10 n hexane: isopropanol, 1 mL/min, 215 nm); R enantiomer: t r = 8. 4 min; S enantiomer: t r = 9. 2 min; All the reactions were finished with in 18 h with a full conversion of 3 1 a Cat: 20% ee ( R R ) product: 18.7 % ee ( S ) Cat: 30% ee ( R R ) product: 2 9.0 % ee ( S ) Cat: 50% ee ( R R ) product: 51.9% ee ( S ) Cat: 6 0% ee ( R R ) product: 60.1 % ee ( S )

PAGE 213

213 Cat: 70% ee ( R R ) product: 71.6% ee ( S ) Cat: 40% ee ( S S ) product: 44.7% ee ( R ) Cat : 80% ee ( S S ) product: 82.4% ee ( R ) Cat: 90 % ee ( S S ) product: 89.7% ee ( R ) Cat: 1 0 % ee ( S S ) product: 11.5 % ee ( R )

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214 CHAPTER 4 CONCLUSION B ase tethered bifunctional aza bis(oxazoline) CuTC systems were successfully developed and exhibited high catalytic activity and enantioselectivity for asymmetric Henry reaction. K inetic stud ies explained the observation of no dramatic dinuclear effect and suggested a base tethered, charge stabilized bifun ctional system for the asymmetric Henry reaction (Figure 4 1) Thus, rate acceleration (2.5 times) was obtained with the optimized bifunctional catalyst. Although the benefit was not dramatic, this might be caused by a non optimized base tethered to the ca talyst It would be also interesting to make current catalytic system more rigid in the fu ture Figure 4 1. Bifunctional base tethered aza bis(oxazoline) CuTC catalyst for asymmetric Henry reaction Bis urea (salen)cobal t bifunctional catalyst s were successfully developed for the enantio and anti diastereoselective Henry reaction with excellent yield, ee, dr and broad substrate scope ( Scheme 4 1) Reactivity/selectivity vs catalyst struct ure was systematically studied, w hich again indicated the importance of linker rigidity for the cooperative activation. Although no direct proof was obtained for the proposed

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215 cooperative activation model, the combined data including kinetic study, nonlinear effect study, catalyst structur e survey and control experiment s coll ectively implied a urea involved catalytic process. Further mechanistic studies as well as application of urea salen ligands to other asymmetric catalysis will be the future topics S cheme 4 1. Bis urea (salen)cobalt catalyst for asymmetric Henry reaction

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225 BIOGRAPHICAL SKETCH Kai Lang was born in Jilin City, Jilin Province, China. From 1995 to 1998 he was a special student for the class of Olympic co mpetition ( spent 1 year to finish supposed 3 and spent 2 years for national Olympic competition education in physics, chemistry, and mathematics ) at Jilin No. 1 high school I n 1998 he attended Changchun University of Technolo gy where he majored in chemical engineering. Then in 2003, he succeeded in the entrance exam for m aster study in organic chemistry at Xiamen Univeristy and worked for the m aster degree in organic chemistry for 3 years. Kai went on to pu r sue his Ph D i n organic chemistry at the University of Florida under the supervision of Professor Sukwon Hong Kai received his Ph D from the University of Florida in the summer of 2011 and will pursue a postdoctoral position at the Princeton University for Professor D avid W.C. MacMillan in hopes of attaining a research professorship