CHIRAL ANION-MEDIATED CATALYSIS: THE CHEMISTRY OF VANOL-DERIVED BOROXINATE AND ZIRCONATE COMPLEXES By Yubai Zhou                         A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry Ð Doctor of Philosophy 2017ABSTRACT CHIRAL ANION-MEDIATED CATALYSIS: THE CHEMISTRY OF VANOL-DERIVED BOROXINATE AND ZIRCONATE COMPLEXES By Yubai Zhou A highly enantioselective asymmetric catalytic synthesis of cis- and trans-aziridines can be achieved with multi-component procedure with primary amines, aldehydes and diazo compounds mediated by a chiral boroxinate (BOROX) catalyst generated from VANOL, VAPOL or t-Bu2VANOL ligands.  A catalyst controlled asymmetric aziridination is reported based on the previously developed method for the multi-component cis-aziridination. The stereochemistry of the newly formed aziridines is the function of chiral boroxinate catalyst and is independent of the chiral centers already present in the aldehyde substrates. A series of aldehydes with the chiral centers presented at either !- or "-positions are investigated to find out the diastereoselectivity of the corresponding aziridines from both enantiomers of the BOROX catalyst, as well as the evaluation of ligand control over the diastereoselectivity from the matched and miss-matched pairs. The synthesis of stereoisomers of isoleucine and polyoxamic acid will be discussed as the application of this method. Meanwhile, The three-component catalytic asymmetric synthesis of trans-aziridines is introduced. This method provides direct aziridination of amines, aldehydes and diazoacetamides to give trans-aziridine-2-carboxamides with the chiral boroxinate catalyst. Taken together with our previous reported on the three-component catalytic asymmetric synthesis of cis-aziridines, the three-component aziridination can be controlled to give either cis- or trans-aziridines. The scope of the trans-aziridination is !""!discussed along with the application in the natural product synthesis. As the extension of this methodology, an asymmetric synthesis of !-amino-"-hydroxy amides is developed by the strategy of trans-aziridination/ring-opening cascade reactions with the presence of nucleophilic phenols and carboxylic acids, with decent yields and asymmetric inductions of aminohydroxy amides achieved. The substrate scope of aldehydes and oxygen-nucleophiles will be further explored. In addition, a parallel kinetic resolution of racemic !-iminols is introduced based on the previously developed method of catalytic asymmetric !-iminol rearrangement based on a chiral zirconate complex derived from VANOL ligand. An excellent resolution of the racemic !-iminols with a phenyl and a alkyl migration group to afford a pair of amino ketone regioisomers with high enantiomeric purity. More studies will focus on the stereochemistry to reveal the mechanism of migration. !#$!ACKNOWLEDGEMENTS I feel lucky that IÕm able to spend five and half years as a graduate student in the Department of Chemistry at Michigan State University. I appreciate Prof. Xuefei Huang, who sent me the email five years ago in 2011 to inform me of the offer. Since then, I have been able to know people from all over the world, work with them, learn new chemistry and do research on the interesting projects in the area of organic chemistry. I would like to thank my advisor Prof. William Wulff, for his kind help and support during my PhD career. He is an encyclopaedia organic chemistry. I have benefited a lot from his lectures, ideas and personal meeting for the discussion of my research that helps me to build up a deep understanding of organic chemistry. When I joined the group, I was worrying about my limited background in inorganic chemistry from my undergraduate lab experience. And right now, IÕm on my way to get the PhD degree in chemistry. Prof. Wulff is a great advisor. He takes seriously for the experimental results and he is strict to every word in manuscript writings. And he makes his students to be among those the best organic chemists. I would also like to thank Prof. Babak Borhan. I am impressive in his lectures. He is a good teacher and always ready to make students keep thinking and push them to solve the problems instead of telling the answers. Also thank my committee members Prof. James Jackson and Prof. Milton Smith, for their useful lectures and valuable advices. And I will always remember the help from Dr. Daniel Holmes for his help of training on the techniques in NMR studies and Dr. Richard Staples for help in X-ray crystallophic analysis. I will thank the faculties in mass spectrum facility center, Prof. Daniel Jones, !$!Dr. Lijun Chen and Dr. Anthony Schilmiller for their help to teach me the skill to use the facility. And I will never forget those days I spent with the senior lab members. I will thank Dr. Munmun Mukherjee and Dr. Anil Gupta for their efforts to make me familiar with the lab introduce the research projects to me and train me the lab skills. I will miss Dr. Wenjun Zhao, Dr. Xin Zhang, Dr. Yong Guan and Dr. Hong Ren for all their kind help during the time I worked together with them. And I have benefited a lot from their suggestions and advices. I will thank my current lab members Xiaopeng Yin, Yijing Dai, Aliakbar Mohammodlou and Li Zheng for their kindness, friendliness and encouragement. And I will remember all my friends in MSU: Jun, Xinliang, Wei, Hadi, Yi, Bardia, Tayeb, Souful, Pengchao, Travis, Yukari, Peng, Chengpeng, Wenjing, Yinan, Yongle and so on. I will give many thanks to my parents. I can understand it is a hard decision for them to support me to leave the home country, be far way from them and perform the work I am interested in. I wish a family re-union in the near future to share my happiness and success with them.   !$#!TABLE OF CONTENTS LIST OF TABLES ............................................................................................................. ix LIST OF FIGURES ........................................................................................................... xi LIST OF SCHEMES ......................................................................................................... xii KEY TO ABBREVIATIONS .......................................................................................... xvi Chapter 1   Chiral Anions in Asymmetric Catalysis ........................................................... 1 1.1 Introduction ............................................................................................................... 1 1.2 Chiral Anions Derived from Br¿nsted Acid Catalysts .............................................. 3 1.2.1 Chiral Anion Catalysis via Proton Activation ................................................... 4 1.2.2 Chiral Anion Catalysis via Electrostatic Ion-Pair Interaction ............................ 5 1.2.3 Chiral Anion Catalysis via Hydrogen-Bonding ................................................. 8 1.2.4 Chiral Anion Catalysis via Transition Metal Coordination ............................. 10 1.3 Chiral Anions Derived from Combined Acid Catalysts ......................................... 12 1.3.1 Chiral Combined Acids in Asymmetric Catalysis ........................................... 12 1.3.2 Chiral Combined Acids as LBAs ..................................................................... 13 1.3.3 Chiral Combined Acids as BLAs ..................................................................... 14 1.3.4 Chiral Combined Acids as LLAs ..................................................................... 16 1.3.5 WulffÕs Chiral Boroxinate Catalysts ................................................................ 17 REFERENCES ................................................................................................................. 21 Chapter 2 Multi-Component cis-Aziridination ................................................................. 25 2.1 Literature Work on Catalytic Asymmetric Aziridination ....................................... 25 2.1.1 Aziridines in natural products .......................................................................... 25 2.1.2 Catalytic Asymmetric Aziridination ................................................................ 27 2.1.3 WulffÕs BOROX-Catalyzed cis-Aziridination ................................................. 30 2.2 Catalytic Asymmetric Multi-Component cis-Aziridination .................................... 34 2.2.1 Optimization of Reaction Conditions .............................................................. 34 2.2.2 Substrate Scope and Screening of BOROX Catalysts ..................................... 37 2.3 Catalyst Control in Multi-Component cis-Aziridination ........................................ 38 2.3.1 Reaction Optimization and Substrate Scope .................................................... 38 2.3.2 Synthetic Utility of Catalyst-Controlled cis-Aziridination .............................. 44 REFERENCES ................................................................................................................. 49 Chapter 3 Multi-Component trans-Aziridination ............................................................. 53 3.1 Catalytic Asymmetric trans-Aziridination .............................................................. 53 3.2 Multi-Component trans-Aziridination .................................................................... 55 3.2.1 trans-Aziridination with Aromatic Aldehydes ................................................ 55 3.2.2 trans-Aziridination with Aliphatic Aldehydes ................................................. 60 3.2.3 Investigation of Absolute Stereochemistry ...................................................... 65 3.3 Synthetic Utility in Natural Products ...................................................................... 71 3.3.1 Synthesis of Sphinganine Stereoisomers ......................................................... 71 3.3.2 Synthesis of Sphingosine Stereoisomers ......................................................... 80 !$##!REFERENCES ................................................................................................................. 83 Chapter 4 Asymmetric Synthesis of Aminohydroxy Amide ............................................ 87 4.1 Introduction of 1,2-Aminohydroxy Functionalization ............................................ 87 4.1.1 "-Amino Alcohols in Natural Products ............................................................ 87 4.1.2 "-Amino Alcohols from C-C Bond Forming Reactions .................................. 88 4.1.3 "-Amino Alcohols from Functional Group Transformations .......................... 91 4.1.4 "-Amino Alcohols from Direct Alkene Aminohydroxylation ......................... 94 4.4.5 "-Amino Alcohols from 1,3-Dipole Cycloaddition ......................................... 97 4.2 BOROX-Catalyzed Aziridination/Ring-Opening Cascade Reaction ...................... 99 4.2.1 Catalytic Ring-Opening of trans-Aziridines .................................................... 99 4.2.2 Asymmetric Synthesis of Aminohydroxy Amides with Phenols .................. 101 4.2.3 Asymmetric Synthesis of Aminohydroxy Amides with Carboxylic Acids ... 108 REFERENCES ............................................................................................................... 112 Chapter 5   Parallel Kinetic Resolution of Racemic !-Iminols ....................................... 116 5.1 Parallel Kinetic Resolution (PKR) ........................................................................ 116 5.1.1 Chemodivergent PKR .................................................................................... 118 5.1.2 Regiodivergent PKR ...................................................................................... 121 5.1.3 Stereodivergent PKR ..................................................................................... 123 5.2 Literature Work on !-Ketol/#minol Rearrangement ............................................. 124 5.2.1 !-Hydroxy Ketones and Aldehydes ............................................................... 124 5.2.1 !-Hydroxy Imines (!-Iminols) ....................................................................... 127 5.3 Asymmetric Catalytic Rearrangement with Non-Chiral !-#minols ...................... 130 5.4 Asymmetric Catalytic Rearrangement with Racemic !-#minols .......................... 134 5.4.1 Non-chiral Iminols vs Racemic Iminols ........................................................ 134 5.4.2 Initial Studies on the Rearrangement of Racemic !-Iminols ......................... 136 5.4.3 Mechanistic Studies on the PKR in the !-Iminol Rearrangement ................. 141 REFERENCES ............................................................................................................... 147 Chapter 6   Experimental Information ............................................................................ 150 6.1 General Information .............................................................................................. 150 6.2 Experimental Information of Chapter 2 ................................................................ 151 6.2.1 Multi-Component cis-Aziridination of Non-Chiral Aldehydes 33a-i ........... 151 General Procure for Multi-Component cis-Aziridination ....................................... 151 6.2.2 Preparation of !- or "-Chiral Aldehydes ........................................................ 162 General Procedure A for Aldehyde 104a, c, g ........................................................ 162 General Procedure B for Dess-Martin Oxidation from Alcohol to Aldehyde ........ 164 6.2.3. Multi-Component cis-Aziridination of Chiral Aldehydes 104a-i ................. 179 General Procedure for the Multi-Component Aziridination of Chiral Aldehydes . 179 Experimental Details for the Multi-Component Aziridination of Chiral Aldehydes ................................................................................................................................. 180 6.3 Experimental Information of Chapter 3 ................................................................ 216 6.3.1 Multi-Component cis-Aziridination of Benzaldehyde ................................... 216 6.3.2 Multi-Component trans-Aziridination of Aromatic Aldehydes .................... 217 General Procedure A for Multi-Component trans-Aziridination of Aromatic Aldehydes ............................................................................................................... 217 !$###!General Procedure B for Multi-Component trans-Aziridination of Aromatic Aldehydes ............................................................................................................... 218 6.3.3 Multi-Component trans-Aziridination of Aliphatic Aldehydes ..................... 237 General procedure A of multi-component trans-aziridination of aliphatic aldehydes ................................................................................................................................. 237 General procedure B of multi-component trans-aziridination of aliphatic aldehydes ................................................................................................................................. 238 General procedure C of multi-component trans-aziridination of aliphatic aldehydes ................................................................................................................................. 238 6.3.4 Absolute Stereochemistry of trans- and cis-Aziridines ................................. 263 General Procedure A of Preparation of Ester from Secondary Amide ................... 263 6.3.5 Ring-Opening of trans-Aziridines ................................................................. 274 General Procedure A: Ring-Opening of trans-Aziridine Carboxamide 125g ........ 274 General Procedure B Ring-Opening of trans-Aziridine Carboxylate 143 and 143Õ ................................................................................................................................. 275 6.3.6 Synthesis of erythro-Sphinganine .................................................................. 277 6.3.7. Experimental Details of BUDAM Amine 101c Recycling ........................... 284 6.4 Experimental Information for Chapter 4 ............................................................... 285 6.4.1 trans-Aziridination/Ring-Opening Cascade Reaction with Phenol ............... 285 6.4.2 trans-Aziridination/Ring-Opening Cascade Reaction with 4-Methoxyphenol ................................................................................................................................. 287 6.4.3 trans-Aziridination/Ring-Opening Cascade Reaction with Benzoic Acid ..... 289 6.4.4 Controlled Experiments ................................................................................. 291 6.4.5 Reaction Monitoring ...................................................................................... 292 6.4.6 Absolute Stereochemistry of Aminohydroxy Amide .................................... 293 6.5 Experimental Information for Chapter 5 ............................................................... 294 6.5.1 General Procedure for Preparation of !-Iminols 286b-e ............................... 294 6.5.2 Kinetic resolution of !-Iminols ...................................................................... 298 General Procedure of Zirconium-Catalyzed !-Iminol Rearrangement29 ................ 298 6.5.3 Preparation of Enantiometic Pure !-Iminol  (R)-286c ................................... 309 6.5.4 Preparation of Enantiometic Pure Amino ketones (R)-287c and (R)-287cÕ .. 311 REFERENCES ............................................................................................................... 316  !#%!LIST OF TABLES Table 2.1 Screening of imine N-substitution13aÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.31 Table 2.2 Screening of benzhydryl substitution13aÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.32 Table 2.3 Optimization of multi-component aziridination with n-butyraldehyde 33aÕ a 16ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.36 Table 2.4 Substrate scope of multi-component cis-aziridination with three ligands-derived catalysts17ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ...38 Table 2.5 Catalyst-controlled cis-aziridination of aldehyde (R)-104a a 20ÉÉÉÉÉÉ.40 Table 2.6 Catalyst-controlled cis-aziridination of (R)-glyceraldehyde acetonide 104b a..41 Table 2.7 Catalyst-controlled cis-aziridination of !- and "-chiral aldehydes a 20ÉÉÉ..43 Table 2.8 Catalyst-controlled cis-aziridination of chiral heterocyclic carboxaldehydes a 20ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.44 Table 3.1 Optimization of the multi-component trans-aziridination with benzaldehyde 33a a 8ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..58 Table 3.2 Aromatic aldehyde scope of multi-component trans-aziridination a 8ÉÉÉ...60 Table 3.3 Optimization of multi-component trans-aziridination with n-hexadecanal 33g a 8ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..61 Table 3.4 Aliphatic aldehyde scope of multi-component trans-aziridination a 8ÉÉÉ...64 Table 3.5 trans-Aziridination with MEDAM amine and n-hexadecanal a 8ÉÉÉÉÉ..65 Table 3.6 trans-Aziridination with MEDAM amine, benzaldehyde and N-phenyl diazoacetamide a 8ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ...68 Table 3.7 trans-Aziridination with MEDAM amine, benzaldehyde and N-butyl diazoacetamide a 8ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ...70 Table 3.8 Ring-opening of trans-aziridine carboxylamide 126g a 8ÉÉÉÉÉÉÉÉ...77 Table 3.9 Ring-opening of trans-aziridine carboxylate 143 and 143Õ a 8ÉÉÉÉÉÉ...78 Table 4.1 Optimization of asymmetric synthesis of aminohydroxy amide aÉÉÉÉ...102 Table 4.2 Optimization of the procedure with pumping at high vacuum aÉÉÉÉÉ..108 !%!Table 5.1 Catalyst screen for !-iminol rearrangement20ÉÉÉÉÉÉÉÉÉÉÉÉ..131 Table 5.2 Initial studies on kinetic resolution of !-iminol rac-286b aÉÉÉÉÉÉÉ.137 Table 5.3 Ligand screening for kinetic resolution of !-iminol rearrangement aÉÉÉ..139 Table 5.4 Zr-catalyzed rearragement of !-iminols aÉÉÉÉÉÉÉÉÉÉÉÉÉÉ140 Table 6.1 Reaction trackingÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.292    !%#!LIST OF FIGURES Figure 1.1 Activation modes in Asymmetric catalysisÉÉÉÉÉÉÉÉ...ÉÉÉÉÉ.2 Figure 1.2 Common classes of chiral Br¿nsted acid catalystsÉÉÉÉÉÉÉÉÉÉÉ.4 Figure 1.3 BINOL spiro-boron complex 56 as the typical example of a combined acid catalyst28ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.13 Figure 1.4 Examples of BLA catalystsÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..16 Figure 1.5 Examples of LLA catalystsÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..17 Figure 1.6 Chiral BOROX anion in asymmetric catalysisÉÉÉÉÉÉÉÉÉÉÉÉ.19 Figure 2.1 Aziridine-containing natural productsÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..26 Figure 2.2 Transformations of disubstituted aziridinesÉÉÉÉÉÉÉÉÉÉÉÉÉ.27 Figure 2.3 Asymmetric induction with N-substitution for a) VANOL BOROX; b) VAPOL BOROX13bÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ...33 Figure 2.4 The non-covalent interactions in BOROX-iminium complex14cÉÉÉÉÉ..33 Figure 2.5 Felkin-Ahn Model in cis-aziridination of chiral imines19cÉÉÉÉÉÉÉ...39 Figure 2.6 Polyoxamic acid 113 and polyoxins 114ÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..47 Figure 3.1 Universal BOROX-catalyzed asymmetric aziridinationÉÉÉÉÉÉÉÉ..54 Figure 3.2 Sphingoid bases and the four stereoisomers of sphinganineÉÉÉÉÉÉ....72 Figure 4.1 "-Aminoalcohols in natural productsÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ...88 Figure 4.2 Reaction TrackingÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..104 Figure 4.3 X-ray crystallographic analysis of aminophenoxy amide 218aÉÉÉÉÉ.106 Figure 5.1 Single crystal structure of VANOL zirconate in the solid state20ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ133      !%##!LIST OF SCHEMES Scheme 1.1 Chiral phosphoric acid catalyzed imine transformationsÉÉÉÉÉ.ÉÉÉ5 Scheme 1.2 ACDC via cationic activated intermediatesÉÉÉÉÉÉÉÉÉÉÉÉÉ.6 Scheme 1.3 Cationic intermediates generated by the catalysis of strong chiral Br¿nsted acidsÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.7 Scheme 1.4 Anion-binding chiral thioureas in asymmetric catalysisÉÉÉÉÉÉÉÉ..8 Scheme 1.5 Aldehyde activation by TADDOL catalystsÉÉÉÉÉÉÉÉÉÉÉÉÉ9 Scheme 1.6 Asymmetric Tsuji-Trost reaction with a palladium catalyst and TRIP couterionÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ11 Scheme 1.7 Asymmetric induction by a chiral ligand and counteranionÉÉÉÉÉ.É.12 Scheme 1.8 LBAs in asymmetric catalysisÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ....14 Scheme 1.9 Formation of VANOL/VAPOL-derived BOROX catalystsÉÉÉÉÉÉ..18 Scheme 2.1 Aziridination from 1,2-amino functionzalized compoundsÉÉÉÉÉÉ...28 Scheme 2.2 Aziridination by nitrene addition to alkenesÉÉÉÉÉÉÉÉÉÉÉÉ..28 Scheme 2.3 Aziridination by carbene/ylid addition to iminesÉÉÉÉÉÉÉÉÉÉ...30 Scheme 2.4 BOROX-catalyzed multi-component cis-aziridinationÉÉÉÉÉÉÉÉ..35 Scheme 2.5 Multi-component cis-aziridination of benzaldehyde 33a16ÉÉÉÉÉÉÉ35 Scheme 2.6 Catalyst-controlled multi-component cis-aziridination20ÉÉÉÉÉÉÉ...39 Scheme 2.7 Catalyst-controlled synthesis of ethylene diaziridines 105n and 105nÕÉÉ.45 Scheme 2.8 Access to !3-homo-D-isoleucine anti-112 and !3-homo-D-alloisoleucine syn-112Õ20ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..46 Scheme 2.9 Proposed synthesis of polyoxamic acid by catalyst-controlled aziridinationÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ...48 Scheme 3.1 Substrate control and catalysts control of stereoselective aziridinationÉÉ53 Scheme 3.2 Multi-component cis-aziridination of benzaldehyde 33a8ÉÉÉÉÉÉÉ.56 Scheme 3.3 Initial studies of multi-component trans-aziridination8ÉÉÉÉÉÉÉÉ.57 !%###!Scheme 3.4 Absolute stereochemistry of N-MEDAM alkyl aziridine carboxylamides 129g8ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..67 Scheme 3.5 Ligand-effects on the diastereoselectivity8ÉÉÉÉÉÉÉÉÉÉÉÉÉ68 Scheme 3.6 Absolute stereochemistry of N-MEDAM alkyl aziridine carboxylamides 123a8ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..69 Scheme 3.7 Absolute stereochemistry of N-MEDAM alkyl aziridine carboxylamides 129a8ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..71 Scheme 3.8 Synthesis of all four stereoisomers of sphinganine by multi-component cis-aziridination3mÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ74 Scheme 3.9 Alternative synthesis of all four sphinganine stereoisomers ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.75 Scheme 3.10 Initial exploration of sphinganine synthesis by trans-aziridinationÉÉÉ.76 Scheme 3.11 Synthesis of erythro-sphinganines from trans-aziridination of n-hexadecanal 33g8ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ...79 Scheme 3.12 Recycling of BUDAM amine 101c8ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ79 Scheme 3.13 De novo biosynthesis of sphinganine and sphingosineÉÉÉÉÉÉÉÉ80 Scheme 3.14 Proposed synthetic strategy of erythro- and threo-sphingosinesÉÉÉÉ.81 Scheme 4.1 Synthesis of "-amino alcohols by C-C bond formationÉÉÉÉÉÉÉÉ.90 Scheme 4.2 Amminolysis of vinylepoxide 177ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.91 Scheme 4.3 Diastereoselectivity control in nucleophilic addition to chiral amino aldehyde 104mÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..92 Scheme 4.4 Asymmetric hydroxyamination of aldehydesÉÉÉÉÉÉÉÉÉÉÉÉ93 Scheme 4.5 Dihydroxylation of allyl amines 181ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..93 Scheme 4.6 Sharpless asymmetric aminohydroxylationÉÉÉÉÉÉÉÉÉÉÉÉ...95 Scheme 4.7 Regioselective aminohydroxylation of styrene 193 and oxaziridines 194É.96 Scheme 4.8 Aminohydroxylation of alkenes and oxycarbamatesÉÉÉÉÉÉÉÉÉ.97 Scheme 4.9 Formation of carbonyl and azomethine ylides and 1,3-dipole cycloadditionsÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ98 Scheme 4.10 Synthesis of "-amino alcohols by 1,3-dipole cycloadditionsÉÉÉÉÉ..99 !%#$!Scheme 4.11 Byproducts in multi-component trans-aziridinationÉÉÉÉÉÉÉÉ..100 Scheme 4.12 Formation of aminophenoxy amide 218a in trans-aziridination of 4-tolualdehyde 33cÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..100 Scheme 4.13 Control experimentsÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ...103 Scheme 4.14 Asymmetric synthesis of aminohydroxy amides with 4-methoxyphenol..107 Scheme 4.15 trans-Aziridination/ring-opening cascade reaction with benzoic acid 222ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ109 Scheme 4.16 trans-Aziridination/ring-opening cascade reaction with carboxylate anionsÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ...110 Scheme 4.17 Synthesis of !-amino-"-hydroxy carboxylamide 226ÉÉÉÉÉÉÉ....111 Scheme 5.1 Kinetic resolution of a racemic compoundÉÉÉÉÉÉÉÉÉÉÉÉ..116 Scheme 5.2 Dynamic kinetic resolution of a racemic compoundÉÉÉÉÉÉÉÉ....117 Scheme 5.3 Parallel kinetic resolution of a racemic compoundÉÉÉÉÉÉÉÉÉ..118 Scheme 5.4 PKR affords non-chiral compoundÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..119 Scheme 5.5 PKR affords pseudoenantiomeric compoundsÉÉÉÉÉÉÉÉÉÉÉ.119 Scheme 5.6 Chemodivergent PKR in the total synthesis of (Ð)-colombiasin AÉÉÉ..121 Scheme 5.7 Regiodivergent PKR in Sharpless epoxidationÉÉÉÉÉÉÉÉÉÉÉ122 Scheme 5.8 Regiodivergent PKR in catalytic hydrofomylationÉÉÉÉÉÉÉÉÉ..123 Scheme 5.9 Regiodivergent PKR in C-C bond formationÉÉÉÉÉÉÉÉÉÉÉ...123 Scheme 5.10 Stereodivergent PKR in an asymmetric HWE reactionÉÉÉÉÉÉÉ.124 Scheme 5.11 Stereodivergent PKR of "-keto nitrilesÉÉÉÉÉÉÉÉÉÉÉÉÉ..124 Scheme 5.12 Pinacol and !-keto rearrangementÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..125 Scheme 5.13 Acyclic !-ketol rearrangementÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ...126 Scheme 5.14 Cyclic !-ketol rearrangementÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.126 Scheme 5.15 !-hydroxy aldehyde rearrangementÉÉÉÉÉÉÉÉÉÉÉÉÉÉ....126 Scheme 5.16 The first example of !-hydroxy imine rearrangementÉÉÉÉÉÉÉ...127 Scheme 5.17 Br¿nsted acid promoted of !-iminol rearrangementÉÉÉÉÉÉÉÉ..128 !%$!Scheme 5.18 !-Iminol rearrangement via an iminium intermediateÉÉÉÉÉÉÉ...128 Scheme 5.19 Stereoselective base-promoted !-iminol rearrangementÉÉÉÉÉÉ....129 Scheme 5.20 Interconversion between a !-iminol and a !-amino ketoneÉÉÉÉÉ...130 Scheme 5.21 One-pot catalytic asymmetric rearrangement of !-hydroxy ketones with anilinesÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ.130 Scheme 5.22 Zr-catalyzed Mannich reaction21ÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ132 Scheme 5.23 Proposed possible iminol activation modes by VANOL zirconium complexÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ134 Scheme 5.24 The asymmetric catalytic rearrangement of !-iminols: a. Rearrangement of a non-chiral !-substrate; b. Kinetic resolution pathway in the rearrangement of a racemic !-iminol; c. Parallel kinetic resolution in the rearrangement of a racemic !-iminolÉ...135 Scheme 5.25 Synthesis of amino ketone 287bÕ as the minor product in !-iminol rearrangementÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..138 Scheme 5.26 Synthesis and Separation of Fmoc-amino ketone regioisomers 296 and 296ÕÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..141 Scheme 5.27 Synthesis of amino ketones 287c and 287cÕ with known stereochemical configurationsÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉÉ..143 Scheme 5.28 Catalytic rearrangement of !-iminol (R)-286cÉÉÉÉÉÉÉÉÉÉ...145 Scheme 5.29 Mechanistic rationalization of PKR in the !-iminol rearrangementÉÉ..146    !%$#!KEY TO ABBREVIATIONS acac  acetylacetone AQN  anthraquinone Ac  acetyl ACDC  asymmetric couteranion-directed catalysis Bh  benzhydryl BINAP  1,1Õ-binaphthyl-2,2Õ-bis(diphenylphosphine) BINOL  1,1Õ-bi(2-naphthol) BPO  benzoyl peroxide Bu  butyl BUDAM  tetra-tert-butyldianisylmethyl CAN  ceric ammonium nitrate Cy  cyclohexyl DAM  dianisylmethyl DHDQ  dihydroquinidine DHQ  dihydroquinine DKR  dynamic kinetic resolution DMAP  4-dimethylaminopyridine DMPAO  2,6-dimethylphenylaminooxalic acid DNA  Deoxyribonucleic acid DOSP  1-(4-dodecylphenylsulfonyl)-2-pyrrolidine carboxylate EDA  ethyl diazoacetate Et  ethyl !%$##!Fmoc  fluorenylmethyloxycarbonyl HMDS  hexamethyldisilazide HMPA  hexamethylphosphoramide IBX  2-iodoxybenzoic acid LDA  lithium diisopropylamide Me  methyl MEDAM  tetramethyldianisylmethyl NBS  N-bromosuccinimide NMI   N-methylimidazole Ns  4-nitrobenzenesulfonyl Ph  phenyl PHAL  phthalazine phen  phenanthroline phth  o-phthaloyl Piv  pivaloyl PKR  parallel kinetic resolution PMP  para-methoxyphenyl PNB para-nitrobenzoate Pr  propyl TADDOL  !,!,!',!'-tetraaryl-2,2-disubstituted 1,3-dioxolane-4,5-dimethanol TEMPO  2,2,6,6-(tetramethylpiperidin-1-yl)oxyl radical Tf  trifluoromethanesulfonyl Tr  triphenylmethyl TRIP  3,3Õ-bis(2,4,6-triisopropylphenyl)-1,1Õ-binaphthyl-2,2-diyl hydrogenphosphate !%$###!Ts  4-toluenesulfonyl VANOL  3,3Õ-diphenyl-2,2Õ-bi(1-naphthol) VAPOL  2,2Õ-diphenyl-(4-biphenanthrol)      !&!Chapter 1   Chiral Anions in Asymmetric Catalysis 1.1 Introduction Chiral anions have been significantly highlighted in the field of asymmetric catalysis during the last score years. Cationic species, reagents and intermediates are frequently involved in many chemical reactions and processes as cations are often generated along the reaction pathways by Lewis/Br¿nsted acid catalysis or nucleophilic/electrophilic fragmentation. A great number of synthetic and biological processes are mediated by ammonium, iminium and imidazolium ions. Considering the purpose of asymmetric induction in asymmetric catalysis, people realized chiral anions can play an important role as counterion species in the asymmetric auxiliaries, ligands and reagents that provide electrostatic, hydrogen-bonding or coordinative interactions to be associated with cationic intermediates.1 A number of activation modes in asymmetric catalysis are fundamental to better understand the interactions of chiral anions with the targets.2 In the most common scenario, the catalytic species can be a chiral Lewis basic ligand with the combination of a Lewis acidic reagent. The resulting chiral catalyst possessing the net Lewis acidity provides coordination with the target substrates at a nucleophilic site such as a carbonyl group that is effectively activated (Figure 1.1a).  Replacement of the Lewis acidic core in the catalyst with a proton gives an activation mode known as Br¿nsted acid catalysis that allows the formation of hydrogen-bonding of the proton to the nucleophilic site with the lone pairs of the target substrates. For weak Br¿nsted acids (pKa 8-20), particularly for chiral ureas and thioureas3, they are excellent !'!H-bond donors to develop double hydrogen-bonding interactions with the substrates providing high asymmetric inductions (Figure 1.1b). Figure 1.1  Activation modes in Asymmetric catalysis2  Significant Br¿nsted acidity (pKa < 4) of the catalysts, typically exemplified by BINOL-derived phosphoric acids4, are likely to be totally deprotonated by the basic functional groups such as amines or imines. The enantioselectivity is likely to result from both electrostatic and hydrogen bonding interactions within the anionic conjugate base of the catalysts and protonated substrates (Figure 1.1c). Since cationic species derived from the substrates are not all H-bond donors or acceptors, the chiral anionic catalysts can be the counterion of the substrates and provide the electrostatic ion-pair interactions as the effective activation mode known as asymmetric counteranion directed catalysis (ACDC) (Figure 1.1d). The substrate can form a cationic !(!intermediate and directly interact with the catalyst, or coordinate with Lewis acidic metals to form a cationic complex, which interacts with the catalysts as the ion pair. 1.2 Chiral Anions Derived from Br¿nsted Acid Catalysts A great number of chiral anionic catalysts are derived from its conjugate Br¿nstend acids. Since early last century, people made use of chiral anions and their conjugate acids from natural compounds from the chiral pool in the resolution and spectroscopic analysis of chiral molecules.2 These natural chiral Br¿nsted acids include camphorsulfonic acid 1, tartaric acid 2, mandelic acid 3 and quinic acid 4, which  have been commonly used for the asymmetric induction (Figure 1.2, Class I).  For the purpose of superior performance and application in asymmetric synthesis, more powerful synthetic chiral Br¿nsted acids have received attention. As a commonly used type of specific Br¿nsted acid catalysts, binaphthol-derived phosphoric acids 5 and 8, phosphoramides 6 and disulfonimides 7 have been widely used in the chemistry of carbonyl and imine activation (Figure 1.2, Class II). This type of chiral acids exhibits strong Br¿nsted acidity and effectively activates carbonyls and imines by protonation. Their anionic conjugate bases are also significant in asymmetric induction via ion-pair interactions or coordination with transition metal catalysts as the ligands.4 The other type of synthetic acids include thioureas 9, TADDOL 10, BINOL 11 and their derivatives behave as general acid catalysts due to their relatively weaker acidity that results in incomplete deprotonation and to the fact that they can only activate carbonyl compounds only by hydrogen bonding interactions (Figure 1.2, Class III).   !)!Figure 1.2  Common classes of chiral Br¿nsted acid catalysts  1.2.1 Chiral Anion Catalysis via Proton Activation Over the recent decade, the family of chiral phosphoric acids has been greatly developed as a popular organocatalyst option in asymmetric transformations due to their strong acidity and promising asymmetric inductions. These substrates are particularly effective for imine activation and thus provide useful synthetic strategies for chiral nitrogen-containing molecules. Moderately basic imines are protonated by phosphoric acids and the resulting iminiums interact with the catalyst via hydrogen bonding and electrostatic attraction. Initial work on asymmetric imine transformation were done by Akiyama6a,7,8 and Terada6b on the Mannich reaction (Scheme 1.1a, b), imine hydrophosphonylation (Scheme 1.1c) and aza-Diels-Alder reaction (Scheme 1.1d). A better interaction of imine HO3SOHO2CCO2HOHOHCO2HOHHOOHOHHOCO2HClass I: Natural Chiral Br¿nsted Acids1234OOPOOHRROOPONHTfRRRRSO2O2SNHOOPOOHRR5678Class II: C2-Chirality Br¿nsted AcidsSNHNHCF3F3CNR2OHOHOOArArArArRROHOH91011Class III: Chiral H-Bond Donors!*!substrates and chiral phosphoric acid catalysts can be promoted by the effects of an adjacent functional group such as a hydroxyl group with the formation of an additional hydrogen bond, since the phosphonyl oxygen is a good H-bond acceptor that promotes a cyclic structure with double hydrogen bonds that stabilize the transition state (Scheme 1.1e). Scheme 1.1  Chiral phosphoric acid catalyzed imine transformations  1.2.2 Chiral Anion Catalysis via Electrostatic Ion-Pair Interaction In the asymmetric transformations of aldehydes and ketones, proton activation of carbonyls by chiral Br¿nsted acids is much less effective than it is for imines, since the carbonyl oxygen is much less basic than an imine. A most common strategy for carbonyl activation is realized by iminium-based organocatalysis9 that is further activated by chiral phosphoric acids to achieve the asymmetric induction. Mayer and List have developed the methodology by the combination of secondary amines and the TRIP catalyst in the OOPOOHRR5a  R = 4-NO2C6H45b  R = 4-!-NaphthylC6H45c  R = 4-3,5-(CF3)2C6H35d  R = 4-2,4,6-(i-Pr)3C6H2HONAr+ROTMSOMe12a135a (10 mol%)toluene, Ð78 ¡CArOMeONHROH81-96% eeaArNBoc+OO1415165b (2 mol%)CH2Cl2, rt.ArOOBocHN1792-98% eebArNOMe+HPOOi-PrOi-Pr5c (10 mol%)m-xyleneArPHNOMeOOi-PrOi-Pr18192052-90% eecHONR12bdOMeOTMS+215d (5 mol%)AcOH (1.2 equiv.)toluene, Ð78 ¡CNOOH2276-91% eeONRHPOOHOO*e!+!asymmetric reduction of conjugated aldehydes 23 with excellent enantioselectivity.10 As illustrated for the activated intermediate generated from the aldehyde 23 and morpholine, the asymmetric induction of the iminium substrate is directed by the TRIP anion only by ion-pair interaction, which is called asymmetric counterion-directed catalysis (ACDC) (Scheme 1.2a).5 Scheme 1.2  ACDC via cationic activated intermediates  There are a couple of ways to generate chiral anionic catalysts from the conjugate Br¿nsted acid in ACDC. Toste made use of a stoichiometric amount of Ag2CO3, which serves both as a base to deprotonate TRIP and a chlorophile to abstract the chloride from racemic chloroamine 27. An anionic conjugate base is generated to stabilize the quaternary meso-aziridinium intermediate 28 by ion-pair interaction without any other CHO23+NHMeO2CCO2Mei-Pri-Pr24morpholine (20 mol%)(R)-5d (20 mol%)dioxane, 50 ¡CCHO2587%, 96% eeNOOOPOOi-Pri-Pri-Pri-Pri-Pri-PrPhPhClN(S)-5d (15 mol%)Ag2CO3 (60 mol%)t-BuCH2OH (4 equiv.)4 † MS, toluene, 50 ¡CPhPh26(R)-5dÐN¥(S)-TRIPÐPhPhON84%, 94% ee272829ab!,!directional interactions such as hydrogen bonds or proton activation.11 The attack of neo-pentanol completes ring-opening of aziridinium 28 to deliver an amino ether 29 in high enantioselectivity (Scheme 1.2b). Scheme 1.3  Cationic intermediates generated by the catalysis of strong chiral Br¿nsted acids  The other way of chiral anion generation is achieved via direct activation of carbonyls or even alcohols by a catalyst with significant Br¿nsted acidity. Rueping et al. have reported a highly enantioselective intramolecular allylic substitution by the N-triflylphosphoramide catalyst 6a12, which promotes the dehydration the racemic allylic alcohol 30 to afford an allylic carbocation 32 performing the ion-pair interaction with the catalyst (Scheme 1.3a). List and his co-workers have reported a novel BINOL-derived disulfonimide catalyst 7a which was found to be highly effective in activation of OHPhOH6a (5 mol%)toluene, Ð78 ¡COPh303192%, 92% eeOOPONPhPhTfPhOH32aHO+OMeOTMS2 mol% 7aEt2O, Ð78 ¡COHOMeO33j343598%, 94% eeSO2O2SNCF3CF3CF3CF3HOMe3Si36b!-!aldehyde 33j in an asymmetric Mukaiyama aldol reaction.13 The disulfonimide 7a displays much greater Br¿nsted acidity than analogous phosphoric acids. It is proposed that the reaction includes oxonium cation 36, which interacts with the catalyst by electrostatic attraction (Scheme 1.3b). 1.2.3 Chiral Anion Catalysis via Hydrogen-Bonding Chiral Br¿nsted acids such as thioureas derivatives are not able to be completely deprotonated to generate an anionic conjugate base, but they are excellent H-bond donor catalysts that provide effective anion recognition. It has been reported that the thiourea catalysts can capture an anion such as halide or carboxylate via double hydrogen-bonding interaction to give a chiral anionic complex that performs as the couterion to provide an effective chiral induction to a cationic reaction intermediate. Scheme 1.4  Anion-binding chiral thioureas in asymmetric catalysis  For example, Jacobsen et al. have reported acyl-Pictet-Spengler reaction of tryptamine 37 with aldehydes catalyzed by chiral thiourea 38.14 It was believed that with the stoichiometric acetyl chloride, the reaction was involved in the chiral ion-pair intermediate consisted of in-situ generated acyl iminium 40 and hydrogen bonded NHNH2n-C5H11CHO (1.05 equiv.)AcCl (1.0 equiv.)2,6-lutidine (1.0 equiv.)38 (10 mol%)Et2O, 3 † MS, Ð60 ¡CNHNAcn-C5H1165%, e.r. 97.5:2.53739SNNNPht-Bu2NOt-Bu38ClHHNHNAcn-C5H1140BrNH241Bz2O (0.5 euiqv.)DMAP (20 mol%)9a (20 mol%)toluene, 4 † MS, Ð78 ¡CBrHN42PhO42% conv.s factor 20SNNCF3F3CHNHNSCF3CF3OOPhHH9aNNMe2PhO43ab!.!chloride by thiourea 38 (Scheme 1.4a). Seidel and his co-workers have made use of anion-binding thiourea catalysts in the kinetic resolution of a racemic benzylic amine 41 and its derivatives.15 The formation of acylated DMAP intermediate 43 and benzoate binding with thiourea catalyst 9a results in a chiral ion-pair which give selectivity factors of 7.1 to 24 (Scheme 1.4b). Scheme 1.5  Aldehyde activation by TADDOL catalysts  The chiral diol catalysts TADDOL 10 derivatives can activate z carbonyl by a single-point hydrogen bond mode as Br¿nsted acid-assisted Br¿nsted acid catalysis proposed by Yamamoto and Rawal.16 The presence of intramolecular hydrogen bond between two hydroxyl groups of TADDOL greatly enhances the Br¿nsted acidity of the catalyst and effectively activates carbonyls by the formation of an intermolecular hydrogen bond (Scheme 1.5a). Rawal et al. have reported a hetero-Diels-Alder reaction of non-activated TMSONMe2+RHO10a (20 mol%)toluene, Ð78 to Ð40 ¡COTMSONMe2RAcCl, CH2Cl2/tolueneÐ78 ¡COORup to 99% eeab44454633RHO33+OOOTMS4710a (20 mol%)toluene, Ð78 ¡CROOOOH48up to 90% eecOOOOArArArAr10aAr = 1-naphthylHHRHO33!&/!aldehydes 33 and an aminodiene 44 with TADDOL 10a as a highly effective catalyst to afford cycloadducts excellent enantioselectivity (Scheme 1.5b).17a They also demonstrated that TADDOL 10a was effective in the vinylogous Mukaiyama aldol reaction to afford the aldol products 48 up to 90% ee (Scheme 1.5c).17b 1.2.4 Chiral Anion Catalysis via Transition Metal Coordination The conventional ways of attempting to induce asymmetry in a transition metal-catalyzed reaction is to use a chiral ligand that tightly coordinates to the metal. However, in many cases the chiral ligand does not provide direct and effective interactions with the substrate and it results in poor enantioselectivity. People realized if there were the cationic intermediates of the substrate-metal complex involved in the catalytic cycle, they could be effectively recognized by the couteranion derived from a chiral Br¿nsted acid catalyst. For example, List et al. have reported an asymmetric Tsuji-Trost reaction of a racemic !-branched aldehyde 33b and an allylamine 49 with a palladium catalyst and chiral phosphate 5d.18 To start the catalytic cycle, the corresponding enamine from 33b and 49 is protonated by TRIP to give the ion-pair species 51. This is followed by Pd(0) oxidative addition to afford $-allyl Pd(II) complex 52. Meanwhile, the substrate enamine interacts with the chiral phosphate catalyst via hydrogen bonding that results in a catalyst assembly 52 that provides an excellent asymmetric induction by ion-pair recognition between chiral phosphate and cationic Pd(II) complex (Scheme 1.6).      !&&!Scheme 1.6  Asymmetric Tsuji-Trost reaction with a palladium catalyst and TRIP couterion  An illustration of the difference in chiral ligand- and chiral counterion-direction asymmetric transition metal catalysis was reported by Toste el at.19 in the gold-catalyzed intramolecular hydroalkoxylation of allenes 54. The gold(I) chloride phosphine complexes 56 were used as the catalysts and silver salts were employed as the chloride precipitators. In their initial catalyst screening, the chiral phosphine ligand 56 and the non-chiral 4-nitrobenzoate as the counteranion of the silver salt were used resulting in poor asymmetric inductions (Scheme 1.7a). They realized that a chiral couteranion of the silver salt such as TRIP phosphate may give improved enantioselectivity. Even with a non-chiral phosphine ligand, an excellent induction was observed (Scheme 1.7b). They proposed that reaction proceeded via an $-allenyl gold(I) complex as the cationic HO+PhNHPhPd(PPh3)4 (3 mol%)(R)-5d (1.5 mol%)5 † MS, MeOt-Bu40 ¡C, then 2 N HClHO33b4950(R)-TRIPNHPOOOO*Ph2HCPOOOO*NCHPh2HPd5152NCHPh2HPOOOOH*53Pd(0)33b + 49H2OH2O50 + H2NCHPh289%, e.r. 97:3!&'!intermediate with the linear relationship of the phosphine ligand, gold(I) metal and the substrate. Instead of tight coordination of a chiral ligand to the gold(I) species, it is nonetheless far way from the substrate. On the other hand, inclusion of a chiral counterion with the gold(I) metal via electrostatic interaction would result in a chiral environment that is much closer to the substrate and thereby provides much a more effective asymmetric induction (Scheme 1.7c). Scheme 1.7  Asymmetric induction by a chiral ligand and counteranion  1.3 Chiral Anions Derived from Combined Acid Catalysts 1.3.1 Chiral Combined Acids in Asymmetric Catalysis People have found the combination of a Lewis acid and a Br¿nsted acid can greatly promote the acidity of each other. Many strong inorganic combined catalysts include the well known examples such as HF!BF3, HCl!AlCl3, HF!SbF5 and so-called magic acid HSO3F!SbF5.20 In the area of organic chemistry, a Lewis acid activation of a Br¿nsted ¥HOPP*AuAuClCl(3 mol%)AgOPNB (3 mol%)CH2Cl2O89%, 8% ee5455OPNB = para-nitrobenzoatePAr2AuClPAr2AuCl56a¥HOPh2PAuCl(2.5 mol%)(R)-AgTRIP (5 mol%)benzeneO90%, 97% ee5455bPh2PAuCl*ligandAu+anionÐsubstratelong distancepoor asymmetric inductionligandAu+*counterionÐsubstratelong distancepoor asymmetric inductionshort distanceeffective asymmetric inductionc(R)-AgTRIPi-Pri-Pri-Pri-Pri-Pri-PrOAgOPOO!&(!acid can increase the acidity up to 24 units for a !-proton of acetaldehyde when itÕs carbonyl oxygen coordinates to a Lewis acid such as BF3.21 Figure 1.3  BINOL Spiro-Boron Complex 56 as the Typical Example of A Combined Acid Catalyst28  Yamamoto et al. developed a number of combined acid catalysts since early 1990s.22a The spiro-BINOL-derived borate 56 is the typical example which consists a boron Lewis acid core with two BINOLs as the chiral Br¿nsted acid ligands. The bis-BINOL borate 56 can function as a Lewis acid and has been proposed to activate both aldehydes and imines by forming a Lewis acid/Lewis base complex with the borate esters.22a a number of different combined acid catalysts have been established to function in different modes including Lewis acid-assisted Br¿nsted acids (LBA), Br¿nsted acid-assisted Lewis acids (BLA) and Lewis acid-assisted Lewis acids (LLA)22. 1.3.2 Chiral Combined Acids as LBAs Diol Br¿nsted acids such as TADDOL or BINOL can provide an effective asymmetric induction in asymmetric catalysis. However, they are relative weak Br¿nsted acids (pKa 9-16) and less efficient in activating the reactive site of target substrates via interactions with their protons. Yamamoto and his co-workers have found that coordination of a Lewis acid to a weakly acidic Br¿nsted acid greatly increase the acidity of latter.23 The combination of a Lewis acid and a chiral Br¿nsted acid can afford a strong acidic complex that can be used as a strong chiral Br¿nsted acid catalyst.  YR1R2HOOBOOY = O, NR56!&)!Scheme 1.8  LBAs in asymmetric catalysis  A LBA catalyst generated in-situ from BINOL and tin tetrachloride was reported by Yamamoto et al. as a stoichiometric acidic reagent in the enantioselective protonation of a non-chiral silyl enol ether 57 to give the !-substituted ketone 58 with 97% ee (Scheme 1.8a).24 They further explored the asymmetric catalytic reactions of LBAs and found that the strong acidity of the catalysts can effectively activate the olefin double-bond and trigger cationic reactions. Thus, they reported the first LBA-catalyzed enantioselective biomimetic cyclization of polyprenoids 59.25 The LBA catalyst was prepared from (R)-BINOL mono-benzoate derivative and SnCl4 and gave good recognition of the terminal trisubstituted olefin in the substrate 59 to generate site-selective carbocations (Scheme 1.8b). 1.3.3 Chiral Combined Acids as BLAs In the complexes with a combination of Lewis acids and Br¿nsted acids, not only is Br¿nsted acidity greatly improved, but also the acidity of Lewis acids is enhanced OSiMe3PhOOSnCl4HH(R)-BINOL¥SnCl4 (1 equiv.)toluene, Ð78 ¡C100% conversionOPh97% eeOBr(R)-BINOL-Bz¥SnCl4(15 mol%)CH2Cl2, Ð78 ¡C, 6 daysOHBrOHBr+90% de, 90% eeab575960a60b58OOSnCl4HOPh!&*!significantly. The BLA catalysts can be highly effective in activating the nucleophilic sites of the substrates, typically carbonyls, and also provide enhanced asymmetric inductions by the chiral Br¿nsted acid ligands. As shown in Figure 1.3, the spiro-BINOL borate can exist in a four-coordinate anionic form 56 or the three-coordinate neutral form 56a. In the acid form 56a, one of BINOL oxygens is not bonded to the boron and remains pronated. The free phenol group is hydrogen bonded to an oxygen of the other BINOL ligand and as a result improves the Lewis acidity of the boron. During the past thirty years, a great number of BLA catalysts have been developed and explored in the applications of the Lewis acid-catalyzed asymmetric transformations (Figure 1.4). Yamamoto et al. reported the asymmetric Diels-Alder reaction in 1986 between naphthoquinone derivatives and siloxy dienes catalyzed by the BLA 61 derived from B(OMe)3 and (R,R)-(+)-tartaramide.26a The high enantioselectivity observed for the BLA catalyst 62 in Diels-Alder reactions (1994) was proposed to the result from attractive $-$ interactions with the substrate.26b,c BLA spiro-BINOL borate 56a displays highly effective stereoselectivity for aza-Diels Alder reactions with chiral imines and Danishefsky dienes, as well as for Mannich reaction of chiral amines.26d In the unpublished work from our laboratories, there is an evidence that these reactions of imines occur via the Br¿nsted acid form of this catalyst 56a. In addition to boron, other Lewis acidic metals can also be used in BLA catalysis. In 2000, Shibasaki et al. developed a lanthanium-BINOL derived complex 63 for asymmetric Michael reactions of cyclohexenone and malonates.26e Kobayashi et al. (1994-1996) developed BLA catalyst 64 which has a piperidine adduct via hydrogen bonded with the BINOL oxygen. The piperidine moieties are effective in extending the !&+!chiral scaffold which result in excellent enantioselectivity in Diels-Alder26f and aza-Diels-Alder reactions26g. Figure 1.4  Examples of BLA catalysts  1.3.4 Chiral Combined Acids as LLAs The replacement of the proton in a BLA catalyst with a Lewis acid metal will give an LLA complex (Figure 1.5). In this way, electron-deficient metals can be further activated by the second electrophilic Lewis acid. One way to assemble an LLA catayst is to have two of the same Lewis acidic metals in a homo-dimetallic complex. For example, LLA 65 designed by Maruoka et al. consists of two titanium cores that increase the interactions with the substrate compounds and provide a well-organized chiral environment. The bis-Ti(IV) oxide 65 was successful for the asymmetric allylation of aldehydes with allyltributylstannane to afford a secondary allylic alcohol in 99% ee. 27a The other type of LLA catalysts are those derived from BLA catalysts, where the free phenol is deprotonated and charge-balanced by lithium as the conjugate bases in the BLA OOBOO56aHOOOBOO61OOBOOH62OLaOOOOH63OOM(OTf)3HHNNM = Sc (64a), Yb (64b)NHHNOO!&,!catalyst. The spiro-BINOL aluminum complex 66 has been used as an efficient LLA catalyst in the Michael addition of cyclohexenone and malonates.27b,c The chelation of lithium by BINOL oxygens further enhances the Lewis acidity of aluminum resulting in highly efficient interactions with non-activated ketones. And a number of ring-opening reactions were developed involving in a bridged-Ga-Li-BINOL complex 67 with up to 96% ee.27d An X-ray crystallographic analysis suggested that LLA 67 functions with a structure similar to that of the BLA catalyst 63. Figure 1.5  Examples of LLA catalysts  1.3.5 WulffÕs Chiral Boroxinate Catalysts In 1999, Antilla and Wulff reported a novel chiral VANOL/VAPOL-derived boroxinate (BOROX) 71 as the combined acid-derived catalyst as applied to the cis-selective aziridination.28a The structure of this catalyst was not determined until 2010.29 The chiral BOROX anion 71 was prepare by one equivalent chiral diol ligand VANOL 68a or VAPOL 68b with three equivalents of triphenylborate or borane dimethyl sulfide. The presence of imine substrate 72a promoted deprotonation to complete the formation of the boroxinate ring, with the resulting iminium balancing the negative charge.  OOTiOOTii-PrOOOi-Pr65OOAlOOLi66OGaOOOOLi67!&-!Scheme 1.9  Formation of VANOL/VAPOL-derived BOROX catalysts  Further investigation of the protocol for BOROX preparation revealed that a precatalyst was generated by heating VANOL or VAPOL with B(OPh)3. The NMR study indicated the precatalyst was a mixture of a cyclic pyro-borate 69 and a linear meso-borate 70 with the pyro/meso ratio of 2.5:1 for VANOL and 8:1 for VAPOL.29a Both species 69 and 70 contain Lewis acidic three-coordinate borons. They are hydrolytically sensitive and easily deprotonated by basic imine substrates to afford BOROX anions. A recent study also found that the treatment of VANOL/VAPOL with imine 72a and B(OPh)3 afforded BOROX 71 within 10 min at room temperature and that the generation of precataysts 69 and 70 was not necessary.29b       OHOH(S)-VANOL 68aOHOH(S)-VAPOL 68bOHOH(S)-681) B(OPh)3 (3 equiv.)H2O (1 equiv.)toluene, 80 ¡C, 1 h2) 0.1 mmHg80 ¡C, 0.5 hOO(S)-meso-borate 70BOPhOOBOBOPhOPh(S)-pyro-borate 69PhPhPhPhPhPhPhPhPhPh+OOBPhPhOBOBOOPhOPhPhPhPh72aB(OPh)3 (3 equiv.)toluene, 25 ¡C, 10 minH72PhPhPh72atoluene, 25 ¡C(S)-BOROX 71!&.!Figure 1.6  Chiral BOROX anion in asymmetric catalysis  The BOROX anion consists of one four-coordinate boron and two three-coordinate borons that feature multiple reactive sites with good Lewis acidity, H-bond acceptors and the VANOL/VAPOL ligand as the chiral scaffold. A number of asymmetric imine transformations were reported by Wulff and his co-workers that exhibited excellent stereoselectivity. The BOROX catalysts can effectively interact with a protonated imine by hydrogen bonding and provide high asymmetric inductions in cis-selective aziridinations28b,c, trans-selective aziridinations30, hetero-Diels-Alder reactions31, quinoline reduction32, aza-Cope rearrangements33 and the Ugi reaction34.  Of articular interest is that benzoic acid was employed as a co-catalyst in the asymmetric aza-Cope rearrangement. It is believed that a dianionic catalytic BOROX species was generated as the result of benzoate coordination to one of the three-coordinate borons. The additional negative charge can strengthen the electrostatic attraction between the BOROX catalyst and the protonated iminium substrates substrate with an improvement of enantioselectivity. In the three-component Ugi reaction, a cationic iminium, generated OOArArBOBOBOOPhOPh(S)-VANOL/VAPOL boroxinate catalyst[H-substrate]1 ligand3 B(OPh)33 H2O1 ligand3 BH3¥SMe22 PhOH3 H2OPhNArAr+N2OEtONPhArArOOEtPhNArAr+N2NHONPhArArOHNPhPhPhNPhPh+OTMSOMeNPhPhPhONBuHantzch esterNHBuPhNArArPhCO2H cat.PhNH2 ¥ HClPhHO+BnNHBn+CNt-BuPhHNOt-BuNBnBncis-aziridinationtrans-aziridinationquinoline reductionhetero-Diels-Alder reactionaza-Cope rearrangementUgi reactionACDC typedianionic boroxinateDesai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100.Antilla, J. C.; Wulff, W. D. Angew. Chem. Int. Ed. 2000, 39, 4518.Zhang, Y.; Lu, Z.; Desai, A. A.; Wulff, W. D. Org. Lett. 2008, 10, 5429.Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 5656.Newman, C. A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7216.Desai, A. A.; Guan, Y.; Odom, A. L.; Majumder, S.; Wulff, W. D.; Vetticatt, M. J. Tetrahedron Lett. 2015, 56, 3481.Zhao, W.; Huang, L.; Guan, Y.; Wulff, W. D. Angew. Chem. Int. Ed. 2014, 53, 3436.!'/!in-situ by an aldehyde and a secondary amine, is involved in the catalytic cycle. The BOROX anion provides an effective ACDC catalyst by ion-pair interaction with iminium cation to give a high enantioselectivity.   !'&!        REFERENCES  !''!REFERENCES  1. To limit the scope of references, see selected recent reviews on chiral anions asymmetric catalysis: a) Basu, A.; Thayumanavan, S. Angew. Chem. Int. Ed. 2002, 41, 716; b) Lacour, J.; Hebbe-Viton, V. Chem. Soc. Rev. 2003, 32, 373. 2. Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nature Chem. 2012, 4, 603. 3. For the selected review on H-bond donor asymmetric catalysis: Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. 4.  For the selected review on chiral phosphoric acid catalysts: Akiyama, T. Chem. Rev. 2007, 107, 5744. 5. For the selected review on ACDC: Mahlau, M.; List, B. Angew. Chem. Int. Ed. 2013, 52, 518. 6. Asymmetric Mannich reactions: a) Akiyama, T.; Itoch, J.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566; b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. 7. Asymmetric hydrophosphonylation of imines: Akiyama, T.; Morita, H.; Itoh, J. Fuchibe, K. Org. Lett. 2005, 7, 2583. 8. Asymmetric azo-Diels-Alder reaction: Akiyama, T. Tamura, Y.; Itoh, J. Morita, H. Fuchibe, K. Synlett, 2006, 141. 9. Iminium-based organocatalysis: Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. J. Am. Chem. Soc. 2005, 127, 32. 10. Mayer, S.; List, B. Angew. Chem. Int. Ed. 2006, 45, 4193. 11. Kamilton, G. L.; Kanai, T.; F. D. Toste; J. Am. Chem. Soc. 2008, 130, 14984. 12. Rueping, M; Uria, U.; Lin, M-Y.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133, 3732. 13. Garc™a-Garc™a, P.; Lay, F.; Garc™a-Garc™a, P.; Rabalakos, C.; List, B. Angew. Chem. Int. Ed. 2009, 48, 4363. 14. Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558. 15. De, C. K.; Klauder, E. G.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 17060. 16. Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336. !'(!17. TADDOL-activated aldehydes: a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146; b) Gondi, V. B.; Gravel, M.; Rawal, V. H. Org. Lett. 2005, 7, 5657. 18. Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 46, 6903. 19. Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature, 2011, 470, 245. 20. Olah, G. A.; Prakash, G. K. S.; Sommer, J. Science, 1979, 206, 13. 21. Ren, J. Cramer, J.; Squires, R. R. J. Am. Chem. Soc. 1999, 121, 2633.  22. Yamamoto, H.; Futatsugi, K.; Angew. Chem. Int. Ed. 2005, 44, 1924. 23. For the review on LBA catalysts: Ishibashi, H.; Ishihara, K.; Yamamoto, H. Chem. Rec. 2002, 2, 177. 24. Enantioselective silyl enol ether protonation by LBA: a) Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179; b) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854; c) Nakamura, S.; Kaneeda, M.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8120. 25. a) Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 4906; b) Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8131. 26. Asymmetric catalysis by BLAs: a) Maruoka, K.; Sakurai, M.; Fujiwara, J.; Yamamoto, H. Tetrahedron Lett. 1986, 27, 4895; b) Ishihara, K. Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561; c) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 6920; d) Ishiharah, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520; e) Kim, Y. S.; Matsunaga, S. Das, J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506; f) Kobayashi, S.; Ishitani, H.; J. Am. Chem. Soc. 1994, 116, 4083; h) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357. 27. Asymmetric catalysis by LLAs: a) Hanawa, H.; Hashimoto, T.; Marouka, K. J. Am. Chem. Soc. 2003, 125, 1708; b) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem. Int. Ed. 1996, 108, 103.; c) Shimizu, S.; Ohori, K.; Arai, T.; Sasai, M.; Shibasaki, M. J. Org. Chem. 1998, 63, 7547; d) Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.; Yamamoto, N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 2252. 28. a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099; b) Antilla, J. C.; Wulff, W. D. Angew. Chem. Int. Ed. 2000, 39, 4518; c) Zhang, Y.; Lu, Z.; Desai, A. A.; Wulff, W. D. Org. Lett. 2008, 10, 5429. !')!29. a) Zhao, W.; Yin, X.; Gupta, A. K.; Zhang, X.; Wulff, W. D. Synlett, 2015, 26, 1606; b) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669. 30. Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100. 31. Newman, C. A.; Antilla, J. C. Chen, P.; Predeus, A. V. Fielding, L. Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7216. 32. Desai, A. A.; Guan, Y.; Odom, A. L. Majumder, S. Wulff, W. D. Vetticatt, M. J. Tetrahedron Lett. 2015, 56, 3481. 33. Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 5656. 34. Zhao, W.; Huang, L.; Guan, Y.; Wulff, W. D. Angew. Chem. Int. Ed. 2014, 53, 3436.   !'*!Chapter 2 Multi-Component cis-Aziridination 2.1 Literature Work on Catalytic Asymmetric Aziridination 2.1.1 Aziridines in natural products Aziridines are important building blocks and many exist natural products and drug reagents that have biological properties including anti-tumor, anti-bacteria and anti-fungus activities.1 A number of aziridine-containing natural products have been reported in thw literature. Miraziridine A 73 was isolated from the marine sponge Theonella mirabilis, which exhibites a variety of bioactivies such as anti-fungal properties and protease inhibitory.2 Azinomycin B 74 is a natural product with potential anti-tumor activity isolated from Streptomyces sahachiroi.3 Ficellomycin 75 was isolated from Streptomyces ficellus with antibiotic activity.4 Azicemicins A 76a and B 76b are a class of antibiotics isolated from the culture broth of the strain MJ126-NF4.5 Maduropeptin 77 is an antibiotic with anticancer activity isolated from Actinomadura madurae.6 The best-known compounds containing aziridine-rings are the family of mitosanes 78 and 79, which were first isolated from soil extracts of Streptomyces verticillatus and exhibit both anti-tumor and anti-biotic activity.1a The aziridine rings are essential in bioactivity of mitosanes that relies on a bioreductive activation to that results in DNA alkylation/aziridine ring-opening followed by DNA cross-linking via cationic intermediates.1a  Danishefsky and his co-worker also proposed an alternative mode of action for mitosanes involving a semi-quinone radical anion as a key intermediate.1c Related compounds also known as FR and FK anti-cancer reagents 80 have similar interactions with DNA, which reveals an intimate relationship in the structural similarity with mitosanes.1d !'+!Figure 2.1  Aziridine-containing natural products  Also, extensive reports have appeared on methods for the prepration of aziridines since they are useful synthetic intermediates and willing to undergo nucleophilic ring-opening process under the mild conditions to afford amino-containing compounds including aminoalcohols, aminosulfides and aminophosphonates, %-aminocarbonyl compounds, dimerization products, polymers and 2,5-dihydropyrrole derivatives by 1,3-dipolar cycloaddition with alkynes (Figure 2.2).7 In addition, there is a substantial body of literature that involves the use of aziridine compounds have been used as chiral ligands or chiral auxiliaries. For example, C2-symmetric bisaziridines give decent stereoselectivity in various asymmetric transformations such as the asymmetric alkylations and syn-aldol reactions.8 Chiral aziridino alcohols have been reported as effective chiral ligands in asymmetric reduction of imines and aldehydes.9  OOR1NNONH2OR2R3Omitomycin A    R1 = OMe, R2 = Me, R3 = Hmitomycin B    R1 = OMe, R2 = H, R3 = Me,mitomycin C    R1 = NH2, R2 = Me, R3 = Hporfiromycin    R1 = NH2, R2 = Me, R3 = MeOOR1NNOR2mitomycin G    R1 = NH2, R2 = Memitomycin H    R1 = OMe, R2 = Hmitomycin K    R1 = OMe, R2 = Me7879OR2OR1NOONOHNH2OOR380FR-900482  R1 = CHO, R2 = R3 = R4 = HFR-66979    R1 = CH2OH, R2 = R3 = R4 = HFR-70496    R1 = CHO, R2 = Me, R3 = H, R4 = AcFK-973        R1 = CHO, R2 = R3 = R4 =AcNHOHOONHHNOOHNHOHNOOHONHNH2NHmiraziridine A 73MeOOOOHNONOONHOOazinomycin B 74H2NONNHHH2NHNOHOficellomycin 75HOMeOOHOHOOHOHOHNHRazicemicin A 76a    R = Hazicemicin B 76b   R = MeHONHOOOHOHOHONOClOMeOOHmaduropeptin 77OH!',!Figure 2.2  Transformations of disubstituted aziridines  2.1.2 Catalytic Asymmetric Aziridination The oldest and most conventional way to synthesize an aziridine ring is from a 1,2-aminoalcohol or 1,2-aminohalide through SN2 ring-closure. As early as 1888, Grabriel synthesized aziridines in a two-step process, by chlorination of ethanolamines followed by cyclization (Scheme 2.1a).10a The stereochemistry of resulting aziridines was total dependent on the stereochemical configurations of the starting materials in avoid with the nature of the SN2 process. Of particular note is reported by Sweeney and co-workers in 1997 that employed a Staudinger reaction in a phosphine-mediated ring-closure of azidoalcohols.10b They started from ring-opening of chiral epoxides 83 by sodium azide to afford the corresponding mixture of azidoalcohol regioisomers 85a and 85b, which was followed by triphenylphosphine mediated Staudinger reaction via five-membered ring oxazaphospholidine intermediates to give aziridines 84, with the inversion of stereochemistry of both carbons in expoxides 83 (Scheme 2.1b).  NRR1R2R1R2NHR3SR4R1R2NHR3NHR4R1R2NNHR3R1R2NR1R2NR3R3nR1R2NHR3P(OR)2R1R2NHR3CH2R4R1R2NHR3CO2R4CO2R4R1R2NHR3OR4aminosulfidesaminoalcoholsdiaminesdimerizationPolymersaminophosphonatesaminesNR1R2R3R3RO1,3-dipolar cycloaddition!'-!Scheme 2.1  Aziridination from 1,2-amino functionzalized compounds  Scheme 2.2  Aziridination by nitrene addition to alkenes  In early studies of direct aziridination was achieved by nitrene addition to alkenes. Nitrenes are highly reactive intermediates and are typically generated by thermal or photochemical decomposition of azides. However, this method leads to a mixture of singlet and triplet nitrenes as only singlet nitrenes react with alkene through concerted processes but triplet ones react with alkenes via radical pathways.10a During the middle 1990s, Evans11a, Jacobsen11b,c and Katsuki11d developed enantioselective aziridination of alkenes by metal-stabilized nitrenes, which were generated in-situ from nitrene precursor HOR2R1NHXR4PXSOCl2, RSO2ClNR1R2XHNR1R2OR1R2NaN3PPh3, MeCNHOR1R2N3+N3R1R2OHR1R2+R1R2OPh3PHNNHPh3PON3PPh38182a848385a85b86a86bbR2R1R3PhI=NTs5-10 mol% Cu(MeCN)4ClO4MeCNNR1R3R2TsPhI=NTsCuOTf, salenMeCNOONTs75% yield, 98% eeEvansJacobsenup to 97% eeONNOPhPh8788899091NNClClClCl92!'.!N-tosyliminophenyliodinane (Scheme 2.2). The utility of chiral bis-oxazoline 89 and 1,2-diimine 92 ligands afforded aziridines with high enantioselectivity. As two C-N bonds form nearly simultaneously, the stereochemistry of aziridines from nitrene addition relies on the double bond configuration of the alkenes. A useful aziridination protocol was established in the late 1990s when it was found a carbene or ylide would react with an imine effectively to obtain the corresponding aziridine at a time when a number of groups explored a direct asymmetric catalytic synthesis of aziridines. It was believed the aziridination proceeds step-wise with the carbene lone-pair attacking an imine followed by nitrogen ring-closure. A number of chiral catalysts were developed to control the asymmetric induction during the carbene addition process. Jacobsen et al. reported that a copper-carbenoid derived from ethyl diazoacetate (EDA) reacts with an N-arylaldimine 93 to afford a mixture of cis- and trans-aziridines 94 in a 10:1 selectivity, however, with relatively low enantioselectivity (Scheme 2.3a).12a The enantioselectivity was greatly improved in a  trans-selective aziridination reported by Aggarwal et al. with benzaldimine 95 and diazotoluene.12b In their strategy, a sulfur-ylid intermediate was generated from an in-situ copper carbenoid in the presence of chiral sulfide reagent 97. They obtained trans-aziridine 96 with a 3:1 trans:cis selectivity and 95% ee for the trans-isomer (Scheme 2.3b). However, a stoichiometric amount of Cu(acac)2 was used to maintain a decent yield. The first Lewis acid catalyzed aziridination was reported by Templeton et al. with imine 93 and EDA in the presence of boron trifluoride diethyl etherate as the Lewis acid.12c A high selectivity for the cis-aziridine 94 was observed in 93% yield and 97:3 cis/trans ratio. They also observed a mixture of enamine regioisomers 98a and 99a derived from phenyl or hydride migration !(/!of diazonium intermediate (Scheme 2.3c). Based on these results, Wulff and Antilla developed a highly efficient asymmtric cis-aziridination catalyzed by the chiral VAPOL-derived BOROX catalyst 71b (Scheme 1.9) that afforded aziridine 100 in 79% yield, 98% ee and with a >50:1 cis-selectivity (Scheme 2.3d).12d  Scheme 2.3  Aziridination by carbene/ylid addition to imines  2.1.3 WulffÕs BOROX-Catalyzed cis-Aziridination In the early work on BOROX-catalyzed cis-aziridination, a benzhydryl (diphenylmethyl) group was employed as the N-substitution in the imine substrates it was later realized that the interactions between the BOROX catalyst and imines are not just limited to hydrogen PhNPhEDA[CuPF6(MeCN)4]89, CH2Cl2NPhCO2EtPhNPhCO2EtPh+NONOPhPh89cis:trans >10:144% ee cis35% ee transJacobsen65%93cis-94trans-94PhNO2SPhN2Cu(acac)2 (1 equiv.)O2SPhPhN83% yield, 95% ee3:1 trans:cisAggarwalab9596PhNPhEDABF3!Et2OhexanesPhCO2EtPhN93% yield93:7 cis:trans+HNHCO2EtPhPh+PhNHCO2EtHPhTempletonc93cis-9498a99aPhNEDA(S)-VAPOL BOROX 71b(2.5 mol%)CH2Cl2CO2EtPhN+HNHCO2EtPh+PhNHCO2EtH79% yield98% ee>50:1 cis:transWulffdPhPhPhPhPhPhPhPh72a10098b99bSO97TMSTMS!(&!bonding, electrostatic attractions and Lewis acid-Lewis base coordination, but also potential CH-$ and $- $ stacking interactions. Further optimization of the asymmetric cis-aziridination was carried out by Yu Zhang, Zhenjie Lu and Aman Desai who focused on the diversity of the imine N-substition.13a The first set of experiments in screening a number of N-substituents revealed the presence of aromatic moieties in N-substituent of imines had a significant effect on the rection rate and the asymmetric induction (Table 2.1). Table 2.1  Screening of imine N-substitution13a  imine relative rates yield% ee% 72a 1.0 83 89 72b 1.7 51 43 72c 0.04 18 74 72d 0.23 27 84 72e 0.3 64 80 72f 1.0 75 95 72g 2.2 65 96 Imine 72f and 72g reacted with a higher induction and faster rates than imine 72a, but with relatively lower yields. Thus, a series of electron-rich and electron-deficient benzhydryl imines were evaluated in the cis-aziridination in a second set of experiments (Table 2.2). Ten imines were explored that indicated electron-rich benzhydryls could greatly enhance the CH-$ and $- $ stacking interactions and 3,4,5-trisubstituted aromatic rings with outstanding inductions. Particularly, imine 72o and 72p display dramtic improvement in yield and ee in the cis-aziridination, with the tetramethyldianisylmethyl (MEDAM) and tetra-tert-butyldianisylmethyl (BUDAM) substituents as the optimum. PhNREDA(S)-VAPOL BOROX 71b(5 mol%)CH2Cl2, rt.RCO2EtPhN72PhNPhNPhNPhNPhNPhNPhN72b72c72d72a72e72f72g!('! Table 2.2  Screening of benzhydryl substitution13a  imine 72h 72i 72j 72k 72a 72l 72m 72n 72o 72p rel. r 0.02 0.05 0.28 0.45 1.0 2.3 3.8 10.0 11.5 16.3 yield% 48 63 80 70 83 82 78 89 89 96 ee% 37 86 88 88 89 92 90 95 98 99 Munmun Mukherjee, Anil Gupta, Yu Zhang and Zhenjie Lu investigated on substrate scope with 36 imines with a combination of imines from nine different aldehydes including electron-rich and electron-poor phenyl and 1¡, 2¡, 3¡ alkyls and four diarylmethyl N-substituents (Bh, DAM, MEDAM and BUDAM) (Bh = benzhydryl, DAM = dianisylmethyl) which provided an extensive profile of asymmetric induction in the cis-aziridination.13b Based on the experimental results, MEDAM and BUDAM substituted imines displayed much better inductions than Bh and DAM imines with excellent ee for the cis-aziridines for all the substrates investigated. And MEDAM imines gave higher ee than BUDAM in most of the protocols as the optimal N-substitution in cis-aziridination (Figure 2.3). Both VANOL- and VAPOL-derived BOROX catalysts were investigated and it was shown VAPOL BOROX 71b gave a better induction than VANOL BOROX 71a for most of substrates, except for 2¡ and 3¡ imines.       PhNArArAr =CF3CF3BrFOMeOMet-But-BuOMe72h72i72j72k72a72l72m72n72o(MEDAM)72p(BUDAM)!((!Figure 2.3 Asymmetric induction with N-substitution for a) VANOL BOROX; b) VAPOL BOROX13b                             a                                                                                               b Figure 2.4  The non-covalent interactions in BOROX-iminium complex14c  A crystal structure of the active BOROX catalyst 71b Ð iminium 72a-H+ complex obtained by Gang Hu, Anil Gupta, Rui Huang and Munmun Mukherjee14a helps to reveal the non-covalent interactions between BOROX 71b and imine 72o with the computational studies using ONIOM(B3LYP/6-31G*:AM1) calculation by Mathew Vetticatt and Aman Desai14b. The strongest interaction is the hydrogen bonding between imine NH+ and one of the oxygens from the six-membered ring of broxinate anion (Figure 2.4, d1)14c. There are several CH-$ interactions within CH3, sp2 C-H bonds of 71b72o-H+!()!MEDAM group and aromatic systems of BOROX (Figure 2.4, d2-d5). In addition, there is a secondary interaction between the MEDAM methine and the VAPOL oxygen (Figure 2.4, d6). The presence of $-$ stacking interaction between phenyl group of imine and aromatic ring of the phenanthrene unit in VAPOL may also play a role in the asymmetric induction (Figure 2.4, d7). 2.2 Catalytic Asymmetric Multi-Component cis-Aziridination 2.2.1 Optimization of Reaction Conditions Multi-component reactions have been extensively studied and applied to asymmetric catalysis for the maximization of synthetic efficiency in the production of chiral molecules.15 Imine substrates are usually less stable due to slow decomposition and in most protocols synthesized from the corresponding amines and aldehydes in advance. Purification of imines can also be a problem because most imines decompose during silica gel column chromatography or upon distillation and sublimation during heating. Thus, Anil Gupta and Munmun Mukherjee, our former lab members have reported the first strategy for the asymmetric multi-component cis-aziridination based on the BOROX-catalyzed cis-aziridination with imines and EDA (Scheme 2.4a).16 In this multi-component procedure, an imine is generated in-situ as an intermediate which is consumed by EDA to afford a cis-aziridine. Given that amines are more basic than imines, the BOROX catalyst 71 could also prepared from VANOL/VAPOL ligands 68 with B(OPh)3 in the presence of primary amines 101a (Scheme 2.4b). The question is if the presence of amines and aldehydes could result in any byproducts. Also, different modes of interactions between the substrates and the catalysts are anticipated, which could have an effect on the asymmetric induction. !(*!Scheme 2.4  BOROX-catalyzed multi-component cis-aziridination  Scheme 2.5  Multi-component cis-aziridination of benzaldehyde 33a16  Procedure A (T = 25 ¡C, t = 1 h) 33a (105 mol%) added before 102  (98% yield, 98% ee) 102 added before 33a (105 mol%)  (94% yield, 98% ee) 33a (60 mol%) added before 102  (<1% yield) Procedure B (T = 80 ¡C, t = 0.5 h) 33a (105 mol%) added before 102  (97% yield, 98% ee) Several experiments were conducted on the multi-component cis-aziridination of benzaldehyde 33a in an effort to evaluated the effects of each component of substrates on the reaction. In the standard conditions, the (S)-VAPOL 68b (5 mol%) was mixed with B(OPh)3 (15 mol%) and MEDAM amine (1 equiv) in toluene at 25 ¡C for 1 h to generate the BOROX catalyst (Procedure A, Scheme 2.5). This was followed by the addition of molecular sieves, benzaldehyde 33a (1.05 equiv) and EDA 102 (1.2 equiv). The resulting mixture was stirred at room temperature for 24 h to afford cis-aziridine 103a in 98% yield and 98% ee. If EDA 102 was added before benaldehyde 33a, a similar result was RHOMEDAMNH2++N2OEtO4 † MS(S)-BOROX (5 mol%)tolueneNRMEDAMOEtOOHOH*+3 B(OPh)3MEDAMNH2tolueneOO*BOBOBOOPhOPhMEDAMNH3101a33102103MeOOMeMEDAMa7168101abMEDAMNH2(S)-VAPOL (5 mol%)B(OPh)3 (15 mol%)toluene, T ¡C, t hPhHO33a(x mol%)4 † MSN2OEtO102(120 mol%)25 ¡C, 24 hNPhMEDAMOEtO103a(100 mol%)101a!(+!obtained (94% yield, 98% ee). However, if only 60 mol% of benzaldehyde 33a was added, no azirine was observed, which suggested that the excess amine could deactivate the catalyst since it is a stronger base than an imine. It was also found that generation of the BOROX catalyst at 80 ¡C for 0.5 h would also lead to a similar result (97% yield, 98% ee) (Procedure B, Scheme 2.5). Table 2.3  Optimization of multi-component aziridination with n-butyraldehyde 33aÕ a 16  entry ligand proc. cat. x mol% T (¡C) EDA (equiv.) yield% 103aÕ b ee% 103aÕ c yield% 104 d yield% 105 d 1 (R)-68a A 5 25 1.2 25d nd 20 38 2 (R)-68a A 5 0 1.2 50d nd 6 21 3 (R)-68a B 5 0 1.2 53d nd 6 17 4 (R)-68a B 10 0 1.2 74 Ð95 2 <1 5 (R)-68a B 10 Ð10 1.2 80 Ð96 <1 <1 6 (S)-68b B 10 Ð10 1.2 82 98 <1 <1 7 (S)-68b B 5 Ð10 8 91 96 <1 <1 8 (S)-68b A 5 Ð10 8 94 96 <1 <1 9 (S)-68b A 3 Ð10 2 92 96 <2 <2 a Unless otherwise specified, all reactions were performed with 0.5 mmol of amine 101a (0.5 M) and 1.05 equiv of n-butyraldehyde 103aÕ and 1.2 equiv EDA 102 with Procedure A or B (see Scheme 2.6) and went to 100% completion. b Isolated yield. c Determined by chiral HPLC. d Yield determined by 1H-NMR with Ph3CH as internal standard. It was quite a different story when it came to aliphatic aldehyde substrates. For non-branched aliphatic imines, there is a problem in the clean in-situ generation of the imino reactor that leads to a very poor outcome in aziridination with non-purified substrate. In the initial study of the multi-component reaction with n-butyraldehyde 33aÕ, it was found that the imine could not be generated in a clean fashion. The self-condensation byproduct conjugate imine 104 was observed in 20% yield after reaction for 24 h at room MEDAMNH2(S)-VAPOL (5 mol%)B(OPh)3 (15 mol%)toluene, T ¡C, t hHO33a'(1.05 equiv)4 † MSEDA (1.2 equiv)T ¡C, 24 hNMEDAMOEtO103a'(100 mol%)+NMEDAM+NMEDAM104105(R)-VANOL 68aPhPh(S)-VAPOL 68bPhPhOHOHOHOH101!(,!temperature along with 38% of the imine 105 (Table 2.3, entry 1). Further optimization of the reaction conditions shown that the self-condensation product could be effectively retarded as the temperature was decreased to Ð10 ¡C. Excess EDA (2.0 equiv) could promote the conversion of in-situ imine 105 into cis-aziridine 103aÕ. VAPOL 68b also provides a better yield than VANOL 68a, which affords 103aÕ in 92% yield and 96% ee with the optimal conditions (Table 2.3, entry 9). 2.2.2 Substrate Scope and Screening of BOROX Catalysts The screening of BOROX catalysts derived from the ligands VANOL 68a, VAPOL 68b and 7,7-di-tert-butyl VANOL 68c has been reported with several aldehyde substrates 33.16,17 The reactions were allowed to proceed for 24 h with 5 mol% catalyst loading to ensure a full conversion of all substrates, however many of the aldehydes were completely converted in far less time. The data (Table 2.4) reveals that all three ligands 68a, 68b, 68c gave significantly high asymmetric inductions for aromatic aldehydes. But for electron-rich 4-anisaldehyde, the yield was relatively low due to the slow in-situ formation corresponding imine. Ligand 68c gave a slighly higher induction than either 68a or 68b for aliphatic aldehydes, which makes the ligand synthetically valuable, especially for the aziridination of n-pentadecanal as the key step in the sphinganine synthesis.       !(-!Table 2.4  Substrate scope of multi-component cis-aziridination with three ligands-derived catalysts17  entry R (S)-VANOL 68a (S)-VAPOL 68b (R)-tBu2VANOL 68c yield% b ee% c yield% b ee% c yield% b ee% c 1 p-NO2C6H4  77 99 92 99 100 Ð99 2 p-CH3C6H4 87 98 95 99 91 Ð99 3 o-CH3C6H4 73 98 96 >99 97 Ð99 4 C6H5 87 97 98 98 100 Ð99 5 p-CH3OC6H4 82 97 78 98 93 Ð99 6 2-pyridyl  95 96 96 90 97 Ð99 7 n-C15H31 d  60 95 85 96 97 Ð98 8 cyclohexyl 94 94 95 90 100 Ð96 9 tert-butyl 70 95 89 94 100 Ð97 a Unless otherwise specified, all reactions were run at 0.5 M in amine in toluene on a 0.5 mmol scale with EDA 102 (1.2 equiv) and aldehyde 33 (1.05 equiv) at 25 ¡C for 24 h and went to 100% completion with the catalyst (5 mol%) with Procedure B (see Scheme 2.6). The data for ligand 68a is from Reference 17 and the data for ligand 68b and 68c are data from this thesis work. b Yield of isolated cis-aziridine 103 purified by silica gel column chromatography. c Determined by chiral HPLC. d Reaction was performed at Ð10 ¡C at 0.2 M with 102 (2.0 equiv). 2.3 Catalyst Control in Multi-Component cis-Aziridination 2.3.1 Reaction Optimization and Substrate Scope Among the range of asymmetric catalytic tactical methods, most do not display true catalyst control in setting the stereochemistry of new chiral centers independently from the chiral centers already present in the substrates. Typically, one finds matched and miss-matched pairs of the catalyst and substrate which affect the disatereoselectivity in the formation of new chiral centers.18 The disatereoselective outcomes of aziridination with chiral imines can be predicted by the Felkin-Ahn Model19 of  nucleophilic attack on an imine. As shown in Figure 2.5, the preferential addition of the nucleophile to the C=N bond will be along -Dunitz angle near the side of smallest substituent which is sterically favored. The chiral imine reacts via Conformer A in Re-face attack of the nucleophile, which is favored to afford the matched diastereomer of the aziridine. MEDAMNH2RHO33NRMEDAMOEtO103101a++N2OEtO102(S)-BOROXtoluene, 25 ¡C, 24 h(R)-7,7'-t-Bu2VANOL 68cPhPhOHOHt-But-Bu!(.!Conformer B of the chiral imine reacts via Si-face attack of the nucleophile, which is disfavored to afford the miss-matched diastereomer. Figure 2.5  Felkin-Ahn Model in cis-aziridination of chiral imines19c  Scheme 2.6  Catalyst-controlled multi-component cis-aziridination20  Our laboratories have developed the first catalyst-controlled multi-component cis-aziridination of aldehydes where the absolute stereochemistry of the newly formed aziridines is a function of the catalyst and not of chiral centers in aldehyde present at either !- or "-positions (Scheme 2.6). One of the reasons that we were driven to develop the multi-component version of the catalyst-controlled aziridination was that in some cases epimerization of the pre-formed imines occurred to result in a poor stereoselectivity.   HNRsRMRLPGNHRLRSRMPGNuNuRe-face attack(Comformer A)Si-face attack(Comformer B)RsRMRLNuHHNHNNuHRLRMRsPGPGN2OEtONu =NEtO2CPGRsRLRMNEtO2CPGRsRLRMmatchedmis-mathcedGFR1R2OH**(S)-BOROX(R)-BOROXNMEDAMR2R1FGOOEtNMEDAMR2R1FGOOEt****104anti-105'syn-105MEDAMNH2101a++N2OEtO102!)/!Table 2.5  Catalyst-controlled cis-aziridination of aldehyde (R)-104a a 20  entry amine ligand T (¡C) yield% b aziridine syn:anti c 1 101a (S)-VAPOL 25 90 105a 4:96 2 101a (R)-VAPOL 25 90 105a 97:3 3 101a (S)-VAPOL 0 92 105a 3:97 4 101a (R)-VAPOL 0 90 105a 99:1 5 101a (S)-VAPOL Ð10 90 105a 2:98 6 101a (R)-VAPOL Ð10 90 105a 99:1 7 101a (S)-VANOL Ð10 85 105a 2:98 8 101a (R)-VANOL Ð10 85 105a 98:2 9 101b (S)-VAPOL Ð10 50 106a 1:99 10 101b (R)-VAPOL Ð10 65 106a 94:6 a Unless otherwise specified, all reactions were run with 0.2 mmol amine 101 (1.0 equiv), EDA (1.2 equiv) and aldehyde (R)-104a (1.05 equiv) in toluene (0.4 M) for 24 h in the presence of powered 4 † molecular sieves and went to 100% conversion. The BOROX catalyst was prepared with Procedure B (Scheme 2.6). b Isolated yield of syn-105a/106a and anti-aziridine 105aÕ/106aÕ purified by silica gel column chromatography. c Determined by 1H-NMR of the crude reaction mixture. The initial investigations of the catalyst-controlled multi-component cis-aziridination with (R)-104a were done by Munmun Mukherjee and gave a 96:4 distereoselectivity of the anti-aziridine 105aÕ over syn-aziridine 105a with (S)-VAPOL-derived BOROX catalyst (Table 2.5, entry 1). The aziridination with (R)-VAPOL-derived BOROX catalyst gave 97:3 ratio of aziridines 105a and 105aÕ in favor of syn-isomer (Table 2.5, entry 2), which indicates a high level of catalyst control in the asymmetric induction, and in addition agrees with the previous experimental results in the cis-aziridination with the (S)-ligand BOROX catalysts giving addition to the Si-face of the non-chiral imines to afford cis-aziridine carboxylates with (2R)-configuration. The diastereoselectivity was slightly improved when the reaction temperature was decreased to Ð10 ¡C (Table 2.5, entry 3-6). The VANOL BOROX catalyst gave the comparable catalyst control level to those of the VAPOL BOROX catalyst (Table 2.5, entry 7, 8). However, replacement of OTBSOH(R)-104a10 mol% BOROXamine 101EDA 102toluene, T ¡C, 24 hNROTBSOEtO+NROTBSOEtOsyn-105asyn-106aanti-105a'syn-106a'R = benzhydylR = MEDAMNH2MeOOMe101aPhPhNH2101b!)&!MEDAM amine 101a with benzhydryl amine 101b resulted in great drop in the yield, although decent catalyst control was still maintained. Table 2.6  Catalyst-controlled cis-aziridination of (R)-glyceraldehyde acetonide 104b a  entry ligand yield% b syn:anti c 1 (S)-VANOL 67 16:84 2 (R)-VANOL 86 92:8 3 (S)-VAPOL 73 16:84 4 (R)-VAPOL 90 94:6 5 (S)-tBu2VANOL 99 3:97 6 (S)-tBu2VANOL 99 97:3 a Unless otherwise specified, all reactions were run with 0.2 mmol MEDAM amine 101a (1.0 equiv), EDA (1.2 equiv) and aldehyde (R)-104b (1.05 equiv) in toluene (0.4 M) for 24 h in the presence of powered 4 † molecular sieves and went to 100% conversion. The BOROX catalyst was prepared with Procedure B (Scheme 2.6). b Isolated yield of syn-105b and anti-aziridine 105bÕ purified by silica gel column chromatography. c Determined by 1H-NMR of the crude reaction mixture. As part of the work in this thesis, the ligand of the catalyst-controlled aziridination was also investigated with (R)-glyceraldehyde acetonide 104b, which has potential synthetic utility of polyoxamic acid. All three ligands VANOL 68a, VAPOL 68b and 7,7Õ-di-tert-VANOL 68c have been tested. It was found that the anti-isomer of aziridine 105b was the miss-matched product with (S)-VANOL and VAPOL ligands and resulted in lower yields and disatereoselectivities than those of syn-105a with (R)-VANOL and VAPOL ligands (Table 2.6, entry 1 and 3 vs 2 and 4). However, complete catalyst control was observed with t-Bu2VANOL ligands, since it gives 97:3/3:97 diastereomeric ratio in a 99% yield for both syn- and anti-105b (Table 2.6, entry 5, 6).  A number of different aldehydes with chiral centers at the !- or "-positions have been evaluated in the catalyst-controlled aziridination (Table 2.7). Replacement of the phenyl group in aldehyde 104a with a methyl or a long chain n-tetradecyl group still results in very good catalyst control for the aldehydes (S)-104c and (R)-104d. However, HOOO5 mol% BOROXMEDAM amine 101aEDA 102toluene, Ð10 ¡C, 24 h(R)-104bNMEDAMOEtOOO+NMEDAMOEtOOOsyn-105banti-105b'!)'!replacement of the tert-butyldimethylsiloxy group in 104a with a methyl group results in drop in the diastereoselectivity for aldehyde (S)-104e to 83:17 ratio in favor of anti-105e in the miss-matched case due to racemization of the intermediate imine (see chapter 6.2.2 b2). The chiral aldehyde (S)-104f with an !-branched alkyl chain did not give a high level of catalyst control with the VAPOL ligand 68b. However, it gave a perfect level of catalyst control with the t-Bu2VANOL ligand 68c at Ð40 ¡C. And the aldehyde (R)-104g with the a cyclohexyl and a tert-butyldimethylsiloxy group in the !-position is the substrate with a strongly miss-matched reaction even with the t-Bu2VANOL ligand 68c and affords 18:82 ratio at the best selectivity for this case. A high level of catalyst control could also be realized with aldehydes (R)-104h and (S)-104i bearing the chiral centers at "-positions. Comparing the case aldehydes 104h with 104c and 104i with 104e, we would expect that a higher level of catalyst control would be seen with the greater distance of the chirality from the reaction center, as the more remote chiral center exhibits weaker negative effects on the asymmetric induction for the miss-matched isomer. In addition, the "-chiral center would not be expected to undergo racemization of the in-situ generated imines. Several chiral heterocyclic aldehydes were also examined with the catalyst-controlled aziridination (Table 2.8). The multi-component aziridination of (S)-104j exhibited very high yields and a decent level of catalyst control with the selectivity around 90:10 ratio for both isomers of the t-Bu2VANOL ligand 68c. A complete and significantly high level of catalyst control was seen for the aziridine carboxaldehyde (2S,3S)-104k and GarnerÕs aldehyde (S)-104m giving 105k, 105kÕ, 105m and 105mÕ as single diastereomers. !)(!Slightly improved selectivity was seen with (R)-glyceraldehyde cyclohexanonide 104l compared to (R)-104b.  Table 2.7  Catalyst-controlled cis-aziridination of !- and "-chiral aldehydes a 20  a Unless otherwise specified, all reactions were carried out as described in Table 2.5 at Ð10 ¡C for 24 h with 10 mol% catalyst. The concentration is 0.4 M in MEDAM amine 101a. Substrates 104a, c, e, g, h and i were done by Munmun Mukherjee. Substrate 104d and f were done by Yijing Dai. b Yield of aziridine 105 diastereomers isolated together by silica gel column chromatography. c Determined by 1H-NMR of the crude reaction mixture. d Reaction at 0.2 M instead of 0.4 M. e 4 equiv of EDA. f Reaction at 0.04 M instead of 0.4 M. g The ee of anti-105e was 80% and syn-105eÕ was 99% from (S)-VAPOL. h The ee of anti-105e was 99% and syn-105eÕ was 43% from (R)-VAPOL. i 2 equiv of EDA. j 5 mol% catalyst instead of 10 mol%. k Reaction at Ð40 ¡C. l Reaction for 48 h instead of 24 h. m Reaction did not go to completion.    !!PhOTBSOH(R)-104aNMEDAMPhOTBSOEtO+NMEDAMPhOTBSOEtOsyn-105aanti-105a'(S)-VAPOL            90            2:98(R)-VAPOL            90            99:1ligand               yield% b   (2S):(2R) cOTBSOH(S)-104cNMEDAMOTBSOEtO+NMEDAMOTBSOEtOanti-105csyn-105c'(S)-VAPOL            85            9:91(R)-VAPOL            87            96:4(R)-VANOL            82            95:5ligand                yield% b    (2S):(2R) cOTBSOH(R)-104dNMEDAMn-C13H27OTBSOEtO+NMEDAMn-C13H27OTBSOEtOsyn-105danti-105d'(S)-VAPOL            88            10:90(R)-VAPOL            94            99:1n-C13H27PhOH(S)-104eNMEDAMPhOEtO+NMEDAMPhOEtOanti-105esyn-105e'(S)-VAPOL            92 g          4:96(R)-VAPOL            90 h          83:17e,fe,fOH(S)-104fNMEDAMOEtO+NMEDAMOEtOanti-105fsyn-105f'   (S)-VAPOL j        60           25:75       (R)-VAPOL j        50           67:33(S)-t-Bu2VANOL j  >99           8:92(R)-t-Bu2VANOL j  80           83:17(S)-t-Bu2VANOL    95            4:96(R)-t-Bu2VANOL    90            96:4iieee,ke,k,lOTBSOH(R)-104gNMEDAMOTBSOEtO+NMEDAMOTBSOEtOsyn-105ganti-105g'   (S)-VAPOL        30 m          48:52   (R)-VAPOL         85             99:1   (R)-VAPOL j       83             99:1   (S)-VANOL        15 m          40:60   (R)-VANOL         80             99:1(S)-t-Bu2VANOL j  75            18:82(R)-t-Bu2VANOL j  93            99:1OH(R)-104hNMEDAMOEtO+NMEDAMOEtOanti-105hsyn-105h'TBSOTBSOTBSO(S)-VAPOL            83            2:98(R)-VAPOL            85            99:1OH(S)-104iNMEDAMPhOEtO+NPhOEtOanti-105isyn-105i'Ph(S)-VAPOL            80            6:94(R)-VAPOL            85            99:1ddMEDAM!))!Table 2.8  Catalyst-controlled cis-aziridination of chiral heterocyclic carboxaldehydes a 20  a Unless otherwise specified, all reactions were carried out as described in Table 2.5 at Ð10 ¡C for 24 h with 5 mol% catalyst. Substrates 104j, b and l were done by this thesis. Substrate 104k and m were done by Munmun Mukherjee. b Yield of aziridine 105 diastereomers isolated together by silica gel column chromatography. c Determined by 1H-NMR of the crude reaction mixture. d 2 equiv of EDA. e 10 mol% catalyst instead of 5 mol%. 2.3.2 Synthetic Utility of Catalyst-Controlled cis-Aziridination My research collaborator Yijing Dai has performed the application of catalyst-controlled aziridination in the synthesis of ethylene diaziridine 105n and 105nÕ as well as !3-homo-D-isoleucine anti-112 and !3-homo-D-alloisoleucine syn-112Õ. The diastereomers ethylene diaziridine 105n and 105nÕ have been synthesized by multi-component aziridination of %,&-aziridinyl aldehyde 104n with (R)- and (S)-VAPOL BOROX catalysts respectively. Aziridine 104n was prepared in 43% total yield over six steps from aziridine 103a, the synthesis of which was previously reported by multi-component cis-aziridination of benzaldehyde 33a in 98% yield and 98% ee with (R)-VAPOL BOROX OH(S)-104jNMEDAMOEt+NMEDAMOEtOanti-105jsyn-105j'   (S)-VANOL         99            87:13   (R)-VANOL         99            12:88(S)-t-Bu2VANOL    99             8:92(R)-t-Bu2VANOL    99            89:11ligand                yield% b    (2S):(2R) cOOOOH(2S,3S)-104kNMEDAMOEt+NMEDAMOEtOanti-105ksyn-105k'(S)-VAPOL e         84           1:99(R)-VAPOL e         80           99:1ligand                yield% b    (2S):(2R) cNNNMEDAMMEDAMMEDAMOOOH(R)-104bNMEDAMOEt+NMEDAMOEtOsyn-105banti-105b'  (S)-VAPOL          73          16:84  (R)-VAPOL          90           94:6  (S)-VANOL          67          16:84  (R)-VANOL          86           92:8(S)-t-Bu2VANOL    99           3:97(R)-t-Bu2VANOL    99           97:3OOOOOOOOH(R)-104lNMEDAMOEt+NMEDAMOEtOsyn-105lanti-105l'  (S)-VANOL         99             9:91  (R)-VANOL         99             97:3(S)-t-Bu2VANOL    99            3:97(R)-t-Bu2VANOL    99            98:2OOOOOOOOH(S)-104mNMEDAMOEt+NMEDAMOEtOanti-105msyn-105m'(S)-VAPOL e          70            1:99(R)-VAPOL e          60            99:1OONBocONBocONBocdddddddd!)*!(Table 2.4, entry 4). The cis-aziridination of 104n with 5 mol% (S)-VAPOL BOROX gave the ethylene diaziridine 105nÕ as a 95:5 mixture of syn- and anti-diastereomers in 95% yield. The anti-isomer 105n was preferentially generated from (R)-VAPOL BOROX in 74% yield with a 96:4 selectivity (Scheme 2.7). Scheme 2.7  Catalyst-controlled synthesis of ethylene diaziridines 105n and 105nÕ  "-amino acids have been of significant interest in research during the last score years21, 22 because they are used as the important building blocks in the synthesis of "-peptides and "-lactams, which exhibits antibiotic resistance23 and, in the case of the former, stability against proteolytic degradation in vitro and in vivo24. As an illustration of the synthetic utility of the catalyst-controlled multi-component aziridination, a concise synthesis of Fmoc-protected !3-homo-D-isoleucine anti-112 and !3-homo-D-alloisoleucine syn-112Õ was carried out starting from the aldehyde (R)-104f prepared from commercially available (S)-2-methyl-1-butanol by Dess-Martin oxidation (Scheme 2.8). The aziridination of (R)-104f with t-Bu2VANOL-derived BOROX catalysts gave 96:4 selectivity for each aziridine diastereomer (Table 2.7). The MEDAM group was then NPhCO2EtMEDAMLiAlH4THF, 0-40 ¡CNPhMEDAMOHDMSO, Et3NCH2Cl2, Ð78¡CNPhMEDAMHOLiOH, THFovernightPOMeOMeOCO2MeNPhMEDAMOMeO100%81%NBSHEt3N, CH2Cl20¡C, 12 hNPhMEDAMOMeONPhMEDAM 81% 85%NPhMEDAMHOOH93%103a, 98% ee104n107108109110111oxalyl chlorideDMSO, Et3NCH2Cl2, Ð78¡C83%LiAlH4THF, 0-40¡CPhNMEDAMCO2EtNMEDAMPhNMEDAMCO2EtNMEDAMMEDAM-NH2101aEDA 102(S)-VAPOLBOROX(5 mol%)(R)-VAPOLBOROX(5 mol%)95%  syn:anti = 95:574%  anti:syn = 96:4105n'105n(COCl)2NPhMEDAMHO104n!)+!removed and replaced by Fmoc, which was followed by the SmI2-mediated reductive ring-opening of the aziridine based on the published procedure by Wenjun Zhao and Zhenjie Lu.25 The "-amino esters anti-112 and syn-112Õ were obtained in a decent overall yield as a single stereoisomer. Scheme 2.8 Access to !3-homo-D-isoleucine anti-112 and !3-homo-D-alloisoleucine syn-112Õ20  The synthesis of polyoxamic acid was also envisioned as an application of catalyst-controlled multi-component cis-aziridination. Polyoxamic acid 113 is a key component of the polyoxins 114 which are a family of important nucleoside antibiotics first isolated in 1960s as the inhibitors of chitin synthesis in a yeast (Figure 2.6).26 They inhibit the growth of fungus and lack human toxicity. A number of synthesis have been published of polyoxamic acid and various derivatives since the early 1990s in an effort to obtain improved biological activity.27 Dolt and Zabel reported the synthesis of polyoxamic acid derivative 121 from aziridine carboxylate 117, (S)-t-Bu2VANOLBOROX(10 mol%)(R)-t-Bu2VANOLBOROX(10 mol%)HOCO2EtNMEDAMCO2EtNMEDAMOEtOFmocHNOEtOFmocHNN-Fmoc-!3-homo-L-isoleucine ethyl esterN-Fmoc-!3-homo-D-alloisoleucine ethyl ester(R)-104fanti-105fsyn-105f'syn-112'  59% 3 steps95%  dr 96:490%  dr 96:4anti-112  58% 3 stepsMEDAMNH2++N2OEtO102101a1) HOTf, MeCN2) FmocCl, NaHCO33) SmI2, DMEAFmoc =OODMEA = dimethylethanolamine1) HOTf, MeCN2) FmocCl, NaHCO33) SmI2, DMEA!),!which was prepared from (R)-glyceraldehyde acetonide 104b by Wittig reaction followed by olefin hydroamination/aziridination cascade (Scheme 2.10a).27b Unfortunately, the aziridine 117 was obtained as a 1:1 mixture of diastereomers. The aziridine 119 underwent Lewis acid catalyzed deprotection of acetonide to the afford diol 120 and subsequent ring-opening with trifluoroacetic acid to give the target molecule 121. Although the aziridine carboxylate anti-105bÕ could be obtained in a high yield and selectivity with a high level of catalyst control by multi-component cis-aziridination, the TFA-catalyzed ring-opening of the aziridine anti-105bÕ failed to give a clean reaction and afford a mixture of ring-opening and acetonide cleavage compounds. Thus, itÕs likely that following a similar synthetic strategy from 105bÕ, involving acetonide deprotection, TFA ring-opening, ester saponification and MEDAM hydrogenolysis would afford polyoxamic acid 113 in four steps (Scheme 2.10b). Figure 2.6  Polyoxamic acid 113 and polyoxins 114           ONNHHOOHNHOROONH2OHOHOH2NOCO2HpolyoxinsHOOHCO2HOHNH2polyoxamic acid113114!)-!Scheme 2.9  Proposed synthesis of polyoxamic acid by catalyst-controlled aziridination    OOCO2EtPh3PCO2EtBrOOCHONH3NHCH2Cl2, rt. 12 hNEt3, EtOHrt. 72 hBr94% yield,94:6 Z :E>98% (3R,4S)LiAlH4THF, rt. 12 h89%TBSClimidazolCH2Cl2, rt. 12 h71%TFAMe2AlClCH2Cl2, rt. 24 h50 ¡CHOOTBSOHNH2OH48%84%OONHOOOHNHOOOTBSNHOTBSHOOH(R)-104bNMEDAMOEtOOO1) Me2AlCl2) TFA, then NaOHanti-105b'99%, 97:3 drHOOHCO2HOHNH2polyoxamic acid113116117'118119120121OOCHO(R)-104b+MEDAMNH2101a+N2OEtO1025 mol%(S)-t-Bu2VANOLBOROX3) Pd(OH)2, H2baCO2EtNHOO117+CO2EtNHOO117CO2Et!).!       REFERENCES  !*/!REFERENCES  1. a) Kasai, M.; Kono, M. Synlett., 1992, 778; b) Skibo, E. B.; Islam, I.; Heileman, L. J.; Schulz, W. G. J. Med. Chem., 1994, 37, 78; c) Danishefsky, S. J.; Schkeryantz, J. M. Synlett., 1995, 475; d) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron, 1997, 53, 10229; e) Hodgekinson, T. J.; Shipman, M. Tetrahedron, 2001, 57, 4467; f) Sente, P. D.; Springer, C. J. Adv. Drug Del. Rev., 2001, 53, 247. 2. Nakao, Y.; Fujita, M.; Warabi, K.; Matsunaga, S.; Fusetani, N. J. Am. Chem. Soc. 2000, 122, 10462. 3. Zhao, Q.; He, Q.; Ding, W.; Tang, M.; Kang, Q.; Yu, Y.; Deng, W.; Zhang, Q.; Fang, J.; Tang, G.; Liu, W. Chem. & Biol. 2008, 15.7, 693. 4. Argoudelis, A. D.; Reusser, F.; Whaley, H. A.; Baczynskyj L.; Mizsak S. A.; Wnuk, R. J. J. Antibiot. 1976, 29, 1001. 5. Tsuchida, T.; Inuma, H.; Kinoshita, N.; Ikeda, T. Sawa, T.; Hamada, M.; Takeuchi, T. J. Antibiot. 1995, 48, 217. 6. Van Lanen, S. G.; Oh, T-J.; Liu, W.; Wendt-Pienkowski, E.; Shen, B. J. Am. Chem. Soc. 2007, 129, 13082. 7. Transformations of aziridines: a) Tanner, D. Angew. Chem. Int. Ed. 1994, 33, 599; b) Ibuka, T. Chem. Soc. Rev., 1998, 27, 145; c) McCoull, W.; Davis, F. A. Synthesis, 2000, 1347; d) Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem. 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A.; Wulff, W. D. 2010, 132, 13104; c) Figure 2.4 cited from Munmun MukherjeeÕs doctoral dissertation, Chapter 4, p185. 15. Ramon, D. J.; Yus, M. Angew. Chem. Int. Ed. 2005, 44, 1602. 16. Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett, 2011, 13, 5866. 17. Mukherjee, M.; Zhou, Y.; Gupta, A. K.; Guan, Y.; Wulff, W. D. Eur. J. Org. Chem. 2014, 1386. 18. Righi, G.; Bovicelli, P.; Tirotta, I.; Sappino, C.; Mandic, E. Chirality, 2016, 28, 387. 19. a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199; b) Anh, N. T. Top. Curr. Chem. 1980, 88, 145; c) Figure 2.5 cited from Munmun MukherjeeÕs doctoral dissertation, Chapter 4, p187. 20. "Catalyst Control in Multi-Component Aziridinations of Chiral Aldehydes." Mukherjee, M.; Zhou, Y.; Dai, Y.; Pulgam, V. R.; Wulff, W. D. Manuscripts in Preparation  21. For reviews of "-amino acids: a) Seebach, D.; Beck, A. K.; Capone, S.; Deniau, G.; Groselj, U.; Zass, E., Synthesis, 2009, 1; b) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. HJ.; Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656; c) Seebach, D. Chimia, 2013, 67, 844; d) Grygorenko, A. A. Tetrahedron 2015, 71, 5169-5216; e) Kiss, L.; Cherepanova, M.; Fop, Tetrahedron, 2015, 71, 2049. 22. For recent literature work on "-amino acids: a) Zhang, D.; Chen, X.; Zhang, R.; Yao, P.; Wu, Q.; Zhu, D. ACS Catal. 2015, 5, 2220; b) Guang, J.; Larson, A. J.; Zhao, C-G. Adv. Synth. Catal. 2015, 357, 523; c) Sundell, R.; Kanerva, L. T. Eur. J. Org. Chem. 2015, 1500; d) Meyer, D.; Marti, R.; Seebach, D. Eur. J. Org. Chem. 2015, 4883; e) Cheng, J.; Qi, X.; Li, M.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2015, 137, 2480; f) Jung, D. J.; Jeon, H. J.; Lee, J. H.; Lee, S-G. Org. Lett. 2015, 17, 3498; g) Dai, J.; Ren, W.; Wang, H.; Shi, Y. Org. Biomol. Chem. 2015, 13, 8429; h) Romanens, A. I.; Belanger, G. Org. Lett. 2015, 17, 322; i) Rangel, H.; Carrillo-Morales, M.; Galindo, J. M.; Castillo, E.; Obregon-Zuniga, A.; Juaristi, E.; Escalante, J. Tetrahedron: Asymm. 2015, 26, 325; j) !*'!Archer, R. M.; Hutchby, M.; Winn, C. L.; Fossey, J. S.; Bull, S. D. Tetrahedron 2015, 71, 8838; k) Gianolio, E.; Mohan, R.; Berkessel, A.; Adv. Synth. Catal. 2016, 358, 30; l) Ye, J.; Wang, C.; Chen, L.; Wu, X.; Zhou, L.; Sun, J. Adv. Synth. Catal. 2016, 358, 1042. 23. a) Seebach, D.; Overhand, M.; Ke, F. N. M.; Martinoni, B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta. 1996, 79, 913; b) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. 1996, 118, 13071. 24. Porter, E. A.; Weisbulm, B.; Gellman, S. H. J. Am. Chem. Soc. 2002, 124, 7324. 25. Zhao, W.; Lu, Z.; Wulff, W. D. J. Org. Chem. 2014, 79, 10068. 26. a) Isono, K.; Asahi, K.; Suzuki, S. J. Am. Chem. Soc. 1969, 91x, 7490; b) Zhang, D.; Miller, M. J. Curr. Pharm. Design, 1999, 5, 73. 27. a) Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J. J. Am. Chem. Soc. 1996, 118, 6520; b) Dolt, H.; Zabel, V. Aust. J. Chem. 1999, 52, 259; c) Enders, D.; Vrettou, M. Synthesis, 2006, 2155; d) Joo, J-E.; Pham, V-T.; Tian, Y-S.; Chung, Y-S.; Oh, C-Y.; Lee, K-Y.; Ham, W-H. Org. Biomol. Chem. 2008, 6, 1498; e) Kim, I. S.; Li, Q. R.; Dong, G. R.; Woo, S. H.; Park, H.; Zee, O. P.; Jung, Y. H. Synlett, 2008, 2985;  f) Lee, Y.; Park, Y.; Kim, M.; Jew, S.; Park, H. J. Org. Chem., 2011, 76, 740.   !*(!Chapter 3 Multi-Component trans-Aziridination 3.1 Catalytic Asymmetric trans-Aziridination Our consideration of catalytic asymmetric aziridination has focused on the construction of two chiral centers. In the protocol of nitrene addition to alkenes, the stereochemistry of the disubsituted aziridines as either cis- or trans- is completely dependent on the configuration of double bond in the alkene. One of the limits of this method is that it requires a pure Z- or E-isomers of alkenes.1 In contrast, this requirement would not exist in the preparation of aziridines from the formal addition of a carbene to an imine of the proper set of catalysts were available to selectively give either cis- or trans-aziridines (Scheme 3.1).  Scheme 3.1  Substrate control and catalysts control of stereoselective aziridination  Since the early 1990s, several efficient catalytic strategies for the aziridination by carbene addition to imine have been reported to realize either cis-selective aziridination2,3 or trans-selective aziridination4. Based on the success of the BOROX-catalyzed asymmetric cis-aziridination of imines with ethyl diazoacetate (EDA) developed by Jon Antilla3a,b, Aman Desai reported an asymmetric trans-aziridination of imines with diazoacetamides catalyzed by the same BOROX anion5, which together provides a universal protocol for catalytic asymmetric aziridination process for either cis- or trans-stereoselectivity. NR1R2YNR1R2YR1R2R1R2cat*cat*cat*cat*NH2-YN-YR1NYHCR2+!*)!Figure 3.1  Universal BOROX-catalyzed asymmetric aziridination  The BOROX-catalyzed trans-aziridination with N-MEDAM benzaldimine 72o and N-phenyl diazoacetamide 122a afford the trans-disubstituted aziridine carboxamide 123a in 90% yield and 96% ee with a 21:1 trans-selectivity, while the same imine 72o and EDA 102 catalyzed by the same BOROX anion 71a affords the cis-aziridine carboxylate 103a in 99% yield and 98% ee with greater than 50:1 cis-selectivity3h,j. This is a significant strategy that allows the stereochemistry to be nicely controlled by the nature of the diazo compound with the same chiral catalyst and with the same imine substrate (Figure 3.1). Mathew Vetticatt and Aman Desai have shown that the hydrogen bonds between the diazo compounds and the BOROX catalyst govern the diasteroselection of aziridine formation.6 The aziridination by carbene addition to the imines happens in step-wise manner with the initial C-C bond formation that is followed by C-N bond formation in the ring closure.7 A previous study suggested that the C-C bond formation step is the enantio- and diastereoselectivity-determining step.2b The transition states have been studied by ONIOM (B3LYP/6-31G*: AM1) calculation to reveal that the substrate-PhNNPhMEDAMOEtONPhMEDAMHNOOOPhPhBOBOBOOPhOPh(S)-71a[H-imine]OBOBOBOOOONPhMEDAMHOBOBOBOOOON2HONPhHPhNHHMEDAMcis-aziridination TStrans-aziridination TSHN2HOEtOEtOOHN2PhHNHPX*PhHNOHN2HPhNHPX*PhN2OEtON2NHOPh99%, 98% eecis:trans >50:190%, 96% eetrans:cis 21:172o103a123aMEDAM102122aX*Ð = (S)-71aX*Ð = (S)-71a!**!catalyst interactions in the most stable conformer controls the asymmetric induction (Figure 3.1).6 In cis-aziridination transition state, a CÐH!!!O interaction is present between the !-hydrogen of EDA 102 and an oxygen of the broxinate. In the trans-aziridination transition state, the similar CÐH!!!O interaction exists between the !-hydrogen of diazoacetamide 122a and one of the VANOL oxygens. In addition, additional H-bonding is provided by the secondary amide hydrogen and an oxygen of the boroxinate. This indicates the secondary amide is the crucial as the active site for trans-selective induction.  3.2 Multi-Component trans-Aziridination 3.2.1 trans-Aziridination with Aromatic Aldehydes We have previously reported catalytic asymmetric multi-component cis-aziridination of an amine, aldehyde and EDA with high enantioselectivity catalyzed by the BOROX catalysts3k, which were generated from either VANOL 68a or VAPOL 68b ligand in the presence of the amine 101 and triphenyl borate (Scheme 3.2). Catalyst generation was followed by the rapid addition of an aldehyde, molecular seives and EDA to give the cis-aziridine with high diasteroselectivity (up to 50:1 cis:trans). After screening three amines 101a, 101b and 101c, the MEDAM protecting group of amine gives the best results in both yield and ee in aziridination. The VAPOL-derived BOROX catalyst also gives the better results than the VANOL-derived BOROX and thus the combination of MEDAM amine 101a and VAPOL ligand 68b was established as the optimal conditions in the multi-component cis-aziridination.  ! !*+!Scheme 3.2  Multi-component cis-aziridination of benzaldehyde 33a8  Since secondary diazoacetamides are known to react with imines to give trans-aziridines in a decent diastereoselectivity5, it was believed a similar multi-component procedure could be applied to trans-aziridination. However, it was not clear that the optimal procedure for the multi-component cis-aziridination would be equally effective for the multi-component trans-aziridination, since cis- and trans-aziridination of imines react via different pathways involving different transition states. Nonetheless, our initial studies on the multi-component trans-aziridination of benzaldehyde employed the optimal conditions for the multi-component cis-aziridination with MEDAM amine 101a at room temperature for 24 h (Scheme 3.3). With VAPOL- and VANOL-derived BOROX catalysts, only moderate yields of trans-aziridine 123a was obtained, with only 2:1 trans/cis diastereoselectivity. There was drop in enantioselectivity for the VAPOL BOROX catalyst from 98% ee to 73% ee, but there was dramatic decreasing for the VANOL BOROX catalyst from 95% to 14% ee (Scheme 3.2 vs 3.3). This indicates that PGNH2101(S)-ligand (5 mol%)B(OPh)3 (15 mol%)toluene, 25 ¡C, 1 hPhHO33a (1.05 equiv.)4 † MSN2OEtO102 (1.2 equiv.)25 ¡C, 24 hNPhPGOEtOPG = MEDAM      103bPG = BUDAM      124aPG = benzhydryl  100NH2MeOOMeNH2MeOt-But-But-BuOMet-BuPhPhNH2101a101b101c   amine            ligand            yield%            ee%            reference ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ    101a              VAPOL             98                 98                   3m    101a              VANOL             95                 95                   3m       101b             VAPOL              77                 92                    3l        101b             VANOL              72                 91                    3l       101c             VAPOL             85                 99               this work        101c             VANOL             91                 97               this work!*,!there is a great difference in the reaction pathways for cis- and trans-aziridine formation and further optimization will be required to develop an effective procedure. Scheme 3.3  Initial studies of multi-component trans-aziridination8  The first effort to optimize the multi-component trans-aziridination was the exploration of the BUDAM N-substituted amine 101c as it was found to be comparable or slightly better than MEDAM N-substitution in the cis-aziridination of imines.3h In the reaction of BUDAM amine 101c, the VANOL-derived catalyst was superior to the VAPOL-derived catalyst (Table 3.1, entry 3, 4), while it was reversed in the reaction with MEDAM amine 101a where the VAPOL-derived catalyst was found to be superior (Table 3.1, entry 1, 2). Dropping the temperature from ambient to Ð20 ¡C resulted in a significant slowing of the reaction with an only 14% yield of aziridine 125a (Table 3.1, entry 5, 9). However, if the pre-catalyst was allowed to interact with the amine and aldehyde for 20 min prior to the addition of the diazoacetamide, a dramatic improvement in yield and ee was realized for aziridine 125a (90% yield, 92% ee, Table 3.1, entry 10). In the diazoacetamide susbtrate, an N-phenyl substituent was found to be superior to an N-butyl substituent (Table 3.1, entry 10, 13). It was found that procedure A gave a lower yield than procedure B (80% vs 90% yield), although the asymmetric induction was slightly higher (95% ee) (Table 3.1, entry 10, 12). The combination of MEDAM amine 101a and the VAPOL ligand 68b was not as efficient as BUDAM amine 101c and VANOL 68a in the optimal conditions MEDAMNH2101a(S)-ligand (5 mol%)B(OPh)3 (15 mol%)toluene, 25 ¡C, 1 hPhHO33a (1.05 equiv.)4 † MSN2NHO122a (1.2 equiv.)25 ¡C, 24 hNPhMEDAMHNOPhPh123a    ligand            yield%            ee%          trans:cisÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ   VAPOL              67                73                  2:1             VANOL              63                14                  2:1!*-!(Table 3.1, entry 10, 14). Benzhydryl amine 101b was also tested with both VANOL and VAPOL and found to be far less effective (Table 3.1, entry 15, 16). The ligand 7,7-di-tert-butyl VANOL 68c was significantly less effective than VANOL in the trans-aziridination (Table 3.1, entry 11 vs entry 10), which was superior to VANOL in cis-aziridination (Table 2.4). Table 3.1  Optimization of the multi-component trans-aziridination with benzaldehyde 33a a 8  entry Proc amine ligand R2 T/¡C t/min aziridine yield% b ee% c trans:cis d imine% e 1 A 101a S-68a Ph 23 0 123a 63 14 2:1 18 2 A 101a R-68b Ph 23 0 123a 67 Ð73 2:1 22 3 A 101c S-68a Ph 23 0 125a 63 70 8:1 3 4 A 101c R-68b Ph 23 0 125a 43 Ð32 2:1 12 5 B 101c S-68a Ph 23 0 125a 38 67 7:1 15 6 f A 101c S-68a Ph 23 20 125a 50 73 7:1 5 7 g B 101c S-68a Ph 23 20 125a 38 71 8:1 5 8 B 101c S-68a Bu 23 0 126a 29 72 6:1 23 9 B 101c S-68a Ph Ð20 0 125a (14) Ð 13:1 59 10 B 101c S-68a Ph Ð20 20 125a 90 92 18:1 0 11 B 101c R-68c Ph Ð20 20 125a 36 40 2:1 23 12 A 101c S-68a Ph Ð20 20 125a 80 95 19:1 0 13 B 101c S-68a Bu Ð20 20 126a 43 86 8:1 21 14 B 101a R-68b Ph Ð20 20 123a 57 Ð87 2:1 32 15 B 101b S-68a Ph Ð20 20 127a 62 69 4:1 20 16 B 101b R-68b Ph Ð20 20 127a 49 Ð75 4:1 11 a Unless otherwise specified, all reactions were on a 0.5 mmol scale at 0.2 M in toluene with 10 mol% catalyst prepared by either Procedure A or B with 1.2 equiv of benzaldehyde 33a and 1.4 equiv of diazo acetamides 112. b Isolated yield. c Determined by HPLC. d Determined by the 1H-NMR spectrum of the crude reaction mixture. e Determined by the 1H-NMR spectrum of the crude reaction mixture with triphenylmethane as an internal standard. f A 24% yield of an amino amide was isolated which resulted from ring-opening of aziridine at the benzylic carbon and was found to be 93% ee. g An 18% yield of an amino amide was isolated which resulted from ring-opening of the aziridine at the benzylic carbon and was found to be 93% ee.  PGNH2101(S)-ligand (5 mol%)B(OPh)3 (15 mol%)toluene, 25 ¡C, 1 hPhHO4 † MST ¡C, 24 hNPhPGHNOR33a25 ¡C, t minProcedure APGNH2101(S)-ligand (5 mol%)B(OPh)3 (15 mol%)toluene, 80 ¡C, 0.5 hPhHO4 † MSN2NHOT ¡C, 24 hNPhPGHNORR233a25 ¡C, t min122a  R2 = Ph122b  R2 = n-BuProcedure BN2NHOR122a  R = Ph122b  R = n-Bu(R)-VAPOL 68bPhPh(S)-VANOL 68aPhPhOHOHOHOH(R)-t-Bu2VANOL 68cPhPhOHOHt-But-BuNH2MeOOMeNH2MeOt-But-But-BuOMet-BuNH2PhPhMEDAM amine101abenzhydrylamine101bBUDAM amine101c!*.!The scope of the multi-component trans-aziridination was investigated with a variety of electron-rich and electron-poor aromatic aldehydes (Table 3.2). Most of these aldehydes were found to be effective in giving high selectivity for trans-aziridines with high yields and excellent asymmetric inductions employing the optimal conditions (Table 3.1, entry 10). The reaction of 4-methoxybenzaldehyde was very sluggish and an only 9% yield of trans-aziridine 125f was detected along with 76% yield of the imine generated from BUDAM amine 101c and aldehyde 33f (Table 3.2, entry 5). However, the acetoxy group could serve as a surrogate for aldehyde 33f since aldehyde 33m gave the trans-aziridine 125m in 82% yield and greater than 99% ee with a 25:1 trans-selectivity (Table 3.2, entry 4). Both of the electron-poor aldehyde 33c and 33s were very slowly converted to their corresponding trans-aziridines (Table 3.2, entry 13, 14). This is in contrast to the electron-poor aldehydes 33q and 33r, which gave the trans-aziridines 125q and 125r in decent yields and inductions (Table 3.2, entry 11, 12). The origin of the failure of the 4-nitro- and 4-cyano-substited remains unclear, but could possibly be due to the incompatibility with the BOROX-catalysts. Given that a 2-bromo substituent on benzaldehyde gave a much lower induction than the 4-bromo isomer (Table 3.2, entry 8, 10), it was surprising to find that the reverse is true for the corresponding methyl derivatives where the 2-methyl isomer gave a higher induction than 4-methyl isomer (Table 3.2, entry 6, 7). Amino amide byproducts were detected in the reaction of aldehyde 33d and 33k that resulted from the nucleophilic ring-opening of trans-aiziridines by phenol, which was generated from triphenylborate during the catalyst formation (Scheme 4.11). It is !+/!necessary to employ high vacuum to the pre-catalyst in order to remove all the volatile substances including phenol. Decent yields were obtained with the modified procedure for aziridine 125d (73%, Table 3.2, entry 6) and 125k (82%, Table 3.2, entry 2). The determination of the absolute configuration of the trans-aziridine 125a from benzaldehyde 33a was previously reported by Aman Desai5 and the trans-aziridines from the other aromatic aldehydes were assumed to be homo-chiral. Table 3.2  Aromatic aldehyde scope of multi-component trans-aziridination a 8  entry R1 trans:cis b yield% c ee% d 1 C6H5 18:1 90 92 2 e 2-naphthyl 62:1 82 92 3 1-naphthyl >99:1 88 87 4 p-AcOC6H4 25:1 82 >99 5 p-MeOC6H4 1.3:1 9f Ð 6 e p-MeC6H4 19:1 73 82 7 o-MeC6H4 >99:1 85 93 8 p-BrC6H4 23:1 82 96 9 m-BrC6H4 27:1 89 95 10 o-BrC6H4 19:1 89 72 11 p-CF3C6H4 31:1 78 95 12 p-CO2MeC6H4 42:1 89 Ð 13 p-NO2C6H4 29:1 16g >99 14 p-CNC6H4 13:1 8h Ð a Unless otherwise specified, all reactions were performed on a 0.2 mmol scale at 0.2 M of amine 101c in toluene with 1.2 equiv aldehyde 33 and 1.4 equiv N-phenyl diazoacetamide 122a with 10 mol% catalyst with procedure B under the conditions of Table 3.1, entry 10. b Determined by the 1H-NMR spectrum of the crude reaction mixture. c Isolated yield. d Determined by HPLC. e Pre-catalyst was subjected to high vacuum at 80 ¡C for 30 min. f A 76% of imine was observed by the 1H-NMR spectrum of the crude reaction mixture. g A 52% yield of imine was observed by the 1H-NMR spectrum of the crude reaction mixture. h A 66% yield of imine was observed by the 1H-NMR spectrum of the crude reaction mixture. 3.2.2 trans-Aziridination with Aliphatic Aldehydes The optimal conditions for the trans-aziridination of aromatic aldehydes did not directly apply to that of aliphatic aldehydes. Re-optimization of the multi-component trans-aziridination of the aliphatic aldehydes were carried out with n-hexadecanal 33g at Ð10 ¡C (Table 3.3), which was the optimal temperature for the multi-component cis-aziridination of n-hexadecanal 33g. With the optimal conditions for benzaldehyde 33a, n-R1HO+BUDAMNH2101c+N2NHOPh122a(S)-VANOL BOROX71a4 † MStoluene, Ð20 ¡C, 24 hNR1BUDAMHNOPh12533!+&!hexadecanal 33g gave a 78% yield and 88% ee at Ð10 ¡C (Table 3.3, entry 9). The reaction of aldehyde 33g with N-phenyl diazoacetamide 122a with the VANOL BOROX catalyst gives superior results if the aldehyde and amine are allowed to interact for 20 min before the addition of the diazo compound (Table 3.3, entry 8 vs 9). In contrast, it was found that the reaction of aldehyde 33g with N-butyldiazoacetamide 122b was essentially the same, whether or not the aldehyde and amine were allowed to interact for 20 min before the addition of the diazo compound (Table 3.3, entry 6 vs 7).  Both VAPOL 68b and t-Bu2VANOL 68c catalysts gave excellent results with BUDAM amine 101c, but not as good as VANOL 68a catalyst (Table 3.3, entry 6, 10, 11). this was in significant contrast to the reaction with benzaldehyde 33a where it was found that the t-Bu2VANOL 68c catalyst was much less effective (Table 3.1, entry 11). All three ligands were slightly less satisfactory with the combination of MEDAM amine 101a (Table 3.3, entry 3, 5). The reactions with benzhydryl amine 101b were much slower and resulted in low yields (Table 3.3, entry 1, 2). Table 3.3  Optimization of multi-component trans-aziridination with n-hexadecanal 33g a 8  a Unless otherwise specified, all reactions were performed at 0.2 M in amine 101 with 0.2 mmol of 1.0 equiv of amine 101, 1.1 equiv of aldehyde 33g and 1.2 equiv of diazoacetamides 122 with 10 mol%  n-C15H31HO+PGNH2101+N2NHOR(S)-BOROX4 † MStoluene, Ð10 ¡C, 24 hNn-C15H31PGHNOR33g122a  R2 = Ph122b  R2 = n-BuVANOL 68aVAPOL 68bt-Bu2VANOL 68cMEDAM amine 101abenzhydrylamine 101bBUDAM amine 101centry amine ligand R2 aziridine trans:cisb yield%c ee%d 1 101b S-68a n-Bu 128g 14:1 33 (30)e 77 2 101b R-68c n-Bu 128g 14:1 45 (36)f 33 3 101a S-68a n-Bu 129g 8:1 67 88 4 101a S-68b n-Bu 129g 15:1 79 86 5 101a R-68c n-Bu 129g 2:1 49 Ð90 6 101c S-68a n-Bu 126g 24:1 85 96 7g 101c S-68a n-Bu 126g 21:1 88 96 8 101c S-68a Ph 125g 6:1 68 68 9g 101c S-68a Ph 125g 12:1 78 88 10 101c S-68b n-Bu 126g 14:1 91 91 11 101c R-68c n-Bu 126g 17:1 71 Ð90 !+'!Table 3.3  (contÕd) catalyst which was prepared by Procedure B in Table 3.1 with t = 0 min. b Determined by the 1H-NMR spectrum of the crude reaction mixture. c Isolated yield of trans-aziridine. Yields in parentheses are 1H-NMR yields with an internal standard. d Determined by HPLC. e Reaction went to 87% conversion. f Reaction went to 92% conversion. g The catalyst was stirred with the aldehyde 33g and amine 101 for 20 min before the diazoacetamide 122 was added. The substrate scope of the multi-component trans-aziridination with aliphatic aldehydes was also investigated (Table 3.4). The aziridination of unbranched aldehydes give the decent results by the optimal conditions of the multi-component procedure, but for the !-branched aldehydes 33h and 33i, a decent conversion in the multi-component method with the optimal conditions could not be achieved (Table 3.4, entry 11, 12). The reasons still remain unclear, but are most likely related to the steric hindrance resulting in the slow formation of the corresponding imines and the negative effect of potential interactions between the catalyst and the excess aldehyde, since the trans-aziridination of a purified imine with diazoacetamides is a successful methodology in Aman DesaiÕs work.5 Thus, the best method to obtain trans-aziridines from secondary and tertiary aldehydes involves the pre-preparation of imines as previously reported. However the "-branched aldehyde 33z proceeds smoothyl to give the trans-aziridine 126z in 88% yield and 95% ee as a single diastereomer when catalyzed by the VANOL BOROX catalyst (Table 3.4, entry 10). The multi-component trans-aziridination of unbranched aliphatic aldehydes is fairly tolerant of a number of functional groups including silyl ethers, esters, epoxides, carbamates and phthalimides. The cyano group, on the other hand, seems to negatively impact the reaction as the aldehyde 33u was converted to trans-aziridine 126u with a low asymmetric induction (Table 3.4, entry 4). The trans/cis selectivity is generally higher than that for aromatic aldehydes. For a few substrtates (33t and 33u) the trans/cis ratio !+(!could not be determined due to overlap of key peaks in the 1H-NMR spectrum of the crude reaction mixtures. There does not seem to be an ideal ligand for these substrates since when VANOL 68a and t-Bu2VANOL 68c were directly compared VANOL gave better asymmetric inductions for five substrates (Table 3.4, entry 1, 2, 7, 8, 10) and t-Bu2VANOL gave better ee for a different set of five substrates (Table 3.4, entry 3, 4, 5, 6, 9). Of particular interest is that the trans-aziridination of epoxide 33s was carried out on the racemic aldehyde 33t but there does not seem to be any effect in asymmetric induction by the chiral center of the substrate since the trans-aziridine 126s was a mixture of isomers with 49:49:1:1 ratio catalyzed by VANOL BOROX catalyst and a mixture of isomers with 49.5:49.5:0.5:0.5 ratio when catalyzed by t-Bu2VANOL BOROX catalyst (Table 3.4, entry 2). The conjugated unsaturated aldehyde 130b could not give the trans-aziridine 131b and it should be noted that it also failed in the cis-aziridination (Table 3.4, entry 13).9 It was reported by Anil Gupta that the corresponding conjugated imine would undergo [3+2] cycloaddition with EDA instead of cis-aziridination.9 It still remains unclear if a similar [3+2] cycloaddition pathway will be involved in the reaction with conjugate imines and diazoacetamides. Interesting, the propargyl aldehyde 132 was also investigated and found to give the cis-aziridine 133 instead of trans-isomer in an excellent yield and asymmetric induction with the VANOL catalyst (Table 3.4, entry 14). It is interesting that this result exactly matches the results reported by Yong Guan et al. in the synthesis of cis-alkynyl aziridines from propargyl imines and N-phenyl diazoacetamide.10    !+)!Table 3.4  Aliphatic aldehyde scope of multi-component trans-aziridination a 8  a Unless otherwise specified, all reactions were run under the conditions of Table 3.3, entry 6. b Isolated yield. c Determined by HPLC on isolated trans-aziridine. d Determined by the 1H-NMR spectrum of the crude reaction mixture. nd means not determined. e de instead of ee. f The isolated trans-isomer was a 49:49:1:1 mixture of isomers. g The isolated trans-isomer was a 49.5:49.5:0.5:0.5 mixture of isomers. h N-butyl diazoacetamide 122b was added 20 min after the aldehyde as indicated in Table 3.1. i The MEDAM amine 101a was used. j N-butyl diazoacetamide 122b was added 20 h after the aldehyde as indicated in n-C15H31OH33gNBUDAMn-C15H31HNO126g                         (S)-VANOL                88             96            28:1                     (R)-t-Bu2VANOL            71            Ð90           17:1entry        aldehyde            ligand                 yield% b      ee% c      trans:cis cn-Bu1OH33sNBUDAMHNO126s                         (S)-VANOL                89             96e            8:1f                         (R)-t-Bu2VANOL          62           Ð98e          >99:1gentry        aldehyde            ligand                 yield% b      ee% c      trans:cis cn-Bu2OOOH33tNBUDAMHNO126t                         (S)-VANOL                78             86            nd                     (R)-t-Bu2VANOL            59            Ð93           ndn-Bu3MeO2CMeO2COH33uNBUDAMHNO126u                      (S)-VANOL               88            40            nd                   (R)-t-Bu2VANOL          51           Ð60           nd                      (R)-VAPOL               61           Ð47           ndn-Bu4NCNCOH33vNBUDAMHNO126v                         (S)-VANOL                60             96            >99:1                     (R)-t-Bu2VANOL            56            Ð98           >99:1n-Bu5OH33wNBUDAMHNO126w                         (S)-VANOL                67             85            25:1                     (R)-t-Bu2VANOL            68            Ð88           10:1n-Bu6BocHNBocHNTBSOTBSOOH33xNBUDAMHNO126x                         (S)-VANOL                71             91            6:1                     (R)-t-Bu2VANOL            64            Ð60           6:1n-Bu7OH130aNBUDAMHNO131a                         (S)-VANOL                87             98            >99:1                     (R)-t-Bu2VANOL            77            Ð73           >99:1n-Bu8PhthNPhthNPhPhOH33yNBUDAMHNO126y                         (S)-VANOL                71             88            >99:1                     (R)-t-Bu2VANOL            86            Ð96           >99:1n-Bu9OH33zNBUDAMHNO126z                         (S)-VANOL               88             95            >99:1                     (R)-t-Bu2VANOL           70            Ð75           >99:1n-Bu10PhPhOH33hNBUDAMHNO126h                         (S)-VANOL                45             28            12:1                       (S)-VANOL h              61              8              nd                         (R)-VAPOL                56           Ð57            16:1n-Bu11OH33iNBUDAMHNO126i            (S)-VANOL                         no reaction                       (S)-VANOL i              6 j             nd             ndn-Bu12OH130bNBUDAMHNO131b             (S)-VANOL                          no reactionn-Bu13OH132NMEDAMHNO133           0 ¡C            (R)-VANOL i              90             91            cis only         Ð20 ¡C          (R)-VANOL i              71             95            cis onlyPh14n-C13H27PhPhn-C13H27!+*!Table 3.4  (contÕd)  Table 3.1. k Reaction went to 24% conversion. Yield was determined by the 1H-NMR spectrum of the crude reaction mixture with an internal standard. 3.2.3 Investigation of Absolute Stereochemistry In the multi-component trans-aziridination for both aromatic and aliphatic aldehydes, BUDAM amine 101c is superior to MEDAM amine 101a and gives an excellent yield, asymmetric induction and trans/cis diastereoselectivity (Table 3.2 and 3.4). The multi-component trans-aziridination with MEDAM amine revealed a great difference in the trans/cis ratio between the ligands VANOL and t-Bu2VANOL. For example, in the trans-aziridination of MEDAM amine 101a and n-hexadecanal 33g, VANOL BOROX-catalyzed reaction affords aziridine 129g with relative high trans-selectivity (59% yield of trans-129g and 8% yield of cis-129g, Table 3.5, entry 1). However, t-Bu2VANOL BOROX gives an almost 1:1 mixture of trans- and cis-isomers (Table 3.5, entry 2). It is necessary to determine the absolute stereochemistry of these aziridine diastereomers in the multi-component trans-aziridine strategy since it may reveal any difference in asymmetric inductions between the reaction with MEDAM amine and BUDAM amine. Table 3.5  trans-Aziridination with MEDAM amine and n-hexadecanal a 8  entry ligand (2S,3R)-129g% b ee% c !!!!!" d (2R,3R)-129g% b ee% c !!!!!" d 1 (R)-68a 57 83 +13.6¡ 8e nd nd 2 (R)-68c 46 93 +19.1¡ 44 83 +7.0¡ a Unless otherwise specified, all reactions were run under the conditions of Table 3.3, entry 6. b Isolated yield. c Determined by HPLC on isolated aziridines. d Determined by polarimeter on the solution of aziridines in ethyl acetate (c 1.0). e determined by the 1H-NMR spectrum of the crude reaction mixture with an internal standard. MEDAMNH2(R)-BOROX(10 mol%)4 †  MSNHOtolueneÐ10 ¡C, 24 hNn-C15H31MEDAMHNOn-BuNn-C15H31MEDAMHNOn-Bu++N2+n-Bun-C15H31OH33g101a122b(2S,3R)-129g(2R,3R)-129gVANOL 68at-Bu2VANOL 68c!++!The absolute configuration of the cis- and trans-isomers of 129g obtained from multi-component trans-aziridination of MEDAM amine 101a and aldehyde 33g were determined and confirmed by the conversion to the compounds with known absolute stereochemistry. The cis-129g was converted to the previously reported cis-aziridine carboxylate 103g, with the (2R,3R)-stereochemistry upon the analysis of the optical rotation (Scheme 3.4a). The absolute stereochemistry of the BUDAM trans-aziridine (2S,3R)-126g was confirmed by the synthesis of sphinganine that will be discussed in the following section 3.3. To confirm that the MEDAM trans-aziridine 129g has the same absolute stereochemistry as the BUDAM trans-aziridine (2S,3R)-126g, both were deprotected with triflic acid to give the same N-H aziridine with the same optical rotation. As a conclusion, the stereochemistry changes at the 2-position when a trans- and cis-isomer  are produced in the multi-component trans-aziridination with MEDAM amine,  aliphatic aldehydes and diazo acetamides. Interestingly, it gives (2R,3R)-stereochemistry for the cis-isomer in the cis-aziridination of aldehyde 33g with (S)-ligand3k, while the cis-isomer as the minor product from trans-aziridination of aldehyde 33g gives the same (2R,3R)-stereochemistry with (R)-ligand.           !+,!Scheme 3.4  Absolute stereochemistry of N-MEDAM alkyl aziridine carboxylamides 129g8  Given that the aromatic and aliphatic aldehydes require quite different optimal conditions in the multi-component trans-aziridination, it is necessary to investigate the absolute stereochemistry with MEDAM amine 101a and aromatic aldehydes as well. A number of optimization experiments on the multi-component trans-aziridination reaction were conducted with benzaldehyde 33a, MEDAM amine 101a and N-phenyl diazoacetamide 122a with both VANOL and t-Bu2VANOL ligands (Table 3.6). The diastereoselectivity with MEDAM amine is much worse than that of the reaction with BUDAM amine (Table 3.1) that a 63% yield of trans-123a and a 17% yield of cis-123a were isolated by VANOL-BOROX catalysis (Table 3.6, entry 1). Surprisingly, the diastereoselectivity was reversed with the VANOL and t-Bu2VANOL catalyst that the latter gave a 9% yield of trans-123a and a 75% yield of cis-123a (Table 3.6, entry 2). The trans-aziridination of Nn-C15H31MEDAMHNOn-Bu1) n-BuLi (1.05 equiv)Boc2O (3.0 equiv)THF, rt. 48 h2) LiOEt (2.2 equiv.)THF, rt. 16 hNn-C15H31MEDAMOEtO70%, 95% ee(2R,3R)-129g(2R,3R)-103g[!]20 +48.2¡ c 1.0 (EtOAc)Lit3k [!]20 +57.9¡ c 1.0 (EtOAc)on 95% ee (2R,3R)-103hNn-C15H31MEDAMHNOn-BuTfOH (5.0 equiv.)anisole, rt. 1 hHNn-C15H31HNOn-BuNn-C15H31BUDAMHNOn-BuTfOH (5.0 equiv.)anisole, rt. 1 hHNn-C15H31HNOn-Buab(2S,3R)-129g(2S,3R)-126g(2S,3R)-134(2S,3R)-134100%88% ee87% ee93%[!]20 +11.5¡ c 1.0 (EtOAc)[!]20 +11.9¡ c 1.0 (EtOAc)!+-!the corresponding imine 72o and N-phenyl diazoacetamide 122a was examined to understand the nature of ligand control on the diastereoselectivity. As reported by Aman Desai, it gave up to 21:1 trans:cis selectivity for aziridine 123a with the VANOL catalyst.5 However, this experiment was reported with the t-Bu2VANOL catalyst to afford cis-123a as the major product in 73% yield and trans-123a in 23% yield, which gives the same trend in diastereoselectivity with the ligand effect (Scheme 3.5). Table 3.6  trans-Aziridination with MEDAM amine, benzaldehyde and N-phenyl diazoacetamide a 8  entry ligand (2S,3R)-123a% b ee% c !!!!!" d (2R,3R)-123a% b ee% c !!!!!" d 1 (R)-68a 63 87 Ð4.6¡ 17 73 Ð13.6¡ 2 (R)-68c 9 55 Ð3.1¡ 75 95 Ð26.2¡ a Unless otherwise specified, all reactions were run under the conditions of Table 3.1, entry 10. b Isolated yield. c Determined by HPLC on isolated aziridines. d Determined by automatic polarimeter on the solution of aziridines in ethyl acetate (c 1.0). Scheme 3.5  Ligand-effects on the diastereoselectivity8  The trans- and cis-isomers of aziridine 123a could be converted into the corresponding aziridine carboxylates 103a with a known optical rotation and compared with the optical rotation that is known for both the cis- and trans-isomers (Scheme 3.6). The cis-aziridine ester 103a exhibits a negative rotation which is consistent with the (2S,3S)-stereochemistry based on a literature report.3k The trans-isomer of 103a exhibits a MEDAMNH2(R)-BOROX(10 mol%)4 †  MSNHOtolueneÐ20 ¡C, 24 hNPhMEDAMHNOPhNPhMEDAMHNOPh++N2+PhPhHO33a101a122a(2S,3R)-123a(2S,3S)-123aVANOL 68at-Bu2VANOL 68cPhNMEDAM+N2NHOPh(S)-BOROX(5 mol%)tolueneÐ20 ¡C, 24 hNPhMEDAMHNOPhNPhMEDAMHNOPh+          ligand                     %yield  %ee                     %yield  %eeÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ       (S)-VANOL                   90       96                          <5       nd    (S)-tBu2VANOL               21       65                          73       9672o122a(2R,3S)-123a(2R,3R)-123a!+.!positive rotation with (2S,3S)-stereochemistry according to a literature report.5 Notably, the configuration changes at the 3-position with trans- and cis-isomers in the multi-component of trans-aziridination with aromatic aldehydes, instead of at the 2-position where is the case for aliphatic aldehyde substrates. The stereochemical configuration of cis-aziridine is consistently obtained from either cis-aziridination as a major product or trans-aziridination as a minor product of aromatic aldehydes by the catalyst with the same chirality. Scheme 3.6  Absolute stereochemistry of N-MEDAM alkyl aziridine carboxylamides 123a8  Finally, the multi-component trans-aziridination with MEDAM amine 101a, benzaldehyde 33a and N-butyl diazoacetamide 122b was also studied to determine the diastereoselectivity as well as the absolute stereochemistry. With N-butyl diazoacetamide 122b, the cis-isomer of aziridine 129a was the major product with both the VANOL and t-Bu2VANOL BOROX catalyst, while a greater cis-selectivity was observed with the t-Bu2VANOL catalyst than that with the VANOL catalyst (Table 3.7). The trans- and cis-isomers of aziridine 129a were also converted to the corresponding aziridine carboxylates NPhMEDAMHNOPh1) DMAP (2.0 equiv)Boc2O (3.0 equiv)CH2Cl2, rt. 24 h2) LiOEt (2.2 equiv.)THF, rt. 16 hNPhMEDAMOEtONPhMEDAMHNOPhNPhMEDAMOEtO(2S,3R)-123a(2S,3R)-103a(2S,3S)-123a(2S,3S)-103a1) DMAP (2.0 equiv)Boc2O (3.0 equiv)CH2Cl2, rt. 24 h2) LiOEt (2.2 equiv.)THF, rt. 16 h67%95% ee87% ee80%[!]20 Ð26.2¡ c 1.0 (EtOAc)Lit3k [!]20 +41.3¡ c 1.0 (EtOAc)on 99% ee (2R,3R)-103a[!]20 +5.6¡ c 1.0 (EtOAc)Lit5 [!]20 Ð4.4¡ c 1.0 (EtOAc)on 90% ee (2R,3S)-103a!,/!103a to confirm the stereochemistry as (2S,3S)- and (2S,3R)-aziridines, which are consistent with the protocol in the multi-component trans-aziridination strategy of MEDAM amine, aromatic aldehydes and N-phenyl diazoacetamide. The specific interactions between the BOROX catalyst and each of the three substrates are unclear, but these results indicate that a more complex process is involved in the multi-component procedure. It was found in this work that cis:trans selectivity could be effected and reversed in the proper combination of ligands, amines, aldehydes and diazoacetamides. Table 3.7  trans-Aziridination with MEDAM amine, benzaldehyde and N-butyl diazoacetamide a 8  entry ligand (2S,3R)-129a% b ee% c !!!!!" d (2R,3R)-129a% b ee% c !!!!!" d 1 (R)-68a 36 76 +20.0¡ 50 86 Ð6.6¡ 2 (R)-68c 8 89 +22.9¡ 73 91 Ð7.5¡ a Unless otherwise specified, all reactions were run under the conditions of Table 3.1, entry 10. b Isolated yield. c Determined by HPLC on isolated aziridines. d Determined by polarimeter on the solution of aziridines in ethyl acetate (c 1.0).             MEDAMNH2(R)-BOROX(10 mol%)4 †  MSNHOtolueneÐ20 ¡C, 24 hNPhMEDAMHNOn-BuNPhMEDAMHNOn-Bu++N2+n-BuPhHO33a101a122b(2S,3R)-129a(2S,3S)-129aVANOL 68at-Bu2VANOL 68c!,&!Scheme 3.7  Absolute stereochemistry of N-MEDAM alkyl aziridine carboxylamides 129a8  3.3 Synthetic Utility in Natural Products 3.3.1 Synthesis of Sphinganine Stereoisomers Sphingolipids consist of several subclasses of compounds that were discovered in brain extracts in the 1870s and are involved in signal transmission and cell recognition.11 They are a class of lipids containing a backbone of sphingoid bases.12 The three major core units in sphingolipids are sphinganine 135, sphingosine 136 and phytosphingosine 137 (Figure 3.2). N-acylated derivatives of the sphingoid bases are members of the ceramide family, of which the well-known members are glycosphingolipids with one or more sugar units attached to the hydroxy group at the 1-position and phosphosphingolipids with a phosphate ester bounded to the hydroxy group at the 1 position. The natural configuration of both sphinganine and sphingosine is the D-erythro isomer. However, it has been found that for both classes of compounds that the stereochemistry can play a large role in their bioactivity. For example, the L-threo diastereomer of sphinganine, usually called safingol (2S,3S)-135, is a lyso-sphingolipid protein kinase C inhibitor.13 Medically, safingol has NPhMEDAMHNOn-Bu1) DMAP (2.0 equiv)Boc2O (3.0 equiv)CH2Cl2, rt. 24 h2) LiOEt (2.2 equiv.)THF, rt. 16 hNPhMEDAMOEtONPhMEDAMHNOn-BuNPhMEDAMOEtO(2S,3R)-129a(2S,3R)-103a(2S,3S)-129a(2S,3S)-103a1) DMAP (2.0 equiv)Boc2O (3.0 equiv)CH2Cl2, rt. 24 h2) LiOEt (2.2 equiv.)THF, rt. 16 h64%91% ee76% ee60%[!]20 Ð24.1¡ c 1.0 (EtOAc)Lit3k [!]20 +41.3¡ c 1.0 (EtOAc)on 99% ee (2R,3R)-103a[!]20 +3.1¡ c 1.0 (EtOAc)Lit5 [!]20 Ð4.4¡ c 1.0 (EtOAc)on 90% ee (2R,3S)-103a!,'!demonstrated promising anticancer potential as a modulator of multi-drug resistance and as an inducer of necrosis. Figure 3.2  Sphingoid bases and the four stereoisomers of sphinganine  A great number of publications in the literature work has reported on the synthesis of sphinganine beginning in 1951.14, 15 The earlier synthesis of sphinganines tended to be nonselective, giving mixtures of diastereomers that needed to be separated and enantiomers that needed to be resolved. The most successful applications with asymmetric catalysis involved the use of the Sharpless asymmetric dihydroxylation16, Sharpless asymmetric epoxidation17, and the Sharpless kinetic resolution of allylic alcohols15n, the asymmetric hydrogenation of "-oxo esters15m and a proline-based Mannich reaction15p, although it has not been demonstrated if these methods can be used for all four of the stereoisomers of the sphinganine. Notably, the shortest synthetic pathway (two steps from hexadecanal) demonstrated by Shibasaki and his co-worker involves an asymmetric catalytic reaction in which the chiral center at the nitrogen-substituted carbon atom is created in the stereogenic step.18 They reported that a 1,1 -bi-2-naphthol (BINOL)Ðlanthanum catalyst will effect the nitroaldol reaction (Henry reaction) between 2-nitroethanol and hexadecanal. Although this reaction gave good 12OHNH2OHsphinganine13512OHNH2OHsphingosine13612OHNH2OHphytosphingosine137OH12OHNH2OHD-erythro-sphinganine(2S,3R)-13512OHNH2OH12OHNH2OH12OHNH2OH(sphinganine)L-threo-sphinganine(2S,3S)-135(safingol)L-erythro-sphinganine(2R,3S)-135D-threo-sphinganine(2R,3R)-135!,(!diastereoselectivity (91:9) and a good asymmetric induction (97 % ee), the reaction was limited in that it could produce only one diastereomer and prolonged reaction times were required: 10 turnovers required 6-7 days. A synthesis of all four stereoisomers of sphinganine has been developed with the strategy of multi-component cis-aziridination and has been published (Scheme 3.8).3m Both enantiomers of cis-aziridine (2R,3R)- and (2S,3S)-103g were obtained in excellent yields and ee from aziridination of n-hexadecanal 33g by BOROX catalysts with opposite chirality. The multi-component cis-aziridination was successful on gram scale (5 mmol, 1.5 g) to afford the cis-aziridine 103g in 85% yield (2.6 g) and 96% ee with VAPOL-BOROX catalyst. The cis-aziridine (2R,3R)-103g was then converted to N-Boc-aziridine (2R,3R)-138 in 80% yield, which could be ring-opened up by oxygen-nucleophiles with inversion of configuration at the 3-position in a known process that typically requires the electron-withdrawing group on the nitrogen.3k, l Thus, N-Boc-aziridine (2R,3R)-138 was treated with neat formic acid which was resulted in ring-opening with formate and subsequent O- to N-formyl migration after Boc-deprotection. The N-formyl group was removed with hydrochloric acid and the ester was reduced to give L-threo-sphinganine (2S,3S)-135 in 70% overall yield. On the other hand, N-Boc-aziridine (2R,3R)-138 could undergo Lewis acid-catalyzed ring-expansion with retention of configuration at the 3-position with the aid of scandium triflate to afford oxazolidinone (4R,5R)-139 in 90% yield. Finally, D-erythro-sphinganine (2S,3R)-135 was prepared in 70% overall yield from (4R,5R)-139 by hydrolysis of the oxazolidinone and reduction of the ester. The isomers of D-threo-sphinganine (2R,3R)-135 and L-erythro-sphinganine (2R,3S)-135 were synthesized in an analogous strategy from aldehyde 33g. !,)!Scheme 3.8  Synthesis of all four stereoisomers of sphinganine by multi-component cis-aziridination3m  Since a successful method for the multi-component trans-aziridination has been developed, an alternative synthetic strategy to achieve all four stereoisomers of sphinganine could be considered from aldehyde 33g (Scheme 3.9). The multi-component synthesis of aziridines can afford two enantiomers of cis-aziridine 103g and two enantiomers of trans-aziridine 126g. Each stereoisomer in aziridine ostensibly should undergo direct ring-opening with an oxygen nucleophilic attack at the 3-position following the published procedure in the presence of trifluroacetic acid (TFA) for the cis-aziridine with an N-MEDAM group nitrogen.3m In the initial exploration to extend this method to trans-aziridines, the trans-aziridine (2S,3R)-126g was prepared on gram-scale 5% (S)-VAPOL BOROX4 † MStoluene, Ð10 ¡C, 24 hMEDAMNH2+N2OEtO85%, 96% ee10% Sc(OTf)3NBocOEtOC13H27NHOOC13H27OHNH2OHC13H27OHNH2OH1) HCO2H2) HCl, MeOH3) LiAlH4, THF80%90%70%70%C13H27HONMEDAMC13H27OEtO1) LiOH, MeOH2) LiAlH4, THF101a10233g(2R,3R)-103g(2R,3R)-138(4R,5R)-139L-threo-sphinganine(2S,3S)-135(safingol)D-erythro-sphinganine(2S,3R)-135(sphinganine)5% (R)-t-Bu2VANOL BOROX4 † MStoluene, Ð10 ¡C, 24 h97%, 98% eeNMEDAMC13H27OEtO(2S,3S)-103g1) TfOH, MeCN2) Boc2ONBocOEtOC13H27C13H27OHNH2OH1) HCO2H2) HCl, MeOH3) LiAlH4, THF82%75%(2S,3S)-138D-threo-sphinganine(2R,3R)-135C13H27OHNH2OH93%75%1) LiOH, MeOH2) LiAlH4, THF10% Sc(OTf)3C13H27OEtONHOO(4S,5S)-139C13H27OEtOL-erythro-sphinganine(2R,3S)-135+1) TfOH, MeCN2) Boc2O!,*!(3 mmol, 1.4 g) with an 88% isolated yield and 96% ee. It was then converted to the ring-opening compound 140 upon the treatment with TFA and subsequent basic hydrolysis. A regioisomer 141 was detected resulted from oxygen-nucleophilic attack at the 2-position. The regioselectivity was optimized to reach a 8:1 mixture of the regioisomers 140 and 141 in 86% total yield (Scheme 3.10).  Scheme 3.9  Alternative synthesis of all four sphinganine stereoisomers  Unfortunately, a number of strategies to obtain N-BUDAM sphinganine 142 by the reduction of amide in 140 to a primary alcohol were tested and came up a failure. The difficulty presumably comes from the bulky nature of N-BUDAM group, which makes the space proximity of the amide carbonyl quite sterically hindered and thus limits access by any hydride reductant. Attempts to force the reduction by heating or adding excess reductant such as LAH, NaBH4, super hydride or LiBH3NH2 gives a mixture of amine and alcohol products and also results in racemization at the !-position of amide (Scheme 3.10).   NMEDAMC13H27OEtONMEDAMC13H27OEtOC13H27OHOHNH2C13H27OHOHNH2C13H27OHOHNH2C13H27OHOHNH2D-threo-sphinganineL-erythro-sphinganineL-threo-sphinganine(sagingol)D-erythro-sphinganine(sphinganine)ring-opeingring-opeingNBUDAMC13H27HNONBUDAMC13H27HNOBuBuC13H27HOcis-aziridinationcis-aziridinationtrans-aziridinationtrans-aziridinationring-opeingring-opeing33g(2S,3R)-135(2R,3R)-135(2R,3S)-135(2S,3S)-135(2R,3R)-103g(2S,3S)-103g(2S,3R)-126g(2R,3S)-126g(S)-BOROX(R)-BOROX(S)-BOROX(R)-BOROX!,+!Scheme 3.10  Initial exploration of sphinganine synthesis by trans-aziridination   The experimental conditions were optimized for the ring-opening of trans-aziridine 126g by TFA (Table 3.8). This reaction gave a 62% total yield of 140 and 141 with 4:1 regioselectivity from aziridine 140 treated with one equivalent of TFA (Table 3.8, entry 1). The reaction was not clean with a complex mixture of byproducts generated, which possibly due to acid-catalyzed polymerization of the aziridine. It was found that the presence of a weaker acid could improve the yield significantly, which indicated the conjugate base would be a better oxygen nucleophile than trifluoroacetate to accelerate the ring-opening. The effects of 0.5 equivalent of three carboxylic acids were examined as additive (Table 3.8, entry 2-4). Acetic acid gave a 3:1 mixture of 140 and 141 in 93% yield (Table 3.8, entry 2). It was found that a lower concentration of the substrate 126g would afford a much greater selectivity (Table 3.8, entry 5-8). Although the yield slightly C13H27HO33gBUDAMÐNH2 101c(S)-VANOL BOROX(10 mol%)4 † MSN2NHOBu122bNBUDAMC13H27HNOBu(2S,3R)-126g85%, 96% eeTFA, NaOHC13H27NHOHHNBUDAMOBu+C13H27NHNHOHOBuBUDAM140141140:141 8:1[HÐ]C13H27OHHNBUDAMOH14286%!,,!dropped with a more diluted solution, the polymerization would presumbly be effectively inhibited to give a cleaner reaction mixture for the ring-opened products. In addition, without acetic acid as the additive and at the concentration of 0.1 M, the reaction will give an 86% yield of an 8:1 mixture of 140 and 141 which indicates that the substrate concentration has a key effect in the ring-opening (Table 3.8, entry 9). Table 3.8  Ring-opening of trans-aziridine carboxylamide 126g a 8  entry additive conc. (M) yield% b 140:141 c 1 Ð 0.5 62 4:1 2 AcOH 0.5 93 3:1 3 HCO2H 0.5 85 2:1 4 PivOH 0.5 92 3:1 5 AcOH 1.0 76 1.6:1 6 AcOH 0.2 88 7:1 7 AcOH 0.1 86 9:1 8 AcOH 0.05 86 8:1 9 Ð 0.1 86 8:1 a Unless otherwise specified, all the reactions were run in 0.2 mmol scale of aziridine 126 with 1 equiv of TFA in CH2Cl2 at room temperature for 48 h. It was followed by the basic hydrolysis of trifluoroacetate with aqueous NaOH. b Isolated yield of a mixture of regioisomers 140 and 141. c Determined by the 1H-NMR spectrum of the crude reaction mixture. The ring-opening of aziridine carboxylate 143 and 143Õ was also investigated (Table 3.9) since the strategy with amide reduction to an alcohol proved not to be feasible for sphinganine synthesis (Scheme 3.10). Both the methyl and ethyl esters were investigated at different concentrations in CH2Cl2. A protocol similar to that used for aziridine carboxylamide 126g was employed with a lower concentration, on which was observed to give better regioselectivity and a higher yield of the ring-opened product for 126g. However, the results were not as good as those for 126g, giving up to a 61% yield of 144 and 145 and a 6:1 selectivity for methyl ester 143 at 0.05 M reaction solution (Table 3.9, entry 5).  1) TFA (1.0 equiv.)additive (0.5 equiv.)CH2Cl2, rt. 48 h2) NaOH, EtOH/H2ONBUDAMC13H27HNOBu(2S,3R)-126gC13H27NHOHHNBUDAMOBu+C13H27NHNHOHOBuBUDAM140141!,-!Table 3.9  Ring-opening of trans-aziridine carboxylate 143 and 143Õ a 8  entry R conc. (M) yield b 144:145 c 1 Me 0.2 46 2:1 2 Et 0.2 48 2:1 3 Me 0.1 55 5:1 4 Et 0.1 49 5:1 5 Me 0.05 61 6:1 a Unless otherwise specified, all the reactions were run in 0.2 mmol scale of aziridine 143 with 1 equiv of TFA in CH2Cl2 at room temperature for 48 h. The compound with a prime is the ethyl ester. b Isolated yield of a mixture of regioisomers 144 and 145. c Determined by the 1H-NMR spectrum of the crude reaction mixture. With these optimization, a synthesis of D- and L-erythro-sphinganines was conceived as shown in Scheme 3.11 involving six steps from n-hexadecanal 33g. Both enantiomers of trans-aziridine 126g were prepared by the multi-component reaction of BUDAM amine 101c, aldehyde 33g and N-butyl diazoacetamide 122b with either the (S)- or (R)-VANOL BOROX catalyst (Table 3.4). The amide 126g could be converted to N-Boc-NÕ-butyl amide and then treated with sodium methoxide (1.5 equiv) to afford the corresponding methyl ester (2S,3R)-143 in 76% yield over two steps. A larger excess of NaOMe (2.2 equiv) improved the overall yield significantly to 91% for the (2R,3S)-enantiomer of 143. Given that the possible acidic hydrolysis of ester 143 and the relatively high yield in the reduction of both methyl carboxylate and trifluoroacetate to alcohols in 144 and 145 (80% yield), a one-pot procedure was developed to combine the TFA-mediated ring-opening and the LiAlH4 reduction. This has a potential advantage that it could also convert any carboxylic acid byproducts and separate the desired alcohol. A mixture of regioisomers 142 and 146 were obtained from methyl aziridine carboxylate 143 and could be isolated and separated in a 56% yield of desired N-BUDAM sphinganine 142 and a 23% yield of TFA (1.0 equiv.)NBUDAMOROOHNOROBUDAMNHOOROBUDAM+OF3COCF3CH2Cl2, rt. 48 hC13H27C13H27C13H27(2S,3R)-143  R = Me(2S,3R)-143'  R = Et144 (144')145 (145')!,.!the regioisomer 146 over two steps. The erythro-sphinganines were finally prepared by the hydrogenolysis of the N-BUDAM substituent with PearlmanÕs catalyst in high yields.  Scheme 3.11  Synthesis of erythro-sphinganines from trans-aziridination of n-hexadecanal 33g8  Notably, BUDAM amine 101c could be recycled to improve the atom economy from the BUDAM hydrocarbon compound 147 isolated in the hydrogenolysis of N-BUDAM sphinganine 142. The hydrocarbon underwent benzylic oxidation by ceric ammonium nitrate to afford ketone 14819 and reductive amination to give BUDAM amine 101c in three steps (Scheme 3.12). Scheme 3.12  Recycling of BUDAM amine 101c8     NBUDAMC13H27HNOBu(2S,3R)-126gNBUDAMC13H27HNOBu(2R,3S)-126g88% from 33g, 96% ee86% from 33g, 96% ee76%NBUDAMC13H27OMeO(2S,3R)-1431) n-BuLiBoc2OTHF2) NaOMe (2.2 equiv) THF, rt.91%NBUDAMC13H27OMeO(2R,3S)-1431) TFA, rt.CH2Cl2 (0.05 M)2) LiAlH4, THF, rt.1) TFA, rt.CH2Cl2 (0.05 M)2) LiAlH4, THF, rt.C13H27OHHNBUDAMOH(2R,3S)-142C13H27OHHNBUDAMOH(2S,3R)-14262%58%H2, Pd(OH)2MeOH, rt.H2, Pd(OH)2MeOH, rt.C13H27OHNH2OH91%D-erythro-sphinganine(2S,3R)-135(sphinganine)C13H27OHNH2OH85%L-erythro-sphinganine(2R,3S)-1351) n-BuLiBoc2OTHF2) NaOMe (1.5 equiv) THF, rt.+NHOHOHBUDAM(2S,3R)-146C13H2723%NHOHOHBUDAM(2R,3S)-146C13H2737%+100% from 142147CANHOAc, 95 ¡C1) NH3 (g), TiCl4THF2) LiAlH4148101cBUDAM amine85%88%MeOt-But-But-BuOMet-BuMeOt-But-But-BuOMet-BuOMeOt-But-But-BuOMet-BuNH2!-/!3.3.2 Synthesis of Sphingosine Stereoisomers Sphingosine 136 is one of the three primary sphingoid bases which has an unsaturated hydrocarbon chain at the 4-position (Figure 3.2) as the important structural and functional component of sphingolipids widely occurring in the plasma membrane of eukaryotic cells. It is biologically synthesized from the condensation of palmitoyl CoA 149 and serine 150 to yield 3-ketosphinganine 151, which is then reduced by NADPH to sphinganine 135. Sphinganine can be acylated to dihydroceramide 152 with the presence of fatty acyl CoA, which was then dehydrogenated by FAD into ceramide 153 and hydrolyzed to sphingosine 136.20 Scheme 3.13  De novo biosynthesis of sphinganine and sphingosine  The early work on sphingosine synthesis was lacking of any asymmetric catalysis, and instead involved the crystallization and resolution to separate the stereoisomers.21a-c Shapiro and Segal reported the first synthesis of sphingosine where they constructed the hydrocarbon chain by a Knoevenagel-Doebner condensation, obtained the erythro-C13H27SOCoApalmitoyl CoA149+OHNH2OOH150serineH+CO2CoA-SHC13H27OOHNH3+151H+NADPHNADP+C13H27OHNH3+OH135C13H27OHHNOHserine-palmitoyltransferase3-ketosphinganinesphinganine3-ketosphinganinereductasefatty-acyl CoACoA-SHceramidesynthasedihydroceramide152dihydroceramidedesaturaseFADFADH2C13H27OHHNOHceramide153fatty-acyl CoACoA-SHfatty acidceramidesynthaseceramidaseC13H27OHNH2OHsphingosine136O(CH2)nCH3O(CH2)nCH3!-&!isomers by fractional crystallization and finally afforded D- and L-configured enantiomers by resolution with the aid of L-(+)-acetylmandeloyl.21a Other asymmetric synthesis of sphingosine have been achieved from the chiral pools including D-ribo-phytosphingosine and serine derivatives to promote the asymmetric induction and obtain the various stereoisomers of sphingosine.21d, e During recent years, several applications of asymmetric catalysis have been reported in successful synthetic strategies to sphingosine. For example, CastillŠn et al. induced three chiral centers by dynamic kinetic resolution of ring-opening of epoxides with subsequent Sharpless asymmetric dihydroxylation of alkenes.21f Kumar et al. developed an efficient synthetic route by employing the kinetic resolution of allylic alcohols by the Sharpless asymmetric epoxidation catalyst and the diastereoselective intramolecular aminohydroxylation of alkenes.21g Scheme 3.14  Proposed synthetic strategy of erythro- and threo-sphingosines  C13H27LDA, DMFTHF, Ð78 ¡CHOC13H27(R)-VANOL BOROX(10 mol%)N2NHO154Phtoluene, Ð20 ¡C, 24 h+MEDAMNH2+132101a122aNMEDAMHNO133PhC13H2771%, 95% ee96%NMEDAMHNO133PhC13H27NBocO155C13H27OMe1) TfOH, MeCN2) Boc2O, DMAPimidazole3) NaOMe10% Sc(OTf)31) HCO2H2) HCl, MeOH3) LiAlH4NHOOC13H27OMeOC13H27OHNH2OHL-threo-sphingosine(2S,3S)-1361) LiOH, MeOH2) LiAlH4C13H27OHOHNH2D-erythro-sphinganine(sphingosine)(2S,3R)-136156!-'!Given that the alkynyl aldehyde 132 could be taken to the cis-aziridine 133 in a decent yield and asymmetric induction by the multi-component reaction of MEDAM amine 101a and N-phenyl diazoacetamide 122a catalyzed by VANOL-BOROX (Table 3.4, entry 14), the total synthesis of all four stereoisomers of sphingosine was proposed as shown in Scheme 3.14 based on the synthetic strategies developed for sphinganine. The synthesis starts from 2-hexadecynal 132 which was prepared from 1-pentadecyne 154 by treatment with LDA and then DMF. With the synthesis of cis-alkynylaziridine carboxylamide 133, it should be possible to convert it to N-Boc-aziridine 155 carboxylate with a procedure that has been established for related aziridines3m. Upon treatment with Sc(OTf)3, aziridine 155 should undergo the ring-expansion to afford oxazolidinone 156 with stereochemical retention at the 3-position. Subsequent hydrolysis of the oxazolidinone, ester and alkyne reduction would then complete the synthesis of erythro-sphingosine. On the other hand, the direct oxygen-nucleophilic ring-opening of aziridine 155 will have the stereochemistry at the 3-position inversed and thus preparation of threo-sphingosine could be completed by formamide hydrolysis and LiAlH4 reduction.   !-(!       REFERENCES   !-)!REFERENCES  1. a) P.; Fruit, C. Chem. Rev. 2003, 103, 2905; b) Zhang, Y.; Lu, Z.; Wulff, W. D. 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Tetrahedron Lett. 2012, 53, 4216; p) Rao, M. V.; Reddy, K. K. S.; Rao, B. V. Tetrahedron Lett. 2012, 53, 5993; q) Li, Q.; Zhang, H.; Li, C.; Xu, P. Chin. J. Chem. 2013, 31, 149; r) Calder, E. D. D.; Zaed, A. M.; Sutherland, A. J. Org. Chem. 2013, 78, 7223. 16. a) Fernandes, R. A.; Kumar, P. Tetrahedron: Asymm. 1999, 10, 4797; ) Fernanders, R. A.; Kumar, P. Eur. J. Org. Chem. 2000, 3447; c) He, L.; Byun, H-S.; Bittman, R.; J. Org. Chem. 2000, 65, 7618. 17. Roush, W. E.; Adam, M. A. J. Org. Chem. 1985, 50, 3752. 18. Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388. 19. Anderson, K. K.; Shultz, D. A.; Dougherty, D. A. J. Org. Chem. 1997, 62, 7575. !-+!20. Hannun, Y. A.; Obeid, L. M. Nat. Rev. Mol. Cell Bio. 2008, 9, 139. 21. a) Shapiro, D.; Segal, K. J. Am. Chem. Soc. 1954, 76, 5894; b) Grob, C. A.; Gadient, F. Helv. Chim. Acta, 1957, 40, 1145; c) Shoyama, Y.; Okabe, H.; Kishimoto, Y.; Costello, C. J. Lipid Res. 1978, 19, 250; d) Kim, S.; Lee, S.; Lee, T.; Ko, H.; Kim, D. J. Org. Chem. 2006, 71, 8661; e) Koskinen, P. M.; Koskinen, A. M. P. Methods in Enzymology, 2000, 311, 458; f) Llaveria, J.; D™az, Y.; Matheu, M. I.; CastillŠn, S. Org. Lett. 2009, 11, 205; g) Kumar, P.; Dubey, A.; Puranik, V. G. Org. Biomol.Chem. 2010, 8, 5074.   !-,!Chapter 4 Asymmetric Synthesis of Aminohydroxy Amide 4.1 Introduction of 1,2-Aminohydroxy Functionalization 4.1.1 "-Amino Alcohols in Natural Products A "-Aminoalcohol is a common structural motif in biological natural products and important molecular moiety in amino acids, hormones, alkaloids and drugs (Figure 4.1). Sphingoids, such as sphingosine 136, exist in cell memberanes and regulate the cell activities (Chapter 3, 3.2.2). Serine and threonine are common amino acids in organisms. Epinephrine 159 is a well-known medication and hormone that can treat severe asthma attacks and allergic reactions in the case of an emergency. Febrifugine 160 is a quinazolinone alkaloid first isolated from the Chinese herb Dichroa fabrifuga that has antimalarial properties.1 Amaninol A syn-161 and B anti-161 were reported in 2000 and found to be cytotoxic against P388 murine leukemia cells.2 Quinine 162 is a well-known alkaloid isolated from the bark of the cinchona trees and widely used for the treatment of malaria and babesiosis. Atazanavir 163 is an antiretroviral drug and a protease inhibitor and used to treat infection by HIV.          !--!Figure 4.1  "-Aminoalcohols in natural products  4.1.2 "-Amino Alcohols from C-C Bond Forming Reactions The stereoselective synthetic routes to "-amino alcohols in early reports were limited to the derivatization of molecules from the chiral pool such as amino acids.3 To access the broadest range of targets, a great number of routes have been developed for the asymmetric synthesis of "-amino alcohols. One of the common ways to construct the amino alcohol moiety is the coupling of two fragments by C-C bond formation, with one component containing oxygen functionalization and the other containing nitrogen functionalization. There are many strategies based reported in the literature for the synthesis of "-amino alcohols that are based on C-C bond formation. One of the strategies involves Mannich-type reaction with nucleophilic addition to imines by !-hydroxy carbonyls or !-alkoxy enolates. 4, 5 Kobayashi et al. have reported a nice 12OHNH2OHsphingosine136OHOOHNH2L-threonine158HOOHONH2L-serine157HOOHNHMeOHepinephrine159NNOOHNOHfebrifugine160NH2OHHHamaminol Asyn-161NMeONHHOquinine162MeONHOt-BuHNOBnOHNNHOHNt-BuOMeONatazanavir163NH2OHHHamaminol Banti-161!-.!example of a stereoselective Mannich-type reaction of imine 164 with !-alkoxy Mukaiyama enolate 165 with the catalysis prepared from zirconium tetra-tert-butoxide and (R)-Br2BINOL ligand. They have shown that the diastereoselectivity of the "-amino alcohols 166 was well controlled by the !-substituent. The reaction gives the syn-isomer of "-amino alcohols 166 with an !-TBS siloxy group while the anti-isomer of amino alcohols 166 can be obtained with an !-benzyloxy group (Scheme 4.1a). The other strategy as the aldol-type reaction in the presence of aldehydes involves in Henry reaction with subsequent reduction of the nitro compounds6, 7 (Scheme 4.1b) or the addition of glycine-derived enolates to aldehydes8 (Scheme 4.1c). Maruoka et al. reported the addition of trimethylsilyl nitroates 167 to aromatic aldehydes 33 in the presence of chiral quaternary ammonium fluoride salt 168 to give greater than >90:10  anti-diastereoselevtivity and 90-97% ee.7a Shibasaki et al. reported a syn-selective Henry reaction of nitroalkanes 169 and aldehyde 33 catalyzed by a Lewis acid-assisted Chiral Lewis acid (LLA) lithium/lanthanum polymetallic complex 171, which gave a syn-isomer of compound 170  in up to 84% yield and 95% ee.7b-d Particularly, a recent work reported a highly stereoselective synthesis of "-amino alcohols by asymmetric Pinacol cross coupling with an aldehyde and imine leading to an enantiomerically pure anti-"-amino alcohol in an excellent yield (Scheme 4.1d).9       !./!Scheme 4.1  Synthesis of "-amino alcohols by C-C bond formation    R1HNAr+R2OOR3OTMSZr(Ot-Bu)4(R)-Br2-BINOLDMI164165R1OR3ONHOR2Ar+R1OR3ONHOR2ArR2 = TBSdr  up to 99:1R2 = Bndr up to 94:641-100%76-98% eesyn-166anti-166aRHO+F3COTMSNOMeOTMS33172Zr(Ot-Bu)4(R)-I2-BINOLPrOHROMeOOHHNCF3O71-93%anti:syn up to 92:885-97% ee173R1HNArHO33TMSONOR167168 (2 mol%)ArROHNO270-94%anti:syn >90:1090-97% eeNR1R1HF2R1 =F3CCF3CF3CF3RCH2NO2169Li3La(R-BINOL)3 171(1 mol%)THF, Ð78 ¡Cthen HClTHF, Ð50/Ð30 ¡CArROHNO2up to 84%up to 95% eeanti-170syn-170bc168St-BuO+R2HO33174SmI2, t-BuOHTHF, Ð78 ¡CR2R1OHHNSOt-BuHClR2R1OHNH295-99% ee17517670-95%d!.&!4.1.3 "-Amino Alcohols from Functional Group Transformations "-Amino alcohols can also be approached by functional group transformations with the pre-existing carbon skeletons. One of synthetic routes commonly investigated is the asymmetric ring-opening of cyclic substrates such as epoxides10, aziridines11, sulfates12 and carbonates13. The regioselectivity can be a challenge and usually controlled by the directing groups such as phenyl, vinyl or carbonyl groups (Scheme 4.2). Scheme 4.2  Amminolysis of vinylepoxide 177  The alternative methods to "-amino alcohols by functional group transformations are related to stereoselective nucleophilic additions of chiral !-amino aldehydes14 or ketones15 through a Grignard addition or Mukaiyama aldol reaction, and also by diastereoselective reduction of !-amino carbonyl compounds16. Notably, with the presence of chirality in the !-amino carbonyl substrate, the diasteroselectivity of the "-amino alcohol formation could either be the anti-configuration by Felkin-Anh control or the syn-configuration by metal-chelation control.14a, c For example, the addition of lithium acetylide 179 to GarnerÕs aldehyde 104m gives a moderate anti-selectivity without any additive. However, the anti:syn ratio is improved to 19:1 in the presence of the polar aprotic reagent HMPA due to the breaking up of lithium aggregates. On the other hand, the presence of a chelating metal such as tin tetrachloride leads to the inversed diastereoselectivity with 1:19 anti:syn ratio (Scheme 4.3).14a   OR1R2R4R3NH4OHR1R4R3OHR2NH2177178!.'!Scheme 4.3  Diastereoselectivity control in nucleophilic addition to chiral amino aldehyde 104m  For the purpose to accessing enantiomerically pure amino aldehydes, Maruoka et al. reported a highly efficient one-pot procedure for the synthesis of "-amino alcohols by the direct asymmetric hydroxyamination of aldehydes with nitroso compounds. For ease of isolation, the aldehyde product was subsequently reduced to the corresponding hydroxyamino alcohol 187a.17 This involved a chiral secondary amine-catalyzed condensation of primary aldehydes 33 and nitrosobenzene 185 to afford "-amino alcohol 187a in a good yield and excellent asymmetric induction.17a Trace amounts of the aminoxylation byproduct 187aÕ was detected but in less than 1:99 ratio to hydroxyamination product 187a. They also modified the procedure with hydroxycarbamate 188 as the substrate, however since the corresponding nitroso compound is unstable and highly reactive, it was in-situ generated by oxidation with BPO and TEMPO (Scheme 4.5).17b,c       HOONBoc104m+LiOTBS179toluene, Ð78 ¡COHONBocOTBS+OHONBocOTBSanti-180syn-180        addtive                anti:syn                yield%        ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ          none                      3:1                      80         HMPA                    19:1                     85          SnCl4                    1:19                     46Felkin-controlchelation-control!.(!Scheme 4.4  Asymmetric hydroxyamination of aldehydes  The third synthetic route to "-amino alcohol by functional group transformations involves oxidation of chiral allylic amines through epoxidation18 or dihydroxylation19. Based on the literature reports, the stereochemical configuration of the product is greatly dependent on the alkene configuration in the substrates. The Z-isomer of allylic amine gives a mixture of diastereoisomers while the E-isomer gives the product as the single anti-isomer of the "-amino alcohol (Scheme 4.5).19 Scheme 4.5  Dihydroxylation of allyl amines 181   PhNO185+RHO3310 mol% (S)-186aNHOR'OR'ArArArAr(S)-186THF, 0 ¡C, 1 hNaBH4MeOHPhNROHOH187a70-90%96-99% eeBocHNOH188+RHO33(S)-186b (10 mol%)BPO, TEMPO(S)-186a  Ar = Ph, R' = H(S)-186b  Ar = 3,5-F2C6H3, R' = TESCH2Cl2, 0 ¡C, 20 hBocNROHOH+ORNHOHBoc187b187b'up to 95%up to 99% ee187b:187b' >20:1+ORNHOHPh187a'187b:187b' >99:1ONBocCO2MeOsO4, NMO3:1 drONBocCO2MeOHOH+ONBocCO2MeOHOHE-181182183ONBocCO2MeOsO4, NMOsingle isomerONBocCO2MeOHOHZ-181184!.)!4.1.4 "-Amino Alcohols from Direct Alkene Aminohydroxylation The most widely used method for the direct enantioselective indroduction of both amino and hydroxyl in the synthesis of "-amino alcohols is the Sharpless asymmetric aminohydroxylation of alkenes (Scheme 4.6).20,21 It has been demonstrated that the !,"-unsaturated esters or phosphonates are the most suitable substrates which give the best regioselectivity for !-hydroxy-"-amino esters 190 over the regioisomer !-amino-"-hydroxy esters 190Õ.20a The optimal conditions for the Sharpless aminohydroxylation allows for the syn-selective preparation of !-hydroxy-"-amino esters, untilizing the salts of N-halosulfonamides, amides, or carbamates as the nitrogen source, water or alcohol as the oxygen source and potassium osmate(VI) as the oxidant.20b,c The excellent enantioselectivity (>95% ee in most of cases) is achieved by dihydroquinine- or dihydroquinidine-derived chiral ligands. Based on the literature reports, the high regioselectivity of the Sharpless aminohydroxylation is limited to !,"-unsaturated esters, sulfonates, phosphonates, allylic alcohols and silanes.21 A mixture of regioisomers are produced with unfunctionalized alkenes. Only the styrene derivatives were reported to stereoselectively give oxazolidinones by the Sharpless aminohydroxylation when treated with carbamates and bases.22 Considering the high toxicity of osmium(VI) or (VIII) reagents, a number of alternative procedures for olefin aminohydroxylation have been developed in recent years with a broader range of substrate scope and better regioselectivity.23     !.*!Scheme 4.6  Sharpless asymmetric aminohydroxylation  Yoon et al. have reported an example of catalyst-controlled in the regioselectivity of olefin aminohydroxylation.23e-h They reported a copper-catalyzed reaction of terminal styrene 193 with oxaziridines 194 to afford a 2,4-disubstitued oxazolidine 195, while the reaction favored the opposite regioselectivity to give a 2,5-disubstituted oxazolidine 197 under iron catalysis (Scheme 4.7). Both regioisomers of "-amino alcohols 196 and 198 were obtained by the subsequent hydrolysis of the oxazolidines.   R1OMeO189N-source:R2NXNa(1.1-3 equiv.)R2 = R3SO2, R3OCO, R3COX = Cl, BrO-source: R4OH (R4 = alkyl, H)catalyst: K2OsO2(OH)4ligand: (DHDQ)2PHAL, (DHDQ)2AQN             (DHQ)2PHAL, (DHQ)2AQNR1OMeO(2S,3R)-190NHOR4R3R1OMeO(2S,3R)-190'OR4HN+R3R1OMeO(2R,3S)-190NHOR4R3R1OMeO(2R,3S)-190'OR4HN+R3up to 20:1 190:190'NNNMeOONNONOMe(DHQ)2PHAL191NNNMeOOONOMe(DHQ)2AQN192OONNNMeOONNONOMe(DHDQ)2PHAL191'NNNMeOOONOMe(DHDQ)2AQN192'OO!.+!Scheme 4.7  Regioselective aminohydroxylation of styrene 193 and oxaziridines 194  Xu et al. developed a highly diastereoselective and atom-economic iron-catalyzed alkene aminohydroxylation with oxycarbamates in the presence of polydentate nitrogen ligands (Scheme 4.8).23i-l They proposed a iron nitrenoid-mediated mechanism that oxycarbamates 200 would allow either syn- or anti-addition to the olefin 199 which afforded "-amino alcohols 203 or cyclic imidates 204 and both could be converted to oxazolidinone 205.23k With a tethered carbamate in the substrate 206, an intramolecular aminohydroxylation to give an "-amino-%-hydroxy alcohol 208 as the final product with the high diastereomeric purity.23j           AcO193ONNsAr194CuCl (2 mol%)Bu4NCl (3 mol%)AcOONsNAr1) conc. HClMeOH, reflux2) PhSH (4 equiv.)K2CO3AcOOHNH219519677%97%AcONNsOAr19790%Fe(acac)3 (5 mol%)1) HClO4 aq.dioxane, 80 ¡C2) PhSH (4 equiv.)K2CO3AcONH2OH19877%!.,!Scheme 4.8  Aminohydroxylation of alkenes and oxycarbamates  4.4.5 "-Amino Alcohols from 1,3-Dipole Cycloaddition Ylides are highly reactive dipoles that have been used as key intermediates in a variety of organic tranforatmions. Carbonyl ylides can form by the reaction of carbonyls with electrophilic metallocarbenes and have been revealed as a 1,3-dipole.24 The most significant reaction involving a carbonyl ylide is the 1,3-dipole cycloaddition with alkenes and alkynes to yield the corresponding five membered oxacycles (Scheme 4.9a).25 Azomethine ylides are nitrogen-based analogs of carbonyl ylides that were first discovered and studied in 1965.26 Huisgen and co-workers have shown that the thermolysis of 1-phenyl-2,3-dicarbomethoxyaziridines 209 could afford the stabilized S- or W-ylides 210 by a conrotary ring opening.27 The S-dipole generated from cis-aziridine 209 reacts with most dipolarophiles to afford heterocycles trans-211 stereospecifically, R3R2R1OONHR4OOHNR2R3R1O206207R4OHONHBocR3R1R2OH208K4Fe(CN)6 (10 mol%)phen (20 mol%)MeCN, rt. 12 hdr up to >20:1yield up to 92%1) Boc2O, Et3NCH2Cl2, rt.2) LiOH, dioxanertR2R1R3+R4ONHOOR5199200R2R3HNR5OR1OR4O+Fe(OTf)2/Fe(NTf2)2 (10 mol%)201 (10 mol%)CH2Cl2/MeCN (20:1)4 † MS, Ð15 ¡C203NOR2R1R3HOR4204TsOHLiOHNHOR2R1R3HO205Intramolecular aminohydroxylationIntermolecular aminohydroxylationR4 = CF3CH2, CCl3CH2, t-BuR5 = ArCONONNO202dr up to >20:1yield up to 84%!.-!while W-ylides 210 from trans-aziridine 209 afford heterocycles with only the syn-configuration (Scheme 4.9b).28 Scheme 4.9  Formation of carbonyl and azomethine ylides and 1,3-dipole cycloadditions  Somfai and co-workers have reported the syn-selective synthesis of aminohydroxycarboxylates via oxazolidine intermediates by 1,3-dipole cycloadditions.29 They developed a three-component procedure involving aldehyde 33a, ethyl diazoacetate (EDA) 102 and aldimines 212 (Scheme 4.10a). A carbonyl ylide is generated in-situ from benzaldehyde 33a and EDA 102 and undergoes rhodium-catalyzed 1,3-dipole cycloaddition with imines 212 to give the trans-substituted oxazolidines 213. Subsequent hydrolysis of the oxazolidine ring affords the "-amino-!-hydroxy esters 214 with up to 98:2 syn-selectivity.29a, b On the other hand, they also reported a 1,3-dipolar cycloaddition of aldehydes 33 and an azomethine ylide generated in-situ from an imino glycine ester 215 upon activation with silver triflate, which was followed by the hydrolysis of trans-oxazolidine intermediates 216 to afford the !-amino-"-hydroxy esters 217 with a 18:1 R1N2R2MLnÐN2R1MLnR2R3R4OÐMLnR1R2OR4R3XYYXOR1R2R3R4aNMeO2CCO2MePhheatcis-209MeO2CNCO2MePhS-ylide 210XYXYNCO2MeMeO2CPhtrans-211NMeO2CCO2MePhheattrans-209MeO2CNPhW-ylide 210XYXYNCO2MeMeO2CPhcis-211CO2Meb!..!syn-selectivity and opposite regioselectivity observed by the carbonyl ylide (Scheme 4.10a vs 4.10b).29c,d Scheme 4.10  Synthesis of "-amino alcohols by 1,3-dipole cycloadditions  4.2 BOROX-Catalyzed Aziridination/Ring-Opening Cascade Reaction 4.2.1 Catalytic Ring-Opening of trans-Aziridines In the studies of the substrate scope in the multi-component trans-aziridination (Table 3.2), a byproduct 218a or 219 was detected and isolated in the reaction of some of the aromatic aldehydes such as 4-tolualdehyde 33c and 2-naphthaldehyde 33j (Scheme 4.11). It was observed that the amount of the byproduct 218a or 219 could be greatly reduced if after the catalyst formation step that al volatiles were removed by heating at 80 ¡C under a high vacuum. Thus, it could inferred that the structure of the unknown compound 218a PhHO+N2OEtO+RNBn33a1022121) Rh2(OAc)4CH2Cl2NBnOPhREtO2C2132) TsOH, MeOHEtOOROHHNBnEtOOROHHNBn+syn-214anti-214up to 98:2 syn:antiup to 87% yieldPhNPhOt-BuO+ArHO332151) AgOTf, PPh3i-Pr2NEtPhCO2H, tolueneNHORCO2t-BuPhPh2161 M HCl, MeOHROt-BuOOHNH2217abup to 18:1 drup to 91% yield!&//!or 219 was an !-amino-"-hydroxy carboxamide generated by nucleophilic ring-opening of the aziridine product since previous experiment has shown that phenol is removed when the catalyst is subjected to a high vacuum at 80 ¡C. The formation of aminohydroxy amide byproduct can be rationalized as a BOROX-catalyzed cascade process of trans-aziridination/nucleophilic ring-opening (Scheme 4.12). The trans-aziridine carboxamide ent-125c, generated from BUDAM amine 101c, aldehyde 33c and N-phenyl diazoacetamide 122a, once formed, could be protonated and activated by the BOROX catalyst since the aziridine nitrogen has the similar basicity to an imine. A BOROX-catalyzed ring-opening of trans-aziridine ent-125c in the presence of phenol derived from triphenylborate would be expected to occurr to afford an 2-amino-3-phenoxy carboxamide 218a by nucleophilic attack at the 3-position. The observation then supports for the assertion that the application of the pumping procedure can effectively remove phenol before the formation of trans-aziridine. Meanwhile, it can be inferred that a stoichiometric amount of phenol as a nucleophile should be able to give a complete conversion of the trans-aziridine intermediate into an aminohydroxy amide as a ring-opened product. Scheme 4.11  Byproducts in multi-component trans-aziridination   BUDAMNH2(S)-VANOL (10 mol%)B(OPh)3 (30 mol%)toluene, 80 ¡C, 30 minpump 0.5 mmHg, 30 min4 † MSArCHO 33(1.1 equiv.)NHON2PhÐ20 ¡C, 24 hNArBUDAMOHNPhrt. 20 minMeCHOCHO64% 125j, 15:1 t/c92% ee17% 21959% 125c, 13:1 t/c85% ee30% 218awithout pumping82% 125j, 62:1 t/c92% ee3% 21973% 125c, 19:1 t/c82% ee2% 218awith pumping+OPhNHOHNPhBUDAM33c33j122a(1.4 equiv.)218a125101cOPhNHOHNPhBUDAM219or(1.0 equiv.)!&/&!Scheme 4.12  Formation of aminophenoxy amide 218a in trans-aziridination of 4-tolualdehyde 33c  4.2.2 Asymmetric Synthesis of Aminohydroxy Amides with Phenols The BOROX-catalyzed synthesis of aminohydroxy amides was optimized in the presence of a stoichiometric amount of phenol 221a (Table 4.1). The trans-aziridination with the removal of phenol was present as the reference reaction where is was observed that a less than 2% yield of aminophenoxy amide 218a was detected and trans-aziridine ent-125c was isolated in 73% yield and 82% ee (Table 4.1, entry 1). With the addition of a slightly excess phenol (1-2 equiv), a moderate yield of product 218a was obtained (~40-50%) with significant high enantiomeric purity (>96% ee), while there was still a 20-30% yield of trans-aziridine ent-125c isolated, however with much lower enantiomeric purity (60-70% ee) compared to the results in entry 1 (Table 4.1, entry 2-4). This unexpected enantiomeric enrichment from the trans-aziridine intermediate ent-125c to aminophenoxy amide 218a was presumably resulted from a kinetic resolution of trans-aziridine as a consequence of the action of the BOROX catalyst. Great drop in the yield of product 218a was observed when the amout of phenol was further increased (3-10 equiv) and at BUDAMNH2+OHNHBUDAMN2NHOPhNHNOPhBUDAMPhOHOPhHNNHOPhBUDAMOOPhPhBOBOBOOPhOPh(R)-VANOL BOROX 71a[H-substrate]101c33c122a220ent-125c218a!&/'!the same time, more trans-aziridine ent-125c remained unreacted. The decrease in ee of both product 218a and ent-125c indicates that the BOROX catalyst is likely deactivated by the interaction with the large amount of excess phenol 221a to give a poorer asymmetric induction (Table 4.1, entry 5-7). Table 4.1  Optimization of asymmetric synthesis of aminohydroxy amide a  entry ligand PhOH/equiv. T/¡C trans-aziridine aminohydroxy amide yield% b ee% c yield% b ee% c 1 d (R)-68a 0 Ð20 73 82 <2 nd 2 (R)-68a 1 Ð20 16 57 52 >99.5 3 (R)-68a 1.5 Ð20 21 69 48 99 4 (R)-68a 2 Ð20 36 69 44 96 5 (R)-68a 3 Ð20 42 70 39 95 6 (R)-68a 5 Ð20 51 72 30 90 7 (R)-68a 10 Ð20 53 55 16 72 8 (R)-68a 1.5 0 <1 e nd 81 94 9 f (R)-68a 1.5 25 <1 e nd 65 87 10 (R)-68b 1.5 Ð20 4 e, g nd 26 28 11 (R)-68c 1.5 Ð20 <1 e, g nd 59 26 a Unless otherwise specified, all the reactions were run in 0.2 mmol scale of BUDAM amine 101c (1 equiv), 4-tolualdehyde 33c (1.2 equiv), N-phenyl diazoacetamide 122a (1.4 equiv) and phenol 221a with 0.2 M in toluene for 48 h. b Isolated yield. c Determined by HPLC. nd = not determined d The pumping at high vacuum was applied in the preparation of pre-catalyst to remove the volatile components. e Determined by the 1H-NMR spectrum of the crude reaction mixture with an internal standard. f Reaction was run for 24 h. g 11% of cis-aziridine was detected. h 7% of cis-aziridine was detected. The optimization of reaction temperature shows that the nucleophilic ring-opening of trans-aziridine ent-125c is greatly accelerated at 0 ¡C to give a complete conversion to the product 218a in a high yield and ee (Table 4.1, entry 8). However, at the room temperature other byproducts are observed that the yield and ee drops even the reaction should be complete in a much shorter time (Table 4.1, entry 9). Finally, by screening the three chiral ligands VANOL 68a, VAPOL 68b and t-Bu2VANOL 68c, it was found that VANOL 68a gives the much more decent results than the other two ligands (Table 4.1, entry 10, 11 vs entry 3). Notably, a small amount of cis-aziridine was detected with the BUDAMNH2(R)-ligand (10 mol%)B(OPh)3 (30 mol%)toluene, 80 ¡C, 0.5 h4 † MSNHON2PhT ¡C, 48 hrt. 20 minCHOPhOH 221aOPhHNNHOPhBUDAM33c122a101c218aVANOL 68aVAPOL 68bt-Bu2VANOL 68c+NBUDAMOHNPhent-125c!&/(!ligands VAPOL 68b and t-Bu2VANOL 68c, which is consistent with the previously observed behavior of these ligands in the multi-component trans-aziridination (Table 3.1, 3.2). In addition, an experiment conducted for comparison has shown there is a background reaction of ring-opening of trans-aziridine ent-125c by phenol 221a without the presence of the BOROX catalyst. The reaction is far slower than the catalytic one with an only 13% conversion of trans-aziridine after 3 days (Scheme 4.13c). Scheme 4.13  Control experiments  A set of control experiments was carried out to confirm the enantiomeric enrichment involved in the catalytic ring-opening of trans-aziridine intermediate. In the first experiment on a 0.2 mmol scale, the optimal conditions were followed (Table 4.1, entry 8) to isolate the aminophenoxy amide 218a (81% yield, 0.158 mmol) in 93% ee (Scheme 4.13a). In a parallel experiment also with 0.2 mmol scale was carried out in exactly the BUDAMNH24 † MS(R)-VANOL BOROX (10 mol%)p-TolCHO 33c (1.2 equiv.)NHON2Ph122a(1.4 equiv.)0 ¡C, 48 hNBUDAMOHNPhrt. 20 minPhOH 221a (1.4 equiv.)NHOPhHNOPhent-125c0.200 mmol, 76% eePhOH 221a (1.2 equiv.)0 ¡C, 28 hBUDAMNHOPhHNOPhBUDAM0.158 mmol, 93% ee0.292 mmol, 91% ee101c0.200 mmolBUDAMNH24 † MS(R)-VANOL BOROX (10 mol%)p-TolCHO 33c (1.2 equiv.)NHON2Ph122a(1.4 equiv.)0 ¡C, 48 hrt. 20 minPhOH 221a (1.4 equiv.)101c0.200 mmol218a218atheoretical 85% eeabNBUDAMOHNPhent-125cPhOH (1.5 equiv.)toluene, rt. 3 dNBUDAMOHNPhent-125c+NHOPhHNOPhBUDAM218a87%13%c!&/)!same way and when the reaction was complete, additional phenol was added along with 0.2 mmol purified trans-aziridine ent-125c (76% ee). The enantiomeric purity of aminophenoxy amide 218a was found to be 91% ee, and was isolated in the amount of 0.292 mmol (Scheme 4.13b). These experiments are consistent with the enantioenriched effects observed during the catalytic ring-opening, the theoretical ee of the product should be 85% if the additional 0.134 mmol of compound 218a where 76% ee and is simply mixed with 0.158 mmol of the same material with 93% ee. Figure 4.2  Reaction Tracking  A plot obtained by tracking the percentage yield of the imine 220, the trans-aziridine ent-125c and the aminophenoxy amide 218a every 30 min by the 1H-NMR spectrum of the reaction mixture with an internal standard (Figure 4.2). The amount of imine reached a 28% yield at 0.5 h and then kept decreasing indicating that the imine 220 was formed almost instantly and was rapidly converted to the trans-aziridine ent-125c within 2 h. The trans-aziridine ent-125c reached a maximum yield of 32% at 1 h and then was slowly converted to the product. Only around 5% yield of the aziridine was left at 12 h. Meanwhile, the amount of aminohydroxy amide kept increasing all the time. Given that the yield of aziridine was decreasing by 26 percentage from 1 h to 12 h, while the yield of !"#"$!"$#"%!"%#"&!"&#"'!"!"#"$!"$#"()*+,-".)/*01"2/)341(,546("2/),*"-".5237829)5),)3*-")/)3*-"!&/*!aminohydroxy amide was increased by 34 percentage in the same period of time, it suggests the evidence that the trans-aziridine can be the intermediate which is directly converted to the product. It is possible that this difference is due to inaccurate integration of the trans-aziridine that the peaks of the rotamers could be observed in the 1H-NMR spectrum of the pure compound with CDCl3 as the solvent. However, in the proton spectrum of the crude reaction mixture, these peaks could not be detected. A single crystal of compound 218a was obtained in the mixed solvent EtOH/H2O, which was isolated and purified from the (R)-VANOL BOROX catalyzed reaction. The structure has two molecules in the unit cell as revealed by the X-ray crystallographic analysis (Figure 4.3). One of molecule (right) perfectly shows the stereochemistry of (2S,3S)-configuration. However, the other molecule (left) could only display the S-configuration at the 2-position, with the 3-position left unresolved due to the disorder in the crystal. The absolute stereochemistry of compound 218a was eventually comfirmed by the independent synthesis of the compound with a known configuration (Scheme 4.17).           !&/+!Figure 4.3  X-ray crystallographic analysis of aminophenoxy amide 218a   To investigate other phenol derivatives as the nucleophile, the optimal conditions with phenol need to be revised, as triphenylborate will always release free phenol during the catalyst formation to the reaction mixture which would result in a mixture of aziridine ring-opened products when there is another external phenol derivative added. For example, 4-methoxyphenol (PMPOH 221b) was tested as a different nucleophile with the standard procedure of aziridination/ring-opening cascade reaction, which afforded a mixture of PMPOH ring-opened product 218b in 58% yield as well as phenol ring-opened product 218a in 26% yield (Scheme 4.14).    NHOPhHNOPhBUDAMNHOPhHNOPhBUDAM(75%)(2S,3S)-218a!&/,!Scheme 4.14  Asymmetric synthesis of aminohydroxy amides with 4-methoxyphenol  In order to avoid the incorporation of phenol liberated during catalyst formation and generate a single aminohydroxy amide, the pumping procedure was applied with the high vacuum during the process of BOROX pre-catalyst preparation to remove the phenol liberated from triphenylborate. The reaction with the pumping procedure was first tested with phenol 221a as the nucleophile at 0 ¡C and it was found that both the yield and the ee dropped (70% yield and 90% ee) compared to the reaction when the phenol liberated during the catalyst formation was not removed (Table 4.2, entry 1 vs Table 4.2, entry 8). If the reaction was run at Ð20 ¡C, an even lower yield was obtained, although the induction was improved to 97% ee (Table 4.2, entry 2). However, replacement of phenol 221a with 4-methoxyphenol 221b will give a reaction with an over 80% yield and excellent ee which suggests that an electron-rich phenol behaves as a better nucleophile. There was no significant difference for the yield and ee at 0 or Ð20 ¡C with PMPOH 221b (Table 4.2, entry 3, 4).      BUDAMNH2(R)-VANOL (10 mol%)B(OPh)3 (30 mol%)toluene, 80 ¡C, 0.5 h1) 4 † MSp-TolCHO 33crt. 20 minNHON2Ph122a0 ¡C, 48 h2) PMPOH 221bNHOPhHNOPhBUDAMNHOPhHNOBUDAM101c+MeO218b218a58%26%!&/-!Table 4.2  Optimization of the procedure with pumping at high vacuum a  entry Ar T/¡C yield% b ee% c 1 Ph 221a 0 70 90 2 Ph 221a Ð20 64 97 3 PMP 221b 0 83 92 4 PMP 221b Ð20 85 93 a Unless otherwise specified, all the reactions were run in 0.2 mmol scale of BUDAM amine 101c (1 equiv), 4-tolualdehyde 33c (1.2 equiv), N-phenyl diazoacetamide 122a (1.4 equiv) and phenols 221 (1.5 equiv) with 0.2 M in toluene for 48 h. A pumping procedure was applied at high vacuum to remove the volatile components in the preparation of pre-catalyst. b Isolated yield. c Determined by HPLC. 4.2.3 Asymmetric Synthesis of Aminohydroxy Amides with Carboxylic Acids In order expand the scope of nucleophiles, the BOROX-catalyzed trans-aziridination/ring-opening cascade reactions need to be evaluated with different types of nucleophilic reagents (Scheme 4.15). The reaction was examined with benzoic acid 222, if it is successful, the aminobenzoyloxy amide 223a should be easily hydrolyzed to afford the "-amino alcohol moiety. In the initial experiment, the optimal conditions in Table 4.2, entry 4 were followed and employed benzoic acid 222 instead of para-methoxyphenol 221b. A moderate yield (66%) of aminobenzoyloxy amide 223a was isolated, however, with an asymmetric induction of only 20% ee. In addition, a 1:1 mixture of trans- and cis-aziridines 125c was detected in 15% yield. It is proposed that benzoic acid 222 can either be hydrogen bonded to the catalyst or protonate the imine intermediate that either way makes the catalyst less effective in interacting with the substrate intermediate, resulting in the poor asymmetric induction. A much better yield and improved asymmetric induction was obtained with for product 223a in a experiment with a modified procedure that has the benzoic acid added to the reaction mixture after the BUDAMNH2(R)-VANOL (10 mol%)B(OPh)3 (30 mol%)toluene, 80 ¡C, 0.5 hpump, 0.05 mmHg, 0.5 h1) 4 † MSp-TolCHO 33c(1.1 equiv.)rt. 20 minNHON2Ph122a(1.4 equiv.)T ¡C, 48 h2) ArOH 221NHOPhHNOArBUDAM101c218!&/.!trans-aziridination was complete. Unlike the protocol in the reaction with phenol that gives improved enantiomeric purity during the ring-opening transformation, the reaction with benzoic acid results in drop in ee from the trans-aziridine to the aminobenzoyloxy amide 223a. Given that the major difference of these two oxygen nucleophiles is their Br¿nsted acidity, future work should focus on studying the Hammett plot between the asymmetric induction and the pKa values of phenols and benzoic acids, which the pKa can be tuned by the electronic nature of the substituents on the aromatic ring.  Scheme 4.15  trans-Aziridination/ring-opening cascade reaction with benzoic acid 222  The anionic carboxylate reagents potassium acetate and sodium trifluoroacetate were examined for the cascade reactions since they could be better nucleophiles than their acidic forms in the ring-opening of the aziridine intermediate (Scheme 4.16). Unfortunately, neither the aminoacetoxy amide 223b nor aminotrifluoroacetoxy amide 223c, could be detected in the reaction mixtures. Instead, only a moderate yield of the trans-aziridine ent-125c was isolated and thus the ring-opening step failed to occur. In addition, achiral compound 224 was detected in the mixture from both experiments in 10-NHON2PhÐ20 ¡C, 24 h(R)-VANOL BOROX(10 mol%)4 † MSp-TolCHO 33c(1.1 equiv.)toluene, rt. 20 minNHOPhHNOBUDAMOPhÐ20 ¡C, 24 h81%, 68% eeNHON2Ph122a(1.4 equiv.)Ð20 ¡C, 24 hBUDAMNH2101cPhCO2H 222 (1.5 equiv.)NHOPhHNOBUDAMOPh66%, 20% ee+NBUDAMOHNPhtrans/cis-125c15%223a223a122a(1.4 equiv.)PhCO2H 222 (1.5 equiv.)!&&/!15% yield. This enamine compound 224 could be generated from the elimination of nitrogen from diazonium intermediate 225 facilitated by the basic nucleophiles. This is consistent with the previous studies that revealed a step-wise mechanism for the aziridination involving diazonium intermediate.30 Scheme 4.16  trans-Aziridination/ring-opening cascade reaction with carboxylate anions  The PMP oxygen substituent in the aminophenoxy 218b is expected to be cleaved by CAN oxidation, however, no reproducible yield of the product 226 could be obtained with severial trials and the reaction conditions were not further optimized (Scheme 4.17a). Fortunately, the aminobenzoyloxy amide 223a prepared by (R)-VANOL BOROX-catalyzed cascade reaction was able to be hydrolyzed to the aminohydroxy amide 226, which gives a negative optical rotation in CHCl3 (Scheme 4.17b). Meanwhile, the same compound with the (2S,3S)-configuration and a negative rotation in CHCl3 could be obtained by the TFA/HOAc-catalyzed ring-opening and basic hydrolysis of (2S,3R)-aziridine 125c (Scheme 4.17c). These results match with the data from (R)-VANOL BOROX(10 mol%)4 † MSp-TolCHO 33ctoluene, rt. 20 minBUDAMNH2101cÐ20 ¡C, 24 hNHON2Ph122aNHOPhHNOBUDAMOF3CKOAc/NaCF3CO2NBUDAMOHNPh+NHNHOBUDAMPhNHOPhHNOBUDAMOent-125c224223b223cornot observedNHNHOBUDAMPhN2RCO2ÐÐN2, ÐH+225ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ          with KOAc                             55%                                               14%       with NaCF3CO2                        61%                                               10%!&&&!crystallographic analysis that the cascade reactions give anti-diastereoisomers due to the inversion of stereochemistry at C3-position in the process of nucleophilic ring-opening. Based on the results in chapter 3 that (R)-VANOL BOROX catalyst gives aziridine 125c with (2S,3R)-configuration, it reveals that the catalytic cascade reaction follows the same stereochemistry of product as that of trans-aziridination. Scheme 4.17  Synthesis of !-amino-"-hydroxy carboxylamide 226    ONHOOPhPhHNBUDAMNaOH (2.0 equiv.)EtOH/H2O (5:1,v/v)rt. 30 minOHNHOPhHNBUDAM98%, 52% ee[!]20 = Ð28.6¡, c = 1.0, CHCl3NBUDAMHNOPh1) TFA (1.0 equiv.)HOAc (5.0 equiv.)2) NaOH (8.0 equiv.)EtOH/H2O, rt. 12 hOHNHOPhHNBUDAM55%ent-125c, 80% ee[!] = Ð33.6¡, c 1.0 in CHCl3from (R)-VANOL BOROX223a, 56% eefrom (R)-VANOL BOROX226226OMeONHHNBUDAMOPhCAN (1.1 equiv.)H2SO4 (1.0 equiv.)MeCN/H2O, rt. 12 hOHNHHNBUDAMOPh20-58%abc218b226!&&'!       REFERENCES  !&&(!REFERENCES  1. McLaughlin, N. P.; Evans, P. J. Org. Chem. 2010, 75, 518. 2. Sata, N.; Fusetani, N. Tetrahedron Lett. 2000, 41, 489. 3. Reetz, M. T. Angew. Chem. Int. Ed. 1991, 30, 1531. 4. Mannich-type reactions: a) Kobayashi, M.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 9685; b) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827; c) CŠodova, A.; Notz, W.; Zhong, G.; Betancort, J. M. Barbas III, C. F. J. Am. Chem. 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React. 2012, 80, 1. 26. Heine, H. W.; Peavy, R. E. Tetrahedron Lett. 1965, 6, 3123. 27. a) Huisen, R.; M−der, H. J. Am. Chem. Soc. 1971, 93, 1777; b) Huigen, R.; Sheer, W.; Huber, H. J. Am. Chem. Soc. 1967, 89, 1753. 28. Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. 29. a) Torssell, S.; Kienle, M.; Somfai, P. Angew. Chem. Int. Ed. 2005, 44, 3096; b) Torssell, S.; Somfai, P. Adv. Synth. Catal. 2006, 348, 2421; c) Seashore-Ludlow, B.; Torssell, S.; Somfai, P. Eur. J. Org. Chem. 2010, 3927; d) Danielsson, J.; Toom, L.; Somfai, P. Eur. J. Org. Chem. 2011, 607. 30. Aggarwal, V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem. Soc. 2002, 124, 5747.   !&&+!Chapter 5   Parallel Kinetic Resolution of Racemic !-Iminols 5.1 Parallel Kinetic Resolution (PKR) Kinetic resolution refers to the rate differentiation of two enantiomers in a racemic compound. Chiral catalysts or reagents are often used to make two enantiomers react in different rates.1 The more reactive enantiomer SR gives a chiral product PR, resulting in enantioenrichment of the less reactive enantiomer SS. When the reaction rate of SR is much greater than that of SS (kR >> kS), the reaction affords high enantiomeric purity of both staring material and product with the overall result of synthetically useful in separation of chiral molecules (Scheme 5.1). A great number of publications have reported extremely effective kinetic resolutions for the preparation of enantiopure starting materials and products introducing alcohol acylation2a, Sharpless epoxidation2b, 2c, Sharpless dihydroxylation2d, 2e, Jacobsen epoxide opening2f, 2g, hydrogenation2h and ring-closing metathesis2i as typical examples of the practicality of kinetic resolution in asymmetric catalysis. Scheme 5.1  Kinetic resolution of a racemic compound  To give an efficent kinetic resolution, the selectivity factor s should have a value (kR/kS) to be greater than 200.1 However, in many cases the difference in reaction rate of both enantiomers is not great enough which results in a decrease in the enantiopurity of the product. The situation is even worse when the conversion passes 50% and the less reactive enantiomer rises to a relative high concentration. One way to avoid this situation is if there is an in situ racemization of two enantiomers of a starting material which has a SRkRPRkSSrackR >> kSSSSS!&&,!lower reaction barrier than the former reaction barrier for either of the enantiomers. This situation is called dynamic kinetic resolution (DKR) that is able to reach a theoretical 100% conversion of starting material into a single enantiomer of product (Scheme 5.2).3 Scheme 5.2  Dynamic kinetic resolution of a racemic compound  There is another way to maximize the enantiopurity as well as the conversion percentage by the use of two selective reagents in parallel. The more reactive enantiomer SR and less reactive enantiomer SS give two different enantiopure products PR and QS through competing reactions, which is called parallel kinetic resolution (PKR) (Scheme 5.3).4 Ideally, there should be an identical rate of parallel reactions maintaining 1:1 ratio of substrate enantiomers SR  and SS and affording products PR and QS with ee values that will depend on each reaction and a 50% theoretical yield for each product. Thus, PKR extends the process of conventional kinetic resolution by overcoming the limitation. The same efficiency can be reached when the s value is 49 in PKR, as when the s value is 200 in regular kinetic resolution. In conclusion, the following basic requirements necessary for a successful PKR process when the parallel reactions are a) totally independent without any mutual interference; b) with similar rate c) highly enantioselective; d) afford non-enantiomeric and easy separated compounds.4     SRkRPRkSSrackrac >> kR > kSPSSSkrackracÐ1!&&-!Scheme 5.3  Parallel kinetic resolution of a racemic compound  5.1.1 Chemodivergent PKR Based on the structural relationship of both products, the processes of PKR can be chemodivergent, regiodivergent and stereodivergent.5 In the chemodivergent PKR, the reactions yield two non-isomeric products. The early studies gave some examples of PKR that afforded two completely different compounds, however, one of them was useless due to the formation of a non-chiral molecule. A typical example is from the work done by Michael Doyle and his co-workers who reported a catalytic PKR that was found during the study of the intramolecular cyclopropanation of racemic cyclic allylic diazoacetate 227.6 With the chiral catalyst dirhodium(II) carboxamiate Rh2(4S-MEOX)4 228, the S-enantiomer of substrate gave the desired cyclopropanation product 229 in 94% ee, while the R-enantiomer surprisingly afforded a non-chiral cyclic unsaturated ketone 230 (Scheme 5.4). However, in most reported cases of chemodivergent PKR, a pair of pseudoenantiomeric reagents was used to afford two pseudoenantiomeric products possessing all the stereocenters with the opposite chirality and differing at a remote position. Vedejs, et al. reported the first application of this strategy in a magnesium bromide mediated acylation of 1 equivalent racemic 1-arylethanol 232 with two chiral DMAP-derived salts 231a and 231b (0.55 equiv), yielding the corresponding trichloro-tert-butyl carbonate 233a and SRkPRPRkQSSracQSSS+PS+QRkQRkPSkPR = kQS >> kPS = kQR[SR]/[SS] = 1!&&.!fenchyl carbonate 233b both in 95% ee after a complete conversion (Scheme 5.5).4 In this process, trichloro-tert-butyl DMAP-derived salt 231a formed a Òmatched-pairÓ with (S)-232 and fenchyl DMAP-derived salt 231b was the matched pair with (R)-232 respectively. Scheme 5.4  PKR affords non-chiral compound  Scheme 5.5  PKR affords pseudoenantiomeric compounds  ORh2(4S-MEOX)4(1 mol%)ON2ORh2(4S-MEOX)4(1 mol%)OOHOOHONOCO2MeRhRh4Rh2(4S-MEOX)4ORh2(4S-MEOX)4(1 mol%)ON2ORh2(4S-MEOX)4(1 mol%)40%, 94% ee40%Z = O, CH2230227228229229230227NNMe2t-BuOOCl3COMeArOHNNMe2t-BuOOOBnArOHmatchedmatchedmis-matchedArOOOCCl3ArOOO231a231b(S)-232(R)-232233a233bMgSO4 (2.25 equiv.), Et3N (3.0 equiv.)CH2Cl2, rt. 36 h95% ee95% ee!&'/!In a recent example of chemodivergent PKR, the catalytic process has been reported to afford two different enantioenriched compounds via dramatically different reaction pathways.7 A beautiful application of chemodivergent PKR was reported by Davies and his co-workers as the key step in the total synthesis of (Ð)-colombiasin A 239. With the catalysis of Rh2(R-DOSP)4 236 and the presence of carbene precursor 235, (R)-enantiomer of compound 234 gives a cyclopropane 237a, while the (S)- enantiomer of compound 234 undergoes C-H activation/Cope rearrangement to afford compound 237b. To separate the PKR products, the mixture was hydrogenated and reduced by LiAlH4 to isolate the desired terminal alcohol 238b as the synthetic intermediate on the way to colombiasin A 239 in 34% overall yield as a single distereoisomer with >95% ee (Scheme 5.6).7b                !&'&!Scheme 5.6  Chemodivergent PKR in the total synthesis of (Ð)-colombiasin A  5.1.2 Regiodivergent PKR The regiodivergent PKR includes substrates containing the same reactive functional groups but at different positions, or one functional group with two reactive sites, or even two different functional groups with similar reactivities.8 Several examples have been described with Sharpless asymmetric epoxidation of allylic secondary alcohols. Zhou, et al. have studied the Sharpless epoxidation of unsymmetrical divinyl methanols 240 which yielded a mixture of epoxides 241a and 241b with decent enantiopurity (Scheme 5.7a).8a Honda, et al. studied the Sharpless epoxidation of 2-MeOMeTBSOTBSOMe+MeOMeTBSOTBSOMeMeO2CN2Rh2(R-DOSP)4(2 mol%)rt. 1.5 hMeOMeTBSOTBSOMeHHCO2Me+MeOMeTBSOTBSOMeHMeO2CMe1) 10 mol% Pd/CH2, EtOH2) LiAlH4 (3.0 equiv)THF, 0 ¡C to rt.MeOMeTBSOTBSOMeHHOH+MeOMeTBSOTBSOMeHMeHO>95% ee34% (68%)over 3 stepsHOMeOOMeMeHMeHcolombiasin ANSO2ArOORhRh4Ar =C12H25(S)-234(R)-234+235236237a237b238a238b239!&''!furylmethanol bearing an alkenyl moiety 242 resulted in the formation of epoxide 243a and the rearrangement product pyranone 243b  (Scheme 5.7b).8b Scheme 5.7  Regiodivergent PKR in Sharpless epoxidation  Fu, et al. reported the kinetic resolution of 4-alkynals by a chiral cationic rhodium bisphospine catalyzed intramolecular hydroformylation of a triple bond, which highlighted the impact of the ligand on the efficiency of the kinetic resolution. The highly regioselective alkyne insertion of cationic (Tol-BINAP)Rh+ species with the two enantiomers of substrate 244 led to the formation of two different enones 245a and 245b with high enantioselectivity (Scheme 5.8).8c An example of regiodivergent PKR involving different functional groups was reported by Feringa, et al. that involved treatment of the vinyloxiran 248 with dialkylzinc catalyzed by a copper complex of chiral phosphoramidite 250 which yielded two regioisomeric alcohols 249a and 249b in 99% ee (Scheme 5.9). The allylic alcohol 249a was formed via a SN2Õ mechanism while the homoallylic alcohol 249b was formed by SN2.8d     OHRR = n-Hex, n-Bu, PhL-(+)-DIPTTi(Oi-Pr)4TBHPOHRO+OHROOOHL-(+)-DIPTTi(Oi-Pr)4TBHPOOHO+OOOHab240241a241b242243a243bup to 28%, 95% eeup to 22%, 95% ee!&'(!Scheme 5.8  Regiodivergent PKR in catalytic hydrofomylation  Scheme 5.9  Regiodivergent PKR in C-C bond formation  5.1.3 Stereodivergent PKR PKR processes can also be stereodivergent that yield a pair of Z/E isomers or diastereomers. The Z/E selectivity in PKR usually happens through the formation of C-C double bond in an asymmetric Wittig-type reaction. Rein, et al. reported a Z/E-divergent PKR by an asymmetric Horner-Wadsworth-Emmons (HWE) reaction where each enantiomer of the Diels-Alder acrolein dimer 251 yields different geometric isomers of the (E)- and (Z)-olefins in compound 253 (Scheme 5.10).9a The stereodivergent PKR can also be involved in the process that a new chiral center forms in the molecule, which already possesses a stereocenter. For example, Gotor, et al. carried out the bioreduction of racemic 1-methyl-2-oxocycloalkanecarbonitrile 254 by the HOPhOMe[Rh(R-Tol-BINAP)]BF4(5 mol%)CH2Cl2, rt.OOMePh+OPhOMeLnRhOPhOMeHLnRhHPhOOMeLnRhPhHOOMe244245a245b247a246247b47%, 84% ee45%, 88% eeOROH+OHRR2Zn (1.5 equiv)1.5 mol% Cu(OTf)23 mol% (R,R,R)-250CH2Cl2, Ð78 ¡C to Ð10 ¡C, 3 hOOPNMeMePhPh(R,R,R)-250248249a249b49%, 96% ee51%, 92% ee!&')!fungus M. isabellina, yielding a mixture of hydroxynitrile diastereomers (1R,2S)- and (1S,2S)-255, which could be re-oxidized by PCC to afford each enantiomer of starting material 254 (Scheme 5.11).9b Scheme 5.10  Stereodivergent PKR in an asymmetric HWE reaction  Scheme 5.11  Stereodivergent PKR of "-keto nitriles  5.2 Literature Work on !-Ketol/#minol Rearrangement 5.2.1 !-Hydroxy Ketones and Aldehydes Since the adjacent carbocation triggered 1,2-rearrangement was first described by Fittig in 1860 (Scheme 5.12a) 10, more rearrangement reactions with !-hydroxy aldehydes and ketones involving cations were discovered with similar mechanisms. Treatment of !-ketols with a base, a Br¿nsted acid, a Lewis acid or even heat will arouse the 1,2-shift of an alkyl or aryl substituent to afford an isomeric compound (Scheme 5.12b).  OOH+OO(RO)2POPhOOOPh+OOOPh251252(E)-253a(Z)-253bKHMDS18-crown-6THFOCNM. isabellinaOHCNOHCN+PCCPCCOCNOCN254(1R,2S)-255(1S,2S)-255(R)-254(S)-254!&'*!Scheme 5.12  Pinacol and !-keto rearrangement  There is less synthetic utility for the rearrangement of acyclic !-ketols, since an equilibrium is usually exists between the two isomers. Efforts have been made to investigate the relative stability of isomers, which was believed to be on the basis of conventional electronic effects, however, more cases have shown there are additional factors which may determine the outcome (Scheme 5.13).11 The !-keto rearrangement is more synthetically useful in the rearrangement of cyclic !-ketols as the ring strain release acts as a driving force to undergo ring expansion in small ring systems (Scheme 5.14a).12a Also, the larger cyclic !-ketol 259 irreversibly contracts to the cyclohexanol 260 under basic conditions (Scheme 5.14b).12b, c  The thermodynamically-controlled !-hydroxy aldehyde rearrangement is unidirectional progressing from the !-hydroxy aldehyde 261 to an !-hydroxy ketone 262 (Scheme 5.15a).13a The thermodynamic advantage associated with the ketone is also highlighted by the ring expansion from 1-hydroxycyclohexanecarboxaldehyde 263 to 2-hydroxycycloheptanone 264 in 80% yield (Scheme 5.15b).13b A common example of the synthetic utility of the !-hydroxy aldehyde rearrangement is the D-homoannulation of a steroid 265 when exposed to silica gel, heat or a Lewis acid(Scheme 5.15c).13c HOOHPhPhPhPhHPhOPhPhPha   pinacol rearrangementb    !-keto rearrangementR1XOHR2R3acid, base orheatXHR3OR1R2X = O, NR'          R1 = alkyl, aryl, HR2 = alkyl, aryl    R3 = alkyl, aryl, H!&'+!Scheme 5.13  Acyclic !-ketol rearrangement  Scheme 5.14  Cyclic !-ketol rearrangement  Scheme 5.15  !-hydroxy aldehyde rearrangement    PhOOHRMeOHMeORPhHOORR1R2OOHR1R2R R              R1              R2            %AÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐn-Pr         n-Pr             Ph             10Me            Me             Cy             40255256ABAl(Ot-Bu)3, tolueneEtOOHOHOOHEtaOOHRPb(NO3)2OHROb257258259260HOOHPhPMPKOH, MeOHor heatOMeOPhOHOHHOH+, EtOHrefluxOOHabHOHOMeOHHHsilica gel or heator BF3¥Et2OMeOHHOHHOc26126226326426526646%52%up to 80%!&',!5.2.1 !-Hydroxy Imines (!-Iminols) The first example !-iminol rearrangement was reported by Schoppee and Prins in 1943 (Scheme 5.16) that the reaction was promoted by heat.14a, there were lots of literature reports on the thermal rearrangement of !-iminols as the early work. The investigation on the mechanistic study has shown the thermal !-iminol rearrangement was unidirectional and concerted.14 Scheme 5.16  The first example of !-hydroxy imine rearrangement  More approaches have been explored for the catalytic !-iminol rearrangement such that Br¿nsted acids, Lewis acids and Br¿nsted bases are commonly found in the literature. For example in weak bases such as imines (pKa 4-5), the C=N double can be activated by strong Br¿nsted acids such as HCO2H, TFA, H2SO4, p-TsOH, etc. promoting the migration of alkyl and aryl substituents. The Br¿nsted acid-catalyzed rearrangement of 3H-indol-3-ol 269 has been studied a lot since indol-3-ones are potentially useful intermediates in the synthesis of alkaloids and pharmaceuticals (Scheme 5.17a). The relative reactivity of migration substituents have been studied by McWhorter, Jr. et al. and they shown an increasing trend of migration in the order of CH3, 1¡, 2¡, 3¡ alkyl, vinyl, allyl, phenyl and benzyl.15a Movassaghi, et al. reported a beautiful application in the total synthesis of (Ð)-trigonoliimine C 273 with 3H-indol-3-ol rearrangement as the key step (Scheme 5.17b).15b HONMeOHHHHPhheatMeOHHHHNHPhO267268!&'-!Imines are good Lewis bases and easy to be activated by Lewis acids. This process is quite similar to iminol activation by Br¿nsted acids. In Particular, there are several examples of !-iminol rearrangement involving an iminium intermediate formed by organometallic Lewis acid catalysis. Sarpong, et al. reported a trans-metalation/!-iminol rearrangement cascade reaction of a pyridine with a tethered propargyl alcohol as in compound 274 (Scheme 5.18).16 The cyclization to the pyridine was achieved by trans-aminoplatination of the alkyne to form the indolizinium intermediate 275, followed by a stereoselective Wagner-Meerwein shift of ethyl group to afford the indolizinone product 276.  Scheme 5.17  Br¿nsted acid promoted of !-iminol rearrangement  Scheme 5.18  !-Iminol rearrangement via an iminium intermediate  NHORArHCO2HtolueneR = Me, 1¡, 2¡, 3¡ alkyl, vilyl, allyl, Ph, BnNHORAraNNHONPhthPhthNOMeTFE100 ¡C93%NNHOMePhthNOPhthNNNNHHNHOOMe(Ð)-trigonoliimine Cb269270271272273NNn-BuOH5 mol% PtCl210 mol% Cs2CO3Pt-Bu2t-Bu2P10 mol%OH[Pt]n-BuNn-BuO97% ee27427527640%!&'.!The acidic property of the hydroxyl group may allow for the activation of an !-iminol by deprotonation with base to promote the 1,2-shift. Lu, et al. reported a base-triggered 1,5-phenyl migration of imidazol-4-ol 277. The stereoselectivity of migration was investigated for each enantiomer of substrate that afforded totally opposite stereochemical configurations of imidazol-4-one products 278, which indicates that 1,5-phenyl migration happens through concerted pathway via an intramolecular three-membered ring (Scheme 5.19).17 Scheme 5.19  Stereoselective base-promoted !-iminol rearrangement  Most !-iminol rearrangement reactions reported in the literature are unidirectional and irreversible, but there are sevel examples involving the reverse reaction from an !-amino ketone to corresponding !-iminol. Nagase and his co-workers reported an example of interconversion between a hydroxyindolenine 279 and a spiroindolinone 280 (Scheme 5.20).18 They reported the base-promoted !-iminol rearrangement of hydroxyindolenine 279 to afford a spiroindolinone 280. They could also convert the spiroindolinone 280 X = F, OMeNNPhOHCF3XNNPhOHCF3XbaseDMSONNPhOXCF3baseDMSONNPhOXCF3NHNPhOCF3XNHNPhOCF3X>92% ee(S)-277(R)-278(R)-277(S)-278!&(/!back to the hydroxyindolenine 279 by treatment with a Lewis acid. This reveral is apparently favored by the ring-stress release from the spiro-ring to the bridged ring. Scheme 5.20  Interconversion between a !-iminol and a !-amino ketone  5.3 Asymmetric Catalytic Rearrangement with Non-Chiral !-#minols The literature examples of asymmetric catalytic !-iminol rearrangement are rare. Frongia and his co-workers have reported the synthesis of an optically active amino ketone via one-pot iminol synthesis/asymmetric imine-enamine tautomerization (Scheme 5.21).19 They investigated the raction of acetoin with p-anisidine, using the chiral bifunctional amino alcohols as the catalysts. The "-isocupreidine was screened as the optimal catalyst to afford the corresponding amino ketone in 95% yield and 71% ee. Scheme 5.21  One-pot catalytic asymmetric rearrangement of !-hydroxy ketones with anilines  Xin Zhang in our research group developed an effective strategy for Zr-catalyzed asymmetric !-iminol rearrangement in 2014.20 The background reaction can be effectively catalyzed by Lewis acids to afford high conversions of the !-iminols. In the study to search for the most effective asymmetric catalyst, the BOROX catalyst 71a with NNOHOHOMeDBUBCl3NOHOMeNHO279280OHO30 mol% 282p-anisidinetoluene, rt.OHNOMeNNOHOH95%, 71% ee281282283!&(&!different ligands were examined but resulted in poor enantioselectivity (Table 5.1, entry 1). Considering that the similarity of the N,O-bifunctional units in the substrates from the previously published work on Mannich reaction of imine 290 to "-amino ester 291 indicates a possible way that a !-imino could interact with the zirconium catalyst (Scheme 5.22).21 Thus, the VANOL-derived zirconate catalyst 289 was examined and found to be remarkably effective in asymmetric induction of the amino ketone 287a with 97% ee (Table 5.1, entry 2). However, replacement of VANOL with VAPOL or BINOL gives a catalyst which fails to promote the enantioselectivity (Table 5.1, entry 3,4). Table 5.1  Catalyst screen for !-iminol rearrangement20  entry catalyst ligand yield% ee% 1 boroxinate (S)-VANOL 60 17 2 zirconate (S)-VANOL 96 97 3 zirconate (S)-VAPOL 86 28 4 zirconate (S)-BINOL 66 10         EtOOEtOEtO1) PhMgBr2) HClHOOHPhPhPhNH2HNOHPhPhPh5% catalysttoluene, 60 ¡C, 1 hPhPhONHPhPhPhOOBOBOBOOPhOPh(S)-VANOL BOROX 71aOOZrOO(S-BINOL)2Zr 288PhPhOOZrPhPhOONN(S-VANOL/VAPOL)2Zr(NMI) 289284285286a287a!&('!Scheme 5.22  Zr-catalyzed Mannich reaction21  A single crystal of the VANOL zirconate catalyst was obtained and its solid state structure was analyzed by X-ray crystallography (Figure 5.1). It was revealed that the zirconium complex was homoleptically hexacoordinated with three VANOL ligands and the charge balanced by two protonated N-methyl imidazolium cations. The protonated imidazolium cations are not directly H-bonded to the oxy-zirconium core. Instead, a molecule of water interacts between each imidazolium cation and zirconate dianionic core by H-bonding. This is the first example of homoleptic zirconium complex with three bis-phenol ligands, although a number of rare earth complexes with three BINOL ligands have been reported but not for zirconium.22 However, the experimental evidence shows that it might be that the zirconium complex is a different species in solution and solid state. The single crystals were grown from a 1:2:1 mixture of Zr/ligand/NMI, which was the catalyst composition proposed in Mannich reaction, but actually the X-ray analysis shows a compose of 1:3:2 ratio. In addition, an in-situ generated catalyst from a 1:3:2 mixture of Zr/ligand/NMI gave a similar yield and enantioselectivity for the amino ketones as the catalyst generated from a 1:2:1 mixture. PhNHO+OTMSOMe40 mol% (S)-VAPOL20 mol% Zr(OiPr)4¥i-PrOH20 mol% NMItoluene, temp.PhOMeONHOHZrOOOO*NN*PhNOHZrOOOO*NN*PhNOHHPhPh100%, 98% ee29034291!&((!This indicated there could be a difference in the structure of the zirconium complex in  the solid state and the solution form.  Figure 5.1  Single crystal structure of VANOL zirconate in the solid state20   Although the interactions between the catalytic zirconate species and the !-iminol substrates still remains unclear, it is possible that the dissociation of one of the VANOL ligands from zirconium can happen during the reaction process, which leaves room for the substrate to access the catalyst. Several possibilities have been proposed for the !-iminol activation with the zirconium complex (Scheme 5.23): a) both nitrogen and oxygen of an iminol were H-bonded to the tris-VANOL zirconium which functions as a Lewis acid-assisted chiral Br¿nsted acid catalyst; b) one of the oxygens is dissociated from the tris-VANOL zirconium to give a combined Br¿nsted/Lewis acid activation of an iminol, with the alcohol coordination with zirconium and the imine nitrogen H-bonded with the free VANOL hydroxyl group; c) one of the VANOL ligands is totally dissociated to afford a charge-neutral bis-VANOL zirconate which functions as a Lewis acid catalyst with bidentate coordination of the iminol nitrogen and oxygen.    ZrOOOOOO***HOHHOHNNNN2Ð!&()!Scheme 5.23  Proposed possible iminol activation by VANOL zirconium complex  5.4 Asymmetric Catalytic Rearrangement with Racemic !-#minols 5.4.1 Non-chiral Iminols vs Racemic Iminols In Xin ZhangÕs work, all substrates are non-chiral and contain two identical alkyl or aryl groups that are under migration. The amino ketones were obtained as the single product of the reaction with an excellent enantiomeric induction (Scheme 5.24a, Table 5.1). We became interested in investigating the asymmetric catalytic rearrangement of !-iminols with two different groups that have the potential to migrate during the rearrangement process. The chemistry will be much more complicated than that with non-chiral !-iminols since it is difficult to predict that which group will migrate with the higher priority. For an optically pure substrate, the outcome will depend on the difference of migration rates between two groups R1 and R2. If R1 migrates much faster than R2 (k1>>k2), the rearrangement will afford a single product by R1 migration only. But if the rate selectivity is not great enough for R1 and R2, a mixture of amino ketone isomers would be expected as the products of rearrangement.  However, the reaction pathways of the two enantiomers could be different and lead to different asymmetric catalytic inductions in the rearrangement of a racemic substrate. Kinetic resolution will occur when one of the !-iminol enantiomers SR reacts much faster than the other enantiomer SS, while the selectivity of two amino ketone isomers would ZrOOOOOO***2ÐNOHPhPhPhHZrOONOOO**HHPhPhPhHZrOOOOOO***ÐOHNPhPhPhHHabc!&(*!still depend on the migration rate differential of the two groups. Thus, the reaction could afford three produtcs; two amino ketone isomers and unreacted substrate enantiomer SS with a 50% conversion of the starting material (Scheme 5.24b). On the other hand, a PKR effect will be expected when there is no great gap in the reaction rates between the two of the substrate enantiomers. For example, R1 migration affording amino ketone P is favored with the substrate enantiomer SR but disfavored with SS. And R2 migration affording Q is favored with SS but disfavored with SR. The better selectivity of R1 and R2 migration with both enantiomers will give higher enantioselectivity of amino ketones products. As the result, the reaction can give a 100% conversion of a racemic !-iminol to afford a pair of optically pure amino ketone regioisomers (Scheme 5.24c). Scheme 5.24  The asymmetric catalytic rearrangement of !-iminols: a. Rearrangement of a non-chiral !-substrate; b. Kinetic resolution pathway in the rearrangement of a racemic !-iminol; c. Parallel kinetic resolution in the rearrangement of a racemic !-iminol     HNPhOHRRZr(S-VANOL)2(NMI)tolueneRNHPhORaHNPhOHR1R2R1NHPhOR2bR2NHPhOR1+k1k2HNPhOHR2R1HNPhOHR1R2R1NHOR2Ph+R1NHOR2PhR2NHOR1PhR2NHOR1Ph+Zr(S-VANOL)2(NMI)SRSSPRPSQRQScZr(S-VANOL)2(NMI)tolueneHNPhOHR2R1Zr(S-VANOL)2(NMI)tolueneSRSSS!&(+!5.4.2 Initial Studies on the Rearrangement of Racemic !-Iminols The initial studies investigated the kinetic resolution of the !-iminol rac-286b with a phenyl and a cyclohexyl substituent, which was treated with zirconium catalyst 289 prepared by one equivalent of zirconium isopropoxide, two equivalents of (S)-VANOL ligand 68a and one equivalent of N-methylimidazole (NMI) with 2.5% catalyst loading (Table 5.2, entry 1). The reaction was quenched at the 50% conversion of the starting material after 12 h, which afforded a mixture of amino ketone regioisomers 287b from cyclohexyl migration and 287bÕ from phenyl migration. Amino ketones 287b and 287bÕ could not be separated by column chromatography due to similar polarities, and the yield of each regioisomer was determined by the NMR studies of the isolated mixture. The ratio of regioisomers 287b and 287bÕ was determined as 3:1 with amino ketone 287b as the major product which indicates that cyclohexyl migration is faster than phenyl migration. The enantiomeric purity of the major amino ketone 287b was significantly high with greater than 99% ee. A change of Zr/ligand/NMI ratio to 1:3:2 in the catalyst preparation, which mirrors the same composition of Zr-catalyst in the crystal state, gave similar 3:1 regioselectivity of amino ketone 287b and 287bÕ (Table 5.2, entry 2). When the catalyst loading was increased from 2.5% to 5%, the reaction was much faster and reached a 49% conversion of substrate 286b in 7 h (Table 5.2, entry 3), and in addition the regioselectivity of amino ketone isomers 287b and 287bÕ was improved to 5:1. The asymmetric inductions of both products was extremely high with 99% ee for amino ketone 287b and 95% ee for amino ketone 287bÕ. Meanwhile, the enantioenriched !-iminol 286b was recovered and hydrolyzed to the corresponding !-hydroxy aldehyde 292b with for the enantiomeric purity determination, since the !-iminol 286b !&(,!decomposes during column chromatographic isolation. The enantiomeric purity of !-hydroxy aldehyde 292b is relatively poor which indicates a low efficiency of kinetic resolution. Table 5.2  Initial studies on kinetic resolution of !-iminol rac-286b a  entry cat. time/h conv.% b (S)-292b 287b 287bÕ 287b:287bÕ e yield% c ee% d yield% b ee% d yield% b ee% d 1 289a 12 50 42 64 37 >99 12 nd 3.1:1 2 289b 12 48 46 58 35 >99 11 nd 3.2:1 3 289a f 7 49 37 60 39 >99 7.5 95 5.2:1 a Unless otherwise specified, the reaction was run by the racemic !-iminol 286b of 0.4 M concetraction in toluene with 2.5% Zr-catalyst loading. The catalyst was prepared by Zr(Oi-Pr)4!i-PrOH, (S)-VANOL and NMI of 0.05 M in toluene resulting a fine suspension. b Determined by the 1H-NMR spectrum of the crude reaction mixture with an internal standard. c isolated yield. d Determined by HPLC. e Determined by the 1H-NMR spectrum of the crude reaction mixture. f 5% Zr-catalyst loading. Since there was only small amount of amino ketone 287bÕ produced as the minor product in the rearrangement of !-iminol rac-286b and since the regioisomers could not be separated, it was necessary to obtain the pure compound 287bÕ by a different method to confirm its structure. The synthesis of compound 287bÕ started from phenylacetyl chloride 293, which could be converted to ketone 294 upon treatment with cyclohexylmagnesium chloride catalyzed by cuprous chloride. Benzylic bromination of ketone 294 afforded !-bromo ketone 295 which was followed by the coupling with p-anisidine in the presence of base to give the desired compound 287bÕ (Scheme 5.25).    PMPNHOHPhtoluene, 40 ¡CPMPNHOHPhCyPhONHPMPOHOHPhHClTHF, rt. 20 min+PhCyONHPMP+2.5% Zr-(S-VANOL)-NMICyCyrac-286b(S)-286bCy(S)-292b287b287b'PMP = para-methoxyphenylZr(S-VANOL)2(NMI) 289aZr(S-VANOL)3(NMI)2 289b!&(-!Scheme 5.25  Synthesis of amino ketone 287bÕ as the minor product in !-iminol rearrangement  To improve the s value of the kinetic resolution, a number of VANOL derivative ligands 68 were screened to investigate their effect on the rate differential of two enantiomers of the racemic substrate 286b (Table 5.3). The results reveal that the ligands can significantly effect the ee of both amino ketones 287b and 287bÕ, the ratio of the amino ketone regioisomers and the ee of recovered !-iminol 286b at around 50% conversion. As these results completely depend on the progress of the reaction, all the experiments were quenched within a narrow range of substrate conversions around 50% (44-53%). The reaction times for the 50% conversion vary a lot among the ligands, but it does not seems directly related to the degree of kinetic resolution. The ee of recovered !-iminol 286b directly reflects the efficiency and is positively correlated to the ratio of amino ketone regioisomers. For example, VANOL ligand 68a gives 60% ee of !-iminol 286b with the ratio 287b:287bÕ as high as 5.1:1 (Table 5.3, entry 1). However, 7,7Õ-dimethoxy VANOL 68d gives only 33% ee of !-iminol 286b and a 2.6:1 regioselectivity (Table 5.3, entry 3). Finally, the rearrangement gives excellent enantiomeric purity for both amino ketone isomers with all either ligands (>87% ee).   PhClOCyMgCl, CuClEt2O, Ð40 ¡C, 1 hPhO294293LDA, NBSTHF, Ð78 ¡C, 1.5 hPhO295Br52%54%p-anisidineEt3N, DMAPCH2Cl2, rt. 10 hPhO287b'NHPMPCy93%!&(.!Table 5.3  Ligand screening for kinetic resolution of !-iminol rearrangement a  entry ligand time/h (S)-286b 287b 287bÕ 287b:287bÕ d yield% b ee% c yield% b ee% c yield% b ee% c 1 68a 7 51 60 39 >99 7.5 95 5.1:1 2 68c 24 47 61 39 >99 10 97 3.9:1 3 68d 8 51 33 36 87 14 94 2.6:1 4 68e 14 52 60 40 90 9.4 95 4.3:1 5 68f 5.5 44 41 30 >99 14 99 2.1:1 6 68g 1.5 45 54 40 99 16 91 2.5:1 7 68h 23 48 41 40 93 17 >99 2.4:1 8 68i 38 53 58 41 96 8.1 >99 5.1:1 a Unless otherwise specified, the reaction was run by the racemic !-iminol 286b of 0.4 M concetraction in toluene with 5% Zr-catalyst loading at 40 ¡C. The catalyst was prepared by Zr(Oi-Pr)4!i-PrOH (1 equiv), (S)-VANOL derivatives 68 (2 equiv) and NMI (1 equiv) of 0.05 M concentraction in toluene. b Determined by the 1H-NMR spectrum of the crude reaction mixture with an internal standard. c Determined by HPLC. d Determined by the 1H-NMR spectrum of the crude reaction mixture. That the best ee for recovered !-iminol 286b was only 60% with the VANOL ligand 68a indicates that there is poor efficiency of kinetic resolution (Table 5.3, entry 1). However, in contrast it is noticed that both amino ketone regioisomers 287b and 287bÕ are formed with a significantly high asymmetric induction of 99% ee with with 7,7Õ-dicyclohexyl VANOL ligand 62f (Table 5.3, entry 5). Further studies focused on the catalytic rearrangement with a 100% conversion of the racemic !-iminols to investigate the PKR effect since the two product amino ketone regioisomers are generated and indicate the possibility of parallel reactions involved in the process. The Zr-catalyzed rearrangement of four racemic !-iminols with a phenyl and four different alkyl substituents has been examined with catalysts generated from VANOL 68a and Cy2VANOL 68f ligands (Table 5.4). It was found that the racemic !-iminols with an ethyl, butyl and cyclohexyl groups afforded close to a 1:1 mixture of highly enantiometic pure amino ketone regioisomers with a 100% conversion of substrates HNOHPhCyPMP5% Zr-catalysttoluene, 40 ¡CCyNHPhPMPO+PhNHCyPMPOHNOHPhCyPMP+(S)-286b287b287b'ArArRROHOH68a R = H, Ar = C6H568c R = t-Bu, Ar = C6H568d R = OMe, Ar = C6H568e R = F, Ar = C6H568f R = Cy, Ar = C6H568g R = 4-tBuC6H4, Ar = C6H568h R = Me, Ar = C6H568i R = H, Ar = 4-FC6H4rac-286b!&)/!(Table 5.4, entry 3-7). However, in the rearrangement of the !-iminol with a methyl group, the phenyl migration product was the major isomer with around 1.5:1 regioselectivity, which is opposite to the regioselectivity seen in the experiments in Table 5.3 and indicates an unusual PKR process involving in the rearrangement of the methyl-substituted !-iminol. The er of the two products are dramtically different with the minor methyl migration product formed with significantly higher er up to 99:1, but the major phenyl migration product was obtained with much lower enantiomeric purity (Table 5.4, entry 1, 2). The reaction with the Cy2VANOL ligand 68f gave excellent enantiomeric purity for both amino ketones from the cyclohexyl-substituted !-iminol (Table 5.4, entry 7), but the same ligand was not as good as VANOL 68a for all the other substrates. Table 5.4  Zr-catalyzed rearragement of !-iminols a  entry R ligand R migration 287 Ph migration 287Õ yield% b erc yield% b er c 1 Me 68a 33 98.5:1.5 48 75.5:24.5 2 Me 68f 30 99:1 51 65.5:34.5 3 Et 68a 48 96.5:3.5 47 97:3 4 Et 68f 33 96:4 35 90:10 5 Bu 68a 46 96.5:3.5 46 98:2 6 Cy 68a 53 d 94:6 44 d 99:1 7 Cy 68f 42 d 99.5:0.5 42 d 99.5:0.5 a Unless otherwise specified, the reaction was run by the racemic !-iminols 286 of 0.4 M concetraction in toluene with 5% Zr-catalyst loading at 40 ¡C for 24 h. The catalyst was prepared by Zr(Oi-Pr)4!i-PrOH (1 equiv), (S)-VANOL derivatives 68a or 68f (2 equiv) and NMI (1 equiv) of 0.05 M concentraction in toluene. b Isolated yield. c Determined by HPLC. d Determined by the 1H-NMR spectrum of crude reaction mixture with an internal standard. The two amino ketone regioisomers are separable for the rearrangement of all of the !-iminol substrates except the cyclohexyl-substituted !-iminol rac-286b. A bulky Fmoc group was introduced in the amino ketones 287b and 287bÕ to better separate the HNOHPhRPMP5% Zr-catalysttoluene, 40 ¡C, 24 hRNHPhPMPO+PhNHRPMPO287287'rac-286PhPhOHOHPhPhOHOH68a68f!&)&!regioisomers (Scheme 5.26). The phenyl migration amino ketone 287bÕ gave a 100% conversion to Fmoc-substituted product 296Õ while the reaction of cyclohexyl migration amino ketone 287bÕ was sluggish with an 81% conversion to the Fmoc-substituted product 296. Meanwhile, slight drop in the enantiometic purity was observed for the phenyl migration amino ketone 296Õ (99:1 vs 95:5 er) due to partial racemization of the benzylic position in the presence of base. This is supported by the evidence that the reaction was heated up to 60 ¡C resulting in the decrease of enantiometic purity of amino ketone 296Õ without any improvement in the conversion of amino ketone 287b. Scheme 5.26  Synthesis and Separation of Fmoc-amino ketone regioisomers 296 and 296Õ   5.4.3 Mechanistic Studies on the PKR in the !-Iminol Rearrangement To help to understand the mechanism of PKR in the rearrangement of racemic !-iminols, itÕs necessary to make clear the stereochemistry involved in the migration for either the phenyl or alkyl group with the asymmetric induction of the chiral zirconium catalyst. In order to confirm the absolute stereochemistry of the amino ketone products, both amino ketone regioisomers 287c and 287cÕ were synthesized with the (R)-configuration. The synthesis of the phenyl migration amino ketone (R)-287cÕ starts from (R)-phenylglycine methyl ester 297 which undergoes C-N bond coupling to give a PMP-amino substituent in compound 298. The amino ketone (R)-287cÕ was obtained by the Weinreb ketone synthesis by treatment of the WeirebÕs amide derived from compound 298 with methyl magnesium bromide and gave a product with a negative optical rotation, which allows the CyNPhOPMPPhNCyOPMP+THF, rt. 60 hFmocFmoc+CyNHPhOPMP77% from 287b94:6 er89% from 287b'95:5 er19% recoveryFmocCl (2.0 equiv.)NaHCO3 (3.0 equiv.)CyNHPhOPMPPhNHCyOPMP+0.094 mmol, 94:6 er0.076 mmol, 99:1 er287b287b'287b296296'!&)'!assignment of the product 287cÕ from the (S)-VANOL catalyst as the (R)-enantiomer (Scheme 5.27a). On the other hand, in the synthesis of the methyl migration amino ketone (R)-287c, (1R,2S)-norephedrine 299 was the starting material and coupling with 4-bromoanisile to afford compound 301, which was in turn converted to the target (R)-287c by the Swern oxidation and had a positive rotation (Scheme 5.27b). So the absolute stereochemistry of both amino ketone regioisomers 287c and 287cÕ was found to be (R)-configuration in the rearrangement of racemic methyl-substituted !-iminol 286c with the catalysis of (S)-VANOL zirconium complex (Scheme 5.27c).                   !&)(!Scheme 5.27  Synthesis of amino ketones 287c and 287cÕ with known stereochemical configurations  To further understand the PKR in the Zr-catalyzed rearrangement of racemic !-iminols, a set of parallel experiments were done to study the mechanism and stereochemistry involved in the reaction of the enantiomerically pure !-iminol (R)-286c with phenyl and methyl substituents, which was prepared in 95% ee from !-methylstyrene 302 over three PhNH2 ¥ HClOMeOPMP-B(OH)2 (2 equiv.)Cu(OAc)¥H2O (1 equiv.)4 † MS, CH2Cl240 ¡C, 24 hPhNHOMeO26%NHOMe¥HCl(2.5 equiv.)1)MeMgBr (5 equiv.)THF, Ð45 ¡C, 1 h2) MeMgBr (3 equiv.)THF, 0 ¡C, 15 minPhNHOPMP42% over 2 steps91% eem.p. 93-95 ¡C[!]20 = Ð194.3¡, c  1.0 in EtOAcNa2CO3 aq.Et2O, rt. 15 minMeOaPhOHNH2+BrOMe(1.5 equiv.)CuI (10 mol%)DMPAO (20 mol%)K3PO4 (2 equiv.)DMSO, 90 ¡C, 48 hPhOHHN59%HNHOOODMPAOOMe(COCl)2 (5 equiv.)DMSO (10 equiv.)Et3N (15 equiv.)CH2Cl2Ð78 to Ð40 ¡C, 5 hPhONHPMP100%[!]20 = +39.4 ¡, c 1.0 in EtOAc>99% ee297298(R)-287c'299301300(R)-287cbHNOHPh5% Zr(S-VANOL)2(NMI)toluene, 40 ¡C, 24 hNHPhO+PhNHOPMPPMP33%, 97% ee48%, 51% ee[!]20 = +32.9 ¡c 1.0 in EtOAc[!]20 = Ð58.3 ¡c 1.0 in EtOAc(R)-287c(R)-287c'PMPcrac-286c!&))!steps by the Sharpless dihydroxylation, IBX oxidation and imine synthesis (Scheme 5.28a). Dramatically different results were observed in the rearrangement of !-iminol (R)-286c with the (S)- or (R)-VANOL zirconium catalysts. With (S)-VANOL ligand, the rearrangement of (R)-286c afforded the methyl migration amino ketone (R)-287c as the major product in 79% yield and 96% ee and the phenyl migration amino ketone (S)-287cÕ as the minor product in 19% yield and only 33% ee. However, the reaction with rac-286c gave an opposite 1.5:1 selectivity of 287cÕ and 287c with both (R)-configuration under the same conditions (Table 5.4, entry 1). With the (R)-VANOL ligand, the phenyl migration amino ketone (S)-287cÕ was almost the only product in 76% yield and 78% ee from the rearrangement of (R)-286c, and only a small amount of 287c was detected, with surprisingly the same (S)-configuration in 24% ee (Scheme 5.28b). The relatively lower enantiomeric purity of amino ketone 287cÕ compared to that for amino ketone 287c is probably due to the partial racemization of benzylic position.             !&)*!Scheme 5.28  Catalytic rearrangement of !-iminol (R)-286c  As the rationalization of the results in the rearrangement of (R)-286c, it is proposed that the zirconium catalyst provides the chiral environment which is source of migratory between the two different substituents. It is believed that zirconium can be chelated by a nitrogen and an oxygen in an !-iminol that inhibits the rotation of C-C bond and locks the conformer in the complex consisted of substrate (R)-286c and Zr-catalyst. Theoretically, in the rearrangement of substrate (R)-286c, the Re-face migration of methyl group will be favored with the induction of (S)-VANOL to afford amino ketone (R)-287c, while on the other hand, the Si-face migration of phenyl group is favored with the induction of (R)-VANOL to the product (S)-287cÕ (Scheme 5.29a). However, the results shown in Scheme 5.26 indicates that the Si-face migration of the phenyl group could also occurs to a small NHOHMePhPMP5% Zr(S-VANOL)2(NMI)toluene, 60 ¡C, 18 hNHPhOPMP+PhNHOPMP5% Zr(R-VANOL)2(NMI)toluene, 60 ¡C, 36 h95% ee79%, 96% ee19%, 33% ee4%, 24% ee76%, 78% eeNHPhOPMP+PhNHOPMPIBX (3 equiv)CH2Cl2, rt. 5 hOHOHMePhOHOHMePhtoluene, rt. 12 h71%66%AD-mix !t-BuOH/H2Ort. 15 h40%, 97% eeNHOHMePhPMP95% ee302(R)-303(R)-304(R)-286c(R)-286c(R)-287c(S)-287c'(S)-287c(S)-287c'abp-anisidinepyrrolidine!&)+!extent in the reaction with (S)-VANOL since a 19% yield of (S)-287cÕ was generated. The Re-face migration of methyl group seems totally inhibited by (R)-VANOL since only a 4% yield of (S)-287c was generated from the small amount of (S)-enantiomer of the substrate 286c. An experimental error could occur given that the enantiometic purity of the substrate (R)-286c was 95% ee, a 2.5% yield of (S)-287c would be expected.  In addition, with the racemic substrate 286c, the (R)-enantiomer will undergo methyl migration to afford amino ketone (R)-287c while the (S)-enantiomer will give amino ketone (R)-287cÕ by phenyl migration, since Re-face migration is favored by the induction of (S)-VANOL (Scheme 5.29b). Considering that there is also a small amount of (R)-286c converting to amino ketone (S)-287cÕ by phenyl migration, it explains that (R)-286cÕ was the major product but with poor enantiomeric purity (Scheme 5.27c). But with a bulky alkyl substituent in a racemic !-iminol, phenyl migration will be greatly inhibited by the miss-matched ligand. Therefore, a perfect PKR with the asymmetric induction of the catalyst leads to a 1:1 mixture of amino regioisomers in a theoretical yield of 50% with significantly decent enantiomeric purity (Table 5.4, entry 3, 5, 6, 7). Scheme 5.29  Mechanistic rationalization of PKR in the !-iminol rearrangement   Zr*NOMePhPMPMe migrationRe-attack(S)-VANOLPh migrationSi-attack(R)-VANOLNHOMePMPPh(R)-287cNHOPhPMPMe(S)-287c'(R)-286cNOHMePhPMP50%(R)-286cNOHPhMePMP50%(S)-286cNHOMePMPPh(R)-287cNHOPhPMPMe(S)-287c'NHOPhPMPMe(R)-287c'NHOMePMPPh(S)-287cRe-migrationRe-migrationSi-migration>50% yieldlower ee%<50% yieldbetter ee%Zr(S-VANOL)2(NMI)ab!&),!       REFERENCES   !&)-!REFERENCES  1. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249. 2. For typical kinetic resolution: a) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492; b) Martin V.; Woodard, S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237; c) Gao, Y.; Klunder, J. M.; Hanson, R. 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Chem. 2003, 1931; f) Mordant, C.; Ratovelomanana-Vidal, V.; Dkelmann, P.; Gen’t, J-P. Eur. J. Org. Chem. 2004, 3017; g) Lee, S. Y.; Murphy, J. M.; Ukai, A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 15149. 4. Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584. 5. Dehli, J. R.; Gotor, V. Chem. Soc. Rev. 2002, 31, 365. 6. Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D. A. J. Am. Chem. Soc. 1995, 117, 11021. 7. a) Tanaka, K.; Hagiwara, Y.; Hirano, M. Angew. Chem. Int. Ed. 2006, 45, 2734; b) Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485. 8. a) Yang, Z-C.; Jiang, X-B.; Wang, Z-M.; Zhou, W-S. J. Chem. Soc., Chem. Commun. 1995, 2389; b) Honda, T.; Sano, N.; Kanai, K. Heterocycles, 1995, 41, 425; c) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 8078; d) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Feringa, B. L. Angew. Chem. Int. Ed. 2001, 40, 930. 9. a) Rein, T.; Kann, N.; Kreuder, R.; Gangloff, B.; Reiser, O. Angew. Chem. Int. Ed. 1994, 33, 556; b) Dehli, J. R.; Gotor, V. J. Org. Chem. 2002, 67, 1716. 10. Fittig, W. R. Annalen der Chemie und Pharmacie 1860, 114, 54. !&).!11. a) Colard, P.; Elphimoff-Felkin, I.; Verrier, M. Bull. Soc. Chim. Fr. 1961, 516; b) Elphimoff-Felkin, I.; Verrier, M. Bull. Chim. Fr. 1967, 1052. 12. a) Denis, J. M.; Conia, J. M. Tetrahedron Lett. 1972, 94, 4593; b) Elphimoff-Felkin, I. Bull. Soc. Chim. Fr. 1956, 1845; c) Elphimoff-Felkin, I.; Tchoubar, B. C. R. Hebd. S”ance Acad. Sci. 1953, 236, 1978. 13. a) Curtin, D. Y.; Brodley, A. J. Am. Chem. Soc. 1954, 76, 5777; b) Danilova, V.; Kazimirova, V. Zh. Obshch. Khim. 1937, 7, 2639; c) Miller, T. C. J. Org. Chem. 1969, 34, 3829. 14. a) Schoppee, C. W.; Prins, D. A. Helv. Chim. Acta. 1943, 26, 185; b) Stevens, C. L.; Ash, A. B.; Thuillier, A.; Amin, J. H.; Balys, A.; Dennis, W. E.; Dickerson, J. P.; Glinski, R. P.; Hanson, H. T.; Pillai, M. D.; Stoddard, J. W. J. Org. Chem. 1966, 31, 2593; c) Stevens, C. L.; Thuillier, A.; Daniher, F. 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Commun. 2014, 50, 1044; d) Robinson, J. R.; Fan, X.; Yadav, J.; Carroll, P. J.; Wooten, A. J.; Pericas, M. A.; Schelter, E. J.; Walsh, P. J. J. Am. Chem. Soc. 2014, 136, 8034; e) Robinson, J. R.; Gu, J.; Carroll, P. J.; Schelter, E. J.; Walsh, P. J. J. Am. Chem. Soc. 2015, 137, 7135.   !&*/!Chapter 6   Experimental Information 6.1 General Information All experiments were performed under an argon atmosphere. Flasks were flame dried and cooled under argon before use. All solvents used were dried appropriately. Toluene, dichloromethane and acetonitrile were dried from calcium hydride under nitrogen. THF was dried from sodium with benzophenone as the indicator under nitrogen. The ligands VANOL 68b, VAPOL 69c and 7,7Õ-disubstituted VANOL derivatives 68d-i were prepared according to the published procedure.1 Phenol was sublimed and stored under argon in a dry desiccator; each batch was used for a maximum of 20 days. The commercially available aldehydes were purchased from Aldrich or other commercial sources and purified appropriately before use. Solid aldehydes were sublimed and liquid aldehydes were distilled. The aldehydes were stored under argon; each batch was used for a maximum of 5 days. Phenol, 4-methoxyphenol and benzoic acid were sublimed before use. Benzhydryl amine was used as purchased from Aldrich and distilled before use. The tetramethyldianisylmethyl (MEDAM) amine and the tetra-tert-butyldianisylmethyl (BUDAM) amine were prepared according to the procedures previously reported by our group.2 The n-butyl diazoacetamide and phenyl diazoacetamide were also prepared according to the previously reported procedures.3 All other reagents were used as freshly purchased either from Aldrich or other commercial sources, or purified appropriately. Melting points were recorded on a Thomas Hoover capillary melting point apparatus and are uncorrected. IR spectra were recorded in KBr matrix (for solids) and on NaCl disc (for liquids) on a Nicolet IR/42 spectrometer. 1H-NMR and 13C-NMR were recorded on a Varian 300 MHz or VXR-500 MHz spectrometer using CDCl3 as solvent (unless !&*&!otherwise noted) with the residual solvent peak as the internal standard (1H-NMR: 7.26 ppm, 13C-NMR: 77 ppm). Chemical shifts were reported in parts per million. Low-resolution Mass Spectrometry and High Resolution Mass Spectrometry were performed in the Department of Chemistry at Michigan State University. Analytical thin-layer chromatography (TLC) was performed on Silicycle silica gel plates with F-254 indicator. Visualization was by short wave (254 nm) and long wave (365 nm) ultraviolet light, or by staining with phosphomolybdic acid in ethanol or with potassium permanganate. Column chromatography was performed with silica gel 60 (230 Ð 450 mesh) purchased from SiliCycle Inc. HPLC analyses were peformed using a Varian Prostar 210 Solvent Delivery Module with a Prostar 330 PDA Detector and a Prostar Workstation. Chiral HPLC data for the aziridines were obtained using a CHIRALCEL OD-H column, CHIRALPAK AD column and PIRKLE COVALENT (R, R) WHELK-O 1 column.  Optical rotations were obtained on a Perkin-Elmer 341 polarimeter at a wavelength of 589 nm (sodium D line) using a 1.0 decimeter cell with a total volume of 1.0 mL. Specific rotations are reported in degrees per decimeter at 20 ¡C and the concentrations are given in gram per 100 mL in ethyl acetate unless otherwise noted. 6.2 Experimental Information of Chapter 2 6.2.1 Multi-Component cis-Aziridination of Non-Chiral Aldehydes 33a-i General Procure for Multi-Component cis-Aziridination  MEDAMNH2RHO33NRMEDAMOEtO103101a++N2OEtO1025% (S)-t-Bu2VANOLBOROX4 † MStoluene, 25 ¡C, 24 h!&*'!To a flame-dried 10 mL Schlenk flask filled with nitrogen was added (S)-t-Bu2VANOL 68c (13.8 mg, 0.0250 mmol), triphenylborate (21.8 mg, 0.0750 mmol) and MEDAM amine 101a (150 mg, 0.500 mmol). The solid was dissolved in toluene (1 mL, freshly distilled) and the resulting solution was heated to 80 ¡C for 0.5 h with the flask filled with nitrogen and sealed with a Teflon valve. The resulting BOROX catalyst solution was allowed to cool down to room temperature before flame-dried 4 † molecular sieves (~ 150 mg) were added, which was followed by the addition of aldehyde 33 (0.525 mmol) and ethyl diazoacetate 102 (63 µL, 0.60 mmol). Tiny bubbles of nitrogen were observed which indicated the initiation of aziridination. The reaction mixture was stirred at room temperature for 24 h. The reaction was quenched by filtering the mixture through a silica gel pad to a 250 mL round-bottom flask, with EtOAc (100 mL) as the eluent. The resulting light yellow colored solution was concentrated and dried under vacuum to give an oily crude residue. The cis/trans ratio was determined by comparing the H1-NMR of the crude reaction mixture. The coupling constants of cis-aziridines (J = 6-7 Hz) and trans-aziridines (J = 2-3 Hz) were used to differentiate the two isomers. Purification of the crude mixture by silica gel chromatography (30 mm ' 300 mm column, 9:1 hexanes/EtOAc as the eluent, gravity column) afforded pure cis-aziridine 103. The enantiomeric purity was determined by HPLC analysis.  (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(4-nitrophenyl) aziridine-2-carboxylate 103b: 4-Nitrobenzaldehyde 33 (83.1 mg, 0.550 mmol) was reacted MEDAMNH2HO33bNMEDAMOEtO103b101a++N2OEtO1025% (S)-t-Bu2VANOLBOROX4 † MStoluene, 25 ¡C, 24 hO2NO2N!&*(!according to the general procedure 6.2.1 with (S)-t-Bu2VANOL as the ligand. The aldehyde 33b was allowed to dissolve in toluene (1 mL), which required gently warming of the solution due to its low solubility at the room temperature. The resulting solution of the aldehyde was introduced into the BOROX catalyst via a 1 mL syringe. Additional toluene (0.5 mL) was used to rinse the flask and was transferred to the catalyst solution. The pure cis-aziridine 103b was separated by silica gel chromatography (9:1 hexanes/EtOAc, gravity column) to afford an off-white semi-solid in 100% yield (264 mg, 0.509 mmol); cis/trans >132:1. The enantiomeric purity was determined to be 99.3% ee by HPLC (CHIRALCEL OD-H column, 99:1 hexane/isopropanol at 226 nm, flow rate 0.7 mL/min); retention times, 19.2 min (major enantiomer, 103b) and 26.5 min (minor enantiomer, ent-103b). The aziridination of aldehyde 33b in the presence of (S)-VANOL catalyst afforded cis-aziridine 103b in >99% ee and 77% yield (200 mg, 0.385 mmol). Spectral data for 103b: 1H-NMR (CDCl3, 500 MHz) & 1.04 (t, 3H, J = 7.0 Hz), 2.20 (s, 6H), 2.27 (s, 6H), 2.70 (d, 1H, J = 7.0 Hz), 3.17 (d, 1H, J = 7.0 Hz), 3.64 (s, 3H), 3.70 (s, 3H), 3.72 (s, 1H), 3.93-3.97 (m, 33m), 7.08 (s, 33m), 7.18 (s, 33m), 7.59 (d, 33m, J = 8.5 Hz), 8.12 (d, 33m, J = 9.0 Hz); 13C-NMR (CDCl3, 125 MHz) & 14.08, 16.21, 16.26, 46.79, 47.26, 59.56, 59.61, 60.89, 76.86, 123.00, 127.22, 127.56, 128.81, 130.84, 130.87, 137.26, 137.47, 142.78, 147.22, 156.07, 156.22, 167.22. These spectral data match those previously reported for this compound.4  MEDAMNH2HO33cNMEDAMOEtO103c101a++N2OEtO1025% (S)-t-Bu2VANOLBOROX4 † MStoluene, 25 ¡C, 24 h!&*)!(2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(4-tolyl)aziridine-2-carboxylate 103c: 4-Tolualdehyde 33c (62 µL, 0.52 mmol) was reacted according to the general procedure with (S)-t-Bu2VANOL as the ligand. The pure cis-aziridine 103c was separated by silica gel chromatography (9:1 hexanes/EtOAc, gravity column) to afford an off-white semi-solid in 91% yield (222 mg, 0.455 mmol); cis/trans >132:1. The enantiomeric purity was determined to be 99.6% ee by HPLC (CHIRALCEL OD-H column, 99:1 hexane/isopropanol at 226 nm, flow rate 0.7 mL/min); retention times, 7.9 min (major enantiomer, 103c) and 11.5 min (minor enantiomer, ent-103c). The aziridination of aldehyde 33c in the presence of (S)-VANOL catalyst afforded cis-aziridine 103c in 98% ee and 87% yield (212 mg, 0.435 mmol). Spectral data for 103c: 1H-NMR (CDCl3, 500 MHz) & 1.03 (t, 3H, J = 7.0 Hz), 2.20 (s, 6H), 2.26 (s, 6H), 2.28 (s, 3H), 2.54 (d, 1H, J = 6.5 Hz), 3.10 (d, 1H, J = 6.5 Hz), 3.64 (s, 3H), 3.66 (s, 1H), 3.70 (s, 3H), 3.93-3.98 (m, 33m), 7.05 (d, 33m, J = 8.0 Hz), 7.11 (s, 33m), 7.20 (s, 33m), 7.26 (d, 33m, J = 8.5 Hz); 13C-NMR (CDCl3, 125 MHz) & 14.05, 16.17, 16.22, 21.12, 46.16, 48.19, 59.52, 59.58, 60.48, 77.07, 127.37, 127.68, 127.77, 128.41, 130.55, 130.58, 132.19, 136.78, 137.84, 137.98, 155.84, 156.00, 168.14. These spectral data match those previously reported for this compound.4  (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(2-tolyl)aziridine-2-carboxylate 103d: 2-Tolualdehyde 33d (61 µL, 0.52 mmol) was reacted according to the general procedure with (S)-t-Bu2VANOL as the ligand. The pure cis-aziridine 103d was MEDAMNH2HO33dNMEDAMOEtO103d101a++N2OEtO1025% (S)-t-Bu2VANOLBOROX4 † MStoluene, 25 ¡C, 24 h!&**!separated by silica gel chromatography (9:1 hexanes/EtOAc, gravity column) to afford an off-white semi-solid in 97% yield (236 mg, 0.485 mmol); cis/trans >260:1. The enantiomeric purity was determined to be 99.7% ee by HPLC (CHIRALCEL OD-H column, 99:1 hexane/isopropanol at 226 nm, flow rate 0.7 mL/min); retention times, 9.3 min (major enantiomer, 103d) and 12.2 min (minor enantiomer, ent-103d). The aziridination of aldehyde 33d in the presence of (S)-VANOL catalyst afforded cis-aziridine 103d in 98% ee and 73% yield (178 mg, 0.365 mmol). Spectral data for 103d: 1H-NMR (CDCl3, 500 MHz) & 0.91 (t, 3H, J = 7.0 Hz), 2.22 (s, 6H), 2.26 (s, 6H), 2.28 (s, 3H), 2.63 (d, 1H, J = 7.0 Hz), 3.10 (d, 1H, J = 6.5 Hz), 3.64 (s, 3H), 3.68 (s, 1H), 3.70 (s, 3H), 3.90 (q, 33m, J = 7.0 Hz), 7.02 (dd, 1H, J = 7.0, 2.0 Hz), 7.09-7.12 (m, 33m), 7.15 (s, 33m), 7.20 (s, 33m), 7.54 (dd, 1H, J = 7.0, 2.0 Hz); 13C-NMR (CDCl3, 125 MHz) & 13.90, 16.17, 16.24, 18.78, 45.51, 47.14, 59.54, 59.60, 60.39, 77.30, 125.28, 127.05, 127.28, 127.92, 128.59, 129.08, 130.62, 130.63, 133.42, 136.01, 137.83, 137.99, 155.85, 156.12, 168.18. These spectral data match those previously reported for this compound.4  (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2-carboxylate 103a: 2-Benzaldehyde 33a (53 µL, 0.52 mmol) was reacted according to the general procedure with (S)-t-Bu2VANOL as the ligand. The pure cis-aziridine 103a was separated by silica gel chromatography (9:1 hexanes/EtOAc, gravity column) to afford an off-white semi-solid in 100% yield (247 mg, 0.52 mmol); cis/trans >62:1. The enantiomeric purity was determined to be 99.7% ee by HPLC (CHIRALCEL OD-H MEDAMNH2PhHO33aNPhMEDAMOEtO103a101a++N2OEtO1025% (S)-t-Bu2VANOLBOROX4 † MStoluene, 25 ¡C, 24 h!&*+!column, 99:1 hexane/isopropanol at 226 nm, flow rate 0.7 mL/min); retention times, 9.0 min (major enantiomer, 103a) and 11.4 min (minor enantiomer, ent-103a). The aziridination of aldehyde 33a in the presence of (S)-VANOL catalyst afforded cis-aziridine 103a in 98% ee and 87% yield (206 mg, 0.435 mmol). Spectral data for 103a: 1H-NMR (CDCl3, 500 MHz) & 1.00 (t, 3H, J = 7.0 Hz), 2.20 (s, 6H), 2.26 (s, 6H), 2.58 (d, 1H, J = 7.0 Hz), 3.13 (d, 1H, J = 7.0 Hz), 3.64 (s, 3H), 3.68 (s, 1H), 3.70 (s, 3H), 3.90-3.97 (m, 33m), 7.11 (s, 33m), 7.20 (s, 33m), 7.23-7.26 (m, 3H), 7.38 (d, 33m, J = 7.0 Hz); 13C-NMR (CDCl3, 125 MHz) & 14.00, 16.16, 16.22, 46.25, 48.20, 59.52, 59.58, 60.49, 77.03, 127.21, 127.40, 127.70, 127.78, 127.84, 130.58, 130.60, 135.30, 137.79, 137.95, 155.92, 156.07, 168.03. These spectral data match those previously reported for this compound.4  (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(4-anisyl)aziridine-2-carboxylate 103e: 4-Anisaldehyde 33e (64 µL, 0.52 mmol) was reacted according to the general procedure with (S)-t-Bu2VANOL as the ligand. The pure cis-aziridine 103e was separated by silica gel chromatography (9:1 hexanes/EtOAc, gravity column) to afford an off-white semi-solid in 93% yield (234 mg, 0.464 mmol); cis/trans >150:1. The enantiomeric purity was determined to be 99.9% ee by HPLC (CHIRALCEL OD-H column, 99:1 hexane/isopropanol at 226 nm, flow rate 0.7 mL/min); retention times, 13.4 min (major enantiomer, 103e) and 20.6 min (minor enantiomer, ent-103e). The MEDAMNH2HO33eNMEDAMOEtO103e101a++N2OEtO1025% (S)-t-Bu2VANOLBOROX4 † MStoluene, 25 ¡C, 24 hMeOMeO!&*,!aziridination of aldehyde 33e in the presence of (S)-VANOL catalyst afforded cis-aziridine 103e in 97% ee and 82% yield (206 mg, 0.410 mmol). Spectral data for 103e: 1H-NMR (CDCl3, 500 MHz) & 1.04 (t, 3H, J = 7.0 Hz), 2.20 (s, 6H), 2.26 (s, 6H), 2.52 (d, 1H, J = 7.0 Hz), 3.07 (d, 1H, J = 7.0 Hz), 3.64 (s, 3H), 3.66 (s, 1H), 3.70 (s, 3H), 3.76 (s, 3H), 3.92-3.99 (m, 33m), 6.78 (d, 33m, J = 8.0 Hz), 7.10 (s, 33m), 7.19 (s, 33m), 7.30 (d, 33m, J = 8.5 Hz); 13C-NMR (CDCl3, 125 MHz) & 14.10, 16.18, 16.23, 46.20, 47.90, 55.20, 59.54, 59.59, 60.47, 77.05, 113.17, 127.42, 127.78, 128.94, 130.56, 130.58, 137.83, 138.01, 155.91, 156.06, 158.84, 168.16 (one sp2 carbon not located). These spectral data match those previously reported for this compound.4  (2R,3S)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(2-pyridyl)aziridine-2-carboxylate 8f: 2-Pyridylcarboxaldehyde 33f (50 µL, 0.52 mmol) was reacted according to the general procedure with (S)-t-Bu2VANOL as the ligand. The pure cis-aziridine 8f was separated by silica gel chromatography (9:1 hexanes/EtOAc, gravity column) to afford an off-white semi-solid in 97% yield (230 mg, 0.48 mmol); cis/trans >49:1. The enantiomeric purity was determined to be 100% ee by HPLC (CHIRALCEL OD-H column, 99:1 hexane/isopropanol at 226 nm, flow rate 0.7 mL/min); retention times, 20.4 min (major enantiomer, 8f) and 33.6 min (minor enantiomer, ent-8f). The aziridination of aldehyde 33f in the presence of (S)-VANOL catalyst afforded cis-aziridine 8f in 96% ee and 95% yield (225 mg, 0.474 mmol). MEDAMNH2HO33fNMEDAMOEtO103f101a++N2OEtO1025% (S)-t-Bu2VANOLBOROX4 † MStoluene, 25 ¡C, 24 hNN!&*-!Spectral data for 8f: 1H-NMR (CDCl3, 500 MHz) & 1.03 (t, 3H, J = 7.0 Hz), 2.20 (s, 6H), 2.26 (s, 6H), 2.68 (d, 1H, J = 6.5 Hz), 3.29 (d, 1H, J = 7.0 Hz), 3.64 (s, 3H), 3.70 (s, 3H), 3.75 (s, 1H), 3.96 (q, 33m, J = 7.0 Hz), 7.10 (s, 33m), 7.11-7.13 (m, 1H), 7.18 (s, 33m), 7.61 (dd, 33m, J = 4.5, 1.5 Hz), 8.44 (dt, 1H, J = 4.5, 1.5 Hz); 13C-NMR (CDCl3, 125 MHz) & 14.00, 16.16, 16.23, 45.91, 49.45, 59.54, 59.60, 60.63, 76.80, 122.29, 122.83, 127.36, 127.78, 130.65, 130.68, 135.87, 137.56, 137.77, 148.56, 155.47, 155.99, 156.12, 167.74. These spectral data match those previously reported for this compound.4  Hexadecanal 105g: To a 100 mL flame-dried round bottom flask equipped with a stir bar was added 1-hexadecanol (1.21 g, 5.00 mmol).  Dry CH2Cl2 (20 mL) was added to dissolve the alcohol.  To the resulting solution were added TEMPO (39.1 mg, 0.250 mmol) and PhIO (1.43 g, 6.50 mmol).  The suspension was cooled to 0 ¡C and Yb(OTf)3 (62.5 mg,  0.100 mmol) was added.  The reaction mixture was stirred at 0 ¡C for 50 min (until the alcohol was no longer detectable by TLC).  The yellow cloudy solution was filtered through Celite pad and concentrated under reduced pressure. Purification of the crude aldehyde by silica gel chromatography (30 mm ' 300 mm column, 3:1 hexanes / dichloromethane as eluent, flash column) afforded pure aldehyde 105g as a white solid (mp 36-38 ¼C) in 88% isolated yield (1.06 g, 4.41 mmol). Spectral data for 105g: Rf = 0.45 (1:1 hexanes/DCM).  1H-NMR (500 MHz, CDCl3): & 0.88 (t, 3H, J = 6.9 Hz), 1.30-1.25 (m, 24H), 1.62 (quintet, 33m, J = 7.3 Hz), 2.41 (td, 33m, J = 7.4, 1.9 Hz), 9.76 (t, 1H, J = 1.8 Hz); 13C-NMR (126 MHz, CDCl3): & 14.09, 22.10, 22.68, 29.17, 29.35, 29.42, 29.57, 29.63, 29.64, 29.65, 29.67, 29.68, 31.92, 43.91, OH12OH12PhIO (1.3 equiv), TEMPO (5 mol%)Yb(OTf)3 (2 mol%)CH2Cl2, 0 ¼C, 50 min33g305!&*.!202.85 (1 sp3 carbon not located). These spectral data match those previously reported for this compound.5  (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-pentadecylaziridine-2-carboxylate 8g:n-Hexadecanal 105g (132 mg, 0.550 mmol) was reacted according to the general procedure with (S)-t-Bu2VANOL as the ligand. The aldehyde 105g was allowed to dissolve in toluene (1 mL) and then pre-cooled to (10 ¡C. The resulting solution of the aldehyde was then introduced into the BOROX catalyst solution via a 1 mL syringe after the catalyst solution was first cooled in an ethanol bath to (10 ¡C. Additional toluene (0.5 mL) was used to rinse the flask and was transferred to the catalyst solution. The pure cis-aziridine 8g was separated by silica gel chromatography (9:1 hexanes/EtOAc, gravity column) to afford an off-white semi-solid in 97% (295 mg, 0.485 mmol). Only a single diastereomer was observed. The enantiomeric purity was determined to be 98.5% ee by HPLC (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/isopropanol at 226 nm, flow rate 0.7 mL/min); retention times, 26.6 min (major enantiomer, 8g) and 47.8 min (minor enantiomer, ent-8g). The aziridination of aldehyde 105g in the presence of (S)-VANOL afforded cis-aziridine 8g in 95% ee and 60% yield (182 mg, 0.299 mmol). Spectral data for 8g: 1H-NMR (CDCl3, 500 MHz) & 0.88 (t, 3H, J = 7.0 Hz), 1.14-1.33 (m, 29H), 1.45-1.56 (m, 33m), 1.96 (q, 1H, J = 6.5 Hz), 2.20 (d, 1H, J = 7.0 Hz), 2.24 (s, 125m), 3.40 (s, 1H), 3.68 (d, 6H, J = 8.0 Hz), 4.15-4.23 (m, 33m), 7.01 (s, 33m), 7.10 (s, 33m); 13C-NMR (CDCl3, 125 MHz) & 14.11, 14.33, 16.11, 16.16, 22.67, 27.22, 27.92, MEDAMNH2C15H31HO33gNC15H31MEDAMOEtO103g101a++N2OEtO1025% (S)-t-Bu2VANOLBOROX4 † MStoluene, Ð10 ¡C, 24 h!&+/!29.15, 29.34, 29.50, 29.61, 29.64, 29.68, 31.91, 43.54, 46.99, 59.57, 60.66, 77.31, 127.36, 128.07, 130.42, 130.47, 137.73, 138.14, 155.75, 156.10, 169.67 (five sp3 carbons not located). These spectral data match those previous reported for this compound.4  (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-cyclohexylaziridine-2-carboxylate 103h: Cyclohexylcarboxaldehyde 33h (64 µL, 0.52 mmol) was reacted according to the general procedure with (S)-t-Bu2VANOL as the ligand. The pure cis-aziridine 103h was separated by silica gel chromatography (9:1 hexanes/EtOAc, gravity column) to afford an off-white semi-solid in 100% yield (243 mg, 0.507 mmol); cis/trans >14:1. The enantiomeric purity was determined to be 96.0% ee by HPLC (CHIRALCEL OD column, 99:1 hexane/isopropanol at 223 nm, flow rate 0.7 mL/min); retention times, 10.4 min (major enantiomer, 103h) and 13.1 min (minor enantiomer, ent-103h). The aziridination of aldehyde 33h in the presence of (S)-VANOL catalyst afforded cis-aziridine 103h in 94% ee and 94% yield (225 mg, 0.469 mmol). Spectral data for 103h: 1H-NMR (CDCl3, 500 MHz) & 0.49-0.56 (m, 1H), 0.83-1.16 (m, 4H), 1.24 (t, 3H, J = 7.0 Hz), 1.16-1.32 (m, 33m), 1.41-1.63 (m, 4H), 1.74 (dd, 1H, J = 9.5, 7.0 Hz), 2.18 (d, 1H, J = 6.5 Hz), 2.23 (s, 6H), 2.24 (s, 6H), 3.36 (s, 1H), 3.66 (s, 3H), 3.69 (s, 3H), 4.16-4.27 (m, 33m), 6.96 (s, 33m), 7.11 (s, 33m); 13C-NMR (CDCl3, 125 MHz) & 14.33, 16.06, 16.17, 25.33, 25.52, 26.15, 30.08, 30.81, 36.33, 46.46, 52.25, 59.60, 59.65, 60.66, 77.47, 127.32, 128.52, 130.33, 130.46, 137.53, 138.08, 155.69, 156.22, 169.81. These spectral data match those previously reported for this compound.4 MEDAMNH2HO33hNMEDAMOEtO103h101a++N2OEtO1025% (S)-t-Bu2VANOLBOROX4 † MStoluene, 25 ¡C, 24 h!&+&! (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-tert-butylaziridine-2-carboxylate 103i: Trimethylacetaldehyde 33i (57 µL, 0.52 mmol) was reacted according to the general procedure  with (S)-t-Bu2VANOL as the ligand. The pure cis-aziridine 103i was separated by silica gel chromatography (9:1 hexanes/EtOAc, gravity column) to afford an off-white semi-solid in 100% yield (226 mg, 0.498 mmol); cis/trans >90:1. The enantiomeric purity was determined to be 97.0% ee by HPLC (CHIRALCEL OD column, 99:1 hexane/isopropanol at 226 nm, flow rate 1.0 mL/min); retention times, 7.1 min (major enantiomer, 103i) and 11.0 min (minor enantiomer, ent-103i). The aziridination of aldehyde 33i in the presence of (S)-VANOL catalyst afforded cis-aziridine 103i in 95% ee and 70% yield (159 mg, 0.351 mmol). Spectral data for 103i: 1H-NMR (CDCl3, 500 MHz) & 0.69 (s, 9H), 1.30 (t, 3H, J = 7.0 Hz), 1.66 (d, 1H, J = 7.0 Hz), 2.09 (d, 1H, J = 7.0 Hz), 2.24 (s, 6H), 2.26 (s, 6H), 3.34 (s, 1H), 3.66 (s, 3H), 3.69 (s, 3H), 4.06-4.26 (m, 33m), 7.01 (s, 33m), 7.28 (s, 33m); 13C-NMR (CDCl3, 125 MHz) & 14.15, 16.10, 16.21, 27.42, 31.60, 43.36, 56.15, 59.57, 59.64, 60.56, 78.43, 127.47, 128.34, 130.27, 130.30, 137.92, 138.85, 155.64, 156.10, 170.01. These spectral data match those previously reported for this compound.4     MEDAMNH2HO33iNMEDAMOEtO103i101a++N2OEtO1025% (S)-t-Bu2VANOLBOROX4 † MStoluene, 25 ¡C, 24 h!&+'!6.2.2 Preparation of !- or "-Chiral Aldehydes General Procedure A for Aldehyde 104a, c, g  Esterification of "-hydroxy acids:6 To a flame-dried round bottom flask equipped with a stir bar and a condenser with a rubber septum and a nitrogen balloon at the top, was added the !-hydroxy acid (5.00 mmol). Dry acetonitrile (120 mL) was added to dissolve the acid. Thereafter, CsF-Celite (2.60 g) and iodoethane (1.20 mL, 15.0 mmol, 3.00 equiv) were added. The flask was placed in an oil (185 ¡C) bath and the reaction mixture was refluxed for 8 h. The flask was then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (15 mL). The mixture was filtered through a Celite pad into a 100 mL round bottom flask. The Celite pad was washed with another 20 mL of ethyl acetate. The resulting solution was concentrated under reduced pressure followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude ester. Purification of the product by silica gel chromatography (30 mm ' 300 mm column, flash column) afforded the pure ester as a white solid. Preparation of "-silyloxy esters: To a flame dried round bottom flask equipped with a stir bar and filled with nitrogen was added the !-hydroxy acid (2.50 mmol). Dry DMF (15 mL freshly distilled and stored over activated 4 † MS) was added to dissolve the ester. The resulting solution was cooled to 0 ¡C. To the reaction flask was added imidazole ROHCO2HEtI, CsF-CeliteMeCN, refulx, 8 hROHCO2EtTBSCl, imidazoleDMF, rt. 12 hROTBSCO2EtDIBAL-HTHF, Ð78 ¡C, 2 hROTBSCHO306a, 306g307a, 307c, 307g308a, 308c, 308g104a, 104c, 104g!&+(!(3.00 mmol, 1.20 equiv) and tert-butyldimethylsilylchloride (3.00 mmol, 1.20 equiv). The flask was fitted with a rubber septum and a nitrogen balloon. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted by addition of hexanes (15 mL). Thereafter, brine was added to the resulting mixture. The organic layer was separated, and the aqueous layer was extracted with hexanes (10 mL ' 3). The combined organic layer was then dried over MgSO4 and concentrated under reduced pressure to afford the crude !-silyloxy ester. Purification of the product by silica gel chromatography (30 mm ' 300 mm column, flash column) afforded the pure ester as a colorless liquid. Reduction of "-silyloxy esters to aldehydes: To a flame dried round bottom flask equipped with a stir bar and filled with nitrogen was added the appropriate !-(tert-butyldimethylsilyloxy) ester (2.00 mmol). Dry diethyl ether (10 mL) was added to dissolve the ester. The flask was fitted with a rubber septum and a nitrogen balloon. The solution was cooled to Ð78 ¡C. To the reaction flask was added DIBAL-H (4.0 mL, 1 M solution in hexanes, 4.0 mmol, 2.0 equiv) over a period of 2 minutes. The resulting reaction mixture was then stirred for 2 h at Ð78 ¡C. To the reaction was added a mixture of methanol and water (0.50 mL, 1:1 v/v), followed by diethyl ether (10 mL) at Ð78 ¡C. The resulting mixture was allowed to warm to room temperature. Thereafter, saturated potassium sodium tartrate solution (10 mL) was added to the reaction flask. The resulting cloudy reaction mixture was stirred for 4 h at room temperature until a clear biphasic mixture was obtained. The organic layer was separated and the aqueous layer was extracted with diethyl ether (10 mL ' 3). The combined organic layer was washed with saturated brine solution (10 mL) then dried over MgSO4 and concentrated under reduced !&+)!pressure to give the crude aldehyde. Purification of the product by silica gel chromatography (20 mm ' 300 mm column, flash column) afforded the pure aldehyde as a colorless liquid. General Procedure B for Dess-Martin Oxidation from Alcohol to Aldehyde Dess-Martin Oxidation of Alcohols to Aldehydes:  To a flame-dried 25 mL round bottom flask flushed with nitrogen and equipped with a stir bar was added the appropriate alcohol (1.00 mmol) and freshly distilled CH2Cl2 (5 mL). To the resulting clear solution was added Dess-Martin periodinane (509 mg, 1.20 mmol, 1.20 equiv). The turbid reaction mixture was stirred for 30 min at room temperature under a nitrogen atmosphere. Thereafter, a buffer solution made from dissolving NaH2PO4 (262 mg) and Na3PO4 (366 mg) in 2.5 mL water, was added to the reaction mixture. The resulting mixture was stirred for 5 min at room temperature. The turbid mixture was filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was washed with CH2Cl2 (3 ' 10 mL) and passed through the same Celite pad. The resulting organic layer was washed with sat. aq. NaHCO3 (2 ' 10 mL) and then with brine (2 ' 10 mL). The organic layer was dried over MgSO4 and the solvents were removed in vacuo. Purification of the product by silica gel chromatography (20 mm ' 150 mm column, 9:1 hexanes/Et2O as eluent, flash column) afforded the pure aldehyde as a colorless liquid.  Ethyl (R)-2-hydroxy-2-phenylacetate (R)-307a:  (R)-mandelic acid (R)-306a (761 mg, 5.00 mmol) was reacted according to the first step of the general procedure A with CsF-Celite (2.60 g) and iodoethane (1.20 mL, 15.0 mmol, 3.00 equiv) in dry acetonitrile (120 PhOHCO2Et(R)-307aEtI, CsF-CeliteMeCN, refulx, 8 hPhOHCO2H(R)-306a!&+*!mL). Purification of the product ester by silica gel chromatography (30 mm ' 300 mm column, 4:1 hexanes/EtOAc, flash column) afforded pure ester (R)-307a as a white solid (mp 33Ð34 ¡C) in 70% isolated yield (631 mg, 3.50 mmol). Spectral data for (R)-307a: Rf = 0.16 (4:1 hexanes/EtOAc) 1H-NMR (500 MHz, CDCl3) & 1.23 (t, 3H, J = 7.2 Hz), 3.51 (d, 1H, J = 6.0 Hz), 4.17-4.26 (m, 33m), 5.16 (d, 1H, J = 6.0 Hz), 7.33-7.44 (m, 104h); 13C-NMR (125 MHz, CDCl3) & 13.92, 62.05, 72.82, 126.43, 128.21, 128.44, 138.34, 173.52; !!!!!" (135.3¡ (c 3.0, CHCl3); Lit !!!!!" (135.0¡ (c 3.0, CHCl3) (Sigma Aldrich).  Ethyl (R)-2-(tert-butyldimethylsilyloxy)-2-phenylacetate (R)-308a:  The ester (R)-307a (901 mg, 5.00 mmol) was reacted according to the second step of the general procedure A with imidazole and tert-butyldimethylsilylchloride in dry DMF (15 mL). Purification of the product by silica gel chromatography (30 mm ' 300 mm column, 50:1 hexanes/Et2O as eluent, flash column) afforded pure ester (R)-308a as a colorless liquid in 92% isolated yield (1.35 g, 4.60 mmol). Spectral data for (R)-308a: Rf = 0.23 (3:1 hexanes/ CH2Cl2); 1H-NMR (300 MHz, CDCl3) & 0.05 (s, 3H), 0.12 (s, 3H), 0.93 (s, 9H), 1.22 (t, 3H, J = 7.1 Hz), 4.15 (q, 33m, J = 7.1 Hz), 5.23 (s, 1H), 7.50 - 7.27 (m, 104h); 13C-NMR (75 MHz, CDCl3) & Ð6.01, Ð5.88, 14.05, 18.33, 25.69, 61.00, 74.45, 126.30, 127.97, 128.24, 139.24, 172.13; !!!!!" Ð38.3¡ (c 1.5,CHCl3). Lit7 !!!!!" +38.8¡ (c 1.5, CHCl3, S-isomer).  (R)-2-(tert-butyldimethylsilyloxy)-2-phenylacetaldehyde (R)-104a:  The ester (R)-308a PhOHCO2Et(R)-307aTBSCl, imidazoleDMF, rt. 12 hPhOTBSCO2Et(R)-308aPhOTBSCO2Et(R)-308aDIBAL-HTHF, Ð78 ¡C, 2 hPhOTBSCHO(R)-104a!&++!(581 mg, 2.00 mmol) was reacted according to the third step of the general procedure A with DIBAL-H (4.0 mL, 1 M solution in hexanes, 4.0 mmol, 2.0 equiv) in dry diethyl ether. Purification of the product by silica gel chromatography (30 mm ' 300 mm column, 25:1 hexanes/Et2O as eluent, flash column) afforded pure aldehyde (R)-104a as a colorless liquid in 85% isolated yield (423 mg, 1.70 mmol).  Spectral data for (R)-104a: Rf = 0.35 (1:1 CH2Cl2/hexanes); 1H-NMR (500 MHz, CDCl3) & 0.04 (s, 3H), 0.12 (s, 3H), 0.95 (s, 9H), 5.01 (d, 1H, J = 2.1 Hz), 7.30-7.41 (m, 104h), 9.51 (d, 1H, J = 2.2 Hz); 13C-NMR (125 MHz, CDCl3) & Ð4.66, Ð4.54, 16.27, 25.71, 80.00, 126.40, 128.33, 128.69, 136.60, 199.40; !!!!!" Ð40.1¡ (c 0.60, ethanol). Lit8 !!!!!! Ð39.5¡ (c 0.61, ethanol).  Methyl (S)-2-(tert-butyldimethylsilyloxy)propanoate (S)-308c:  (S)-methyl lactate (S)-307c (520 mg, 5.00 mmol) was reacted according to the second step of the general procedure A with imidazole and tert-butyldimethylsilylchloride in dry DMF (15 mL). Purification of the product by silica gel chromatography (30 mm ' 300 mm column, 100:1 hexanes/Et2O as eluent, flash column) afforded pure ester (S)-308c as a colorless liquid in 85% isolated yield (928 mg, 4.25 mmol).  Spectral data for (S)-308c: Rf = 0.55 (9:1 hexanes/EtOAc); 1H-NMR (300 MHz, CDCl3) & 0.07 (s, 3H), 0.10 (s, 3H), 0.90 (s, 9H), 1.40 (d, 3H, J = 6.7 Hz), 3.72 (s, 3H), 4.33 (q, 1H, J = 6.7 Hz); 13C-NMR (75 MHz, CDCl3) & Ð5.02, Ð4.73, 18.51, 21.56, 25.91, 51.96, 68.50, 174.42; !!!!!" Ð28.0¡ (c 0.90, CHCl3). Lit9 !!!!!" Ð26.7¡ (c 0.86, CHCl3).  TBSCl, imidazoleDMF, rt. 12 hOTBSCO2Me(S)-308cOHCO2Me(S)-307cDIBAL-HTHF, Ð78 ¡C, 2 hOTBSCO2Me(S)-308cOTBSCHO(S)-104c!&+,!(S)-2-(tert-butyldimethylsilyloxy)propanal (S)-104c: The ester (S)-308c (437 mg, 2.00 mmol) was reacted according to the third step of the general procedure A with DIBAL-H (4.0 mL, 1 M solution in hexanes, 4.0 mmol, 2.0 equiv) in dry diethyl ether. Purification of the product by silica gel chromatography (20 mm ' 300 mm column, 50:1 hexanes/Et2O as eluent, flash column) afforded pure aldehyde (S)-104c as colorless liquid in 75% isolated yield (282 mg, 1.50 mmol).  Spectral data for (S)-104c: Rf = 0.54 (6:1 hexanes/EtOAc) 1H-NMR (500 MHz, CDCl3) & 0.09 (s, 3H), 0.11 (s, 3H), 0.92 (s, 9H), 1.28 (d, 3H, J = 6.8 Hz), 4.09 (qd, 1H, J = 6.8, 1.0 Hz), 9.61 (d, 1H, J = 1.0 Hz); 13C-NMR (125 MHz, CDCl3) & Ð4.91, Ð4.82, 18.22, 18.54, 25.69, 73.80, 204.21; !!!!!" +12.3¡ (c 2.0, CHCl3). Lit10 !!!!!" +12.1¡ (c 2.0, CHCl3).   2-Tetradecyloxirane 310: To an oven dried 500 mL round bottom flask was added 1-hexadecene 309 (14.3 mL, 50.0 mmol) and freshly distilled dichloromethane (250 mL). The solution was cooled to 0 ¡C. To this solution was added 3-chloroperoxybenzoic acid (77%, remainder 3-chlorobenzoic acid and water), (15.0 g, 65.0 mmol, 1.30 equiv) was added in one portion.  After 10 min, the resulting suspension was warmed to room temperature and was stirred at that temperature for 16 h. The reaction mixture was then diluted with hexanes (600 mL) and filtered through a Celite pad into a 1L round bottom flask to remove undissolved 3-chlorobenzoic acid from the reaction mixture. The filtrate was washed sequentially with saturated aqueous sodium bicarbonate solution (1 ' 800 mL), saturated aqueous sodium bisulfite solution (1 ' 800 mL), saturated aqueous sodium bicarbonate solution (1 ' 800 mL) and brine (1 ' 800 mL).  The organic layer 90% yieldm-CPBACH2Cl2, rt, 16 h3091212O(±)-310!&+-!was then separated, dried over MgSO4 and concentrated under reduced pressure to afford crude epoxide 310 as a colorless oil.  The epoxide was purified by simple distillation under reduced pressure (bp 93 ¼C at 0.1 Hg) to afford 21 as a colorless oil in 90% yield (10.8 g, 44.9 mmol).  Spectral data for (±)-310: 1H-NMR (500 MHz, CDCl3) & 0.88 (t, 3H, J = 7.0 Hz), 1.30-1.33 (m, 26H), 2.46 (dd, 1H, J = 5.1, 2.8 Hz), 2.74 (dd, 1H, J = 5.0, 4.0 Hz), 2.90 (tdd, 1H, J = 5.5, 3.9, 2.7 Hz); 13C-NMR (151 MHz, CDCl3) & 14.11, 22.69, 25.97, 29.36, 29.45, 29.56, 29.64, 29.65, 29.67, 29.68, 29.70, 31.93, 32.50, 47.13, 52.41 (one sp3 carbon not located). The spectral data matched with those reported for this compound.11  (R)-hexadecane-1,2-diol (R)-312: The hydrolytic kinetic resolution of racemic epoxide 310 was carried out with JacobsenÕs protocol.12 To a 50 mL round bottom flask (1S,2S)-312 (151 mg, 0.250 mmol), toluene (1.3 mL), and acetic acid (29 µL, 0.50 mmol, 2.0 equiv to catalyst) were added. The mixture was stirred while open to the air for 1 h at room temperature. The solvent was removed by rotary evaporation, and the brown residue was dried under vacuum (0.05 mm Hg) for 2 h. To the reaction flask, (±)-2-tetradecyloxirane 310 (12.0 g, 50.0 mmol) was added in one portion, and the stirred mixture was cooled in an ice-water bath. Water (496 µL, 27.5 mmol, 0.550 equiv) was slowly added to the reaction mixture. Thereafter, the ice-water bath was removed and the reaction mixture was vigorously stirred at room temperature for 12 h. Hexanes (10 mL) was added to the thick slurry and the mixture was filtered through a sintered glass funnel (±)-31012O(R)-3121240% yield1) (1S,2S)-311 (0.5 mol%)HOAc (0.5 mol%)2) H2O (0.55 equiv)NNt-But-But-But-BuOOCo (1S,2S)-311OHOH!&+.!under mild vacuum. The solid precipitate was washed with ice-cold hexanes (4 ' 20 mL). The hexanes washing removes the left over chiral epoxide 310. The light reddish white solid (R)-312 was crystallized from EtOAc/hexanes (1:3) mixture. The first crop was collected in 35% yield (4.52 g, 17.6 mmol) of (R)-312 as an off-white flakey solid (mp 83-84 ¼C). The mother liquor was concentrated and again crystallized from EtOAc/hexanes (1:3) mixture. The second crop was collected in 5% yield (646 mg, 2.51 mmol) of (R)-312 (mp 83-84 ¼C). Spectral data for (R)-312: 1H-NMR (300 MHz, CDCl3) & 0.88 (t, 3H, J = 6.7 Hz), 1.30-1.26 (m, 24H), 1.41-1.43 (m, 33m), 1.80 (t, 1H, J = 5.7 Hz), 1.94 (d, 1H, J = 4.3 Hz), 3.44 (ddd, 1H, J = 10.9, 7.5, 5.0 Hz), 3.75-3.63 (m, 33m); 13C-NMR (151 MHz, CDCl3) & 14.10, 22.68, 25.55, 29.35, 29.55, 29.59, 29.65, 29.66, 29.68, 29.69, 31.91, 33.19, 66.82, 72.34 (two sp3 carbon not located); !!!!!" +9.5¡ (c 1.0 EtOH).  (R)-tert-butyldimethyl((1-(trityloxy)hexadecan-2-yl)oxy)silane (R)-313: To an oven dried 100 mL round bottom flask equipped with a stir bar and a rubber septum with a nitrogen balloon at the top, was added 1,2-diol (R)-312 (1.03 g, 4.00 mmol) and pyridine (22 mL). The mixture was stirred at room temperature until it  became a clear solution. Thereafter, the flask was transferred to an ice water bath and stirred for another 10 min at 0 ¼C.  To the reaction mixture was added triphenylmethyl chloride (2.34 g, 8.40 mmol, 2.10 equiv) at 0 ¼C.  The reaction mixture was warmed to room temperature and stirred for 24 h under a nitrogen atmosphere.  The reaction mixture was concentrated under reduced pressure to 12OHOH12OTrOTBS1) Ph3CCl, pyridine    rt, 24 h2) TBSCl, imidazole     DMF, rt, 32 h(R)-31395% yield(R)-312!&,/!afford a pale yellow solid. The crude trityl ether was dissolved in freshly distilled DMF (10 ml) under a nitrogen atmosphere.  To the clear solution was added imidazole (544 mg, 8.00 mmol, 2.00 equiv) and TBSCl (1.21 g, 8.00 mmol, 2.00 equiv). The reaction mixture was stirred at room temperature for 32 h under a nitrogen atmosphere. Upon completion, the reaction mixture was diluted with hexanes (30 mL) and then brine (50 mL) was added to the flask.  The organic layer was separated and the aqueous layer was extracted with ether (4 ' 20 mL).  The combined organic layer was dried with MgSO4 and concentrated under reduced pressure to afford the crude reaction mixture.  Purification of the product by silica gel chromatography with a rubber septum and a nitrogen balloon at the top of the column (30 mm $ 300 mm column, 50:1 hexanes/Et2O as eluent) afforded pure (R)-313 as a colorless liquid in 95 % isolated yield (2.34 g, 3.80 mmol) over two steps from (R)-312.  Spectral data for (R)-313:  Rf = 0.35 (1:40 Et2O / hexanes) 1H-NMR (300 MHz, CDCl3) & Ð0.03 (s, 3H), Ð0.01 (s, 3H), 0.84-0.89 (m, 125m), 1.18-1.33 (m, 24H), 1.39-1.45 (m, 1H), 1.60-1.67 (m, 1H), 2.96 (dd, 1H, J = 9.2, 5.8 Hz), 3.05 (dd, 1H, J = 9.2, 5.2 Hz), 3.76 (quintet, 1H, J = 5.7 Hz), 7.19-7.32 (m, 9H), 7.46 (dd, 6H, J = 8.3, 1.4 Hz); 13C-NMR (151 MHz, CDCl3) & Ð4.75, Ð4.39, 14.12, 18.12, 22.70, 24.96, 25.89, 29.37, 29.60, 29.67, 29.69, 29.70, 29.79, 31.93, 34.97, 67.66, 71.77, 86.37, 126.82, 127.66, 128.78, 144.31 (three sp3 carbons not located); IR (thin film) 2926vs, 2855s, 1464s, 1448s, 1257s, 1076s cm-1; HRMS (ESI-TOF) m/z 615.4520 [(M+ + H); calcd for C41H63O2Si: 615.4515]; !!!!!" +9.0¡ (c 1.0, CH2Cl2).  (R)-2-((tert-butyldimethylsilyl)oxy)hexadecan-1-ol (R)-314: To a flame dried 100 mL 12OTrOTBS(R)-31312OHOTBS(R)-314CH2Cl2, 0 ¡C85% yieldTFA, Et3SiH!&,&!round bottom flask flushed with nitrogen and equipped with a stir bar was added the trityl ether (R)-313 (615 mg, 1.00 mmol) and freshly distilled CH2Cl2 (10 mL).  The resulting clear solution was cooled to 0 ¡C.  Triethylsilane (186 mg, 1.60 mmol) was added and the solution was stirred for 10 min after which TFA (153 µL, 2.00 mmol) was added dropwise at 0 ¡C until the yellow color stopped reappearing.  The reaction mixture was quenched immediately by the addition of sat.aq NaHCO3 solution (30 mL) at 0 ¼C.  The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (4 ' 50 mL).  The combined organic layers were dried over MgSO4 and the solvents were removed in vacuo.  Purification of the crude product by silica gel chromatography with a rubber septum and a nitrogen balloon at the top of the column (30 mm $ 150 mm column, 20:1 hexanes/Et2O as eluent) afforded pure (R)-314 as a colorless liquid in 85 % isolated yield (317 mg, 0.851 mmol).  Spectral data for (R)-314: Rf  = 0.22 (10:1 hexanes / Et2O); 1H-NMR (300 Hz, CDCl3) & 0.08 (s, 6H), 0.86-0.91 (m, 125m), 1.30-1.21 (m, 24H), 1.44-1.51 (m, 33m), 1.85 (t, 1H, J = 6.3 Hz), 3.40-3.49 (m, 1H), 3.56 (ddd, 1H, J = 11.0, 6.3, 3.6 Hz), 3.72 (qd, 1H, J = 5.9, 3.6 Hz); 13C-NMR (126 MHz, CDCl3) & Ð4.56, Ð4.43, 14.11, 22.69, 25.34, 25.86, 29.35, 29.56, 29.57, 29.65, 29.67, 29.69, 29.78, 31.93, 33.98, 66.30, 72.96, (three sp3 carbons not located); IR (thin film) 3400br, 2926vs, 2855s, 1464s, 1255s, 1109s cm-1; HRMS (ESI-TOF) m/z 373.3564 [(M+ + H); calcd for C22H49O2Si: 373.3578]; !!!!" Ð6.5¡ (c 1.0, CH2Cl2).  (R)-2-((tert-butyldimethylsilyl)oxy)hexadecanal (R)-104d: Alcohol (R)-314 (410 mg, 1.10 12OHOTBS(R)-31412HOTBS(R)-104d85% yieldDess-Martin periodinaneCH2Cl2, rt, 30 minO!&,'!mmol) was reacted according to the general procedure B with Dess-Martin periodinane (560 mg, 1.32 mmol, 1.20 equiv) in CH2Cl2 (5.5 mL) for 30 min (until the alcohol was no longer detectable by TLC). Purification of the crude aldehyde by silica gel chromatography (20 mm $ 150 mm column, 10:1hexanes/Et2O as eluent, flash column) afforded pure (R)-104d as a colorless liquid in 85 % isolated yield (346 mg, 0.935 mmol). Spectral data for (R)-104d: Rf = 0.12 (10:1 hexanes/Et2O); 1H-NMR (300 MHz, CDCl3) & 0.07 (s, 3H), 0.08 (s, 3H), 0.88 (t, 3H, J = 6.8 Hz), 0.92 (s, 9H), 1.22-1.41 (m, 24H), 1.57-1.65 (m, 33m), 3.96 (ddd, 1H, J = 6.9, 5.6, 1.5 Hz), 9.59 (d, 1H, J = 1.8 Hz); 13C-NMR (126 MHz, CDCl3) & Ð4.93, Ð4.62, 14.10, 18.20, 22.69, 25.75, 29.36, 29.43, 29.45, 29.53, 29.62, 29.66, 29.68, 29.69, 31.93, 32.64, 77.71, 204.32 (two sp3 carbons not located); IR (thin film) 2928vs, 2855vs, 1738s, 1464s, 1253s cm-1; !!!!!" +18.6¡ (c 1.0, CH2Cl2).  (S)-2-phenyl propanal (S)-104e: (S)-2-phenyl propanol (S)-315 (150 µL, 1.10 mmol) was reacted according to the general procedure B with Dess-Martin periodinane (560 mg, 1.32 mmol, 1.20 equiv) in CH2Cl2 (5.5 mL) for 30 min (until the alcohol was no longer detectable by TLC). Purification of the product by silica gel chromatography (20 mm ' 150 mm column, 9:1 hexanes/Et2O as eluent, flash column) afforded pure aldehyde (S)-104e as a colorless liquid in 70% isolated yield (103 mg, 0.77 mmol).  Spectral data for (S)-104e: Rf = 0.14 (1:1 CH2Cl2/hexanes) 1H-NMR (500 MHz, CDCl3) & 1.45 (d, 3H, J = 7.1 Hz), 3.64 (qd, 1H, J = 7.1, 1.3 Hz), 7.21-7.23 (m, 33m), 7.29-7.32 (m, 1H), 7.37- 7.40 (m, 33m), 9.69 (d, 1H, J = 1.5 Hz); 13C-NMR (125 MHz, CDCl3) & 14.61, 53.02, 127.52, PhOHDMPCH2Cl2, rt. 30 minPhCHO(S)-104e(S)-315!&,(!128.30, 129.08, 137.76, 201.03; !!!!!" +290.0¡ (c 0.45, benzene) Lit13 !!!!!" +314.6¡ (c 0.45, benzene).  (S)-2-Methylbutanal (S)-104f: (S)-2-methylbutan-1-ol (S)-316 (5.4 mL, 50 mmol) was reacted according to general procedure B with Dess-Martin periodinane (25.4 g, 60.0 mmol, 1.20 equiv) in freshly distilled CH2Cl2 (100 mL) for 2 h (until the alcohol was no longer detectable by TLC). The crude mixture was treated with bulb-to-bulb distillation under vacuum (0.5 mmHg) to afforded 2.15 g of an oil that was a mixture of the aldehyde (S)-104f (1.70 g, 19.8 mmol, 40%) and CH2Cl2 (5.2 mmol). The aldehyde (S)-104f was dissolved into dry toluene at a 2 M concentration and stored under nitrogen at Ð10 ¡C to be used for the next step without further purification.  Spectral data for (S)-104f: 1H-NMR (500 MHz, CDCl3) & 0.94 (t, 3H, J = 7.5 Hz), 1.09 (d, 3H, J = 7.5 Hz), 1.39-1.47 (m, 1H), 1.71-1.77 (m, 1H), 2.25-2.29 (m, 1H), 9.64 (d, 1H); 13C-NMR (125 Hz, CDCl3) d 11.33, 12.83, 23.48, 47.73, 205.45.  These spectral data matched those previously described.14  Ethyl (R)-2-cyclohexyl-2-hydroxyacetate (R)-307g: (R)-hexahydromandelic acid (R)-306g (791 mg, 5.00 mmol) was reacted according to the first step of the general procedure A with CsF-Celite (2.60 g) and iodoethane (1.20 mL, 15.0 mL, 3.00 equiv) in dry acetonitrile (120 mL).  Purification of the product by silica gel chromatography (30 mm ' 300 mm column, 20:1 hexanes/EtOAc, flash column) afforded pure ester (R)-307g as a OHDMPCHO(S)-104f(S)-316CH2Cl2, rt. 2 hOHCO2Et(R)-307gEtI, CsF-CeliteMeCN, refulx, 8 hOHCO2H(R)-306g!&,)!white solid (mp 39Ð40 ¡C) in 65% isolated yield (605 mg, 3.25 mmol). Spectral data for (R)-307g: Rf = 0.34 (20:1 hexanes/EtOAc) 1H-NMR (500 MHz, CDCl3) & 1.17-1.28 (m, 104h), 1.31 (t, 3H, J = 7.1 Hz), 1.44-1.45 (m, 1H), 1.64-1.79 (m, 104h), 2.65 (d, 1H, J = 6.3 Hz), 4.00 (dd, 1H, J = 6.2, 3.5 Hz), 4.25 (qd, 33m, J = 7.1, 1.3 Hz); 13C-NMR (125 MHz, CDCl3) & 14.26, 26.01, 26.05, 26.27, 26.34, 29.09, 42.01, 61.51, 74.82, 174.88. !!!!!" Ð17.8¡ (c 1.5, CHCl3). Lit16 !!!!!" +17.7¡ (c 1.5, CHCl3, S-isomer).  Ethyl (R)-2-(tert-butyldimethylsilyloxy)-2-cyclohexylacetate (R)-308g: The ester (R)-307g (500 mg, 2.68 mmol) was reacted according to the second step of the general procedure A with imidazole and tert-butyldimethylsilylchloride in dry DMF (15 mL). Purification of the product by silica gel chromatography (30 mm ' 300 mm column, 100:1 hexanes/EtOAc as eluent, flash column) afforded pure ester (R)-308g as a colorless liquid in 85% isolated yield (685 mg, 2.28 mmol).  Spectral data for (R)-308g: Rf = 0.68 (20:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.03 (s, 3H), 0.04 (s, 3H), 0.90 (s, 9H), 1.08-1.23 (m, 6H), 1.27 (t, 3H, J = 7.1 Hz), 1.53-1.55 (m, 1H), 1.62-1.74 (m, 104h), 3.93 (d, 1H, J = 5.2 Hz), 4.17 (qd, 33m, J = 7.1, 2.9 Hz); 13C-NMR (125 MHz, CDCl3) & Ð5.39, Ð5.01, 14.23, 18.26, 25.93, 26.12, 26.21, 27.42, 29.32, 42.38, 60.32, 76.81, 173.41 (one sp3 carbon not located).  (R)-2-(tert-butyldimethylsilyloxy)-2-cyclohexylacetaldehyde (R)-104g: The ester (R)-308g TBSCl, imidazoleDMF, rt. 12 hOHCO2Et(R)-307gOTBSCO2Et(R)-308gDIBAL-HTHF, Ð78 ¡C, 2 hOTBSCO2Et(R)-308gOTBSCHO(R)-104g!&,*!(581 mg, 2.00 mmol) was reacted according to the third step of the general procedure A with DIBAL-H (4.0 mL, 1 M solution in hexanes, 4.0 mmol, 2.0 equiv) in dry diethyl ether. Purification of the product by silica gel chromatography (30 mm ' 300 mm column, 20:1 hexanes/Et2O as eluent, flash column) afforded pure aldehyde (R)-104g as a colorless liquid in 85% isolated yield (400 mg, 1.70 mmol). Spectral data for (R)-104g: Rf = 0.31 (20:1 hexanes/EtOAc) 1H-NMR (500 MHz, CDCl3) & 0.05 (s, 3H), 0.06 (s, 3H), 0.93 (s, 9H), 1.12-1.26 (m, 104h), 1.61-1.76 (m, 6H), 3.70 (dd, 1H, J = 5.1, 2.2 Hz), 9.59 (d, 1H, J = 2.2 Hz); 13C-NMR (125 MHz, CDCl3) & Ð4.82, Ð4.34, 18.45, 26.00, 26.20, 26.37, 26.43, 27.53, 29.23, 41.39, 82.01, 205.11; 1H-NMR and 13C-NMR data are well in agreement with literature reported value.16  Ethyl (R)-3-((tert-butyldimethylsilyl)oxy)butanoate (R)-318: Ethyl (R)-3-hydroxybutanoate (R)-318 (0.90 mL, 7.00 mmol) was reacted according to the second step of the general procedure A with imidazole (724 mg, 10.5 mmol, 1.50 equiv) and tert-butyldimethylsilylchloride (1.60 g, 10.5 mmol, 1.50 equiv) in dry DMF (15 mL). Purification of the product by silica gel chromatography (30 mm ' 300 mm column, 50:1 hexanes/Et2O as eluent, flash column) afforded pure ester (R)-318 as a colorless liquid in 85% isolated yield (1.47 g, 5.95 mmol).  Spectral data for (R)-318: Rf = 0.31 (20: hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.01 (s, 3H), 0.03 (s, 3H), 0.83 (s, 9H), 1.16 (d, 3H, J = 6.1 Hz), 1.23 (t, 3H, J = 7.1 Hz), 2.43 (dd, 1H, J = 14.5, 7.6 Hz), 2.43 (dd, 1H, J = 14.5, 7.6 Hz), 4.14-4.05 (m, 33m), 4.28-4.22 (m, 1H); 13C-NMR (125 MHz, CDCl3) & Ð5.08, Ð4.56, 14.15, 17.90, 23.88, 25.69, 44.93, 60.16, 65.81, 171.54; !!!!!" ÐOHCO2EtTBSCl, imidazoleDMF, rt. 16 hOTBSCO2Et(R)-318(R)-317!&,+!26.3¡ (c 1.0, CH2Cl2). Lit17 !!!!!" Ð25.5¡ (c 1.0, CH2Cl2).   (R)-3-((tert-butyldimethylsilyl)oxy)butanal (R)-104h: The "-silyloxy ester (R)-318 (487 mg, 2.0 mmol) was reacted according to the third step of the general procedure A with DIBAL-H (4.0 mL, 1 M solution in hexanes, 4.0 mmol, 2.0 equiv) in dry diethyl ether (7 mL) at Ð78 ¡C for 1 h. Purification of the product by silica gel chromatography (20 mm ' 300 mm column, 25:1 hexanes/Et2O as eluent, flash column) afforded pure aldehyde (R)-104 as a colorless liquid in 80% isolated yield (320 mg, 1.60 mmol). Spectral data for (R)-104h: Rf = 0.41 (1:1 CH2Cl2/hexanes); 1H-NMR (500 MHz, CDCl3) & 0.02 (s, 3H), 0.04 (s, 3H), 0.83 (s, 9H), 1.19 (d, 3H, J = 6.2 Hz), 2.38-2.55 (m, 33m), 4.32 (sextet, 1H, J = 6.0 Hz), 9.75 (t, 1H, J = 2.3 Hz); 13C-NMR (125 MHz, CDCl3) & Ð5.03, Ð4.47, 17.87, 24.08, 25.65, 52.90, 64.48, 202.02; !!!!!" Ð11.6¡ (c 1.0, CH2Cl2). Lit17 !!!!!" Ð11.3¡ (c 1.0, CH2Cl2).   Methyl (S)-3-phenylbutanoate (S)-320: To a 100 mL flame dried round bottom flask equipped with a stir bar and filled with nitrogen was added (S)-3-phenylbutanoic acid (S)-318 (647 mg, 4.00 mmol). Methanol (50 mL) was added to dissolve the acid. The flask was fitted with a rubber septum and a nitrogen balloon. The solution was cooled to 0 ¡C. To the reaction flask was added (trimethylsilyl)diazomethane (6.0 mL, 2 M in hexanes, 12 mmol, 3.0 equiv) over a period of 2 minutes. The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under DIBAL-HEt2O, Ð78 ¡C, 1 hOTBSCHO(R)-104hOTBSCO2Et(R)-318PhCO2HTMSCHN2MeOH, rt. 1 hPhCO2Me(S)-320(S)-319!&,,!reduced pressure. Purification of the product by silica gel chromatography (20 mm ' 150 mm column, 1:1 hexanes/Et2O as eluent, flash column) afforded pure ester (S)-320 as a colorless liquid in 94% isolated yield (673 mg, 3.76 mmol). Spectral data for (S)-320: Rf = 0.21 (9:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 1.32 (d, J = 7.0 Hz, 3H), 2.57 (dd, J = 15.2, 8.2 Hz, 1H), 2.65 (dd, J = 15.2, 6.9 Hz, 1H), 3.30 (sextet, J = 7.3 Hz, 1H), 3.63 (s, 3H), 7.25-7.21 (m, 3H), 7.33-7.30 (m, 33m); 13C-NMR (125 MHz, CDCl3) & 21.69, 36.37, 42.66, 51.38, 126.33, 126.63, 128.43, 145.63, 172.73; !!!!!" (43.7¡ (c 1.0, benzene). Reported !!!!!" (44.0¡ (c 1.0, benzene) (Sigma Aldrich).  (S)-3-phenylbutanal (S)-104i: The ester (S)-320 (585 mg, 2.00 mmol) was reacted according to the third step of the general procedure A with DIBAL-H (4.0 mL, 1 M solution in hexanes, 4.0 mmol, 2.0 equiv) in dry diethyl ether (10 mL) at Ð78 ¡C for 1 h. Purification of the product by silica gel chromatography (30 mm ' 300 mm column, 50:1 hexanes//Et2O as eluent, flash column) afforded pure aldehyde (S)-104i as a colorless liquid in 75% isolated yield (333 mg, 2.25 mmol).  Spectral data for (S)-104i: Rf  = 0.31 (6:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.33 (d, J = 7.0 Hz, 3H), 2.66 (ddd, J = 16.6, 7.7, 2.2 Hz, 1H), 2.76 (ddd, J = 16.6, 6.8, 1.8 Hz, 1H), 3.36 (dt, J = 14.3, 7.1 Hz, 1H), 7.22-7.24 (m, 3H), 7.30-7.33 (m, 33m), 9.71 (t, J = 2.0 Hz, 1H); 13C-NMR (125 MHz, CDCl3) & 22.13, 34.28, 51.70, 126.50, 126.72, 128.64, 145.42, 201.80; !!!!!" Ð39.5¡ (c 0.20, Et2O). Lit18 !!!!!" Ð38.0¡ (c 0.20, Et2O).    PhCO2Me(S)-320PhHO(S)-104iDIBALEt2O, Ð78 ¡C!&,-! (S)-oxirane-2-carbaldehyde (S)-104j:19 To a 250 mL flame-dried round bottom flask equipped with a stir bar was added (R)-glycidol (R)-321 (2.66 mL, 40.0 mmol) into dry CH2Cl2 (150 mL).  To the resulting solution was added TEMPO (312 mg, 2.00 mmol, 0.0500 equiv) and PhIO (10.6 g, 48.0 mmol, 1.20 equiv).  The suspension was cooled to 0 ¡C and Yb(OTf)3 (496 mg, 0.800 mmol, 0.0200 equiv) was added. The reaction mixture was stirred at 0 ¡C for 50 min (until the alcohol was no longer detectable by TLC). The resulting suspension was filtered through a Celite pad and concentrated under reduced pressure at room temperature. The crude mixture was bulb-to-bulb distilled at 0 ¡C under vacuum (0.05 mmHg). The aldehyde (S)-104j was collected in the receiving round-bottom flask cooled in liquid nitrogen as a colorless liquid (1.82 g) and was determined to be a mixture of aldehyde (S)-104j (12.4 mmol), iodobenzene (3.60 mmol) and CH2Cl2 (2.23 mmol). The mixture was dissolved in dry toluene to a 2 M concentration and stored under nitrogen at Ð10 ¡C to be used for the next step without further purification.  Spectral data for (S)-104j: 1H-NMR (500 MHz, CDCl3) & 3.02 (dd, J = 5.2, 2.5 Hz, 1H), 3.13 (dd, J = 5.2, 4.5 Hz, 1H), 3.34 (ddd, J = 6.5, 4.5, 2.2 Hz, 1H), 8.94 (d, J = 6.5 Hz, 1H); 13C-NMR (125 MHz, CDCl3) & 44.51, 53.02, 198.13; !!!!!" Ð38.2¡ (c 1.0, CHCl3) on 99% material.  (2S,3S)-1-bis((4-methoxy-3,5-dimethylphenyl)methyl)-3-propylaziridine-2-carboxaldehyde (2S,3S)-104k:  The previously reported aziridine 2-carboxylate (2S,3S)-OHOPhIO, TEMPOYb(OTf)3CH2Cl2, 0 ¡C, 1 hCHOO(S)-104j(R)-321NMEDAMCO2EtDIBAL-HEt2O, Ð78 ¡C, 1 hNMEDAMCHO(2S,3S)-322(2S,3S)-104k!&,.!3224 (527 mg, 1.20 mmol) was reacted according to the third step of the general procedure A with DIBAL-H (2.40 mL, 1 M solution in hexanes, 2.40 mmol, 1.20 equiv) in dry diethyl ether (4 mL) at Ð78 ¡C for 1 h. Purification of the crude aldehyde by silica gel chromatography (30 mm ' 300 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded pure aldehyde (2S,3S)-104k as a colorless liquid in 70% isolated yield (332 mg, 0.84 mmol). Spectral data for (2S,3S)-104k: Rf  = 0.31 (2:1:0.2 hexanes/ CH2Cl2/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.80 (t, J = 7.3 Hz, 3H), 1.12-1.18 (m, 1H), 1.22-1.29 (m, 1H), 1.50-1.57 (m, 1H), 1.63-1.70 (m, 1H), 2.11-2.20 (m, 33m), 2.25 (s, 6H), 2.29 (s, 6H), 3.49 (s, 1H), 3.70 (s, 3H), 3.71 (s, 3H), 7.03 (s, 33m), 7.06 (s, 33m), 9.44 (d, J = 5.6 Hz, 1H); 13C-NMR (125 MHz, CDCl3) & 13.51, 16.15, 16.19, 20.65, 31.34, 48.89, 49.86, 59.54, 59.60, 76.86, 127.26, 127.72, 130.63, 130.70, 137.42, 138.04, 156.02, 156.16, 201.03; IR (thin film) 2959vs, 2930vs, 1719s, 1483s, 1221s, 1140s cm-1; HRMS (ESI-TOF) m/z 396.2465 [(M+H+); calcd. for C2104h34NO3 396.2460]; !!!!!" Ð85.0¡ (c 1.0, CH2Cl2).  6.2.3. Multi-Component cis-Aziridination of Chiral Aldehydes 104a-i General Procedure for the Multi-Component Aziridination of Chiral Aldehydes  To a 10 mL flame-dried home-made Schlenk flask, prepared from a 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added ligand 68a, 68b or 68c (0.020 mmol), B(OPh)3 (17 mg, 0.060 mmol) and amine 101a or 101b (0.200 mmol). Under an FGR1R2**OH5 or 10 mol% catalystamine 101, EDA 1024 † MStolueneÐ10 ¡C, 24 hNR2R1FGOOEtNR2R1FGOOEt+104a-m105a-mArArArAr105a'-m'!&-/!argon flow through the side arm of the Schlenk flask, dry toluene (0.5 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ¡C) for 0.5 h. The flask was then allowed to cool to room temperature and opened to argon through side arm of the Schlenk flask. To the flask containing the catalyst was added the 4† Molecular Sieves (50 mg, freshly flame-dried). The flask was then allowed to cool to Ð10 ¡C and aldehyde (0.22 mmol, 1.1 equiv) was added to the reaction mixture. To this solution was rapidly added ethyl diazoacetate (EDA) 102 (25 µL, 0.24 mmoL, 1.2 equiv). The resulting mixture was stirred for 24 h at Ð10 ¡C. The reaction was diluted by addition of hexane (3 mL) at Ð10 ¡C before the reaction mixture was filtered through a silica gel plug into a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL ' 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a yellow colored viscous oil. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, gravity column) afforded an inseparable disatereomeric mixture of aziridines. Experimental Details for the Multi-Component Aziridination of Chiral Aldehydes  (2S,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-(tert-butyldimethylsilyloxy) (phenyl) methyl)aziridine-2-carboxylate (2S,4R)-105aÕ (Table 2.5, entry 6): Aldehyde (R)-104a was reacted according to the general procedure with (R)-VAPOL (11 mg, 0.020 mmol) as ligand at Ð10 ¡C to afford aziridines (2S,4R)-105aÕ and 10 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(R)-104aNOTBSPhMEDAMOOEt(2S,4R)-105a'NOTBSPhMEDAMOOEt(2R,4R)-105aOTBSPhOH!&-&!(2R,4R)-105a with 99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105a and 105aÕ as a white solid (mp 139-140 ¡C on 99:1 dr material) in 90% isolated yield (111 mg, 0.180 mmol). The diastereomeric ratio of (2S,4R)-105aÕ to (2R,4R)-105a was determined to be 99:1 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 8.49 min (minor diastereomer, (2R,4R)-105a) and Rt = 17.92 min (major diastereomer, (2S,4R)-105aÕ).  (Table 2.5, entry 8): Aldehyde (R)-104a was reacted according to the general procedure with (R)-VANOL (8.8 mg, 0.020 mmol), as ligand at Ð10 ¡C to afford aziridines (2S,4R)-105aÕ and (2R,4R)-105a with 98:2 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105aÕ and 105a in a 98:2 ratio as a white solid in 85% isolated yield (105 mg, 0.170 mmol).  Single crystals of 105aÕ were grown and an X-ray diffraction analysis performed and the results deposited with the CCDC (1495343).  The cif can be found in the supporting information as a separate file.  Spectral data for (2S,4R)-105aÕ: Rf = 0.28 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (500 MHz, CDCl3) & Ð0.26 (s, 3H), Ð0.23 (s, 3H), 0.60 (s, 9H), 1.17 (t, 3H, J = 7.1 Hz), 1.99 (d, 1H, J = 7.0 Hz), 2.23 (s, 6H), 2.26 (s, 6H), 2.43 (t, 1H, J = 7.5 Hz), 3.49 (s, 1H), 3.68 (s, 3H), 3.70 (s, 3H), 4.06 (dq, 1H, J = 10.8, 7.1 Hz), 4.14 (dq, 1H, J = 10.8, 7.1 Hz), 4.70 (d, 1H, J = 7.9 Hz), 7.05 (s, 4H), 7.21-7.28 (m, 104h); 13C-NMR (125 MHz, CDCl3) & Ð!&-'!5.12, Ð5.07, 14.12, 16.17, 16.24, 17.84, 25.55, 41.68, 55.25, 59.40, 59.54, 60.63, 73.40, 77.65, 126.54, 127.23, 127.47, 128.03, 128.63, 130.35, 130.44, 137.97, 138.20, 142.67, 155.64, 156.15, 169.78; IR (thin film) 2955vs, 2928vs, 1742vs, 1483s, 1221s, 1188vs, 1140s cm-1; HRMS (ESI-TOF) m/z 618.3631 [(M+H+); calcd. for C3105h52NO5Si: 618.3615]; !!!!!" Ð92.6¡ (c 1.0, CH2Cl2) on 99:1 dr material (HPLC).   (2R,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-(tert-butyldimethylsilyloxy)(phenyl) methyl)aziridine-2-carboxylate (2R,4R)-105a (Table 2.5, entry 5): Aldehyde (R)-104a was reacted according to the general procedure with (S)-VAPOL (11 mg, 0.020 mmol) as ligand to afford aziridines (2R,4R)-105a and (2S,4R)-105aÕ in 98:2 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105a and 105aÕ as a white solid (mp 49-50 ¡C on 98:2 dr material) in 90% isolated yield (111 mg, 0.180 mmol). The diastereomeric ratio of (2R,4R)-105a and (2S,4R)-105aÕ was determined to be 98:2 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2-propanol at 222nm), flow-rate: 0.7 mL/min, retention times: Rt = 8.30 min (major diastereomer, (2R,4R)-105a) and Rt = 18.48 min (minor diastereomer, (2S,4R)-105aÕ).  (Table 2.5, entry 7): Aldehyde (R)-104a was reacted according to the general procedure with (S)-VANOL (8.8 mg, 0.020 mmol), as ligand at Ð10 ¡C to afford aziridines (2R,4R)-10 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(R)-104aNOTBSPhMEDAMOOEt(2S,4R)-105a'NOTBSPhMEDAMOOEt(2R,4R)-105aOTBSPhOH!&-(!105a and (2S,4R)-105aÕ in 98:2 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105a and 105aÕ as a white solid in 85% isolated yield (105 mg, 0.170 mmol). Spectral data for (2R,4R)-105a: Rf = 0.28 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (600 MHz, CDCl3) & Ð0.33 (s, 3H), Ð0.09 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 0.79 (s, 9H), 2.01 (s, 6H), 2.21 (s, 6H), 2.28 (d, 1H, J = 6.4 Hz), 2.40 (dd, 1H, J = 8.2, 6.4 Hz), 3.32 (s, 1H), 3.59 (s, 3H), 3.67 (s, 3H), 4.16 (dq, 1H, J = 10.8, 7.2 Hz), 4.29 (dq, 1H, J = 10.8, 7.1 Hz), 4.61 (d, J = 8.2 Hz, 1H), 6.51 (s, 33m), 6.99 (s, 33m), 7.00-7.01 (m, 3H), 7.11 (dd, 33m, J = 6.6, 2.9 Hz); 13C-NMR (150 MHz, CDCl3) & 14.18, 15.25, 16.03, 16.13, 17.92, 25.63, 25.63, 42.92, 54.13, 59.25, 59.55, 60.82, 65.82, 72.33, 126.49, 126.91, 127.14, 127.23, 128.07, 129.69, 130.39, 136.99, 137.66, 142.32, 155.61, 155.63, 169.56; IR (thin film) 2955vs, 2930vs, 1742s, 1483s, 1221s, 1188vs, 1147s cm-1; HRMS (ESI-TOF) m/z 618.3641 [(M+H+); calcd. for C3105h52NO5Si: 618.3615]; !!!!!" +107.0¡ (c 1.0, CH2Cl2) on 98:2 dr material (HPLC).  (2S,3R)-ethyl 1-benzhydryl-3-((R)-(tert-butyldimethylsilyloxy)(phenyl)methyl)aziridine-2-carboxylate (2S,4R)- 106aÕ (Table 2.5, entry 10): Aldehyde (R)-104a was reacted according to the general procedure with (R)-VAPOL (11 mg, 0.020 mmol) as ligand to afford aziridines (2S,4R)-106aÕ and (2R,4R)-106a with 94:6 diastereomeric ratio. Purification of the crude 10 mol% (R)-BOROXamine 101bEDA 1024 † MStolueneÐ10 ¡C, 24 h+(R)-104aNOTBSOOEt(2S,4R)-106a'NOTBSPhOOEt(2R,4R)-106aOTBSPhOHPhPhPhPhPh!&-)!aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 106a and 106aÕ as a white solid (mp 93-97 ¡C on 94:6 dr material) in 65% isolated yield (65.4 mg, 0.130 mmol). The diastereomeric ratio of (2S,4R)-106aÕ and (2R,4R)-106a was determined to be 94:6 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 6.43 min (minor diastereomer, (2R,4R)-106a) and Rt = 11.47 min (major diastereomer, (2S,4R)-106aÕ).   Spectral data for (2S,4R)-106aÕ: Rf = 0.25 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (500 MHz, CDCl3) & Ð0.24 (s, 3H), Ð0.21 (s, 3H), 0.63 (s, 9H), 1.16 (t, 3H, J = 7.1 Hz), 2.09 (d, 1H, J = 7.0 Hz), 2.49 (dd, 1H, J = 8.0, 7.0 Hz), 3.79 (s, 1H), 4.14-4.07 (m, 33m), 4.74 (d, 1H, J = 8.0 Hz), 7.19-7.30 (m, 11H), 7.42-7.45 (m, 4H); 13C-NMR (125 MHz, CDCl3) & Ð4.95, Ð4.80, 14.07, 17.98, 25.76, 41.68, 54.57, 60.72, 73.31, 77.85, 126.51, 126.97, 127.29, 127.33, 127.54, 128.08, 128.29, 128.36, 128.40, 142.36, 142.57, 142.66, 169.59; IR (thin film) 2933vs, 1730vs, 1454s, 1256s, 1199vs cm-1; HRMS (ESI-TOF) m/z 502.2765 [(M+H+); calcd. for C31H40NO3Si: 502.2777]; !!!!!" Ð70.5¡ (c 1.0, CH2Cl2) on 94:6 dr material (HPLC).  (2R,3S)-ethyl 1-benzhydryl-3-((R)-(tert-butyldimethylsilyloxy)(phenyl)methyl)aziridine-2-carboxylate (2R,4R)-7a (Table 2.5, entry 9): Aldehyde (R)-104a was reacted according to the general procedure with (S)-VAPOL (11 mg, 0.020 mmol) as ligand to afford 10 mol% (S)-BOROXamine 101bEDA 1024 † MStolueneÐ10 ¡C, 24 h+(R)-104aNOTBSOOEt(2S,4R)-106a'NOTBSPhOOEt(2R,4R)-106aOTBSPhOHPhPhPhPhPh!&-*!aziridines (2R,4R)-106a and (2S,4R)-106aÕ in 99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 106a and 106aÕ as a white solid (mp 126-131 ¡C on 99:1 dr material) in 50% isolated yield (49.7 mg, 0.100 mmol). The diastereomeric ratio of (2R,4R)-106a and (2S,4R)-106aÕ was determined to be 99:1 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 6.44 min (major diastereomer, (2R,4R)-106a) and Rt = 11.76 min (minor diastereomer, (2S,4R)-106aÕ).  Spectral data for (2R,4R)-106a: Rf = 0.25 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (500 MHz, CDCl3) & Ð0.33 (s, 3H), Ð0.10 (s, 3H), 0.78 (s, 9H), 1.28 (t, 3H, J = 7.2 Hz), 2.35 (d, 1H, , J = 6.4 Hz), 2.44 (t, 1H, J = 7.2 Hz), 3.58 (s, 1H), 4.12-4.28 (m, 33m), 4.62 (d, 1H, J = 7.9 Hz), 6.84-7.13 (m, 10H), 7.24 (t, 3H, J = 7.3 Hz), 7.36 (d, 33m, J = 7.4 Hz); 13C-NMR (125 MHz, CDCl3) & Ð5.10, Ð4.61, 14.11, 17.95, 25.66, 42.93, 53.86, 60.88, 72.22, 77.75, 126.64, 126.76, 126.89, 127.05, 127.12, 127.52, 127.74, 127.87, 128.28, 141.37, 142.35, 142.40, 169.37; IR (thin film) 2932vs, 1728vs, 1454s, 1252s, 1198vs cm-1; HRMS (ESI-TOF) m/z 502.2761 [(M+H+); calcd for C31H40NO3Si: 502.2777]; !!!!!" +105.3¡ (c 1.0, CH2Cl2) on 99:1 dr material (HPLC).    !&-+! (2S,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-(tert-butyldimethylsilyloxy)ethyl) aziridine-2-carboxylate (2S,4S)-7bÕ: Aldehyde (S)-5b was reacted according to the general procedure with (R)-VAPOL (11 mg, 0.020 mmol) as ligand at Ð10 ¡C to afford aziridines (2S,4S)-7bÕ and (2R,4S)-7b with 96:4 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 7b and 7bÕ as a sticky solid in 87% isolated yield (96.6 mg, 0.174 mmol). The diastereomeric ratio of (2S,4S)-7bÕ and (2R,4S)-7b was determined to be 96:4 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention imes: Rt = 12.36 min (minor diastereomer, (2R,4S)-7b) and Rt = 13.94 min (major diastereomer, (2S,4S)-7bÕ).  Aldehyde (R)-5b was reacted according to the general procedure with (R)-VANOL (8.8 mg, 0.020 mmol), as ligand at Ð10 ¡C to afford aziridines (2S,4S)-7bÕ and (2R,4S)-7b with a 95:5 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 7b and 7bÕ as a sticky solid in 82 % isolated yield (91 mg, 0.164 mmol).   Spectral data for (2S,4S)-7bÕ: Rf = 0.37 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (500 MHz, CDCl3) & Ð0.06 (s, 3H), Ð0.04 (s, 3H), 0.71 (d, 3H, J = 6.2 Hz), 0.82 (s, 9H), 1.26 (t, 3H, J = 7.1 Hz), 2.06 (dd, 1H, J = 8.2, 6.5 Hz), 2.22-2.24 (m, 13H), 3.45 (s, 1H), 3.66 10 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(S)-104bOTBSOHNOTBSMEDAMOOEt(2S,4S)-105b'NOTBSMEDAMOOEt(2R,4S)-105b!&-,!(s, 3H), 3.70 (s, 3H), 3.72- 3.81 (m, 1H), 4.06-4.28 (m, 33m), 6.95 (s, 33m), 7.07 (s, 33m); 13C-NMR (125 MHz, CDCl3) & Ð 4.91, Ð4.34, 14.15, 16.05, 16.16, 17.84, 22.18, 25.70, 43.47, 53.01, 59.59, 59.64, 60.78, 66.12, 127.16, 128.66, 130.43, 130.53, 137.48, 137.76, 155.76, 156.42, 169.50 (one sp3 carbon not located); IR (thin film) 2957vs, 2930vs, 1744s, 1483s, 1221s, 1194vs cm-1; HRMS (ESI-TOF) m/z 556.3470 [(M+H+); calcd for C333m50NO5Si: 556.3458]; !!!!!" Ð93.3¡ (c 0.6, CH2Cl2) on 96:4 dr material (HPLC).  (2R,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-(tert-butyldimethylsilyloxy)ethyl) aziridine-2-carboxylate (2R,4S)-7b: Aldehyde (S)-5b was reacted according to the general procedure with (S)-VAPOL (11 mg, 0.020 mmol) as ligand at Ð10 ¡C to afford aziridines (2R,4S)-7b and (2S,4S)-7bÕ in a 91:9 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 7b and 7bÕ as a sticky solid in 85% isolated yield (94.1 mg, 0.170 mmol). The diastereomeric ratio of (2R,4S)-7b to (2S,4S)-7bÕ was determined to be 91:9 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 11.63 min (major diastereomer, (2R,4S)-7b) and Rt = 13.67 min (minor diastereomer, (2S,4S)-7bÕ).  Spectral data for (2R,4S)-7b: Rf = 0.37 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (500 MHz, CDCl3) & Ð0.33 (s, 3H), Ð0.02 (s, 3H), 0.70 (s, 9H), 1.05 (d, 3H, J = 6.3 Hz), 1.27 10 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(S)-104bOTBSOHNOTBSMEDAMOOEt(2S,4S)-105b'NOTBSMEDAMOOEt(2R,4S)-105b!&--!(t, 3H, J = 7.1 Hz), 2.07 (d, 1H, J = 7.1 Hz), 2.14-2.19 (m, 1H), 2.22 (s, 6H), 2.23 (s, 6H), 3.42 (s, 1H), 3.66 (s, 3H), 3.68 (s, 3H), 3.75-3.84 (m, 1H), 4.11-4.26 (m, 33m), 6.96 (s, 33m), 7.04 (s, 33m); 13C-NMR (125 MHz, CDCl3) & Ð5.13, Ð5.00, 14.32, 16.18, 17.93, 21.52, 25.69, 41.53, 54.44, 59.38, 59.57, 60.71, 67.51, 77.78, 127.28, 128.76, 130.35, 130.40, 137.87, 138.15, 155.63, 156.14, 169.80 (one sp3 carbon not located); IR (thin film) 2928vs, 2956s, 1746s, 1484s, 1221s, 1188vs, 1097s cm-1; HRMS (ESI-TOF) m/z 556.3475 [(M+H+); calcd. for C333m50NO5Si: 556.3458]; !!!!!" +69.8¡ (c 0.6, CH2Cl2) on 91:9 dr material (HPLC).  (2S,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-1-((tertbutyldimethylsilyl)oxy) penta- decyl)aziridine-2-carboxylate 105cÕ  (Table 2 entry 5): Aldehyde (R)-104c was reacted according to the general procedure with 5 mol% catalyst prepared from (R)-VAPOL at Ð10 ¡C and 0.2 M to afford aziridine (2S,4R)-105cÕ.  Purification of the crude aziridine by neutral alumina chromatography (30 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded aziridine 105cÕ as a colorless oil in 94 % isolated yield (347 mg, 0.470 mmol).  The diastereomeric ratio of 105cÕ and 105c was determined to be >99:1 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R,R) WHELK-O 1 column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major diastereomer, 105cÕ) and Rt = 12.52 min (minor diastereomer, 105c).  Spectral data for 105cÕ: Rf = 0.44 (2:1:0.1 hexanes/CH2Cl2/Et2O); 1H NMR (300 MHz, 5 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(R)-104cOTBSOHNOTBSMEDAMOOEt(2S,4R)-105c'NOTBSMEDAMOOEt(2R,4R)-105c121212!&-.!CDCl3): & Ð0.35 (s, 3H), Ð0.02 (s, 3H), 0.88 (t, 3H, J = 6.7 Hz), 0.70 (s, 9H), 1.21-1.37 (m, 29H), 2.05 (d, J = 7.0 Hz, 1H), 2.16-2.18 (m, 1H), 2.21 (s, 6H), 2.22 (s, 6H), 3.48 (s, 1H), 3.66-3.73 (m, 105h), 4.22-4.11 (m, 33m), 6.95 (s, 33m), 7.00 (s, 33m); 13C-NMR (126 MHz, CDCl3): & Ð4.91, Ð4.82, 14.10, 14.32, 16.17, 16.19, 17.94, 22.68, 24.17, 25.79, 29.35, 29.51, 29.57, 29.64, 29.67, 29.68, 30.03, 31.92, 36.24, 41.59, 53.23, 59.38, 59.58, 60.68, 70.44, 77.61, 127.51, 128.86, 130.33, 130.39, 137.81, 138.01, 155.66, 156.11, 170.05 (one sp3 carbon not located); IR (thin film) 2928vs, 2855vs, 1747s, 1485s, 1221s, 1184vs cm-1; HRMS (ESI-TOF) m/z 738.5469 [(M++H); calcd. for C4104h76NO5Si: 738.5472];!!!!!!" Ð68.3¡ (c 1.0, CH2Cl2).  (2R,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-1-((tertbutyldimethylsilyl)oxy) penta-decyl)aziridine-2-carboxylate 105c: Aldehyde (R)-104c was reacted according to the general procedure with 5 mol% catalyst prepared from (S)-VAPOL at Ð10 ¡C and 0.2 M to afford a mixture of aziridines (2R,4R)-105c and (2S,4R)-105cÕ with a 90:10 diastereomeric ratio.  Purification of the crude aziridine by neutral alumina chromatography (30 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105c and 105cÕ as a colorless oil in 88% isolated yield (325 mg, 0.440 mmol).  Spectral data for 105c: Rf = 0.44 (2:1:0.1 hexanes/CH2Cl2/Et2O); 1H-NMR (500 MHz, CDCl3): & Ð0.05 (s, 3H), Ð0.03 (s, 3H), 0.85 (s, 9H), 0.90 (t, 3H, J = 7.0 Hz), 1.22-1.30 (m, 29H), 2.13- 2.15 (m, 1H), 2.21-2.24 (m, 13H), 3.44 (s, 1H), 3.67 (s, 3H), 3.69 (s, 3H), 5 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(R)-104cOTBSOHNOTBSMEDAMOOEt(2S,4R)-105c'NOTBSMEDAMOOEt(2R,4R)-105c121212!&./!3.71-3.74 (m, 1H), 4.09-4.28 (m, 33m), 6.99 (s, 33m), 7.07 (s, 33m); 13C-NMR (126 MHz, CDCl3): & Ð4.65, Ð4.56, 14.08, 14.14, 16.08, 16.13, 18.00, 22.67, 23.74, 25.77, 25.78, 29.34, 29.58, 29.60, 29.63, 29.65, 29.68, 29.94, 31.91, 35.90, 43.34, 51.96, 59.47, 59.54, 60.74, 69.01, 77.73, 127.01, 128.55, 130.41, 130.50, 137.69, 137.77, 155.71, 156.43, 169.70 (one sp3 carbon not located); IR (thin film) 2928vs, 2855vs, 1744s, 1483s, 1221s, 1186vs cm-1; HRMS (ESI-TOF) m/z 738.5471 [(M++H); calcd for C4104h76NO5Si: 738.5472]; !!!!!" +36.0¡ (c 1.0, CH2Cl2).  (2S,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-1-phenylethyl)aziridine-2-carboxylate (2S,4S)-105dÕ: Aldehyde (S)-104d was reacted according to the general procedure with (R)-VAPOL (11 mg, 0.020 mmol) as ligand and EDA (83 µL, 0.80 mmol, 4.0 equiv) at Ð10 ¡C and at 0.04 M in amine 101a.  Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105d and 105dÕ as a sticky solid in 90% isolated yield (90.3 mg, 0.180 mmol). The stereoisomeric ratio of 105dÕ, 105d, ent-105dÕ and ent-105d was determined to be 83.16:10.71:0.05:6.07 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min), retention times: Rt = 14.90 min (ent-105dÕ), Rt = 15.79 min (105d), Rt = NMEDAMOOEtNMEDAMOOEt(2R,4S)-105d(2S,4S)-105d'10 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+NMEDAMOOEtNMEDAMOOEt(2R,4R)-105d'(2S,4R)-105d++CHO(S)-104dHNMEDAMintermediate imine(S)-323!&.&!21.82 min (105dÕ) and Rt = 26.25 min (ent-105d).  Analysis of the HPLC data lead to the following results: dr = 5:1 (105dÕ + ent-105dÕ) : (105d + ent-105d); % ee 105dÕ 99.9%; % ee of  105d 43%.  Although no imine 34d was detected at the end of the reaction, the % ee of intermediate imine (S)-34d was calculated as 93% from the ratio (105dÕ + 105d) : (ent-105dÕ + ent-105d).  The reaction was repeated at 0.4 M in amine 123a and gave the following results:  90% yield, dr = 3.5:1 (105dÕ + ent-105dÕ) : (105d + ent-105d); % ee 105dÕ 99.5%; % ee of  105d Ð35%.  Although no imine 34d was detected at the end of the reaction, the % ee of intermediate imine (S)-34d was calculated as 69% from the ratio (105dÕ + 105d) : (ent-105dÕ + ent-105d).  Spectral data for (2S,4S)-105dÕ: Rf = 0.31 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.15 (d, 3H, J = 7.2 Hz), 1.31 (t, 3H, J = 7.1 Hz), 2.02 (s, 6H), 2.19 (dd, 1H, J = 6.4, 3.1 Hz), 2.22 (s, 6H), 2.26 (d, 1H, J = 6.8 Hz), 2.80-2.86 (m, 1H), 3.33 (s, 1H), 3.61 (s, 3H), 3.67 (s, 3H), 4.23-4.30 (m, 33m), 6.63 (s, 33m), 6.96-7.00 (m, 104h), 7.04 (s, 33m); 13C-NMR (125 MHz, CDCl3) & 14.37, 16.02, 16.15, 19.21, 38.37, 42.99, 53.46, 59.32, 59.55, 60.77, 77.52, 125.78, 126.93, 127.22, 127.60, 127.99, 129.84, 130.40, 137.46, 137.78, 143.95, 155.70, 169.70 (one sp2 carbon not located); IR (thin film) 2932vs, 1741s, 1483s, 1221s, 1186vs, 1148s cm-1; HRMS (ESI-TOF) m/z 502.2976 [(M+H+); calcd. for C333m40NO4: 502.2957]; !!!!!" Ð73.9¡ (c 0.6, CH2Cl2) on dr = 4:1 material (HPLC). !&.'! (2R,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-1-phenylethyl)aziridine-2-carboxylate (2R,4S)-7c: Aldehyde (S)-104d was reacted according to the general procedure with (S)-VAPOL (11 mg, 0.020 mmol) as ligand and EDA (83 µL, 0.80 mmol, 4.0 equiv) at Ð10 ¡C and at 0.04 M in amine 101a.  Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105d and 105dÕ as a sticky solid in 92% isolated yield (91.8 mg, 0.184 mmol).  The diastereomeric ratio of 105dÕ, 105d, ent-105dÕ and ent-105d was determined to be 0.37:95.40:3.49:0.74 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min). Comparing the HPLC data following results were determined: dr = 24:1 (105d + ent-105d):(105d + ent-105dÕ); % ee of 105d is 99%; % ee of ent-105dÕ is Ð80%.  Although no imine 34d was detected at the end of the reaction, the % ee intermediate imine (S)-34d was calculated as 91% ee from the ratio (105d + 105dÕ):(ent-105d + ent-105dÕ).  The reaction was repeated at 0.4 M in amine 123a and gave the following results:  85% yield, dr = 11:1 (105d + ent-105d):(105d + ent-105dÕ); % ee of 105d is 96.4%; % ee of ent-105dÕ is Ð86%.  Although no imine 34d was detected at the end of the reaction, the % ee intermediate imine (S)-34d was calculated as 81% ee from NMEDAMOOEtNMEDAMOOEt(2R,4S)-105d(2S,4S)-105d'10 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+NMEDAMOOEtNMEDAMOOEt(2R,4R)-105d'(2S,4R)-105d++CHO(S)-104dHNMEDAMintermediate imine(S)-323!&.(!the ratio (105d + 105dÕ):(ent-105d + ent-105dÕ).  Spectral data for (2R,4S)-105d: Rf = 0.31 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.90 (d, 3H, J = 7.0 Hz), 1.10 (t, 3H, J = 7.1 Hz), 2.14 (dd, 1H, J = 9.4, 6.8 Hz), 2.20 (d, 1H, J = 6.8 Hz), 2.26 (s, 6H), 2.28 (s, 6H), 2.81-2.87 (m, 1H), 3.47 (s, 1H), 3.69 (s, 3H), 3.70 (s, 3H), 4.07 (q, 33m, J = 7.1 Hz), 7.07 (s, 33m), 7.10 (dd, 33m, J = 8.2, 1.2 Hz), 7.14 (s, 33m), 7.16-7.19 (m, 1H), 7.23-7.27 (m, 33m); 13C-NMR (125 MHz, CDCl3) & 14.06, 16.10, 16.17, 19.96, 38.14, 44.02, 52.85, 59.56, 59.65, 60.60, 77.44, 126.29, 127.00, 127.23, 128.29, 128.53, 130.49, 130.53, 137.51, 138.10, 144.11, 155.78, 156.37, 169.47; IR (thin film) 2932vs, 1742s, 1485s, 1221s, 1188vs, 1148s cm-1; HRMS (ESI-TOF) m/z 502.2978 [(M+H+); calcd. for C333m40NO4: 502.2957]; !!!!!" +108.9¡ (c 0.6, CH2Cl2) on 23:1 dr material (HPLC).  (2S,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-sec-butyl)aziridine-2-carboxylate (2S,4S)-105eÕ: Aldehyde (S)-104e (1.62 mL, 2 M in toluene, 3.24 mmol, 1.20 equiv) was reacted according to the general procedure with (R)-tBu2VAPOL (145 mg, 0.270 mmol) as ligand and B(OPh)3 (235 mg, 0.810 mmol) at Ð40 ¡C for 48 h to afford aziridines (2S,4S)-105eÕ and (2R,4S)-105e with 96:4 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 10:1 hexanes/EtOAc as eluent, gravity column) afforded an inseparable mixture of aziridines 105eÕ and 105e as a viscous liquid in 90% isolated yield (1.10 g, 2.43 mmol). The diastereomeric ratio of (2S,4S)-105eÕ and (2R,4S)-105e was determined to be 10 mol% (R)-BOROXamine 101a EDA 1024 † MStolueneÐ40 ¡C, 48 hNMEDAMOOEt(2R,4S)-105e+NMEDAMOOEt(2S,4S)-105e'OH(S)-104e!&.)!96:4 by 1H-NMR with Ph3CH as the internal standard.  Spectral data for (2S,4S)-105eÕ: Rf = 0.70 (3:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.56 (t, 3H, J = 5.0 Hz), 0.76 (d, 3H, J = 5.0 Hz), 1.03-1.09 (m, 1H), 1.25 (t, 3H, J = 5.0 Hz), 1.27 (m, 1H), 1.35-1.42 (m, 1H), 1.71 (dd, 1H, J = 10.0, 5.0 Hz), 2.20 (d, 1H, J = 5.0 Hz), 2.23 (s, 6H), 2.24 (s, 6H), 3.38 (s, 1H), 3.66 (s, 3H), 3.69 (s, 3H), 4.14-4.27 (m, 33m), 6.98 (s, 33m), 7.11 (s, 33m); 13C-NMR (125 MHz, CDCl3) & 10.09, 14.35, 15.78, 16.05, 16.18, 26.91, 33.15, 43.61, 52.65, 59.61, 59.65, 60.67, 77.53, 127.29, 128.57, 130.38, 130.47, 137.56, 138.10,155.69, 156.27, 169.76; IR (thin film) 2960vs, 1750s, 1442s, 1275vs, 1260vs, 1038s cm-1; HRMS (ESI-TOF) m/z 476.2770 [(M+Na+); calcd. for C28H39NO4Na: 476.2777]; !!!!!" Ð99.5¡ (c 0.4, CH2Cl2) on 96:4 dr material (NMR).  (2R,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-sec-butyl)aziridine-2-carboxylate (2R,4S)-105e: Aldehyde (S)-104e (2.40 mL, 2 M in toluene, 4.80 mmol, 1.20 equiv) was reacted according to the general procedure with (S)-tBu2VAPOL (215 mg, 0.400 mmol) as ligand and B(OPh)3 (348 mg, 1.20 mmol) at Ð40 ¡C for 24 h afforded aziridines (2R,4S)-105e and (2S,4S)-105eÕ with a 96:4 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 10:1 hexanes/EtOAc as eluent, gravity column) afforded an inseparable mixture of aziridines 105e and 105eÕ as a viscous liquid in 95% isolated yield (1.72 g, 3.80 mmol). The diastereomeric ratio of (2R,4S)-105e to (2S,4S)-105eÕ was determined to be 96:4 by 10 mol% (S)-BOROXamine 101a EDA 1024 † MStolueneÐ40 ¡C, 24 hNMEDAMOOEt(2R,4S)-105e+NMEDAMOOEt(2S,4S)-105e'OH(S)-104e!&.*!1H-NMR with Ph3CH as the internal standard.  Spectral data for (2R,4S)-105e: Rf = 0.70 (3:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.48 (d, 3H, J = 5 Hz), 0.78 (t, 3H, J = 5.0 Hz), 1.11-1.14 (m, 1H), 1.25 (t, 3H, J = 5.0 Hz), 1.26 (m, 1H), 1.39-1.42 (m, 1H), 1.71 (dd, 1H, J = 10.0, 5.0 Hz), 2.20 (d, 1H, J = 5.0 Hz), 2.23 (s, 6H), 2.24 (s, 6H), 3.37 (s, 1H), 3.66 (s, 3H), 3.69 (s, 3H), 4.16-4.24 (m, 33m), 6.91 (s, 33m), 7.11 (s, 33m); 13C-NMR (125 MHz, CDCl3) & 11.23, 14.34, 16.08, 16.19, 17.65, 27.46, 33.37, 44.14, 53.08, 59.61, 59.66, 60.66, 77.64, 127.30, 128.60, 130.37, 130.48, 137.66, 138.09, 155.70, 156.27, 169.91; IR (thin film) 2958vs, 1744s, 1438s, 1275vs, 1260vs, 1017s cm-1; HRMS (ESI-TOF) m/z 476.2769 [(M+Na+); calcd. for C28H39NO4Na: 476.2777]; !!!!!" +70.1¡ (c 1.0, CH2Cl2) on 96:4 dr material (NMR).  (2S,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-(tert-butyldimethylsilyloxy) (cyclohexyl) methyl)aziridine-2-carboxylate (2S,4R)-105fÕ: Aldehyde (R)-104f was reacted according to the general procedure with 5 mol% catalyst prepared from (R)-tBu2VAPOL (5.5 mg, 0.010 mmol) as ligand and B(OPh)3 (8.7 mg, 0.030 mmol) to afford aziridines (2S,4R)-105fÕ and (2R,4R)-105f with a 99:1 diastereomeric ratio.  Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105fÕ and 105f as a white solid (mp 48-50 ¡C on 99:1 dr material) in 93% isolated yield (116 mg, 0.186 mmol). 5-10 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(R)-104fOTBSOHNOTBSMEDAMOOEt(2S,4R)-105f'NOTBSMEDAMOOEt(2S,4R)-105f!&.+!The diastereomeric ratio of (2S,4R)-105fÕ to (2R,4R)-105f was determined to be 99.9:0.1 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 10.73 min (minor diastereomer, (2R,4R)-105f) and Rt = 13.51 min (major diastereomer, (2S,4R)-105fÕ). Aldehyde (R)-104f was reacted according to the general procedure with 10 mol% catalyst prepared from (R)-VAPOL (5.4 mg, 0.010 mmol) to afford aziridines (2S,4R)-105fÕ and (2R,4R)-105f with 99:1 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105fÕ and 105f as a white solid in 85% isolated yield (106 mg, 0.170 mmol).  Aldehyde (R)-104f was reacted according to the general procedure b1 with 10 mol% catalyst prepared from (R)-VANOL (4.4 mg, 0.010 mmol) to afford aziridines (2S,4R)-105fÕ and (2R,4R)-105f with 99:1 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105fÕ and 105f as a white solid in 80% isolated yield (100 mg, 0.160 mmol).  Spectral data for (2S,4R)-105fÕ: Rf = 0.30 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (500 MHz, CDCl3) & Ð0.30 (s, 3H), Ð0.03 (s, 3H), 0.72 (s, 9H), 0.98-1.18 (m, 6H), 1.28 (t, 3H, J = 7.1 Hz), 1.55-1.73 (m, 104h), 2.04 (d, 1H, J = 6.9 Hz), 2.21-2.25 (m, 13H), 3.52 (dd, 1H, J = 8.5, 3.8 Hz), 3.63 (s, 1H), 3.67 (s, 3H), 3.70 (s, 3H), 4.18 (qd, 33m, J = 7.1, 1.7 Hz), 6.92 (s, 33m), 6.96 (s, 33m); 13C-NMR (125 MHz, CDCl3) & Ð4.64, Ð4.40, 14.35, 16.16, 16.19, 17.96, 25.91, 26.57, 26.63, 26.65, 27.72, 28.78, 41.72, 44.05, 50.94, 59.39, !&.,!59.59, 60.63, 73.50, 76.97, 127.96, 129.05, 130.22, 130.34, 137.45, 137.63, 155.69, 156.04, 170.34; IR (thin film) 2930vs, 2855s, 1744s, 1483s, 1257s, 1221s, 1186vs, 1146vs, 1018vs cm-1; HRMS (ESI-TOF) m/z 624.4073 [(M+H+); calcd. for C37H58NO5Si: 624.4084]; !!!!!" Ð90.4¡ (c 1.0, CH2Cl2) on 99:1 dr material (HPLC).  (2R,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-(tert-butyldimethylsilyloxy) (cyclohexyl) methyl)aziridine-2-carboxylate (2R,4R)-105f: Aldehyde (R)-104f was reacted according to the general procedure with 5 mol% catalyst prepared from (S)- tBu2VAPOL (5.5 mg, 0.010 mmol) as ligand and B(OPh)3 (8.7 mg, 0.030 mmol) to afford aziridines (2R,4R)-105f and (2S,4R)-105fÕ with a 82:18 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105f and 105fÕ as a white solid (mp 42-45 ¡C on 82:18 dr material) in 75% isolated yield (93.5 mg, 0.150 mmol).  Aldehyde (R)-104f was reacted according to the general procedure b1 with 10 mol% catalyst prepared from (S)-VAPOL (5.4 mg, 0.010 mmol) to afford aziridines (2R,4R)-105f and (2S,4R)-105fÕ with 52:48 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105f and 105fÕ as a white solid in 30% isolated yield (37.0 mg, 0.060 mmol).  Aldehyde (R)-104f was reacted according to the general procedure  with 10 mol% 5-10 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(R)-104fOTBSOHNOTBSMEDAMOOEt(2S,4R)-105f'NOTBSMEDAMOOEt(2S,4R)-105f!&.-!catalyst prepared from (S)-VANOL (4.4 mg, 0.010 mmol) to afford aziridines (2R,4R)-105f and (2S,4R)-105fÕ with 60:40 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105f and 105fÕ as a white solid in 15% isolated yield (19.1 mg, 0.030 mmol).  Spectral data for (2R,4R)-105f: Rf = 0.30 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (600 MHz, CDCl3) & Ð0.07 (s, 3H), Ð0.06 (s, 3H), 0.85 (s, 9H), 0.91-1.18 (m, 6H), 1.26 (t, 3H, J = 7.1 Hz), 1.57- 1.86 (m, 104h), 2.14 (d, 1H, J = 6.4 Hz), 2.21-2.23 (m, 13H), 3.42 (s, 1H), 3.54 (d, 1H, J = 8.1 Hz), 3.67 (s, 3H), 3.68 (s, 3H), 4.05-4.31 (m, 33m), 7.03 (s, 4H); 13C-NMR (150 MHz, CDCl3) & Ð4.00, Ð3.50, 14.38, 16.17, 16.20, 18.03, 26.20, 26.62, 26.65, 27.65, 28.90, 29.57, 41.82, 44.09, 50.95, 59.38, 59.59, 60.66, 73.55, 77.02, 128.03, 129.05, 130.26, 130.38, 137.45, 137.65, 155.78, 156.09, 170.48. IR (thin film) 2929vs, 2854s, 1737s, 1472s, 1250s, 1221s, 1181vs, 1147vs, 1051vs cm-1; HRMS (ESI-TOF) m/z 624.4098 [(M+H+); calcd. for C37H58NO5Si: 624.4084; !!!!!" +40.3¡ (c 1.0, EtOAc) on 82:18 dr material (HPLC).  (2S,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-2-(tert-butyldimethylsilyloxy) propyl) aziridine-2-carboxylate (2S,5R)-105gÕ: Aldehyde (R)-104g was reacted according to the general procedure with (R)-VAPOL (11 mg, 0.020 mmol) as ligand to afford aziridines (2S,5R)-105gÕ and (2R,5R)-105g with a 99:1 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an 10 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(R)-104gCHOTBSONMEDAMOOEtTBSO(2S,5R)-105g'NMEDAMOOEtTBSO(2R,5R)-105g!&..!inseparable mixture of aziridines 105gÕ and 105g as a viscous liquid in 85% isolated yield (97.3 mg, 0.170 mmol). The diastereomeric ratio of (2S,5R)-105gÕ to (2R,5R)-105g was determined to be 99:1 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 20.83 min (minor diastereomer, (2R,5R)-105g) and Rt = 28.04 min (major diastereomer, (2S,5R)-105gÕ).  Spectral data for (2S,5R)-105gÕ: Rf = 0.34 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (300 MHz, CDCl3) & Ð0.21 (s, 3H), Ð0.10 (s, 3H), 0.80 (s, 9H), 1.04 (d, 3H, J = 6.2 Hz), 1.24 (t, 3H, J = 7.1 Hz), 1.77-1.59 (m, 33m), 2.16-2.24 (m, 14H), 3.43 (s, 1H), 3.68 (s, 6H), 3.70-3.76 (m, 1H), 4.17 (q, 33m, J = 7.1 Hz), 7.07 (s, 33m), 7.08 (s, 33m); 13C-NMR (75 MHz, CDCl3) & Ð5.21, Ð4.64, 14.29, 16.11, 16.16, 17.92, 23.75, 25.78, 37.63, 43.10, 44.34, 59.51, 59.54, 60.66, 67.11, 77.34, 127.23, 127.72, 130.48, 130.50, 138.03, 138.23, 155.75, 155.99, 169.71; IR (thin film) 2955vs, 2930vs, 2856s, 1746s, 1483s, 1221s, 1183vs, 1140s cm-1; HRMS (ESI-TOF) m/z 570.3632 [(M+H+); calcd. for C33H52NO5Si: 570.3615]; !!!!!" Ð33.5¡ (c 1.0, CH2Cl2) on 99:1 dr material (HPLC).   (2R,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-(tert-butyldimethylsilyloxy) ethyl) aziridine-2-carboxylate (2R,5R)-105g: Aldehyde (R)-104g was reacted according to the general procedure with (S)-VAPOL (11 mg, 0.020 mmol) as ligand to afford aziridines (2R,5R)-105g and (2S,5R)-105gÕ with a 98:2 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 10 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(R)-104gCHOTBSONMEDAMOOEtTBSO(2S,5R)-105g'NMEDAMOOEtTBSO(2R,5R)-105g!'//!150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105g and 105gÕ as a sticky solid in 83% isolated yield (94.0 mg, 0.160 mmol). The diastereomeric ratio of (2R,5R)-105g to (2S,5R)-105gÕ was determined to be 98:2 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 20.28 min (major diastereomer, (2R,4S)-105g) and Rt = 29.15 min (minor diastereomer, (2S,4S)-105gÕ).  Spectral data for (2R,5R)-105g: Rf = 0.34 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (300 MHz, CDCl3) & 0.00 (s, 3H), 0.02 (s, 3H), 0.86 (s, 9H), 0.88 (d, 3H, J = 6.1 Hz), 1.26 (t, 3H, J = 7.1 Hz), 1.56 (ddd, 1H, J = 13.6, 6.7, 6.7 Hz), 1.78 (ddd, 1H, J = 13.6, 6.7, 6.7 Hz), 2.07 (q, 1H, J = 6.5 Hz), 2.19 (d, 1H, J = 6.8 Hz), 2.24 (s, 125m), 3.56 (q, 1H, J = 6.3 Hz), 3.68 (s, 3H), 3.68 (s, 3H), 4.25-4.13 (m, 33m), 6.99 (s, 33m), 7.08 (s, 33m); 13C-NMR (75 MHz, CDCl3) & Ð4.81, Ð4.55, 14.33, 16.16, 16.19, 18.05, 23.22, 25.84, 37.72, 43.12, 44.14, 59.57, 60.65, 67.15, 77.26, 127.36, 128.03, 130.47, 130.50, 137.72, 138.06, 155.77, 156.12, 169.62, (one sp3 carbon not located); IR (thin film) 2957vs, 2930vs, 1746s, 1483s, 1223s, 1184vs, 1145s cm-1; HRMS (ESI-TOF) m/z 570.3634 [(M+H+); calcd. for C33H52NO5Si: 570.3615]; !!!!!" +38.5¡ (c 0.6, CH2Cl2) on 98:2 dr material (HPLC).  (2S,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-2-phenylpropyl)aziridine-2-carboxylate (2S,5S)-105hÕ: Aldehyde (S)-104h was reacted 10 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(S)-104hOHPhNMEDAMOOEtPh(2S,5S)-105h'NMEDAMOOEtPh(2R,5S)-105h!'/&!according to the general procedure with (R)-VAPOL (11 mg, 0.020 mmol) as ligand to afford aziridines (2S,5S)-105hÕ and (2R,5S)-105h with >99:1 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105hÕ and 105h as a white solid (mp 101-102 ¡C on 99:1 dr material) in 85% isolated yield (87.8 mg, 0.170 mmol). The diastereomeric ratio of (2S,5S)-105hÕ to (2R,5S)-105h was determined to be 99.4:0.6 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 18.49 min (minor diastereomer, (2R,5S)-105h) and Rt = 31.04 min (major diastereomer, (2S,5S)-105hÕ).  Spectral data for (2S,5S)-105hÕ: Rf = 0.32 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (300 MHz, CDCl3) & 1.02 (d, 3H, J = 6.9 Hz), 1.27 (t, 3H, J = 7.1 Hz), 1.71-1.81 (m, 1H), 1.85-1.97 (m, 33m), 2.22-2.54 (m, 13H), 2.45-2.55 (m, 1H), 3.40 (s, 1H), 3.68 (s, 3H), 3.69 (s, 3H), 4.20 (qd, 33m, J = 7.1, 2.3 Hz), 7.02 (s, 33m), 7.08 (s, 33m), 7.10-7.28 (m, 104h); 13C-NMR (75 MHz, CDCl3) & 14.34, 16.13, 16.17, 21.29, 35.73, 37.96, 43.44, 45.49, 59.56, 59.60, 60.72, 77.07, 125.93, 126.78, 127.32, 127.95, 128.31, 130.49, 137.66, 138.17, 146.99, 155.76, 156.09, 169.65 (one sp2 carbon not located); IR (thin film) 2959vs, 2930vs, 1744s, 1483s, 1221s, 1183vs cm-1; HRMS (ESI-TOF) m/z 516.3120 [(M+H+); calcd. for C33H42NO4: 516.3114]; !!!!!" Ð20.0¡ (c 1.0, CH2Cl2) on 99:1 dr material (HPLC). !'/'! (2R,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-2-phenylpropyl)aziridine-2-carboxylate (2R,5S)-105h: Aldehyde (S)-104h was reacted according to the general procedure with (S)-VAPOL (11 mg, 0.02 mmol) as ligand to afford aziridines (2R,5S)-105h and (2S,5S)-105hÕ with a 94:6 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105h and 105hÕ as a sticky solid in 80% isolated yield (82.4 mg, 0.16 mmol). The diastereomeric ratio of (2R,5S)-105h to (2S,5S)-105hÕ was determined to be 94:6 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 17.68 min (major diastereomer, (2R,5S)-105h) and Rt = 32.01 min (minor diastereomer, (2S,5S)-105hÕ).   Spectral data for (2S,5S)-105h: Rf = 0.32 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (300 MHz, CDCl3) & 1.14 (d, 3H, J = 7.0 Hz), 1.25 (t, 3H, J = 7.1 Hz), 1.73-1.83 (m, 33m), 2.07 (d, 1H, J = 6.3 Hz), 2.22-2.25 (m, 105h), 2.31 (s, 6H), 2.43-2.53 (m, 1H), 3.30 (s, 1H), 3.67 (s, 3H), 3.73 (s, 3H), 4.13- 4.20 (m, 33m), 6.68 (dd, 33m, J = 7.7, 1.7 Hz), 7.06 (s, 33m), 7.07 (s, 33m), 7.12-7.20 (m, 3H); 13C-NMR (75 MHz, CDCl3) & 14.28, 16.15, 23.17, 36.39, 38.40, 43.13, 45.44, 59.54, 59.65, 60.72, 77.25, 125.83, 127.08, 128.06, 128.18, 130.48, 130.61, 137.91, 138.44, 146.09, 155.68, 156.24, 169.66 (one sp2 and one sp3 carbon not located); IR (thin film) 2957vs, 2930vs, 1742s, 1483s, 1221s, 1186vs cm-1; 10 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+(S)-104hOHPhNMEDAMOOEtPh(2S,5S)-105h'NMEDAMOOEtPh(2R,5S)-105h!'/(!HRMS (ESI-TOF) m/z 516.3119 [(M+H+); calcd. for C33H42NO4: 516.3114]; !!!!!" +70.6¡ (c 1.0, CH2Cl2) on 94:6 dr material (HPLC).  (2S,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-oxiran-2-yl)aziridine-2-carboxylate (2S,4S)-105iÕ: Aldehyde (S)-104i (0.15 mL, 2 M in toluene, 0.30 mmol, 1.5 equiv) was reacted according to the general procedure with (R)-tBu2VAPOL (5.5 mg, 0.010 mmol) as ligand and B(OPh)3 (8.7 mg, 0.030 mmol) and EDA (48 µL, 0.40 mmol, 2.0 equiv) to afford aziridines (2S,4R)-105iÕ and (2R,4R)-105i with an 89:11 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105iÕ and 105i as a viscous liquid in >99% isolated yield (87.8 mg, 0.200 mmol). The diastereomeric ratio of (2S,4R)-105iÕ to (2R,4R)-105i was determined to be 89:11 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 85:15 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 21.53 min (major diastereomer, (2S,4R)-105iÕ) and Rt = 31.19 min (minor diastereomer, (2R,4R)-105i). Aldehyde (S)-104i was reacted according to the general procedure with (R)-VANOL (4.4 mg, 0.010 mmol) as ligand to afford aziridines (2S,4R)-105iÕ and (2R,4R)-105i with 88:12 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105iÕ and 105i as a viscous liquid in >99% isolated yield (88.0 mg, 0.200 mmol).   NMEDAMOOEtNMEDAMOOEt(2R,4S)-105i(2S,4S)-105i'+OOCHOO(S)-104i5 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h!'/)!Spectral data for (2S,4R)-105iÕ: Rf = 0.30 (1:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.26 (t, 3H, J = 7.2 Hz), 1.76 (t, 1H, J = 6.8 Hz), 2.22 (s, 125m), 2.34 (dd, 1H, J = 5.2, 4.2, 2.2 Hz), 2.37 (d, 1H, J = 7.0 Hz), 2.70 (dd, 1H, J = 4.2, 5.2 Hz), 3.11 (ddd, 1H, J = 2.2 Hz), 3.48 (s, 1H), 3.67 (d, 6H, J = 2.0 Hz), 4.20 (dq, 33m, J = 2.5, 7.2 Hz), 6.70 (s, 33m), 7.05 (s, 33m); 13C-NMR (125 MHz, CDCl3) & 14.18, 16.14, 16.18, 42.53, 46.14, 46.31, 48.83, 59.58, 59.61, 76.45, 115.25, 127.31, 127.69, 130.65, 130.69, 137.20, 137.50, 155.99, 156.14, 168.79; IR (thin film) 2937.5vs, 1743vs, 1484vs, 1220vs, 1192s, 1014s cm-1; HRMS (ESI-TOF) m/z 462.2282 [(M+Na+); calcd. for C26H33NO5Na: 462.2251]; !!!!!" Ð59.7¡ (c 1.0, CHCl3) on 89:11 dr material (HPLC).  (2R,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-oxiran-2-yl)aziridine-2-carboxylate (2R,4S)-105i: Aldehyde (S)-104i (0.15 mL, 2 M in toluene, 0.30 mmol, 1.5 equiv) was reacted according to the general procedure with (S)-tBu2VAPOL (5.5 mg, 0.010 mmol) as ligand and B(OPh)3 (8.7 mg, 0.030 mmol) and EDA (48 µL, 0.40 mmol, 2.0 equiv) to afford aziridines (2R,4R)-105i and (2S,4R)-105iÕ with 92:8 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105i and 105iÕ as a viscous liquid in 96% isolated yield (84.3 mg, 0.192 mmol). The diastereomeric ratio of (2R,4R)-105i to (2S,4R)-105iÕ was determined to be 92:8 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 85:15 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 22.17 min (minor diastereomer, (2S,4R)-105iÕ) and Rt = 29.74 min NMEDAMOOEtNMEDAMOOEt(2R,4S)-105i(2S,4S)-105i'+OOCHOO(S)-104i5 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h!'/*!(major diastereomer, (2R,4R)-105i). Aldehyde (S)-104i was reacted according to the general procedure with (S)-VANOL (4.4 mg, 0.010 mmol), as ligand to afford aziridines (2R,4S)-105i and (2S,4S)-105iÕ with 87:13 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105i and 105iÕ as a viscous liquid in 99% isolated yield (86.6 mg, 0.198 mmol).   Spectral data for (2S,4R)-105i: Rf = 0.30 (1:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.24 (t, 3H, J = 7.0 Hz), 1.77 (t, 1H, J = 6.8 Hz), 2.23 (d, 125m, J = 5.0 Hz), 2.31 (d, 1H, J = 7.0 Hz), 2.53 (dd, 1H, J = 4.8, 2.8 Hz), 2.72 (t, 1H, J = 4.8 Hz), 3.22 (td, 1H), 3.53 (s, 1H, J = 4.8, 2.8 Hz), 3.67 (d, 6H, J = 2.0 Hz), 4.18 (q, 33m, J = 7.2 Hz), 7.05 (s, 4H); 13C-NMR (125 MHz, CDCl3) & 14.18, 16.15, 16.17, 41.50, 45.14, 46.88, 50.07, 59.34, 61.10, 76.28, 115.24, 127.54, 127.58, 130.57, 130.62, 137.18, 137.40, 155.97, 156.04, 169.07; IR (thin film) 2937vs, 1743vs, 1439vs, 1221vs, 1192vs, 1015s cm-1; HRMS (ESI-TOF) m/z 462.2288 [(M+Na+); calcd. for C26H33NO5Na: 462.2251]; !!!!!" +30.8¡ (c 1.0, CHCl3) on 92:8 dr material (HPLC).  (2S,2'S,3S,3'S)-ethyl 1,1'-bis(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3'-propyl-[2,2'-biaziridine]-3-carboxylate (2S,4S)-105jÕ: Aldehyde (2S,3S)-104j was reacted according to the general procedure with (R)-VAPOL (11 mg, 0.020 mmol) as ligand to afford aziridines (2S,4S)-105jÕ and (2R,4S)-105j with 99:1 diastereomeric ratio. Purification of 10 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+NMEDAMOOEtNMEDAM(2S,4S)-105j'NMEDAMOOEtNMEDAM(2R,4S)-105jNMEDAMOH(2S,3S)-104j!'/+!the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105jÕ and 105j as a white solid (mp 79-82 ¡C on 99:1 dr material) in 80% isolated yield (122 mg, 0.160 mmol). The diastereomeric ratio of (2S,4S)-105jÕ to (2R,4S)-105j was determined to be 99.5:0.5 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.7:0.3 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 16.30 min (minor diastereomer, (2R,4S)-105j) and Rt = 19.75 min (major diastereomer, (2S,4S)-105jÕ). Spectral data for (2S,4S)-105jÕ: Rf = 0.25 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (300 MHz, CDCl3) & 0.49 (t, 33m, J = 6.5 Hz), 0.55-0.64 (m, 33m), 0.68-0.77 (m, 33m), 1.00 (t, 3H, J = 7.1 Hz), 1.50-1.56 (m, 1H), 1.80 (dd, 1H, J = 8.7, 6.7 Hz), 2.01-2.06 (m, 1H), 2.20-2.28 (m, 25H), 3.28 (s, 1H), 3.45 (s, 1H), 3.64 (brs, 6H), 3.66-3.67 (m, 6H), 6.87 (s, 33m), 6.97 (s, 4H), 7.04 (s, 33m); 13C-NMR (75 MHz, CDCl3) & 13.69, 13.87, 15.99, 16.04, 16.05, 16.10, 20.39, 29.84, 41.35, 42.78, 43.31, 45.42, 59.43, 59.46, 59.50, 59.52, 60.47, 77.21, 77.36, 127.09, 127.11, 128.12, 128.38, 130.04, 130.20, 130.45, 137.52, 137.58, 138.04, 138.97, 155.37, 155.72, 155.88, 156.29, 168.92 (one sp2 carbon not located); IR (thin film) 2955vs, 1736s, 1483s, 1221s, 1190vs, 1138s cm-1; HRMS (ESI-TOF) m/z 763.4703 [(M+H+); calcd. for C48H63N2O6: 763.4686]; !!!!!" Ð62.8¡ (c 1.0, CH2Cl2) on 99:1 dr material (HPLC).  (2R,2'S,3R,3'S)-ethyl 1,1'-bis(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3'-propyl-[2,2'-10 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+NMEDAMOOEtNMEDAM(2S,4S)-105j'NMEDAMOOEtNMEDAM(2R,4S)-105jNMEDAMOH(2S,3S)-104j!'/,!biaziridine]-3-carboxylate (2R,4S)-105j: Aldehyde (2S,3S)-104j was reacted according to the general procedure with (S)-VAPOL (11 mg, 0.020 mmol) as ligand to afford aziridines (2R,4S)-105j and (2S,4S)-105jÕ with a 99:1 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded an inseparable mixture of aziridines 105j and 105jÕ as a white solid (mp 67-70 ¡C on >99:1 dr material) in 84% isolated yield (129 mg, 0.168 mmol).   Spectral data for (2R,4S)-7i: Rf = 0.25 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1H-NMR (300 MHz, CDCl3) & 0.61 (t, 3H, J = 7.2 Hz), 0.75-1.02(m, 33m), 1.07-1.28 (m, 5H), 1.50-1.57 (m, 1H), 2.01 (dd, 1H, J = 6.5, 5.3 Hz), 2.05 (s, 125m), 2.11-2.15 (m, 1H), 2.21-2.26 (m, 13H), 3.45 (s, 1H), 3.63 (s, 3H), 3.64 (s, 3H), 3.65 (s, 3H), 3.67 (s, 3H), 3.82 (s, 1H), 4.14 (q, 33m, J = 7.1 Hz), 6.85 (s, 33m), 6.91 (s, 33m), 6.95 (s, 4H); 13C-NMR (75 MHz, CDCl3) & 13.67, 14.22, 15.92, 16.03, 16.13, 20.36, 31.22, 40.43, 41.67, 43.75, 45.57, 59.44, 59.46, 59.50, 59.56, 60.62, 75.06, 77.17, 127.10, 127.12, 128.19, 128.48, 129.92, 130.17, 130.19, 130.42, 137.17, 137.20, 137.87, 139.12, 155.34, 155.63, 155.89, 155.91, 169.78 (one sp2 carbon not located); IR (thin film) 2955vs, 1743s, 1483s, 1221s, 1186vs, 1140s cm-1; HRMS (ESI-TOF) m/z 763.4706 [(M+H+); calcd. for C48H63N2O6: 763.4686]; !!!!!" Ð97.6¡ (c 1.0, CH2Cl2) on 99:1 dr material (HPLC).  (2S,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)aziridine -2-carboxylate (2S,4S)-105kÕ: (R)-2,2-dimethyl-1,3-dioxolane-4-5 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+NMEDAMOOEtOO(2S,4S)-105k'NMEDAMOOEt(2R,4S)-105kOOOOOH(R)-104k!'/-!carboxaldehyde 104k was reacted according to the general procedure with (R)-tBu2VAPOL (5.5 mg, 0.010 mmol) as ligand and B(OPh)3 (8.7 mg, 0.030 mmol) to afford aziridines (2S,4S)-105kÕ and (2R,4S)-105k with 97:3 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105kÕ and 105k as a viscous liquid in 99% isolated yield (99.0 mg, 0.198 mmol). The diastereomeric ratio of (2S,4S)-105kÕ to (2R,4S)-105k was determined to be 97:3 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 98:2 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 16.88 min (minor diastereomer, (2R,4S)-105k) and Rt = 31.23 min (major diastereomer, (2S,4S)-105kÕ). Aldehyde (R)-104k was reacted according to the general procedure with (R)-VAPOL (5.4 mg, 0.010 mmol) as ligand to afford aziridines (2S,4S)-105kÕ and (2R,4S)-105k with 94:6 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105kÕ and 105k as a viscous liquid in 90% isolated yield (90.3 mg, 0.18 mmol).  Aldehyde (R)-104k was reacted according to the general procedure with (R)-VANOL (4.4 mg, 0.010 mmol) as ligand to afford aziridines (2S,4S)-105kÕ and (2R,4S)-105k with 92:8 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105kÕ and 105k as a viscous liquid in 86% isolated yield (85.5 mg, 0.172 mmol).   !'/.!Spectral data for (2S,4S)-105kÕ: Rf = 0.27 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.22 (s, 3H), 1.24 (t, 3H, J = 7.2 Hz), 1.28 (s, 3H), 2.12 (dd, 1H, J = 8.0, 6.5 Hz), 2.24 (d, 125m, J = 3.5 Hz), 2.27 (d, 1H, J = 6.5 Hz), 3.06 (dd, 1H, J = 9.0, 6.5 Hz), 3.58 (s, 1H), 3.66-3.69 (m, 1H), 3.68 (s, 3H), 3.70 (s, 3H), 3.92 (dd, 1H, J = 8.0, 6.0 Hz), 4.10-4.23 (m, 3H), 7.05 (s, 33m), 7.09 (s, 33m); 13C-NMR (125 MHz, CDCl3) & 14.20, 16.05, 16.15, 25.40, 26.63, 41.46, 48.17, 59.54, 59.57, 61.00, 67.02, 75.05, 76.31, 109.46, 127.84, 128.23, 130.18, 130.50, 137.09, 137.34, 156.00, 169.07 (one sp2 carbon not located); IR (thin film) 2987vs, 2938vs, 1739vs, 1483vs, 1381s, 1220vs, 1149s cm-1; HRMS (ESI-TOF) m/z 498.2848 [(M+H+); calcd. for C29H40NO6: 498.2856]; !!!!!" Ð32.2¡ (c 1.0, CH2Cl2) on 97:3 dr material (HPLC).  (2R,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)aziridine -2-carboxylate (2R,4S)-105k: (R)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde 104k was reacted according to the general procedure with (S)-tBu2VAPOL (5.5 mg, 0.010 mmol) as ligand and B(OPh)3 (8.7 mg, 0.030 mmol) to afford aziridines (2R,4S)-105k and (2S,4S)-105kÕ with 97:3 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105k and 105kÕ as a viscous liquid in 99% isolated yield (99.1 mg, 0.198 mmol). The diastereomeric ratio of (2R,4S)-105k and (2S,4S)-105kÕ was determined to be 97:3 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) 5 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+NMEDAMOOEtOO(2S,4S)-105k'NMEDAMOOEt(2R,4S)-105kOOOOOH(R)-104k!'&/!WHELK-O 1 column, 98:2 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 16.64 min (major diastereomer, (2R,4S)-105k) and Rt = 30.26 min (minor diastereomer, (2S,4S)-105kÕ). Aldehyde (R)-104k was reacted according to the general procedure with (S)-VAPOL (5.4 mg, 0.010 mmol) as ligand to afford aziridines (RS,4S)-105k and (SR,4S)-105kÕ with 84:16 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105k and 105kÕ as a viscous liquid in 73% isolated yield (72.8 mg, 0.146 mmol).  Aldehyde (R)-104k was reacted according to the general procedure with (S)-VANOL (4.4 mg, 0.010 mmol) as ligand to afford aziridines (2R,4S)-105k and (2S,4S)-105kÕ with an 84:16 diastereomeric ratio.  Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105k and 105kÕ as a viscous liquid in 67% isolated yield (67.0 mg, 0.134 mmol).   Spectral data for (2R,4S)-105k: Rf = 0.27 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.25 (s, 3H), 1.26 (t, 3H, J = 7.2 Hz), 1.34 (s, 3H), 2.08 (dd, 1H, J = 8,5, 6.5 Hz), 2.24 (d, 125m, J = 3.5 Hz), 2.38 (d, 1H, J = 6.5 Hz), 3.06 (dd, 1H, J = 8.5, 6.5 Hz), 3.48 (s, 1H), 3.67 (s, 3H), 3.68 (s, 3H), 3.80 (dd, 1H, J = 8.5, 6.5 Hz), 4.10 (ddd, 1H, J = 12.5, 8.0, 6.0 Hz), 4.22 (q, 33m, J = 7.0 Hz), 6.97 (s, 33m), 7.06 (s, 33m); 13C-NMR (125 MHz, CDCl3) & 14.18, 16.08, 16.15, 25.18, 26.66, 42.69, 47.59, 59.55, 59.65, 60.98, 68.07, 73.27, 76.75, 109.27, 127.07, 127.92, 130.65, 130.76, 137.23, 137.74, 155.93, 156.47, 168.88; IR (thin film) 2987vs, 2938vs, 1737vs, 1483vs, 1382s, 1373s, 1220vs, !'&&!1148s cm-1; HRMS (ESI-TOF) m/z 498.2850 [(M+H+); calcd. for C29H40NO6: 498.2856]; !!!!!" +62.3¡ (c 1.0, CH2Cl2) on 97:3 dr material (HPLC).  (2S,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)aziridine-2-carboxylate (2S,4S)-105lÕ: (R)-1,4-dioxaspiro[4.5]decane-2-carboxaldehyde 104l20 (0.15 mL, 2 M in toluene, 0.30 mmol, 1.5 equiv) was reacted according to the general procedure with (R)-tBu2VAPOL (5.5 mg, 0.010 mmol) as ligand, B(OPh)3 (8.7 mg, 0.060 mmol) and EDA (48 µL, 0.40 mmol, 2.0 equiv) to afford aziridines (2S,4S)-105lÕ and (2R,4S)-105l with 98:2 diastereomeric ratio.  Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105lÕ and 105l as a viscous liquid in >99% isolated yield (108 mg, 0.200 mmol).  The diastereomeric ratio of (2S,4S)-7kÕ to (2R,4S)-7k was determined to be 98:2 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 95:5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 13.93 min (minor diastereomer, (2R,4S)-105l) and Rt = 23.99 min (major diastereomer, (2S,4S)-105lÕ). Aldehyde (R)-104l was reacted according to the general procedure with (R)-VANOL (4.4 mg, 0.010 mmol), as ligand to afford aziridines (2S,4S)-105lÕ and (2R,4S)-105l with 97:3 diastereomeric ratio.  Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 4:1 hexanes/Et2O as eluent, flash column) 5 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+OOOH(R)-104lNMEDAMOOEtOO(2S,4S)-105l'NMEDAMOOEt(2R,4S)-105lOO!'&'!afforded an inseparable mixture of aziridines 105lÕ and 105l as a viscous liquid in >99% isolated yield (108 mg, 0.200 mmol).   Spectral data for (2S,4S)-105lÕ: Rf = 0.48 (1:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.22 (t, 3H, J = 7.2 Hz), 1.39-1.53 (m, 10H), 2.09 (dd, 1H, J = 4.5, 6.5 Hz), 2.22 (s, 125m), 2.24 (d, 1H, J = 6.0 Hz), 3.53 (s, 1H), 3.64 (dd, 1H, J = 5.5, 7.5 Hz), 3.66 (d, 6H, J = 10.0 Hz), 3.90 (dd, 1H, J = 7.5, 8.0 Hz), 4.08-4.19 (m, 3H), 7.03 (s, 33m), 7.06 (s, 33m); 13C-NMR (125 MHz, CDCl3) & 14.22, 16.15, 16.17, 23.66, 23.69, 25.09, 34.87, 36.54, 41.34, 48.39, 59.48, 59.58, 61.05, 66.64, 74.72, 76.50, 110.09, 127.70, 128.18, 130.22, 130.53, 137.14, 137.49, 155.92, 156.00, 169.11; IR (thin film) 2936vs, 2861s, 1743vs, 1484vs, 1448s, 1221vs, 1190vs, 1163s, 1146s, 1040s, 1016s cm-1; HRMS (ESI-TOF) m/z 560.3011 [(M+Na+); calcd. for C333m43NO6Na: 560.2988]; !!!!!" Ð44.6¡ (c 1.0, CHCl3) on 98:2 dr material (HPLC).   (2R,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)aziridine-2-carboxylate (2R,4S)-105l: (R)-1,4-dioxaspiro[4.5]decane-2-carboxaldehyde 104l20 (0.15 mL, 2 M in toluene, 0.30 mmol, 1.50 equiv) was reacted according to the general procedure with (S)-tBu2VAPOL (5.5 mg, 0.010 mmol) as ligand, B(OPh)3 (8.7 mg, 0.030 mmol) and EDA (48 µL, 0.40 mmol, 2.0 equiv) to afford aziridines (2R,4S)-105l and (2S,4S)-105lÕ with a 97:3 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 5 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+OOOH(R)-104lNMEDAMOOEtOO(2S,4S)-105l'NMEDAMOOEt(2R,4S)-105lOO!'&(!150 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105l and 105lÕ as a viscous liquid in >99% isolated yield (108 mg, 0.200 mmol).  The diastereomeric ratio of (2R,4S)-105l to (2S,4S)-105lÕ was determined to be 97:3 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 95:5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 13.91 min (major diastereomer, (2R,4S)-105l) and Rt = 25.94 min (minor diastereomer, (2S,4S)-105lÕ). Aldehyde (R)-104l was reacted according to the general procedure with (S)-VANOL (4.4 mg, 0.010 mmol) as ligand to afford aziridines (2R,4S)-105l and (2S,4S)-105lÕ with 91:9 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105l and 105lÕ as a viscous liquid in >99% isolated yield (108 mg, 0.200 mmol).   Spectral data for (2R,4S)-105l: Rf = 0.48 (1:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.25 (t, 3H, J = 7.0 Hz), 1.41-1.54 (m, 10H), 2.05 (dd, 1H, J = 6.5, 8.0 Hz), 2.22 (d, 125m, J = 2.5 Hz), 2.37 (d, 1H, J = 6.5 Hz), 3.05 (dd, 1H, J = 6.0, 8.5 Hz,) 3.45 (s, 1H), 3.66 (d, 6H, J = 5.0 Hz), 3.79 (dd, 1H, J = 6.2, 8.8 Hz), 4.06 (qd, 1H), 4.17-4.23 (m, 33m, J = 2.0, 6.2 Hz), 6.95 (s, 33m), 7.04 (s, 33m); 13C-NMR (125 MHz, CDCl3) & 14.22, 16.11, 16.17, 23.72, 23.97, 25.08, 34.61, 36.31, 42.74, 47.73, 59.57, 59.66, 60.99, 67.74, 72.88, 76.63, 109.83, 127.07, 127.87, 130.65, 130.75, 137.27, 137.74, 155.88, 156.38, 168.94; IR (thin film) 2936vs, 2861s, 1743vs, 1484vs, 1448s, 1221vs, 1190vs, 1038s, 1100s, 1038s, 1016s cm-1; HRMS (ESI-TOF) m/z 560.3021 [(M+Na+); calcd. for C333m43NO6Na: 560.2988]; !!!!!" +53.2¡ (c 1.0, CHCl3) on 97:3 dr material (HPLC). !'&)! tert-Butyl (R)-4-((2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(ethoxycarbonyl)aziridin-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (2S,4R)-105mÕ: (S)-3-Boc-2,2-dimethyl oxazolidine-4-carboxaldehyde 104m was reacted according to the general procedure with (R)-VAPOL (11 mg, 0.020 mmol) as ligand to afford aziridines (2S,4R)-105mÕ and (2R,4R)-105m with 99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm ' 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105mÕ and 105m as a viscous liquid in 60% isolated yield (72.0 mg, 0.120 mmol).   Spectral data for (2S,4R)-105mÕ: Rf = 0.31 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.26-1.28 (m, 5H), 1.36-1.38 (m, 4H), 1.43 (s, 9H), 2.16 (t, 1H, J = 6.8 Hz), 2.26-2.68 (m, 13H), 3.47 (s, 1H), 3.66-3.73 (m, 8H), 3.88-3.91 (m, 1H), 4.18-4.26 (m, 33m), 6.95 (s, 33m), 7.04 (s, 33m); 13C-NMR (125 MHz, CDCl3) & 14.17 16.27, 16.19, 26.15, 28.40, 28.47, 43.62, 47.02, 59.49, 59.56, 60.91, 63.72, 64.81, 79.60, 105.11, 127.70, 128.20, 130.45, 137.11, 137.16, 137.90, 155.81, 169.21, (one sp2 carbon not located); IR (thin film) 2989vs, 2938vs, 1756s, 1747s, 1486s, 1220s, 1192vs, 1149s cm-1; HRMS (ESI-TOF) m/z 597.4229 [(M+H+); calcd. for C34H49N2O7: 597.4230]; !!!!!" Ð90.5¡ (c 1.0, CH2Cl2) on 99:1 dr material (NMR).  10 mol% (R)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+ONBocOH(R)-104mNMEDAMOOEtONBoc(2S,4R)-105m'NMEDAMOOEt(2R,4R)-105mONBoc!'&*! tert-butyl (R)-4-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(ethoxycarbonyl)aziridin-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (2R,4R)-105m: (S)-3-Boc-2,2-dimethyloxazolidine-4-carboxaldehyde 104m was reacted according to the general procedure with (S)-VAPOL (10.8 mg, 0.020 mmol) as ligand to afford aziridines (2R,4R)-105m and (2S,4R)-105mÕ with 99:1 diastereomeric ratio. Purification of the crude aziridines by neutral alumina chromatography (20 mm ' 150 mm column, 2:1 hexane/Et2O as eluent, flash column) afforded an inseparable mixture of aziridines 105m and 105mÕ as a viscous liquid in 70% isolated yield (83.1 mg, 0.140 mmol). The diastereomeric ratio of (2R,4R)-105m to (2S,4R)-105mÕ was determined to be 99.4:0.6 by HPLC analysis of the crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 98:2 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min), retention times: Rt = 16.26 min (major diastereomer, (2R,4R)-105m) and Rt = 18.98 min (minor diastereomer, (2S,4R)-105mÕ).  Spectral data for (2R,4R)-105m: Rf = 0.31 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.16-1.29 (m, 9H), 1.41 (s, 9H), 2.15 (d, 1H, J = 6.6 Hz), 2.19-2.27 (m, 13H), 3.53 (s, 1H), 3.63 (s, 3H), 3.67 (s, 3H), 3.69-3.72 (m, 1H), 3.93-3.96 (m, 1H), 4.01-4.08(m, 1H), 4.15 (q, 33m, J = 7.1 Hz), 6.89 (s, 33m), 7.11 (s, 33m); 13C-NMR (125 MHz, CDCl3) & 14.15, 16.07, 16.18, 26.17, 28.35, 28.47, 43.51, 47.00, 59.45, 59.55, 60.77, 63.73, 64.85, 79.62, 104.12, 127.65, 128.15, 130.39, 137.11, 137.12, 137.84, 155.81, 168.76, (one sp2 carbon not located); IR (thin film) 2988vs, 2938vs, 1755s, 10 mol% (S)-BOROXamine 101aEDA 1024 † MStolueneÐ10 ¡C, 24 h+ONBocOH(R)-104mNMEDAMOOEtONBoc(2S,4R)-105m'NMEDAMOOEt(2R,4R)-105mONBoc!'&+!1748s, 1486s, 1221s, 1194vs, 1149s cm-1; HRMS (ESI-TOF) m/z 597.4225 [(M+H+); calcd. for C34H49N2O7: 597.4230]; !!!!!" +70.3¡ (c 1.0, CH2Cl2) on 99:1 dr material (HPLC). 6.3 Experimental Information of Chapter 3 6.3.1 Multi-Component cis-Aziridination of Benzaldehyde  Ethyl (2R,3R)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-phenylaziridine-2-carboxylate (2R,3R)-124a (Scheme 3.2): Benzaldehyde 33a (21 µL, 0.21 mmol) was reacted according to the general procedure in 6.2.1 with BUDAM amine 101c (93.5 mg, 0.200 mmol) and EDA 102 (29 µL, 0.24 mmoL, 1.2 equiv). The pre-catalyst was prepared at room temperature for 1 h. Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 15:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3R)-124a as a white foam (mp 155-156 ¡C on 97% ee material) in 91% yield (117 mg, 0.182 mmol); trans/cis 8:1. The enantiomeric purity of (2R,3R)-124a was determined to be 91% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 13.25 min (minor enantiomer, ent-124a) and Rt = 29.14 min (major enantiomer, 124a). The aziridination of 33a in the presence of (S)-VAPOL BOROX catalyst afforded (2R,3R)-ent-124a in 99% ee and 85% yield (109 mg, 0.170 mmol); trans/cis 6:1. Spectral data for 124a: Rf = 0.56 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.91 BUDAMNH2101c(S)-ligand (5 mol%)B(OPh)3 (15 mol%)toluene, 25 ¡C, 1 hPhHO33a (1.05 equiv.)4 † MSN2OEtO102 (1.2 equiv.)25 ¡C, 24 hNPhBUDAMOEtO124a!'&,!(t, 3H, J = 7.2 Hz), 1.26 (s, 18H), 1.34 (s, 18H), 2.58 (d, 1H, J = 7.0 Hz), 3.10 (d, 1H, J = 6.8 Hz), 3.53 (s, 3H), 3.60 (s, 3H), 3.76 (s, 1H), 3.79-3.91 (m, 33m), 7.12 (t, 1H, J = 7.0 Hz), 7.18 (t, 33m, J = 7.0 Hz), 7.26 (d, 33m, J = 3.0 Hz), 7.36 (d, 33m, J = 3.5 Hz), 7.41 (d, 33m, J = 8.0 Hz); 13C-NMR (125 MHz, CDCl3) & 13.94, 32.02, 32.11, 35.69, 35.76, 46.33, 48.78, 60.51, 63.91, 64.01, 77.22, 125.33, 125.44, 127.23, 127.57, 128.13, 135.29, 136.68, 136.83, 142.96, 143.04, 158.21, 168.28 (one sp2 carbon not located). These spectral data match those previously reported for this compound.2 6.3.2 Multi-Component trans-Aziridination of Aromatic Aldehydes  General Procedure A for Multi-Component trans-Aziridination of Aromatic Aldehydes To a 10 mL flame-dried home-made Schlenk flask, prepared from a 10 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added ligand 68a, 68b or 68c (0.020 mmol), B(OPh)3 (17 mg, 0.060 mmol) and amine 101a, 101b or 101c (0.200 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (1.0 mL) was added. The flask was sealed by closing the Teflon valve and the mixture was stirred at room temperature for 1 h. To the flask containing the catalyst was added the 4† Molecular Sieves (60 mg, freshly flame-dried) and aldehyde (0.24 mmol, 1.2 equiv). The reaction mixture was allowed to stirred at room temperature for 20 min that the corresponding imine was formed completely. This solution was then allowed to cool to ÐPGNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 or 23 ¡C, 24 hNArPGHNOR+N2+R33101R = Ph, 122aR = Bu, 122b123a, 125a126a, 127aArHO!'&-!20 ¡C and rapidly added diazoacetamide 122a or 122b (0.28 mmoL, 1.4 equiv). The resulting mixture was stirred for 24 h at Ð20 ¡C. The reaction was dilluted by addition of pre-cooled hexane (3 mL) under Ð20 ¡C before the reaction mixture was filtered through a silica gel plug to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL ' 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a yellow-colored viscous oil. Purification of the crude aziridine by silica gel chromatography (20 mm ' 150 mm column, gravity column) afforded an trans-aziridine as a white solid. General Procedure B for Multi-Component trans-Aziridination of Aromatic Aldehydes To a 10 mL flame-dried home-made Schlenk flask, prepared from a 10 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added ligand 68a, 68b or 68c (0.020 mmol), B(OPh)3 (17 mg, 0.060 mmol) and amine 101a, 101b or 101c (0.200 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (1.0 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ¡C) for 0.5 h. The flask was then allowed to cool to room temperature and open to argon through side arm of the Schlenk flask. The following procedure to complete the aziridination was according to the general procedure A. Purification of the crude aziridine by silica gel chromatography (20 mm ' 150 mm column, gravity column) afforded an trans-aziridine as a white solid. !'&.! (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N,3-diphenylaziridine-2-carboxamide (2R,3S)-125a: (Table 3.1, entry 10) Benzaldehyde 33a (24 µL, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 12:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-125a as a white foam (mp 88-90 ¡C on 92% ee material) in 90% yield (124 mg, 0.180 mmol); trans/cis 18:1. The enantiomeric purity of (2R,3S)-125a was determined to be 92% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 13.56 min (minor enantiomer, ent-125a) and Rt = 21.43 min (major enantiomer, 125a). (Table 3.1, entry 11) The aziridination of 33a in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2S,3R)-ent-125a in Ð40% ee and 36% yield (49.6 mg, 0.072 mmol); trans/cis 2:1. (Table 3.1, entry 12) The aziridination of 33a according to the General Procedure A of multi-component trans-aziridination of aromatic aldehydes in the presence of (S)-VANOL BOROX catalyst afforded (2R,3S)-125a in 95% ee and 80% yield (110 mg, 0.160 mmol); trans/cis 18:1. Spectral data for (2R,3S)-125a: Rf = 0.44 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, DMSO-d6) & 1.22 (d, 36H, J = 5.5 Hz), 2.99 (d, 1H, J =2.5 Hz), 3.38 (d, 1H, J = 2.5 Hz), BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNPhBUDAMHNOPh+N2+Ph33a101c122a125aPhHO!''/!3.41 (s, 3H), 3.53 (s, 3H), 5.23 (s, 1H), 7.02 (t, 1H, J = 7.2 Hz), 7.20 (s, 33m), 7.22-7.26 (m, 3H), 7.31 (s, 33m), 7.32-7.37 (m, 4H), 7.50 (d, 33m, J =8.5 Hz), 10.30 (s, 1H); 13C-NMR (125 MHz, DMSO-d6) & 31.76, 31.78, 35.19, 35.25, 46.26, 46.58, 63.69, 63.89, 65.41, 118.98, 123.44, 125.19, 125.68, 126.06, 127.27, 128.30, 128.56, 137.80, 138.73, 139.01, 142.13, 142.25, 157.31, 157.37, 165.13; These spectral data match those previous reported for this compound.3   (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-phenylaziridine-2-carboxamide (2R,3S)-126a: (Table 3.1, entry 13) Benzaldehyde 33a (24 µL, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (40 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 6:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-126a as a white solid (mp 212-215 ¡C on 86% ee material) in 43% yield (58 mg, 0.086 mmol); trans/cis 8:1. The enantiomeric purity of (2R,3S)-126a was determined to be 86% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 10.22 min (minor enantiomer, ent-126a) and Rt = 27.49 min (major enantiomer, 126a). Spectral data for (2R,3S)-126a: Rf = 0.38 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.95 (t, 3H, J = 7.2 Hz), 1.32 (s, 18H), 1.38 (s, 18H), 1.40-1.41 (m, 33m), 1.50-BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNPhBUDAMHNOBu+N2+Bu33a101c122b126aPhHO!''&!1.53 (m, 33m), 2.96 (d, 1H, J =3.0 Hz), 3.20 (dt, 1H, J = 8.5, 1.8 Hz), 3.32 (dt, 1H, J = 8.7, 1.8 Hz), 3.43 (d, 1H, J = 3.0 Hz), 3.59 (s, 1H), 3.64 (s, 3H), 3.66 (s, 3H), 3.80 (s, 1H), 6.87 (d, 33m), 7.07 (d, 33m, J =7.5 Hz), 7.19 (s, 33m), 7.22 (d, 33m, J = 8.0 Hz), 7.30-7.32 (m, 1H); 13C-NMR (125 MHz, CDCl3) & 13.78, 20.14, 31.73, 32.05, 35.59, 35.69, 38.62, 42.99, 49.62, 64.04, 64.20, 67.74, 125.32, 125.38, 127.79, 128.07, 130.14, 131.86, 136.77, 136.81, 142.61, 143.31, 158.10, 158.35, 170.19; IR (thin film) 3447s, 2960s, 2870s, 1647vs, 1546s, 1455s, 1413vs, 1264s, 1222vs, 1115s, 1014s cmÐ1; HRMS (ESI-TOF) m/z 669.4978 [(M+H+); calcd. for C44H65N2O3: 669.4995]; !!!!!" Ð13.6¡ (c 1.0, CH2Cl2) on 86% ee material (HPLC).  (2S,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N,3-diphenylaziridine-2-carboxamide (2S,3R)-ent-123a: (Table 3.1, entry 15) Benzaldehyde 33a (61 µL, 0.60 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with MEDAM amine 101a (150 mg, 0.500 mmol), (R)-VAPOL (27 mg, 0.050 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (112 mg, 0.700 mmol, 1.40 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 6:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3R)-ent-123a as a white foam (mp 86-88 ¡C on 87% ee material) in 57% yield (148 mg, 0.284 mmol). The enantiomeric purity of (2S,3R)-ent-123a was determined to be 87% ee by HPLC analysis (CHIRALCEL OD-H column, 97:3 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 23.68 min MEDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNPhMEDAMHNOPh+N2+Ph33a101a122aent-123aPhHO!'''!(major enantiomer, ent-123a) and Rt = 36.64 min (minor enantiomer, 123a).  Spectral data for (2R,3S)-ent-123a: Rf = 0.57 (2:1 hexanes/EtOAc); 1H-NMR (500 MHz, DMSO-d6) & 2.02 (s, 6H), 2.07 (s, 6H), 2.93 (d, 1H, J = 2.8 Hz), 3.35 (d, 1H, J = 2.8 Hz), 3.49 (s, 3H), 3.55 (s, 3H), 5.06 (s, 1H), 6.99 (s, 33m), 7.05 (s, 33m), 7.05-7.07 (m, 1H), 7.28-7.31 (m, 3H), 7.33-7.36 (m, 3H), 7.49 (d, 33m, J = 7.5 Hz), 10.30 (s, 1H); 13C-NMR (125 MHz, DMSO-d6) & 15.74, 15.93, 45.93, 47.48, 58.97, 59.09, 65.37, 119.22, 123.56, 126.06, 127.26, 127.34, 127.90, 128.35, 128.68, 129.70, 129.73, 138.64, 138.72, 138.88, 138.91, 155.13, 155.26, 164.87; These spectral data match those previous reported for this compound.3   (2R,3S)-1-benzhydryl-N,3-diphenylaziridine-2-carboxamide (2R,3S)-127a: (Table 3.1, entry 19) Benzaldehyde 33a (24 µL, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with benzhydrylamine 101b (34 µL, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 5:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-127a as a white semi-solid in 62% yield (50 mg, 0.12 mmol). The enantiomeric purity of (2R,3S)-127a was determined to be 69% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 85:15 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 27.41 min (minor enantiomer, ent-127a) and Rt = 34.78 min (major enantiomer, 127a). NH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNPhHNOPh+N2+Ph101b122a127aPhPhPhPh33aPhHO!''(!(Table 3.1, entry 20) The aziridination of 33a in the presence of (R)-VAPOL BOROX catalyst afforded (2S,3R)-ent-127a in Ð75% ee and 49% yield (40 mg, 0.098 mmol).  Spectral data for (2R,3S)-127a: Rf = 0.34 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, DMSO-d6) & 2.96 (d, 1H, J = 2.5 Hz), 3.43 (d, 1H, J = 2.5 Hz), 5.39 (s, 1H), 7.02 (t, 1H, J = 7.5 Hz), 7.09-7.16 (m, 2H), 7.20-7.28 (m, 7H), 7.31-7.38 (m, 4H), 7.42-7.45 (m, 6H), 10.26 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 45.96, 47.31, 65.85, 119.33, 123.60, 125.94, 126.78, 127.15, 127.30, 128.13, 128.25, 128.37, 128.66, 138.46, 138.82, 143.65, 143.88, 165.00 (two sp2 carbon not located); These spectral data match those previous reported for this compound.3  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(naphthalen-2-yl)-N-phenylaziridine-2-carboxamide (2R,3S)-125j: To a 10 mL flame-dried home-made Schlenk flask, prepared from a 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv), B(OPh)3 (17 mg, 0.060 mmol) and BUDAM amine 101c (94 mg, 0.20 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (0.40 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ¡C) for 0.5 h. The pre-catalyst was subjected to high vacuum (0.05 mmHg) at 80 ¡C for 30 min to remove all the volatile substances. The flask was then allowed to cool to room temperature and open to argon through side arm of the Schlenk flask. To the flask containing the catalyst was added dry toluene (1.0 mL) to dissolve all the materials, BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33j101c122a125jHO!'')!followed by the addition of the 4† Molecular Sieves (60 mg, freshly flame- dried) and 2-Naphthaldehyde 33j (38 mg, 0.24 mmol, 1.2 equiv). The reaction mixture was allowed to stirred at room temperature for 20 min that the corresponding imine was formed completely. This solution was then allowed to cool to Ð20 ¡C and rapidly added N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). The resulting mixture was stirred for 24 h at Ð20 ¡C. The reaction was dilluted by addition of pre-cooled hexane (3 mL) under Ð20 ¡C before the reaction mixture was filtered through a silica gel plug to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL ' 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a yellow-colored viscous oil. Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-125j as a white foam (mp 65-68 ¡C on 92% ee material) in 82% yield (121 mg, 0.164 mmol); trans/cis 62:1. The enantiomeric purity of (2R,3S)-125j was determined to be 92% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 20.65 min (minor enantiomer, ent-125j) and Rt = 33.34 min (major enantiomer, 125j). Spectral data for (2R,3S)-125j: Rf = 0.28 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, DMSO-d6) & 1.16 (s, 18H), 1.23 (s, 18H), 3.11 (d, 1H, J = 2.5 Hz), 3.40 (s, 3H), 3.48 (s, 3H), 3.57 (d, 1H, J = 2.0 Hz), 5.29 (s, 1H), 7.00 (t, 1H, J = 7.5 Hz), 7.22 (s, 2H), 7.24 (t, 2H, J = 7.2 Hz), 7.35 (s, 2H), 7.43-7.48 (m, 3H), 7.51 (d, 2H, J = 7.5 Hz), 7.81 (d, 1H, J = 8.0 Hz), 7.86-7.89 (m, 3H), 10.33 (s, 1H); 13C-NMR (125 MHz, DMSO-d6) & 31.77, !''*!31.80, 35.24, 35.36, 46.65, 47.54, 63.72, 63.88, 65.61, 115.25, 119.04, 123.48, 123.87, 125.28, 125.74, 126.34, 127.39, 128.60, 129.40, 132.46, 132.82, 136.63, 137.83, 138.79, 142.19, 142.32, 157.40, 157.43, 165.18 (one sp2 carbon not located); IR (thin film) 3439s, 2963s, 1636vs, 1445s, 1413s, 1384s, 1265vs, 1222s, 1115s cmÐ1; HRMS (ESI-TOF) m/z 739.4840 [(M+H+); calcd. for C50H63N2O3: 739.4839]; !!!!!" +13.9¡ (c 1.0, CH2Cl2) on 92% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(naphthalen-1-yl)-N-phenylaziridine-2-carboxamide (2R,3S)-125k: 1-Naphthaldehyde 33k (38 mg, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-125k as a white foam (mp 68-71 ¡C on 87% ee material) in 88% yield (130 mg, 0.176 mmol); trans/cis >99:1. The enantiomeric purity of (2R,3S)-125k was determined to be 87% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 16.25 min (minor enantiomer, ent-125k) and Rt = 49.74 min (major enantiomer, 125k). BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33k101c122a125kHO!''+!Spectral data for (2R,3S)-125k: Rf = 0.23 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, DMSO-d6) & 1.24 (s, 18H), 1.28 (s, 18H), 3.01 (d, 1H, J = 2.5 Hz), 3.36 (s, 3H), 3.52 (s, 3H), 3.98 (d, 1H, J = 2.5 Hz), 5.20 (s, 1H), 7.01 (t, 1H, J = 7.2 Hz), 7.05-7.11 (m, 1H), 7.24 (t, 2H, J = 7.8 Hz), 7.28-7.39 (m, 2H), 7.32 (s, 2H), 7.43-7.56 (m, 2H), 7.52 (s, 2H), 7.65 (d, 2H, J = 6.5 Hz), 7.83 (d, 1H, J = 8.0 Hz), 7.87-7.96 (m, 1H), 10.20 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 31.82, 31.88, 35.24, 35.37, 44.71, 46.52, 63.67, 63.91, 67.14, 115.25, 119.04, 122.69, 123.26, 123.50, 124.58, 125.51, 125.93, 126.46, 127.61, 128.57, 129.40, 131.12, 133.00, 134.36, 137.72, 138.05, 138.74, 142.22, 142.54, 157.42, 157.62, 165.10; IR (thin film) 3327s, 2960vs, 2869s, 1675vs, 1529vs, 1445vs, 1413s, 1222vs, 1115s, 1013s cmÐ1; HRMS (ESI-TOF) m/z 739.4836 [(M+H+); calcd. for C50H63N2O3: 739.4839]; +19.6¡ (c 1.0, CH2Cl2) on 87% ee material (HPLC).  4-((2S,3R)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(phenylcarbamoyl)aziridin-2-yl)phenyl acetate (2S,3R)-125l: 4-Fomylphenyl acetate 33l (34 µL, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3R)-125l as a white foam (mp 106-108 ¡C on >99% ee material) in 82% yield (123 mg, 0.164 mmol); trans/cis 25:1. The enantiomeric purity of (2S,3R)-125l was determined to be 99.6% ee by HPLC analysis (PIRKLE BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33l101c122a125lHOAcOAcO!'',!COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 34.72 min (minor enantiomer, ent-125l) and Rt = 38.27 min (major enantiomer, 125l). Spectral data for (2S,3R)-125l: Rf = 0.30 (5:1 hexanes/EtOAc); 1H-NMR (500 MHz, DMSO-d6) & 1.21 (s, 36H), 2.24 (s, 3H), 2.98 (s, 1H), 5.23 (s, 1H), 3.40 (s, 3H), 3.52 (s, 3H), 7.00 (t, 1H, J = 7.5 Hz), 7.08 (d, 2H, J = 8.0 Hz), 7.18 (s, 2H), 7.24 (t, 2H, J = 7.5 Hz), 7.29 (s, 2H), 7.37 (d, 2H, J = 8.0 Hz), 7.49 (d, 2H, J = 8.0 Hz), 10.30 (s, 1H) (one proton not located); 13C-NMR (125 MHz, CDCl3) & 20.86, 31.80, 31.84, 35.23, 35.29, 45.79, 47.62, 63.73, 63.93, 65.43, 119.03, 121.80, 123.49, 125.23, 125.72, 127.07, 128.60, 131.12, 136.54, 137.77, 138.76, 142.18, 142.33, 149.76, 157.39, 157.42, 165.12, 169.16; IR (thin film) 3331s, 2960s, 1765vs, 1682vs, 1601vs, 1538s, 1447s, 1413s, 1367s, 1262vs, 1194vs, 1115s, 1013s cmÐ1; HRMS (ESI-TOF) m/z 747.4734 [(M+H+); calcd. for C48H63N2O5: 747.4737]; !!!!!" +46.6¡ (c 1.0, CH2Cl2) on >99% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(4-methoxyphenyl)-N-phenylaziridine-2-carboxamide (2R,3S)-125e: 4-anisaldehyde 33e (29 µL, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). A 76% of imine and 9% of aziridine (2R,3S)-125e was observed in the 1H NMR spectrum of the crude reaction mixture; trans/cis 1.3:1. BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33e101c122a125eHOMeOMeO!''-! (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-phenyl-3-(p-tolyl)aziridine-2-carboxamide (2R,3S)-125c: To a 10 mL flame-dried home-made Schlenk flask, prepared from a 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv), B(OPh)3 (17 mg, 0.060 mmol) and BUDAM amine 101c (94 mg, 0.20 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (0.40 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ¡C) for 0.5 h. The pre-catalyst was subjected to high vacuum (0.05 mmHg) at 80 ¡C for 30 min to remove all the volatile substances. The flask was then allowed to cool to room temperature and open to argon through side arm of the Schlenk flask. To the flask containing the catalyst was added dry toluene (1.0 mL) to dissolve all the materials, followed by the addition of the 4† Molecular Sieves (60 mg, freshly flame- dried) and 4-tolualdehyde 33c (28 µL, 0.24 mmol, 1.2 equiv). The reaction mixture was allowed to stirred at room temperature for 20 min that the corresponding imine was formed completely. This solution was then allowed to cool to Ð20 ¡C and rapidly added N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). The resulting mixture was stirred for 24 h at Ð20 ¡C. The reaction was dilluted by addition of pre-cooled hexane (3 mL) under Ð20 ¡C before the reaction mixture was filtered through a silica gel plug to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL ' 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33c101c122a125cHO!''.!vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a yellow-colored viscous oil. Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-125c as a white foam (mp 82-83 ¡C on 85% ee material) in 73% yield (103 mg, 0.146 mmol); trans/cis 19:1. The enantiomeric purity of (2R,3S)-125c was determined to be 85% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 14.46 min (minor enantiomer, ent-125c) and Rt = 34.63 min (major enantiomer, 125c). Spectral data for (2R,3S)-125c: Rf = 0.23 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.33 (s, 36H), 2.32 (s, 3H), 3.03 (d, 1H, J = 2.8 Hz), 3.58 (d, 1H, J = 2.8 Hz), 3.62 (d, 6H, J = 7.5 Hz), 6.89 (s, 33m), 6.98 (d, 33m, J = 7.8 Hz), 7.03 (d, 33m, J = 7.8 Hz), 7.10 (t, 1H, J = 7.5 Hz), 7.25 (s, 33m), 7.33 (t, 33m, J = 7.8 Hz), 7.54 (d, 33m, J = 7.5 Hz), 8.76 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 21.12, 32.02, 35.60, 35.67, 43.34, 49.52, 64.00, 64.21, 67.59, 119.35, 124.12, 125.26, 125.44, 128.34, 128.64, 128.99, 129.97, 136.59, 136.64, 137.44, 137.96, 142.68, 143.39, 143.51, 158.20, 158.45, 168.37 (one sp3 carbon not located); IR (thin film) 3317s, 2961vs, 2869s, 1668vs, 1602vs, 1533vs, 1446vs, 1413s, 1394s, 1361s, 1222vs, 1115s, 1013s cmÐ1; HRMS (ESI-TOF) m/z 703.4850 [(M+H+); calcd. for C47H63N2O3: 703.4839]; !!!!!" +11.9¡ (c 1.0, CH2Cl2) on 85% ee material (HPLC).   !'(/! (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-phenyl-3-(o-tolyl)aziridine-2-carboxamide (2R,3S)-125d: 2-Tolualdehyde 33d (28 µL, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-125d as a white foam (mp 72-74 ¡C on 93% ee material) in 85% yield (120 mg, 0.170 mmol); trans/cis >99:1. The enantiomeric purity of (2R,3S)-125d was determined to be 93% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 34.37 min (minor enantiomer, ent-125d) and Rt = 43.62 min (major enantiomer, 125d). Spectral data for (2R,3S)-125d: Rf = 0.27 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, DMSO-d6) & 1.22 (s, 18H), 1.28 (s, 18H), 2.14 (s, 3H), 2.90 (d, 1H, J = 2.0 Hz), 3.34 (s, 3H), 3.45 (d, 1H, J = 2.5 Hz), 3.54 (s, 3H), 5.12 (s, 1H), 6.99 (t. 1H, J = 7.5 Hz), 7.06-7.18 (m, 2H), 7.22 (t, 2H, J = 8.0 Hz), 7.26 (s, 2H), 7.29-7.37 (m, 2H), 7.42 (s, 2H), 7.46 (d, 2H, J = 8.0 Hz), 10.19 (s, 1H); 13C-NMR (125 MHz, DMSO-d6) & 18.44, 31.78, 31.85, 35.20, 35.34, 63.65, 63.95, 66.60, 115.22, 118.98, 123.39, 125.11, 125.43, 125.73, 126.97, 128.53, 129.61, 135.82, 136.81, 137.75, 138.10, 138.76, 142.13, 142.41, 157.34, 157.53, 165.22; IR (thin film) 3323s, 2960vs, 2869s, 1678vs, 1602vs, 1531vs, 1445vs, BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33d101c122a125dHO!'(&!1413vs, 1392s, 1361s, 1221vs, 1115s, 1013s cmÐ1; HRMS (ESI-TOF) m/z 703.4838 [(M+H+); calcd. for C47H63N2O3: 703.4839]; !!!!!" +3.0¡ (c 1.0, CH2Cl2) on 92% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(4-bromophenyl)-N-phenylaziridine-2-carboxamide (2R,3S)-125m: 4-Bromobenzaldehyde 33m (44 mg, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-125m as a white foam (mp 74-76 ¡C on 96% ee material) in 82% yield (126 mg, 0.164 mmol); trans/cis 23:1. The enantiomeric purity of (2R,3S)-125m was determined to be 96% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 18.83 min (major enantiomer, 125m) and Rt = 25.16 min (minor enantiomer, ent-125m). Spectral data for (2R,3S)-125m: Rf = 0.58 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, DMSO-d6) & 1.21 (s, 36H), 2.98 (d, 1H, J = 2.5 Hz), 3.38 (d, 1H, J = 2.5 Hz), 3.40 (s, 3H), 3.52 (s, 3H), 5.23 (s, 1H), 7.00 (t, 1H, J = 7.2 Hz), 7.17 (s, 2H), 7.23 (t, 2H, J = 7.5 Hz), 7.27 (s, 2H), 7.30 (d, 2H, J = 7.5 Hz), 7.50 (d, 4H, J = 8.0 Hz), 10.32 (s, 1H); 13C-NMR (125 MHz, DMSO-d6) & 31.77, 31.79, 35.20, 35.27, 45.55, 47.74, 63.71, 63.92, BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33m101c122a125mHOBrBr!'('!65.38, 115.22, 119.00, 123.50, 125.15, 125.68, 128.29, 128.58, 131.22, 137.63, 137.68, 138.63, 138.72, 142.18, 142.31, 157.38, 157.42, 164.88; IR (thin film) 3313s, 2960vs, 1663vs, 1602s, 1534s, 1489s, 1445s, 1413s, 1393s, 1361s, 1222vs, 1115s, 1011s cmÐ1; HRMS (ESI-TOF) m/z 767.3763 [(M+H+); calcd. for C46H60N2O3Br: 767.3787]; !!!!!" +7.2¡ (c 1.0, CH2Cl2) on 96% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(3-bromophenyl)-N-phenylaziridine-2-carboxamide (2R,3S)-125n: 3-Bromobenzaldehyde 33n (28 µL, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-125n as a white foam (mp 64-67 ¡C on 95% ee material) in 89% yield (137 mg, 0.178 mmol); trans/cis 27:1. The enantiomeric purity of (2R,3S)-125n was determined to be 95% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 14.48 min (major enantiomer, 125n) and Rt = 19.11 min (minor enantiomer, ent-125n). Spectral data for (2R,3S)-125n: Rf = 0.58 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, DMSO-d6) & 1.22 (d, 36H, J = 6.5 Hz), 3.00 (d, 1H, J = 2.0 Hz), 3.39 (s, 3H), 3.43 (d, 1H, J = 2.0 Hz), 3.52 (s, 3H), 5.24 (s, 1H), 6.99 (t, 1H, J = 7.5 Hz), 7.19 (s, 2H), 7.20-BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33n101c122a125nHOBrBr!'((!7.29 (m, 3H), 7.31 (s, 2H), 7.35 (d, 1H, J = 7.5 Hz), 7.42 (d, 1H, J = 7.5 Hz), 7.49 (d, 2H, J = 8.0 Hz), 7.54 (s, 1H), 10.28 (s, 1H); 13C-NMR (125 MHz, DMSO-d6) & 31.76, 31.80, 35.20, 35.27, 45.30, 47.77, 63.68, 63.89, 65.38, 115.22, 118.97, 121.91, 123.48, 125.14, 125.50, 125.63, 128.55, 129.35, 130.08, 130.45, 137.61, 137.68, 138.70, 141.96, 142.18, 142.37, 157.44, 164.78; IR (thin film) 3316s, 2960vs, 1664vs, 1600vs, 1534vs, 1445vs, 1412vs, 1360s, 1222vs, 1115s, 1013s cmÐ1; HRMS (ESI-TOF) m/z 767.3783 [(M+H+); calcd. for C46H60N2O3Br: 767.3787]; !!!!!" +5.4¡ (c 1.0, CH2Cl2) on 95% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(2-bromophenyl)-N-phenylaziridine-2-carboxamide (2R,3S)-125o: 2-Bromobenzaldehyde 33o (28 µL, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-125o as a white foam (mp 170-172 ¡C on 93% ee material) in 86% yield (132 mg, 0.172 mmol); trans/cis 19:1. The enantiomeric purity of (2R,3S)-125o was determined to be 93% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33o101c122a125oHOBrBr!'()!retention times; Rt = 13.14 min (minor enantiomer, ent-125o) and Rt = 31.61 min (major enantiomer, 125o). Spectral data for (2R,3S)-125o: Rf = 0.35 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, DMSO-d6) & 1.23 (s, 18H), 1.27 (s, 18H), 2.92 (d, 1H, J = 2.5 Hz), 3.36 (s, 3H), 3.53 (s, 3H), 3.64 (d, 1H, J = 2.5 Hz), 5.18 (s, 1H), 7.00 (t, 1H, J = 7.5 Hz), 7.18 (t, 1H, J = 8.0 Hz), 7.22 (t, 2H, J = 8.2 Hz), 7.25 (s, 2H), 7.37 (t, 1H, J  = 7.5 Hz), 7.38 (s, 2H), 7.45 (d, 1H, J = 7.5 Hz), 7.47 (d, 2H, J = 7.5 Hz), 7.54 (d, 1H, J = 8.5 Hz), 10.24 (s, 1H); 13C-NMR (125 MHz, DMSO-d6) & 31.77, 31.84, 35.20, 35.33, 46.63, 46.89, 63.65, 63.92, 66.24, 115.22, 118.99, 122.84, 123.48, 125.33, 125.49, 127.44, 127.73, 128.54, 129.36, 132.18, 137.44, 137.77, 138.66, 142.18, 142.47, 157.42, 157.55, 164.56; IR (thin film) 3324s, 2960vs, 1665vs, 1602vs, 1531vs, 1444vs, 1413vs, 1394s, 1361s, 1262s, 1222s, 1115s, 1014s cmÐ1; HRMS (ESI-TOF) m/z 767.3777 [(M+H+); calcd. for C46H60N2O3Br: 767.3787]; !!!!!" +1.7¡ (c 1.0, CH2Cl2) on 93% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-phenyl-3-(4-(trifluoromethyl)phenyl)aziridine-2-carboxamide (2R,3S)-125p: 4-Trifluoromethylbenzaldehyde 33p (33 µL, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-125p as a white foam BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33p101c122a125pHOF3CF3C!'(*!(mp 82-84 ¡C on 96% ee material) in 78% yield (118 mg, 0.156 mmol); trans/cis 31:1. The enantiomeric purity of (2R,3S)-125p was determined to be 96% ee by HPLC analysis (CHIRALCEL OD-H column, 95:5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.11 min (minor enantiomer, ent-125p) and Rt = 14.56 min (major enantiomer, 125p). Spectral data for (2R,3S)-125p: Rf = 0.27 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, DMSO-d6) & 1.18 (s, 18H), 1.21 (s, 18H), 3.08 (d, 1H, J = 2.5 Hz), 3.42 (s, 3H), 3.48 (d, 1H, J = 2.5 Hz), 3.51 (s, 3H), 5.24 (s, 1H), 7.02 (t, 1H, J = 7.2 Hz), 7.16 (s, 2H), 7.24 (s, 2H), 7.26 (t, 2H, J = 8.0 Hz), 7.51 (d, 2H, J = 8.0 Hz), 7.58 (d, 2H, J = 8.5 Hz), 7.71 (d, 2H, J = 7.5 Hz), 10.37 (s, 1H); 13C-NMR (125 MHz, DMSO-d6) & 31.74, 31.77, 35.21, 35.24, 45.46, 48.05, 63.75, 63.93, 65.26, 115.22, 119.02, 123.58, 125.14, 125.29, 125.73, 126.97, 128.63, 129.38, 137.55, 138.68, 142.25, 142.33, 144.05, 157.38, 157.48, 164.73; IR (thin film) 3319s, 2960vs, 2871s, 1665vs, 1602vs, 1536vs, 1446s, 1413s, 1395s, 1361s, 1325vs, 1223vs, 1168s, 1129s, 1116s, 1067s, 1016s cmÐ1; HRMS (ESI-TOF) m/z 757.4536 [(M+H+); calcd. for C47H60F3N2O3: 757.4556]; !!!!!" +8.5¡ (c 1.0, CH2Cl2) on 96% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(4-nitrophenyl)-N-phenylaziridine-2-carboxamide (2R,3S)-125b: 4-nitrobenzaldehyde 33b (36 mg, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 BUDAMNH2BOROX(10 mol%)4  MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33bb101c122a125bHOO2NO2N!'(+!mg, 0.28 mmol, 1.4 equiv). A 52% of imine and 16% of aziridine (2R,3S)-125b was observed in the 1H NMR spectrum of the crude reaction mixture; trans/cis 29:1.   Methyl 4-((2S,3R)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(phenylcarbamoyl)aziridin-2-yl)benzoate (2S,3R)-125q: Methyl 4-fomylbenzoate 33q (39 mg, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 5:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2S,3R)-125q as a white foam (mp 94-95 ¡C on >99% ee material) in 89% yield (133 mg, 0.178 mmol); trans/cis 42:1. The enantiomeric purity of (2S,3R)-125q was determined to be 99.5% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 32.11 min (minor enantiomer, ent-125q) and Rt = 39.16 min (major enantiomer, 125q). Spectral data for (2S,3R)-125q: Rf = 0.37 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3/DMSO-d6 1:1, v/v) & 1.20 (s, 18H), 1.22 (s, 18H), 3.04 (d, 1H, J = 2.0 Hz), 3.42 (s, 3H), 3.45 (d, 1H, J = 2.5 Hz), 3.52 (s, 3H), 3.82 (s, 3H), 5.23 (s, 1H), 6.97 (t, 1H, J = 7.0 Hz), 7.16 (s, 2H), 7.20 (t, 2H, J = 7.5 Hz), 7.24 (s, 2H), 7.45 (d, 2H, J = 8.0 Hz), 7.51 (d, 2H, J = 8.0 Hz), 7.91 (d, 2H, J = 8.0 Hz), 10.27 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 30.17, 30.21, 35.58, 35.68, 43.80, 48.92, 52.18, 64.01, 64.29, 68.32, 115.30, 119.46, BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33q101c122a33qHOMeO2CMeO2C!'(,!120.36, 124.41, 125.06, 125.12, 125.80, 128.98, 129.05, 129.54, 129.98, 142.94, 143.69, 155.87, 158.33, 158.60, 166.50, 167.82; IR (thin film) 3348s, 2960vs, 1725vs, 1688vs, 1602vs, 1543vs, 1445vs, 1413s, 1395s, 1279vs, 1222s, 1115vs, 1016vs cmÐ1; HRMS (ESI-TOF) m/z 747.4731 [(M+H+); calcd. for C48H63N2O5: 747.4737]; !!!!!" +49.4¡ (c 1.0, EtOAc) on >99% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(4-cyanophenyl)-N-phenylaziridine-2-carboxamide (2R,3S)-125r: 4-Fomylbenzonitrile 33r (26 mg, 0.24 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.28 mmol, 1.4 equiv). A 66% of imine and 8% of aziridine (2R,3S)-125r was observed in the 1H NMR spectrum of the crude reaction mixture; trans/cis 13:1. 6.3.3 Multi-Component trans-Aziridination of Aliphatic Aldehydes  General procedure A of multi-component trans-aziridination of aliphatic aldehydes To a 10 mL flame-dried home-made Schlenk flask, prepared from a 10 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added ligand 68a, 68b or 68c (0.020 mmol), B(OPh)3 (17 mg, 0.060 mmol) and amine 101a, 101b or 101c (0.200 mmol). BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNBUDAMHNOPh+N2+Ph33r101r122r125rHONCNCPGNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNR1PGHNOR1+N2+R233, 130101122126, 131R1HO!'(-!Under an argon flow through the side arm of the Schlenk flask, dry toluene (1.0 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ¡C) for 0.5 h. The flask was cooled to room temperature, then Ð10 ¡C and open to argon through side arm of the Schlenk flask. To the flask containing the catalyst was rapidly added the 4† Molecular Sieves (60 mg, freshly flame-dried), aldehyde (0.22 mmol, 1.1 equiv) and diazoacetamide 122a, 122b (0.24 mmoL, 1.2 equiv). The resulting mixture was stirred for 24 h at Ð10 ¡C. The reaction was dilluted by addition of pre-cooled hexane (3 mL) under Ð10 ¡C before the reaction mixture was filtered through a silica gel plug to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL ' 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a yellow-colored viscous oil. Purification of the crude aziridine by silica gel chromatography (20 mm ' 150 mm column, gravity column) afforded an trans-aziridine as a white solid. General procedure B of multi-component trans-aziridination of aliphatic aldehydes In the general procedure B, the catalyst was stirred with the aldehyde and amine for 20 min at room temperature, before the solution was cooled to Ð10 ¡C and the diazoacetamide was added. The rest of the procedure follows the general procedure A. General procedure C of multi-component trans-aziridination of aliphatic aldehydes In the general procedure B, the catalyst was stirred with the aldehyde and amine for 20 h at room temperature, before the solution was cooled to Ð10 ¡C and the diazoacetamide was added. The rest of the procedure follows the general procedure A. !'(.! (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-pentadecylaziridine-2-carboxamide 126g: (Table 3.3, entry 6) Hexadecanal 33g21 (53 mg, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 6:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-126g as an off-white solid (mp 78-80 ¡C on 96% ee material) in 85% yield (137 mg, 0.170 mmol); trans/cis 24:1. The enantiomeric purity of (2R,3S)-126g was determined to be 96% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 95:5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.25 min (minor enantiomer, ent-126g) and Rt = 19.24 min (major enantiomer, 126g). (Table 3.3, entry 7) The aziridination of 33g according to the General Procedure B of multi-component trans-aziridination of aliphatic aldehydes in the presence of (S)-VANOL BOROX catalyst afforded (2R,3S)-126g in 96% ee and 88% yield (141 mg, 0.176 mmol); trans/cis 21:1. (Table 3.3, entry 10) The aziridination of 33g in the presence of (S)-VAPOL BOROX catalyst afforded (2R,3S)-126g in 91% ee and 91% yield (146 mg, 0.182 mmol); trans/cis 14:1. (Table 3.3, entry 11) The aziridination of 33g in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2S,3R)-ent-126g in Ð90% ee and 71% yield (114 mg, 0.142 mmol); trans/cis 17:1. BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNC15H31BUDAMHNOBu+N2+Bu33g101c122b126gC15H31HO!')/!Spectral data for (2R,3S)-126g: Rf = 0.44 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.88 (t, 3H, J =6.8 Hz), 0.91 (t, 3H, J = 7.2 Hz), 1.13-1.33 (m, 30H), 1.38 (s, 18H), 1.41 (s, 18H), 1.53-1.62 (m, 2H), 2.08 (d, 1H, J = 3.0 Hz), 2.18 (td, 1H, J = 6.3, 2.8 Hz), 3.10 (m, 1H), 3.21 (m, 1H), 3.65 (d, 6H, J = 2.5 Hz), 4.18 (s, 1H), 6.66 (t, 1H, J = 5.8 Hz), 7.21 (s, 2H), 7.30 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.76, 14.13, 20.08, 22.68, 26.43, 28.22, 29.35, 29.47, 29.48, 29.51, 29.63, 29.66, 29.68, 31.70, 31.92, 32.07, 32.12, 35.68, 35.72, 38.42, 44.98, 47.29, 64.03, 64.16, 68.46, 125.15, 125.33, 137.26, 137.43, 143.06, 143.21, 158.20, 158.29, 170.77 (three sp3 carbon not located); IR (thin film) 3312vs, 2958vs, 2926s, 2855s, 1652vs, 1540s, 1456s, 1413s, 1264s, 1223s, 1116s, 1014s cmÐ1; HRMS (ESI-TOF) m/z 803.7001 [(M+H+); calcd. for C53H91N2O3: 803.7030]; !!!!!" Ð10.5¡ (c 1.0, EtOAc) on 96% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-pentadecyl-N-phenylaziridine-2-carboxamide 125g: (Table 3, entry 9) Hexadecanal 33g (53 mg, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (39 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-125g as a semi-solid in 78% yield (128 mg, 0.156 mmol); trans/cis 12:1. The enantiomeric purity of (2R,3S)-125g was determined to be 88% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 98:2 hexane/2-BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNC15H31BUDAMHNOPh+N2+Ph33g101c122a125gC15H31HO!')&!propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 20.53 min (minor enantiomer, ent-125g) and Rt = 35.84 min (major enantiomer, 125g). (Table 3.3, entry 8) The aziridination of 33 according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes in the presence of (S)-VANOL BOROX catalyst afforded (2R,3S)-125g in 68% ee and 70% yield (115 mg, 0.140 mmol); trans/cis 6:1. Spectral data for (2R,3S)-125g: Rf = 0.57 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.88 (t, 3H, J = 7.0 Hz), 1.10-1.31 (m, 26H), 1.34 (s, 18H), 1.43 (18H), 1.62-1.67 (m, 2H), 2.20 (d, 1H, J = 3.0 Hz), 2.38-2.41 (m, 1H), 3.62 (s, 3H), 3.68 (s, 3H), 4.27 (s, 1H), 7.07 (t, 1H, J = 7.8 Hz), 7.27 (s, 2H), 7.30 (t, 2H, J = 8.0 Hz), 7.48 (d, 2H, J = 8.0 Hz), 8.57 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 14.13, 22.69, 26.44, 28.14, 29.35, 29.41, 29.48, 29.51, 29.63, 29.67, 29.69, 31.92, 32.03, 32.14, 35.68, 35.77, 45.29, 47.54, 64.02, 64.17, 68.38, 119.15, 123.90, 125.15, 125.24, 128.94, 137.00, 137.17, 137.56, 143.22, 143.48, 158.33, 158.44, 168.87 (two sp3 carbon not located); IR (thin film) 3327vs, 2924vs, 2854s, 1679vs, 1602s, 1528s, 1465s, 1412s, 1221s, 1115s, 1014s cmÐ1; HRMS (ESI-TOF) m/z 823.6707 [(M+H+); calcd. for C55H87N2O3: 823.6717]; !!!!!" +17.6¡ (c 1.0, EtOAc) on 88% ee material (HPLC).  (2R,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-butyl-3-pentadecylaziridine-2-carboxamide 128g: (Table 3.3, entry 4) Hexadecanal 33g (132 mg, 0.220 mmol, 1.10 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with MEDAM amine 101a (150 mg, 0.200 mmol), MEDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNC15H31MEDAMHNOBu+N2+Bu33g101a122b128gC15H31HO!')'!(S)-VAPOL (22 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (85 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 3:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-128g as an oily liquid in 79% yield (251 mg, 0.395 mmol); trans/cis 15:1. The enantiomeric purity of (2R,3S)-128g was determined to be 86% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 12.62 min (minor enantiomer, ent-128g) and Rt = 26.32 min (major enantiomer, 128g). (Table 3.3, entry 3) The aziridination of 33g according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes in the presence of (S)-VANOL BOROX catalyst afforded (2R,3S)-128g in 88% ee and 67% yield (213 mg, 0.335 mmol); trans/cis 8:1. (Table 3.3, entry 5) The aziridination of 33g in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2S,3R)-ent-128g in Ð93% ee and 46% yield (146 mg, 0.230 mmol). Spectral data for (2R,3S)-128g: Rf = 0.46 (1:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.86 (t, 3H, J = 6.8 Hz), 0.88 (t, 3H, J = 7.0 Hz), 1.14-1.27 (m, 30H), 1.34-1.56 (m, 2H), 2.01 (d, 1H, J = 3.0 Hz), 2.20 (s, 6H), 2.21-2.24 (m, 1H), 2.25 (s, 6H), 2.94-3.00 (m, 1H), 3.29-3.36 (m, 1H), 3.64 (s, 3H), 3.67 (s, 3H), 4.08 (s, 1H), 6.61 (dd, 1H, J = 7.2, 4.8 Hz), 6.92 (s, 2H), 7.95 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.79, 14.11, 16.21, 16.29, 19.90, 22.68, 26.07, 28.11, 29.31, 29.35, 29.46, 29.50, 29.60, 29.64, 29.68, 31.85, 31.90, 38.26, 44.81, 47.33, 59.52, 59.60, 67.55, 126.90, 127.63, 130.52, 130.71, 138.59, 155.77, 156.05, 170.48 (three sp3 carbon and one sp2 carbon not located); IR (thin film) 2924vs, 2853s, 1646vs, 1538s, 1483s, 1466s, 1221s, 1137s, 1019s cmÐ1; HRMS (ESI-!')(!TOF) m/z 635.5176 [(M+H+); calcd. for C41H67N2O3: 635.5152]; !!!!!" +19.1¡ (c 1.0, CH2Cl2) on Ð93% ee material (HPLC).  4-Oxiranylbutanal 33s:22 Hex-5-en-1-ol 324 (1.20 mL, 10.0 mmol) was dissolved in 60 mL of dry CH2Cl2 and cooled to 0 ¡C. m-CPBA (77 wt%, 2.69 g, 12.0 mmol, 1.2 equiv) was added in portions, and the resulting mixture was left stirring at 0 ¡C for 2h, and was then allowed to slowly warm to room temperature. After another 12 h, the mixture was cooled to 0 ¡C and 10 mL of sat. Na2S2O3 was added. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were washed with sat. NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated. The crude product (895 mg) contained 22% 324 and 56% 325 as a mixture of both diastereomers, and was used in the next step without further purification. Spectral data for 325: Rf = 0.31 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.40-1.70 (m, 4H), 2.06 (q, 1H, J = 7.0 Hz), 2.46 (dd, 1H, J = 5.8, 2.8 Hz), 2.74 (t, 1H, J = 4.5 Hz), 2.89-2.92 (m, 1H), 3.62 (d, 1H, J = 7.0 Hz), 3.64 (t, 2H, J = 6.5 Hz). To a 50 mL flame-dried round bottom flask equipped with a stir bar was added alcohol 325 (5.25 mmol) into dry CH2Cl2 (28 mL).  To the resulting solution was added TEMPO (41 mg, 0.26 mmol, 0.050 equiv) and PhIO (1.39 g, 6.30 mmol, 1.20 equiv). The suspension was cooled to 0 ¡C and Yb(OTf)3 (65 mg, 0.10 mmol, 0.020 equiv) was added. The reaction mixture was stirred at room temperature for 12 h (until the alcohol was no longer detectable by TLC). The resulting suspension was filtered through a Celite pad and concentrated under reduced pressure. Purification of the crude aldehyde by silica HOMCPBA, NaHCO3CH2Cl2, 0-25 ¡C, 12 h56%HOO324325PhIO, TEMPOYb(OTf)3CH2Cl2, rt. 12 hHOO33s48%!'))!gel chromatography (20 mm ' 200 mm column, 3:1 hexanes/Et2O as eluent, flash column) afforded a mixture of both diastereomers of aldehyde 33s as a colorless liquid in 48% yield (287 mg, 2.52 mmol). Spectral data for 33s: Rf = 0.31 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.42-1.52 (m, 1H), 1.61-1.70 (m, 1H), 1.75-1.83 (m, 2H), 2.46 (dd, 1H, J = 5.0, 2.5 Hz), 2.51 (td, 2H, J = 7.0, 1.2 Hz), 2.74 (dd, 1H, J = 5.0, 4.0 Hz), 2.86-2.93 (m, 1H), 9.77 (t, 1H, J = 1.5 Hz); 13C-NMR (125 MHz, CDCl3) & 18.55, 31.67, 43.45, 46.80, 51.83, 201.96.  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-(3-oxiranylpropyl)aziridine-2-carboxamide (2R,3S)-126s: 4-Oxiranylbutanal 33s (25 µL, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-126s as a white foam in 89% yield (121 mg, 0.178 mmol); trans/cis 8:1. The diastereomeric ratio of (2R,3S)-126s isomers was determined to be 49:49:1:1 by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 18.47, 18.98 min (minor diastereomer, (2S,3R)-126s) and Rt = 35.33, 36.71 min (major diastereomer, (2R,3S)-126s). The aziridination of 33s in the presence of (R)-tBu2VANOL BOROX BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNBUDAMHNOBu+N2+Bu33s101c122b126sHOOO!')*!catalyst afforded (2S,3R)-ent-126s in 0.5:0.5:49.5:49.5 dr and 62% yield (85 mg, 0.12 mmol); trans/cis 17:1. Spectral data for (2R,3S)-126s: Rf = 0.32 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.89 (t, 3H, J = 7.5 Hz), 1.10-1.48 (m, 8H), 1.35 (s, 18H), 1.38 (s, 18H), 1.59-1.66 (m, 2H), 2.10 (dd, 1H, J = 6.8, 2.8 Hz), 2.13-2.21 (m, 1H), 2.31-2.38 (m, 1H), 2.60-2.67 (m, 1H), 2.73 (d, 1H, J = 2.5 Hz), 3.03-3.13 (m, 1H), 3.15-3.25 (m, 1H), 3.63 (d, 6H, J = 2.0 Hz), 4.15 (s, 1H), 6.62 (t, 1H, J = 5.2 Hz), 7.18 (s, 2H), 7.28 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.73, 20.04, 24.61, 26.01, 26.02, 32.04, 32.10, 35.66, 35.71, 38.41, 44.98, 46.73, 46.81, 51.82, 51.89, 64.00, 64.14, 68.60, 125.08, 125.26, 137.11, 137.25, 143.16, 143.25, 158.24, 158.31, 170.48; HRMS (ESI-TOF) m/z 677.5252  [(M+H+); calcd. for C43H69N2O4: 677.5257];   Methyl 4-hydroxybutyrate 327:23 To a solution of %-butyrolactone 326 (0.76 mL, 10 mmol) in MeOH (50 mL) was added triethylamine (8.4 mL, 60 mmol, 6.0 equiv). The reaction was heated up to 60 ¡C and stirred for 20 h. The reaction solution was then cooled, dilute with hexanes (50 mL) and concentrated in vacuo. The residual MeOH was removed azeotropically with hexanes (2 ' 20 mL). Purification by silica gel chromatography (20 mm ' 200 mm column, 6:1 hexanes/EtOAc as eluent, flash column) afforded 327 as a colorless liquid in 59% yield (696 mg, 5.89 mmol). Spectral data for 327: Rf = 0.60 (2:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 1.86 (pent, 2H, J = 6.5 Hz), 1.87-1.92 (br, 1H), 2.42 (t, 2H, J = 7.0 Hz), 3.65 (s, 3H), 3.66 (t, 2H, J = 6.0 Hz); 13C-NMR (125 MHz, CDCl3) & 27.61, 30.74, 51.68, 61.99, 174.40. OOMeOH, Et3N60 ¡C, 20 h59%MeOOOH326327PhIO, TEMPOYb(OTf)3CH2Cl2, 0 ¡C, 3 h58%MeOOH33tO!')+!Methyl 4-oxobutyrate 33t:22b To a 25 mL flame-dried round bottom flask equipped with a stir bar was added alcohol 327 (390 mg, 3.30 mmol) into dry CH2Cl2 (28 mL).  To the resulting solution was added TEMPO (26 mg, 0.16 mmol, 0.050 equiv) and PhIO (871 mg, 3.96 mmol, 1.20 equiv). The suspension was cooled to 0 ¡C and Yb(OTf)3 (41 mg, 0.066 mmol, 0.020 equiv) was added. The reaction mixture was stirred at 0 ¡C for 3 h (until the alcohol was no longer detectable by TLC). The resulting suspension was filtered through a Celite pad and concentrated under reduced pressure. Purification of the crude aldehyde by silica gel chromatography (20 mm ' 200 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded aldehyde 33t as a colorless liquid in 58% yield (222 mg, 1.91 mmol). Spectral data for 33t: Rf = 0.52 (1:2 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) 2.60 (t, 2H, J = 6.8 Hz),  & 2.77 (t, 2H, J = 6.8 Hz), 3.66 (s, 3H), 9.78 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 26.25, 38.47, 51.90, 172.67, 199.95.  Methyl 3-((2S,3R)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(butylcarbamoyl)aziridin-2-yl)propanoate 18c: Methyl 4-Oxobutyrate 33t (26 µL, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 4:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3R)-126t as a white foam (mp 160-162 ¡C on 86% ee material) in 78% yield (106 mg, 0.156 mmol). The enantiomeric purity of (2S,3R)-126t isomers was determined BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNBUDAMHNOBu+N2+Bu33t101c122b126tHOMeOMeOOO!'),!to be 86% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 15.72 min (minor enantiomer, ent-126t) and Rt = 30.32 min (major enantiomer, 126t). The aziridination of 33t in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2R,3S)-ent-126t in Ð93% ee and 59% yield (80 mg, 0.12 mmol). Spectral data for (2R,3S)-126t: Rf = 0.28 (2:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.89 (t, 3H, J = 7.5 Hz), 1.23-1.31 (m, 4H), 1.36 (s, 18H), 1.39 (s, 18H), 1.77-1.84 (m, 1H), 1.86-1.92 (m, 1H), 1.97-2.11 (m, 2H), 2.13 (d, 1H, J = 3.0 Hz), 2.20 (td, 1H, J =6.2, 2.8 Hz), 3.10 (m, 1H), 3.17 (m, 1H), 3.59 (s, 3H), 3.63 (s, 6H), 4.12 (s, 1H), 6.58 (t, 1H, J = 5.5 Hz), 7.20 (s, 2H), 7.30 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 13.74, 20.07, 21.82, 31.67, 32.06, 32.14, 32.20, 35.70, 35.73, 38.47, 44.80, 45.63, 51.60, 64.03, 64.18, 68.73, 136.95, 137.14, 143.34, 143.45, 158.40, 170.17, 172.89 (one sp2 carbon not located); IR (thin film) 3320s, 2959vs, 2872s, 1740vs, 1656vs, 1534s, 1446s, 1412vs, 1361s, 1265s, 1221vs, 1115s, 1013s cmÐ1; HRMS (ESI-TOF) m/z 679.5049 [(M+H+); calcd. for C42H67N2O5: 679.5050]; !!!!!" +13.9¡ (c 1.0, EtOAc) on Ð93% ee material (HPLC).  4-Oxobutanenitrile 15d:24 A mixture of 4,4-dimethoxybutanenitrile 328 (1.29 g, 10.0 mmol), acetone (50 mL) and 6 N HCl (20 mL) was stirred at 0 ¡C for 8 h. The mixture was then concentrated to approximately 5 mL and was extracted with CHCl3 (4 ' 15 mL). The combined organic phase was dried with Na2SO4. The solvent was remove by rotary evaporation to give crude aldehyde 33u as an oil. Purification of the crude alcohol MeOOMeCNHClacetone, 0 ¡C, 8 hHOCN33u32876%!')-!by silica gel chromatography (20 mm ' 200 mm column, 2:1 hexanes/EtOAc as eluent, flash column) afforded aldehyde 33u as a colorless liquid in 76% yield (635 mg, 7.64 mmol). Spectral data for 33u: Rf = 0.26 (1:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 2.60 (t, 2H, J = 7.0 Hz), 2.88 (t, 2H, J = 7.0 Hz), 9.76 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 9.95, 38.87, 118.48, 197.03.  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-(2-cyanoethyl)aziridine-2-carboxamide 126u: 4-Oxobutanenitrile 33u (20 µL, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 3:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2R,3S)-126u as a white foam (mp 164-167 ¡C on 60% ee material) in 88% yield (114 mg, 0.176 mmol). The enantiomeric purity of (2R,3S)-18d isomers was determined to be 40% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 16.97 min (minor enantiomer, ent-126u) and Rt = 28.53 min (major enantiomer, 126u). The aziridination of 33u in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2S,3R)-ent-126u in Ð60% ee and 51% yield (66 mg, 0.10 mmol). The aziridination of 33u in the presence of (R)-VAPOL BOROX catalyst afforded (2S,3R)-ent-126u in Ð47% ee and 61% yield (79 mg, 0.12 mmol). BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNBUDAMHNOBu+N2+Bu33u101c122b126uHONCNC!').!Spectral data for (2R,3S)-126u: Rf = 0.57 (1:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.89 (t, 3H, J = 7.0 Hz), 1.09-1.22 (m, 2H), 1.22-1.32 (m, 2H), 1.36 (s, 18H), 1.40 (s, 18H), 1.75-1.87 (m, 2H), 1.87-1.96 (m, 1H), 2.06-2.13 (m, 1H), 2.20 (d, 1H, J = 2.5 Hz), 2.24-2.32 (m, 1H), 3.04-3.24 (m, 2H), 3.64 (d, 6H, J = 8.5 Hz), 4.09 (s, 1H), 6.51 (t, 1H, J = 5.8 Hz), 7.20 (s, 2H), 7.32 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.73, 15.63, 20.04, 22.75, 32.02, 32.09, 32.19, 35.72, 35.81, 38.57, 44.13, 44.95, 64.06, 64.36, 69.35, 118.44, 124.81, 125.02, 125.37, 136.69, 143.56, 144.06, 158.59, 169.41; IR (thin film) 3323s, 2962vs, 2872s, 1645vs, 1550s, 1446s, 1413vs, 1394s, 1360s, 1261s, 1221vs, 1114s, 1014s cmÐ1; HRMS (ESI-TOF) m/z  [(M+H+); calcd. for C41H64N3O3: 646.4948]; !!!!!" Ð43.4¡ (c 1.0, EtOAc) on 40% ee material (HPLC).  3-(tert-Butyldimethylsilyl)oxypropan-1-ol 330:25 n-BuLi (12.5 mL, 1.6 M in hexanes, 20.0 mmol) was added in dropwise under 0 ¡C to a solution of distilled 1,3-propanediol 329 (1.44 mL, 20.0 mmol) in THF (40 mL). A solution of tert-butyldimethylsilyl chloride (3.01 g, 20.0 mmol) in THF (2.0 mL) was added after 30 min via cannula. The solution was allowed to warm up to room temperature and stirred for 3 h. The reaction was quenched by water (5 mL) and concentrated in vacuo. Extract the residue with CH2Cl2 (3 ' 30 mL) and wash the combined organic phase with brine (10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to afford a yellow oil. Purification by silica gel chromatography (20 mm ' 200 mm column, 6:1 hexanes/EtOAc as eluent, flash column) afforded alcohol 330 as a colorless liquid in 83% yield (3.16 g, 16.6 mmol). Spectral data for 330: Rf = 0.61 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.05 HOOHn-BuLi, TBSClTHF, Ð78 ¡C!rt. 3 hTBSOOH32933083%PhIO, TEMPOYb(OTf)3CH2Cl2, 0 ¡C, 2 h98%TBSOH33vO!'*/!(s, 6H), 0.87 (s, 9H), 1.75 (pent, 2H, J = 5.8 Hz), 2.61-2.64 (br, 1H), 3.78 (q, 2H, J = 5.5 Hz), 3.81 (t, 2H, J = 5.8 Hz); 13C-NMR (125 MHz, CDCl3) & Ð5.52, 25.85, 34.11, 62.46, 62.48, 62.96. 3-(tert-Butyldimethylsilyl)oxypropanal 15e:22b To a 25 mL flame-dried round bottom flask equipped with a stir bar was added alcohol 330 (390 mg, 5.02 mmol) into dry CH2Cl2 (20 mL).  To the resulting solution was added TEMPO (39 mg, 0.25 mmol, 0.050 equiv) and PhIO (1.38 mg, 6.26 mmol, 1.20 equiv). The suspension was cooled to 0 ¡C and Yb(OTf)3 (62 mg, 0.10 mmol, 0.020 equiv) was added. The reaction mixture was stirred at 0 ¡C for 2 h (until the alcohol was no longer detectable by TLC). The resulting suspension was filtered through a Celite pad and concentrated under reduced pressure. Purification of the crude aldehyde by silica gel chromatography (20 mm ' 200 mm column, 15:1 hexanes/EtOAc as eluent, flash column) afforded aldehyde 33v as a colorless liquid in 98% yield (927 mg, 4.92 mmol). Spectral data for 33v: Rf = 0.34 (10:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.04 (s, 6H), 0.86 (s, 9H), 2.57 (td, 2H, J = 6.0, 2.0 Hz), 3.96 (t, 2H, J = 6.0 Hz), 9.78 (t, 1H, J = 2.0 Hz); 13C-NMR (125 MHz, CDCl3) & Ð5.43, 18.23, 25.82, 46.58, 57.42, 202.05.  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)aziridine-2-carboxamide 126v: 3-(tert-Butyldimethylsilyl)propanal 33v (51 µL, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNBUDAMHNOBu+N2+Bu33v101c122b126vHOTBSOTBSO!'*&!equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-126v as a white foam (mp 61-62 ¡C on 96% ee material) in 60% yield (90 mg, 0.12 mmol); trans/cis >99:1. The enantiomeric purity of (2R,3S)-126v isomers was determined to be 96% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 95:5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 14.09 min (minor enantiomer, ent-126v) and Rt = 21.85 min (major enantiomer, 126v). The aziridination of 33v in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2S,3R)-ent-126v in Ð98% ee and 56% yield (84 mg, 0.11 mmol); trans/cis >99:1. Spectral data for (2R,3S)-126v: Rf = 0.34 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & Ð0.07 (s, 6H), 0.81 (s, 9H), 0.89 (t, 3H, J = 7.2 Hz), 1.35 (s, 18H), 1.39 (s, 18 H), 1.31-1.42 (m, 4H), 1.81 (q, 2H, J = 6.5 Hz), 2.11 (d, 1H, J = 3.0 Hz), 2.34 (td, 1H, J = 6.4, 2.8 Hz), 3.03-3.10 (m, 1H), 3.20-3.27 (m, 1H), 3.40-3.51 (m, 2H), 3.64 (d, 6H, J = 7.0 Hz), 4.14 (s, 1H), 6.65 (t, 1H, J = 6.0 Hz), 7.18 (s, 2H), 7.28 (s, 2H); 13C-NMR (125 MHz, CDCl3) & Ð5.45, Ð5.37, 13.75, 20.04, 25.83, 29.68, 31.67, 32.06, 32.09, 35.67, 35.73, 38.40, 44.06, 44.53, 61.43, 64.01, 64.12, 68.54, 125.13, 125.31, 137.13, 137.20, 143.17, 143.24, 158.24, 158.32, 170.52; IR (thin film) 3396s, 2958s, 1653vs, 1412s, 1361s, 1260s, 1221s, 1114s, 1015s cmÐ1; HRMS (ESI-TOF) m/z 751.5803 [(M+H+); calcd. for C46H79N2O4Si: 751.5809]; !!!!!" Ð2.6¡ (c 1.0, EtOAc) on 96% ee material (HPLC).  !'*'! tert-Butyl (3-oxopropyl)carbamate 33w:22b To a 25 mL flame-dried round bottom flask equipped with a stir bar was added alcohol 331 (0.85 mL, 5.0 mmol) into dry CH2Cl2 (20 mL).  To the resulting solution was added TEMPO (39 mg, 0.25 mmol, 0.050 equiv) and PhIO (1.32 mg, 6.00 mmol, 1.20 equiv). The suspension was cooled to 0 ¡C and Yb(OTf)3 (62 mg, 0.10 mmol, 0.020 equiv) was added. The reaction mixture was stirred at room temperature for 5 h (until the alcohol was no longer detectable by TLC). The resulting suspension was filtered through a Celite pad and concentrated under reduced pressure. Purification of the crude aldehyde by silica gel chromatography (20 mm ' 200 mm column, 3:1 hexanes/EtOAc as eluent, flash column) afforded aldehyde 33w as a colorless liquid in 92% yield (797 mg, 4.60 mmol). Spectral data for 33w: Rf = 0.46 (1:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 1.40 (s, 9H), 2.69 (t, 2H, J = 5.8 Hz), 3.40 (q, 2H, J = 6.0 Hz), 4.81-5.07 (br, 1H), 9.79 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 28.01, 33.75, 43.91, 78.91, 155.62, 201.27.  tert-butyl (2-((2S,3R)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(butylcarbamoyl)aziridin-2-yl)ethyl)carbamate 126w: tert-Butyl (3-oxopropyl)carbamate 33w (42 µL, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl 33wHOBocHNPhIO, TEMPOYb(OTf)3CH2Cl2, rt. 5 h68%OHBocHN331BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNBUDAMHNOBu+N2+Bu33w101c122b126wHOBocHNBocHN!'*(!diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 3:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3R)-126w as a white solid (113-115 ¡C on 88% ee material) in 67% yield (99 mg, 0.13 mmol); trans/cis 25:1. The enantiomeric purity of (2S,3R)-126w isomers was determined to be 85% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 95:5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 19.10 min (minor enantiomer, ent-126w) and Rt = 24.78 min (major enantiomer, 126w). The aziridination of 33w in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2R,3S)-ent-126w in Ð88% ee and 68% yield (100 mg, 0.136 mmol); trans/cis 10:1. Spectral data for (2S,3R)-126w: Rf = 0.23 (2:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.87 (t, 3H, J = 7.2 Hz), 1.09-1.20 (m, 4H), 1.35 (s, 18H), 1.38 (d, 9H, J = 11.5 Hz), 1.39 (s, 18H), 1.68-1.76 (m, 1H), 1.78-1.88 (m, 1H), 2.13 (d, 1H, J = 3.0 Hz), 2.14-2.21 (m, 1H), 2.86-2.95 (m, 1H), 3.06-3.13 (m, 2H), 3.14-3.23 (m, 1H), 3.60 (s, 1H), 3.63 (d, 6H, J = 2.5 Hz), 4.13 (s, 1H), 6.58 (t, 1H, J = 5.5 Hz), 7.18 (s, 2H), 7.28 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.75, 20.08, 28.35, 28.44, 31.67, 32.06, 32.11, 32.21, 35.70, 35.75, 38.47, 44.75, 64.04, 64.20, 68.76, 125.05, 125.26, 126.30, 136.98, 137.05, 143.34, 155.70, 158.34, 158.40, 170.21 (two sp3 carbon not located); IR (thin film) 3427s, 2961s, 1653vs, 1412s, 1365s, 1261s, 1222s, 1173s, 1115s, 1014s cmÐ1; HRMS (ESI-TOF) m/z 736.5618 [(M+H+); calcd. for C45H74N3O5: 736.5628]; !!!!!" +15.6¡ (c 1.0, EtOAc) on Ð88% ee material (HPLC). !'*)! N-(3-Oxopropyl)phthalimide 33x:22b To a 25 mL flame-dried round bottom flask equipped with a stir bar was added alcohol 332 (1.03 g, 5.00 mmol) into dry CH2Cl2 (20 mL).  To the resulting solution was added TEMPO (39 mg, 0.25 mmol, 0.050 equiv) and PhIO (1.32 mg, 6.00 mmol, 1.20 equiv). The suspension was cooled to 0 ¡C and Yb(OTf)3 (62 mg, 0.10 mmol, 0.020 equiv) was added. The reaction mixture was stirred at room temperature for 24 h (until the alcohol was no longer detectable by TLC). The resulting suspension was filtered through a Celite pad and concentrated under reduced pressure. Purification of the crude aldehyde by silica gel chromatography (20 mm ' 200 mm column, 3:1 hexanes/EtOAc as eluent, flash column) afforded aldehyde 33x as a white solid (mp 136-138 ¡C) in 49% yield (498 mg, 2.45 mmol). Spectral data for 33x: Rf = 0.42 (1:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 2.85 (td, 2H, J = 7.0, 1.2 Hz), 4.01 (t, 2H, J = 7.0 Hz), 7.70 (dd, 2H, J = 5.8, 3.2 Hz), 7.82 (dd, 2H, J = 5.5, 3.5 Hz), 9.79 (t, 1H, J = 1.2 Hz); 13C-NMR (125 MHz, CDCl3) & 31.62, 42.32, 123.34, 131.89, 134.10, 167.98, 199.44.  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-(2-phthalylethyl)aziridine-2-carboxamide 126x: N-(3-Oxopropyl)phthalimide 33x (45 mg, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 33xHONPhIO, TEMPOYb(OTf)3CH2Cl2, rt. 24 h49%OHN332OOOOBUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNBUDAMHNOBu+N2+Bu33x101c122b126xHONNOOOO!'**!0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 4:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2R,3S)-126x as a white foam (mp 57-60 ¡C on 60% ee material) in 71% yield (109 mg, 0.142 mmol); trans/cis 6:1. The enantiomeric purity of (2R,3S)-126x isomers was determined to be 91% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 85:15 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 26.41 min (minor enantiomer, ent-126x) and Rt = 37.97 min (major enantiomer, 126x). The aziridination of 33x in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2S,3R)-ent-126x in Ð60% ee and 64% yield (98 mg, 0.13 mmol); trans/cis 6:1. Spectral data for (2R,3S)-126x: Rf = 0.62 (1:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.84 (t, 3H, J = 7.8 Hz), 1.18-1.32 (m, 4H), 1.37 (s, 18H), 1.40 (s, 18H), 2.06 (d, 1H, J = 3.0 Hz), 2.26-2.32 (m, 1H), 3.00-3.11 (m, 1H), 3.13-3.24 (m, 2H), 3.46-3.54 (m, 1H), 3.61 (d, 6H, J = 1.0 Hz), 3.65 (t, 2H, J = 7.5 Hz), 4.17 (s, 1H), 6.55 (t, 1H, J = 5.8 Hz), 7.18 (s, 2H), 7.32 (s, 2H), 7.68 (dd, 2H, J = 5.5, 3.0 Hz), 7.80 (dd, 2H, J = 5.0, 3.0 Hz); 13C-NMR (125 MHz, CDCl3) & 13.78, 20.04, 25.90, 32.06, 32.08, 32.18, 35.69, 35.74, 36.18, 38.44, 44.20, 44.56, 64.01, 64.16, 68.60, 123.11, 123.24, 125.10, 125.21, 125.88, 132.04, 133.83, 133.95, 136.99, 143.20, 143.28, 158.32, 168.16, 169.82; IR (thin film) 3370s, 2957s, 2926s, 2870s, 1773s, 1717vs, 1451s, 1396s, 1372s, 1273vs, 1224vs, 1115s, 1011s cmÐ1; HRMS (ESI-TOF) m/z 766.5152 [(M+H+); calcd. for C48H68N3O5: 766.5159]; !!!!!" Ð5.8¡ (c 1.0, EtOAc) on 91% ee material (HPLC). !'*+! (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-phenethylaziridine-2-carboxamide 131a: Hydrocinnamaldehyde 130a (29 µL, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 3:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-131a as a white foam (mp 114-117 ¡C on 98% ee material) in 87% yield (121 mg, 0.174 mmol); trans/cis >99:1. The enantiomeric purity of (2R,3S)-131a isomers was determined to be 98% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 10.04 min (minor enantiomer, ent-131a) and Rt = 18.39 min (major enantiomer, 131a). The aziridination of 130a in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2S,3R)-ent-131a in Ð73% ee and 77% yield (107 mg, 0.154 mmol); trans/cis >99:1. Spectral data for (2R,3S)-131a: Rf = 0.20 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.89 (t, 3H, J = 7.5 Hz), 1.23-1.31 (m, 4H), 1.36 (s, 18H), 1.40 (s, 18H), 1.79-1.87 (m, 1H), 1.93-2.00 (m, 1H), 2.13 (d, 1H, J = 3.0 Hz), 2.22 (td, 1H, J = 6.1, 2.7 Hz), 2.30-2.36 (m, 1H), 2.41-2.47 (m, 1H), 3.06-3.12 (m, 1H), 3.16-3.23 (m, 1H), 3.63 (d, 6H, J = 5.5 Hz), 4.19 (s, 1H), 6.62 (t, 1H, J = 5.8 Hz), 6.94 (d, 2H, J =7.5 Hz), 7.13 (t, 1H, J = 7.2 Hz), 7.19-7.22 (m, 2H), 7.20 (s, 2H), 7.34 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.58, 20.05, 28.21, 31.66, 32.06, 32.11, 34.35, 35.70, 35.76, 38.46, 44.85, 46.42, 64.03, BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNBUDAMHNOBu+N2+Bu130a101c122b131aHOPhPh!'*,!64.23, 68.59, 125.11, 125.25, 125.97, 128.24, 128.32, 129.59, 137.17, 137.31, 141.02, 143.31, 158.34, 158.37, 170.57; IR (thin film) 3441s, 2961s, 1645vs, 1412s, 1221s, 1115s, 1014s cmÐ1; HRMS (ESI-TOF) m/z 697.5319 [(M+H+); calcd. for C46H69N2O3: 697.5308]; !!!!!" Ð15.7¡ (c 1.0, EtOAc) on 98% ee material (HPLC).  (2R,3S)-3-benzyl-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butylaziridine-2-carboxamide 126y: Phenylacetaldehyde 33y(25 µL, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-126y as a white foam (mp 82-84 ¡C on 98% ee material) in 71% yield (97 mg, 0.14 mmol); trans/cis >99:1. The enantiomeric purity of (2R,3S)-126y isomers was determined to be 88% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.80 min (major enantiomer, 126y) and Rt = 31.03 min (minor enantiomer, ent-126y). The aziridination of 33y in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2S,3R)-ent-126y in Ð96% ee and 86% yield (119 mg, 0.174 mmol); trans/cis >99:1. Spectral data for (2R,3S)-126y: Rf = 0.30 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.88 (t, 3H, J = 7.5 Hz), 1.23-1.30 (m, 2H), 1.37 (s, 36H), 1.34-1.43 (m, 2H), BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNBUDAMHNOn-Bu+N2+n-Bu33y101c122b126yHOPhPh!'*-!2.31 (d, 1H, J = 3.0 Hz), 2.45-2.48 (m, 1H), 2.89 (dd, 1H, J = 10.0, 6.0 Hz), 3.00 (dd, 1H, J = 10.0, 6.0 Hz), 3.05-3.12 (m, 1H), 3.14-3.21 (m, 1H), 3.65 (d, 6H, J = 4.5 Hz), 4.29 (s, 1H), 6.61 (t, 1H, J = 5.8 Hz), 6.96 (d, 2H, J = 8.0 Hz), 7.10 (t, 1H, J = 7.2 Hz), 7.15 (t, 2H, J = 7.5 Hz), 7.21 (s, 2H), 7.30 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.74, 20.07, 31.66, 32.08, 35.71, 38.45, 45.21, 47.18, 64.04, 64.15, 68.87, 125.19, 125.32, 126.30, 128.38, 128.41, 137.04, 137.09, 138.46, 143.21, 143.34, 158.31, 158.39, 170.21 (three sp3 carbon not located); IR (thin film) 3323s, 2960vs, 2871s, 1656vs, 1531s, 1454vs, 1412vs, 1394s, 1361s, 1265s, 1221vs, 1115s, 1013s cmÐ1; HRMS (ESI-TOF) m/z 683.5182 [(M+H+); calcd. for C45H67N2O3: 683.5152]; !!!!!" +9.7¡ (c 1.0, EtOAc) on Ð96% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-isobutylaziridine-2-carboxamide 126z: Isovaleraldehyde 33z (24 µL, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 5:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-126z as a white foam (mp 136-139 ¡C on 95% ee material) in 88% yield (114 mg, 0.176 mmol); trans/cis 12:1. The enantiomeric purity of (2R,3S)-126z isomers was determined to be 95% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 95:5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.80 min BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNBUDAMHNOBu+N2+Bu33z101c122b126zHO!'*.!(minor enantiomer, ent-126z) and Rt = 21.43 min (major enantiomer, 126z). The aziridination of 33z in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2S,3R)-ent-126z in Ð75% ee and 70% yield (91 mg, 0.14 mmol); trans/cis 19:1. Spectral data for (2R,3S)-126z: Rf = 0.42 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.75 (d, 3H, J = 6.5 Hz), 0.86 (d, 3H, J = 6.5 Hz), 0.89 (t, 3H, J = 7.5 Hz), 1.15-1.47 (m, 7H), 1.36 (s, 18H), 1.39 (s, 18H), 2.08 (d, 1H, J = 3.0 Hz), 2.14-2.22 (m, 1H), 3.07-3.13 (m, 1H), 3.16-3.23 (m, 1H), 3.63 (s, 6H), 4.14 (s, 1H), 6.63 (t, 1H, J = 5.8 Hz), 7.20 (s, 2H), 7.28 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.76, 20.08, 21.90, 23.05, 27.30, 31.71, 32.08, 32.10, 35.02, 35.69, 38.41, 45.34, 45.84, 64.03, 64.16, 68.54, 125.21, 125.34, 137.24, 137.44, 143.06, 143.22, 158.21, 158.30, 170.71; IR (thin film) 3318s, 2958vs, 2870s, 1648vs, 1533vs, 1466vs, 1443vs, 1412vs, 1393s, 1361s, 1265s, 1221vs 1115vs, 1014vs cmÐ1; HRMS (ESI-TOF) m/z  [(M+H+); calcd. for C42H69N2O3: 649.5308]; !!!!!" Ð14.9¡ (c 1.0, EtOAc) on 98% ee material (HPLC).  (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-cyclohexylaziridine-2-carboxamide 126h: Cyclohexanecarboxaldehyde 33h (24 µL, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 5:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-126h BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNBUDAMHNOBu+N2+Bu33h101c122b126hHO!'+/!as a white foam (mp 174-178 ¡C on 57% ee material) in 45% yield (114 mg, 0.176 mmol); trans/cis 12:1. The enantiomeric purity of (2R,3S)-126h isomers was determined to be 28% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 95:5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 10.18 min (minor enantiomer, ent-126h) and Rt = 20.87 min (major enantiomer, 126h). The aziridination of 33h according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes in the presence of (R)-VAPOL BOROX catalyst afforded (2S,3R)-126h in Ð57% ee and 56% yield. The aziridination of 33h according to the General Procedure B of multi-component trans-aziridination of aliphatic aldehydes in the presence of (S)-VANOL BOROX catalyst afforded (2R,3S)-126h in 8% ee and 61% yield. Spectral data for (2R,3S)-126h: Rf = 0.36 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.56-0.69 (m, 2H), 0.77-0.93 (m, 2H), 0.90 (t, 3H, J = 7.5 Hz), 0.95-1.18 (m, 5H), 1.19-1.46 (m, 2H), 1.36 (s, 18H), 1.39 (s, 18H), 1.50-1.65 (m, 3H), 1.68-1.75 (m, 1H), 1.76-1.83 (m, 1H), 1.90 (dd, 1H, J = 4.5, 3.0 Hz), 2.03 (d, 1H, J = 3.0 Hz), 3.04-3.13 (m, 1H), 3.15-3.24 (m, 1H), 3.60 (s, 3H), 3.63 (s, 3H), 4.11 (s, 1H), 6.60 (t, 1H, J = 5.8 Hz), 7.25 (s, 2H), 7.33 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.77, 20.09, 25.79, 25.98, 26.00, 29.68, 31.72, 32.07, 32.13, 35.00, 35.69, 38.40, 44.23, 52.89, 64.00, 64.29, 69.52, 125.05, 125.12, 137.43, 137.68, 143.22, 143.24, 158.29, 158.38, 170.80; IR (thin film) 3423s, 2959s, 2926s, 1647vs, 1448s, 1413s, 1360s, 1221vs, 1115s, 1014s cmÐ1; HRMS (ESI-TOF) m/z 675.5459 [(M+H+); calcd. for C44H71N2O3: 675.5465]; !!!!!" Ð2.9¡ (c 1.0, EtOAc) on 28% ee material (HPLC). !'+&! (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(tert-butyl)-N-butylaziridine-2-carboxamide 126i: Pivaldehyde 33i (24 µL, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure C of multi-component trans-aziridination of aliphatic aldehydes with BUDAM amine 101c (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (34 mg, 0.24 mmol, 1.2 equiv). A 76% of imine and 6% of aziridine (2R,3S)-18l was observed in the 1H-NMR spectrum of the crude reaction mixture.  2-Hexadecynal 15n:11 n-BuLi (2.5 M in hexanes, 18.8 mL, 30.0 mmol) was added dropwise to a solution of 1-hexadecyne 333 (6.67 g, 30 mmol) in dry Et2O (25 mL) at Ð40 ¡C under nitrogen. After 30 min, dry DMF (3.5 mL, 45 mmol, 1.5 equiv) was added, and then the mixture was allowed to warm up to room temperature, and stirring was continued for 30 min. The mixture was poured into ice water and acidified slightly with concentrated HCl. The mixture was then neutralized with saturated NaHCO3 aq. until a pH between 6 and 7 was reached. The organic layer was separated and the aqueous layer was extracted with Et2O (3 ' 30 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated. Purification of the crude aldehyde by silica gel chromatography (20 mm ' 200 mm column, 2:1 hexanes/CH2Cl2 as eluent, flash column) afforded aldehyde 132 as a colorless liquid in 68% yield (4.82 g, BUDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNt-BuBUDAMHNOBu+N2+Bu33i101c122b125it-BuHOn-C13H27H1) n-BuLi, THFÐ78 ¡C2) DMFHOn-C13H2733313268%!'+'!20.4 mmol). Spectral data for (2R,3R)-132: Rf = 0.28 (1:1 hexanes/CH2Cl2); 1H-NMR (500 MHz, CDCl3) & 0.86 (t, 3H, J = 7.0 Hz), 1.19-1.31 (m, 18H), 1.33-1.42 (m, 2H), 1.57 (pent, 2H, J = 7.5 Hz), 2.39 (t, 2H, J = 7.2 Hz), 9.16 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 14.12, 19.12, 22.68, 27.53, 28.82, 29.00, 29.34, 29.41, 29.57, 29.63, 29.65, 31.90, 81.67, 99.45, 177.30 (one sp3 carbon not located).  (2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(pentadec-1-yn-1-yl)-N-phenylaziridine-2-carboxamide 18n: 2-Hexadecynal 132 (52 mg, 0.22 mmol, 1.1 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with MEDAM amine 101a (60 mg, 0.20 mmol), (R)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (45 mg, 0.24 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 8:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2R,3R)-133 as an oily liquid in 71% yield (92 mg, 0.14 mmol). The enantiomeric purity of (2R,3R)-133 isomers was determined to be 95% ee by HPLC analysis (CHIRALCEL AD column, 85:15 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 7.98 min (minor enantiomer, ent-133) and Rt = 21.54 min (major enantiomer, 133). The aziridination of 132 in the presence of (R)-VANOL BOROX catalyst at 0 ¡C afforded (2R,3R)-133 in 91% ee and 92% yield (120 mg, 0.184 mmol). Spectral data for (2R,3R)-133: Rf = 0.41 (3:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.86 (t, 3H, J = 7.0 Hz), 1.06-1.33 (m, 22H), 2.05 (t, 3H, J = 6.8 Hz), 2.22 (s, MEDAMNH2BOROX(10 mol%)4 † MSNHOtolueneÐ20 ¡C, 24 hNMEDAMHNOPh+N2+Ph132101a122a133HOn-C13H27n-C13H27!'+(!6H), 2.28 (s, 6H), 2.50 (d, 1H, J = 6.2 Hz), 2.53 (d, 2H, J = 6.2 Hz), 3.66 (s, 4H), 3.70 (s, 3H), 6.95 (s, 2H), 7.07 (s, 2H), 7.08 (t, 1H, J = 7.2 Hz), 7.30 (t, 2H, J = 7.5 Hz), 7.49 (d, 2H, J = 7.5 Hz), 8.38 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 14.12, 16.27, 16.30, 18.65, 22.68, 28.45, 28.70, 29.07, 29.35, 29.42, 29.65, 29.67, 29.69, 31.91, 35.72, 45.89, 59.57, 59.63, 74.58, 75.38, 84.14, 119.84, 124.21, 127.38, 127.84, 128.88, 130.74, 131.06, 136.69, 136.91, 137.19, 156.06, 156.43, 165.82 (one sp3 carbon not located); IR (thin film) 3427s, 2924s, 2853s, 1659vs, 1602s, 1529vs, 1444s, 1262s, 1222vs, 1146s, 1096s, 1017s cmÐ1; HRMS (ESI-TOF) m/z  [(M+H+); calcd. for C43H59N2O3: 651.4526]; !!!!!" Ð20.4¡ (c 1.0, EtOAc) on 91% ee material (HPLC). 6.3.4 Absolute Stereochemistry of trans- and cis-Aziridines General Procedure A of Preparation of Ester from Secondary Amide  To a flame dried 10 mL round bottom flask flushed with nitrogen was added aziridine (0.20 mmol) and THF (1.2 mL). The reaction flask was placed into the ice-bath for 5 min before the slow addition of n-butyllithium (0.14 mL, 1.6 M in hexanes, 0.22 mmol, 1.1 equiv) in dropwise. The mixture was stirred at 0 ¡C for another 10 min until the complete deprotonation of the secondary amide. A solution of Boc2O (131 mg, 0.600 mmol, 3.00 equiv) in THF (0.8 mL) was added to the reaction mixture. The resulting mixture was stirred for 2 days at room temperature under nitrogen atmosphere. The reaction was quenched by sat. aq. NH4Cl (2 mL) and brine (4 mL). The aqueous layer was extracted with Et2O (3 ' 10 mL). The combined organic layer was dried by MgSO4 and concentrated under reduced pressure. Purification of the crude product by silica gel !'+)!chromatography (20 mm ' 200 mm column, 12:1 hexanes/EtOAc as eluent, flash column) afforded N-Boc aziridinecarboxylamide, which was used immediately in the next step. To a flame dried 10 mL round bottom flask flushed with nitrogen was added ethanol (58 µL, 1.0 mmol, 5.0 equiv) and THF (1.2 mL). The reaction flask was placed into the ice-bath for 5 min before the slow addition of n-butyllithium (0.28 mL, 1.6 M in hexanes, 0.44 mmol, 2.2 equiv) in dropwise. The mixture was stirred at 0 ¡C for another 10 min until the complete formation of lithium ethoxide. A solution of N-Boc aziridinecarboxamide in THF (0.8 mL) was added to the reaction mixture. The resulting mixture was warmed up to room temperature and stirred over night until the N-Boc amide was no longer detectable by TLC. The reaction was quenched by sat. aq. NH4Cl (2 mL) and brine (4 mL). The aqueous layer was extracted with Et2O (4 ' 10 mL). The combined organic layer was dried by MgSO4 and concentrated under reduced pressure. Purification of the crude ester by silica gel chromatography (20 mm ' 200 mm column, 9:1 hexanes/EtOAc as eluent, flash column) afforded ethyl aziridinecarboxylate. General Procedure B of Preparation of Ester from Secondary Amide  To a flame dried 10 mL round bottom flask flushed with nitrogen was added aziridine (0.20 mmol) and dichloromethane (1.0 mL). To the resulting solution was added DMAP (49 mg, 0.40 mmol, 2.0 equiv) and Boc2O (131 mg, 0.600 mmol, 3.00 equiv). The reaction mixture was stirred for 24 h at room temperature under nitrogen atmosphere. Thereafter, the reaction mixture was concentrated under reduced pressure to afford crude !'+*!dark yellow oil. Purification of the crude product by silica gel chromatography (20 mm ' 200 mm column, 12:1 hexanes/EtOAc as eluent, flash column) afforded N-Boc aziridinecarboxylamide, which was used immediately in the next step. Ethyl aziridinecaboxylate was prepared from N-Boc aziridinecarboxylamide according to second step in General Procedure A.  (2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-butyl-3-pentadecylaziridine-2-carboxamide (2R,3R)-129g: Palmitaldehyde 33g (132 mg, 0.220 mmol, 1.10 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic aldehydes with MEDAM amine 101a (150 mg, 0.200 mmol), (R)-tBu2VANOL (28 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 122b (85 mg, 0.24 mmol, 1.2 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3R)-129g as an oily liquid in 44% yield (140 mg, 0.220 mmol). The enantiomeric purity of (2R,3R)-129g was determined to be 90% ee by HPLC analysis (CHIRARCEL OD-H column, 99:1 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 14.96 min (major enantiomer, ent-129g) and Rt = 21.33 min (minor enantiomer, ent-129g). Spectral data for (2R,3R)-129g: Rf = 0.33 (1:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.88 (t, 3H, J = 7.0 Hz), 0.91 (t, 3H, J = 7.5 Hz), 1.13-1.30 (m, 30H), 1.33-1.41 (m, 6H), 1.90 (q, 1H, J = 6.8 Hz), 2.25 (d, 13H, J = 18.5 Hz), 3.12 (hex, 1H, J = 6.5 Hz), 3.33 (hex, 1H, J = 7.0 Hz), 3.43 (s, 1H), 3.68 (d, 6H, J = 6.0 Hz), 6.65 (t, 1H, J = 6.0 Hz), MEDAMNH2(R)-BOROX(10 mol%)4 †  MSNHOtolueneÐ10 ¡C, 24 hNC15H31MEDAMHNOBuNC15H31MEDAMHNOBu++N2+Bun-C15H31OH33g101a122b(2S,3R)-129g(2R,3R)-129g!'++!6.94 (s, 2H), 7.02 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.75, 14.10, 16.20, 19.99, 22.67, 27.10, 28.48, 29.30, 29.34, 29.49, 29.64, 29.68, 31.90, 38.45, 45.21, 47.00, 59.54, 59.58, 76.80, 127.50, 127.51, 130.52, 130.72, 137.76, 137.90, 155.99, 156.06, 168.84 (five sp3 carbon not located); IR (thin film) 2924vs, 2853s, 1646vs, 1538s, 1483s, 1465s, 1221s, 1137s, 1019s cmÐ1; HRMS (ESI-TOF) m/z 635.5178 [(M+H+); calcd. for C41H67N2O3: 635.5152]; !!!!!" +7.0¡ (c 1.0, CH2Cl2) on 90% ee material (HPLC).  Ethyl (2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-pentadecylaziridine-2-carboxylate (2R,3R)-103g: (2R,3R)-129g (88 mg, 0.14 mmol) was reacted according to General Procedure A of preparation of eater from secondary amide with n-butyllithium (96 µL, 1.6 M in hexanes, 0.15 mmol, 1.1 equiv) and Boc2O (92 mg, 0.42 mmol, 3.0 equiv). Purification of the crude product by silica gel chromatography (20 mm ' 200 mm column, 12:1 hexanes/EtOAc as eluent, flash column) afforded N-Boc aziridinecarboxylamide as a colorless oil. The Boc-protected aziridine was then reacted with n-butyllithium (0.19 mL, 1.6 M in hexanes, 0.31 mmol, 2.2 equiv) and ethanol (41 µL, 0.70 mmol, 5.0 equiv). Purification of the crude ester by silica gel chromatography (20 mm ' 200 mm column, 9:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2R,3R)-103g as a white foam (mp 41-42 ¡C on 95% ee material) in 70% yield (60 mg, 0.098 mmol) over two steps. The optical purity of (2R,3R)-103g was determined to be 95% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 24.86 min (major enantiomer, 103g) and Rt = 42.23 min (minor enantiomer, ent-103g). NC15H31MEDAMHNOBu1) n-BuLi (1.05 equiv)Boc2O (3.0 equiv)THF, rt. 48 h2) LiOEt (2.2 equiv.)THF, rt. 16 hNC15H31MEDAMOEtO(2R,3R)-129g(2R,3R)-103g!'+,!!!!!!" +48.2¡ (c 1.0, EtOAc) on 95% ee material (HPLC); Lit4 !!!!!" +57.9¡ (c 1.0, EtOAc) on 95% ee (2R,3R)-isomer.  (2S,3R)-N-butyl-3-pentadecylaziridine-2-carboxamide (2S,3R)-134: To a flame dried 10 mL round bottom flask flushed with nitrogen was added (2S,3R)-129g (140 mg, 0.220 mmol) and anisole (2.2 mL). The resulting solution was cooled in the ice-bath for 5 min before the slow addition of trifluoromethanesulfonic acid (97 µL, 1.1 mmol, 5.0 equiv). The reaction mixture was gradually warmed up to room temperature and continually stirred for 1 h. The reaction was quenched by pouring the mixture into sat. aq. Na2CO3 (20 mL). The aqueous layer was extracted by EtOAc (4 ' 10 mL). The combined organic layer was dried by anhydrous Na2SO4 and concentrated by reduced pressure. Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 1:2 hexanes/EtOAc as eluent, flash column) afforded the deprotected aziridine (2S,3R)-134 as a white solid (mp 73-74 ¡C) in 93% yield (72 mg, 0.20 mmol). (2S,3R)-126g (161 mg, 0.200 mmol) was reacted according to the general procedure of aziridine nitrogen deprotection with trifluoromethanesulfonic acid (88 µL, 1.1 mmol, 5.0 equiv) in anisole (2.0 mL). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 1:2 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3R)-134 as a white solid in 100% yield (72 mg, 0.20 mmol). Spectral data for (2S,3R)-134: Rf = 0.24 (1:2 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.88 (t, 3H, J = 6.8 Hz), 0.92 (t, 3H, J = 7.2 Hz), 1.25-1.52 (m, 33H), 2.05 (m, NC15H31MEDAMHNOBuTfOH (5.0 equiv.)anisole, rt. 1 hHNC15H31HNOBuNC15H31BUDAMHNOBuTfOH (5.0 equiv.)anisole, rt. 1 h(2S,3R)-129g(2S,3R)-126g(2S,3R)-13488% ee87% ee!'+-!1H), 2.17 (m, 1H), 3.26 (q, 2H, J = 6.7 Hz), 6.06 (br, 1H); 13C-NMR (CDCl3, 125 MHz) & 13.71, 14.11, 20.01, 22.68, 27.31, 29.32, 29.35, 29.54, 29.56, 29.64, 29.66, 29.68, 31.57, 31.91, 37.28, 39.26, 170.68 (five sp3 carbons not located); IR (thin film) 3288s, 2915vs, 2847s, 1770s, 1759s, 1640s, 1248vs cmÐ1; HRMS (ESI-TOF) m/z 353.3501 [(M+H+); calcd. for C22H45N2O: 353.3532]; !!!!!" +11.9¡ (c 1.0, EtOAc) on 87% ee material.  (2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N,3-diphenylaziridine-2-carboxamide (2S,3S)-123a: Benzaldehyde 33a (61 µL, 0.60 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with MEDAM amine 101a (150 mg, 0.500 mmol), (R)-tBu2VANOL (28 mg, 0.050 mmol, 0.10 equiv) and N-phenyl diazoacetamide 122a (112 mg, 0.700 mmol, 1.40 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 6:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3S)-123a as a white foam (mp 67-69 ¡C on 95% ee material) in 75% yield (195 mg, 0.375 mmol). The enantiomeric purity of (2S,3S)-123a was determined to be 95% ee by HPLC analysis (CHIRALCEL OD-H column, 97:3 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 10.56 min (minor enantiomer, ent-21a) and Rt = 25.75 min (major enantiomer, 123a). The aziridination of 33a in the presence of (R)-VANOL BOROX catalyst afforded (2S,3S)-123a in 73% ee and 17% yield (44 mg, 0.085 mmol). Spectral data for (2S,3S)-123a: Rf = 0.35 (2:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 2.27 (s, 12H), 2.75 (d, 1H, J = 7.2 Hz), 3.30 (d, 1H, J = 7.2 Hz), 3.70 (s, 6H), MEDAMNH2(R)-BOROX(10 mol%)4 †  MSNHOtolueneÐ20 ¡C, 24 hNPhMEDAMHNOPhNPhMEDAMHNOPh++N2+PhPhHO33a101a122a(2S,3R)-123a(2S,3S)-123a!'+.!3.83 (s, 1H), 7.03 (t, 1H, J = 7.5 Hz), 7.11-7.16 (m, 6H), 7.18-7.32 (m, 7H), 8.10 (s, 1H); 13C-NMR (CDCl3, 125 MHz) & 16.23, 16.32, 47.28, 48.72, 59.60, 59.62, 76.69, 120.32, 124.44, 127.47, 127.53, 127.63, 127.70, 128.26, 128.78, 130.90, 131.11, 134.89, 136.61, 137.15, 137.21, 156.25, 156.32, 165.99; These spectral data match those previous reported for this compound.3 !!!!!" Ð26.2¡ (c 1.0, CH2Cl2) on 95% ee material (HPLC); Lit3 !!!!!" +4.0¡ (c 1.0, CH2Cl2) on 13% ee (2R,3R)-isomer.  (2S,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-butyl-3-phenylaziridine-2-carboxamide (2S,3R)-129a: Benzaldehyde 33a (61 µL, 0.60 mmol, 1.2 equiv) was reacted according to the General Procedure B of multi-component trans-aziridination of aromatic aldehydes with MEDAM amine 101a (150 mg, 0.500 mmol), (R)-VANOL (22 mg, 0.050 mmol, 0.10 equiv) and N-butyl diazoacetamide (99 mg, 0.70 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 6:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3R)-129a as a white foam (mp 51-52 ¡C on 76% ee material) in 36% yield (90 mg, 0.18 mmol). The enantiomeric purity of (2S,3R)-129a was determined to be 76% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 85:15 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 16.74 min (major enantiomer, 129a) and Rt = 48.70 min (minor enantiomer, ent-129a). (Table 1, entry 18) The aziridination of 33a in the presence of (R)-tBu2VANOL BOROX catalyst afforded (2S,3R)-129a in 89% ee and 8% yield (20 mg, 0.040 mmol). MEDAMNH2(R)-BOROX(10 mol%)4 †  MSNHOtolueneÐ20 ¡C, 24 hNPhMEDAMHNOBuNPhMEDAMHNOBu++N2+BuPhHO33a101a122b(2S,3R)-129a(2S,3S)-129a!',/!Spectral data for (2R,3S)-129a: Rf = 0.45 (2:1 hexanes/EtOAc); 1H-NMR (500 MHz, DMSO-d6) & 0.78 (t, 3H, J = 7.0 Hz), 1.05-1.11 (m, 2H), 1.12-1.19 (m, 2H), 2.05 (s, 6H), 2.17 (s, 6H), 2.71 (s, 1H), 2.79-2.86 (m, 1H), 3.09-3.21 (m, 1H), 3.54 (s, 3H), 3.59 (s, 3H), 5.07 (s, 1H), 7.01 (s, 4H), 7.22-7.37 (m, 5H), 8.24 (t, 1H, J = 5.7 Hz); 13C-NMR (125 MHz, DMSO-d6) & 13.61, 15.93, 16.01, 19.34, 30.94, 39.01, 45.18, 46.92, 59.06, 59.08, 64.97, 125.98, 127.07, 127.34, 127.68, 128.28, 128.54, 129.54, 129.66, 139.12, 139.25, 155.05, 155.26, 165.90; These spectral data match those previous reported for this compound.3 !!!!!" +20.0¡ (c 1.0, CH2Cl2) on 76% ee material (HPLC). Lit3 !!!!!" +39.8¡ (c 1.0, CH2Cl2) on 98% ee (2S,3R)-isomer. (2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-butyl-3-phenylaziridine-2-carboxamide (2S,3S)-129a: Purification of the crude aziridine from the aziridination with (R)- tBu2VANOL BOROX by silica gel chromatography (20 mm ' 200 mm column, 2:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3S)-129a as a white foam (mp 155-157 ¡C on 91% ee material) in 73% yield (183 mg, 0.365 mmol). The enantiomeric purity of (2S,3S)-129a was determined to be 91% ee by HPLC analysis (CHIRALCEL OD-H column, 97:3 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 8.70 min (minor enantiomer, ent-129a) and Rt = 16.43 min (major enantiomer, 129a). The aziridination of 33a in the presence of (R)-VANOL BOROX catalyst afforded (2S,3S)-129a in 86% ee and 50% yield (125 mg, 0.250 mmol). Spectral data for (2S,3S)-129a: Rf = 0.18 (2:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.77 (t, 3H, J = 7.2 Hz), 0.99-1.10 (m, 4H), 2.26 (d, 12H, J = 2.5 Hz), 2.61 (d, 1H, J = 7.2 Hz), 2.88-2.98 (m, 2H), 3.18 (d, 1H, J = 7.2 Hz), 3.69 (d, 6H, J = 8.0 Hz), 3.73 (s, 1H), 6.32 (t, 1H, J = 6.0 Hz), 7.03 (s, 2H), 7.11 (s, 2H), 7.19-7.25 (m, 5H); 13C-!',&!NMR (CDCl3, 125 MHz) & 13.68, 16.22, 16.25, 31.50, 38.23, 46.90, 48.15, 59.59, 59.61, 76.82, 127.38, 127.46, 127.73, 127.77, 128.05, 130.79, 130.84, 135.27, 137.26, 137.52, 156.16, 156.18, 167.48; IR (thin film) 3350vs, 2954vs, 2870s, 1645vs, 1536vs, 1485s, 1222s, 1147s, 1015s cmÐ1; HRMS (ESI-TOF) m/z 501.3110 [(M+H+); calcd. for C22H45N2O: 501.3117]; !!!!!" Ð7.5¡ (c 1.0, CH2Cl2) on 91% ee material (HPLC).  Ethyl (2S,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2-carboxylate (2S,3R)-103a: (2S,3R)-123a (130 mg, 0.250 mmol) was reacted according to General Procedure B of preparation of eater from secondary amide with DMAP (61 mg, 0.50 mmol, 2.0 equiv) and Boc2O (164 mg, 0.750 mmol, 3.00 equiv). Purification of the crude product by silica gel chromatography (20 mm ' 200 mm column, 12:1 hexanes/EtOAc as eluent, flash column) afforded N-Boc aziridinecarboxylamide as a colorless oil. The Boc-protected aziridine was then reacted with n-butyllithium (0.35 mL, 1.6 M in hexanes, 0.55 mmol, 2.2 equiv) and ethanol (73 µL, 1.2 mmol, 5.0 equiv). Purification of the crude ester by silica gel chromatography (20 mm ' 200 mm column, 12:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3R)-103a as a semi-solide in 80% yield (95 mg, 0.20 mmol) over two steps. NPhMEDAMHNOPh1) DMAP (2.0 equiv)Boc2O (3.0 equiv)CH2Cl2, rt. 24 h2) LiOEt (2.2 equiv.)THF, rt. 16 hNPhMEDAMOEtO(2S,3R)-123a(2S,3R)-103a87% eeNPhMEDAMHNOBu1) DMAP (2.0 equiv)Boc2O (3.0 equiv)CH2Cl2, rt. 24 h2) LiOEt (2.2 equiv.)THF, rt. 16 hNPhMEDAMOEtO(2S,3R)-129a(2S,3R)-103a76% ee!','!(2S,3R)-129a (90 mg, 0.18 mmol) was reacted according to General Procedure B of preparation of eater from secondary amide with DMAP (44 mg, 0.36 mmol, 2.0 equiv) and Boc2O (118 mg, 0.540 mmol, 3.00 equiv) for 3 days. Purification of the crude product by silica gel chromatography (20 mm ' 200 mm column, 12:1 hexanes/EtOAc as eluent, flash column) afforded N-Boc aziridinecarboxylamide as a colorless oil. The Boc-protected aziridine was then reacted with n-butyllithium (0.25 mL, 1.6 M in hexanes, 0.40 mmol, 2.2 equiv) and ethanol (41 µL, 0.90 mmol, 5.0 equiv). Purification of the crude ester by silica gel chromatography (20 mm ' 200 mm column, 12:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3R)-103a as a semi-solide in 60% yield (51 mg, 0.11 mmol) over two steps. Spectral data for (2S,3R)-103a: Rf = 0.48 (5:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 1.04 (t, 3H, J = 7.0 Hz), 2.16 (s, 6H), 2.26 (s, 6H), 2.83 (d, 1H, J = 2.5 Hz), 3.41 (d, 1H, J = 2.5 Hz), 3.64 (s, 3H), 3.68 (s, 3H), 3.95-4.08 (m, 2H), 4.91 (s, 1H), 7.03-7.11 (m, 2H), 7.07 (d, 2H, J = 4.0 Hz), 7.23-7.25 (m, 1H), 7.28-7.36 (m, 2H), 7.30 (d, 2H, J = 4.0 Hz); 13C-NMR (CDCl3, 125 MHz) & 13.89, 16.15, 16.18, 45.07, 48.70, 59.51, 59.54, 60.92, 67.01, 126.45, 127.36, 127.73, 127.87, 128.22, 130.26, 130.36, 138.31, 138.49, 138.74, 155.68, 155.77, 168.66; These spectral data match those previous reported for this compound.3 !!!!!" +5.6¡ (c 1.0, EtOAc) on 87% ee material; Lit3 !!!!!" Ð4.4¡ (c 1.0, EtOAc) on 90% ee (2R,3S)-isomer. !',(! Ethyl (2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2-carboxylate (2S,3S)-103a: (2S,3S)-123a (161 mg, 0.310 mmol) was reacted according to General Procedure B of preparation of eater from secondary amide with DMAP (76 mg, 0.62 mmol, 2.0 equiv) and Boc2O (203 mg, 0.930 mmol, 3.00 equiv). Purification of the crude product by silica gel chromatography (20 mm ' 200 mm column, 12:1 hexanes/EtOAc as eluent, flash column) afforded N-Boc aziridinecarboxylamide as a colorless oil. The Boc-protected aziridine was then reacted with n-butyllithium (0.43 mL, 1.6 M in hexanes, 0.68 mmol, 2.2 equiv) and ethanol (91 µL, 1.6 mmol, 5.0 equiv). Purification of the crude ester by silica gel chromatography (20 mm ' 200 mm column, 9:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3S)-103a as a white foam (mp 105-107 ¡C) in 67% yield (98 mg, 0.21 mmol) over two steps. (2S,3S)-129a (190 mg, 0.380 mmol) was reacted according to General Procedure A of preparation of eater from secondary amide with n-butyllithium (0.26 mL, 1.6 M in hexanes, 0.42 mmol, 1.1 equiv) and Boc2O (249 mg, 1.14 mmol, 3.00 equiv). Purification of the crude product by silica gel chromatography (20 mm ' 200 mm column, 12:1 hexanes/EtOAc as eluent, flash column) afforded N-Boc aziridinecarboxylamide as a colorless oil. The Boc-protected aziridine was then reacted with n-butyllithium (0.52 mL, NPhMEDAMHNOPhNPhMEDAMOEtO(2S,3S)-123a(2S,3S)-103a1) DMAP (2.0 equiv)Boc2O (3.0 equiv)CH2Cl2, rt. 24 h2) LiOEt (2.2 equiv.)THF, rt. 16 h95% eeNPhMEDAMHNOBuNPhMEDAMOEtO(2S,3S)-129a(2S,3S)-103a1) DMAP (2.0 equiv)Boc2O (3.0 equiv)CH2Cl2, rt. 24 h2) LiOEt (2.2 equiv.)THF, rt. 16 h91% ee!',)!1.6 M in hexanes, 0.84 mmol, 2.2 equiv) and ethanol (111 µL, 1.90 mmol, 5.00 equiv). Purification of the crude ester by silica gel chromatography (20 mm ' 200 mm column, 9:1 hexanes/EtOAc as eluent, flash column) afforded aziridine (2S,3S)-103a as a white foam in 64% yield (136 mg, 0.290 mmol) over two steps. !!!!!" Ð26.2¡ (c 1.0, EtOAc) on 95% ee material; Lit4 !!!!!" +41.3¡ (c 1.0, EtOAc) on 99% ee (2R,3R)-isomer. 6.3.5 Ring-Opening of trans-Aziridines General Procedure A: Ring-Opening of trans-Aziridine Carboxamide 125g  (2S,3S)-2-((bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)amino)-N-butyl-3-hydroxyoctadecanamide 140: (Table 3.7, entry 7) To a 25 mL flame-dried round-bottom flask equipped with a nitrogen balloon was added trans-aziridine 126g (161 mg, 0.200 mmol) and dry CH2Cl2 (2 mL). The solution was cooled in the ice bath. Thereafter, trifluoroacetic acid (15 µL, 0.20 mmol) and acetic acid (5.7 µL, 0.10 mmol) was added to the solution. The resulting reaction mixture was stirred at room temperature for 48 h (monitored by TLC). The reaction mixture was concentrated in vacuo to afford an oil. The reaction mixture was dissolved in ethanol (0.8 mL) and a solution of NaOH (8.0 mg, 0.20 mmol) in EtOH/H2O (0.4/0.2 mL) was added. The mixture was stirred for 30 min and diluted with H2O (2 mL). The white slurry was extracted by Et2O and the combined organic layer was dried with Na2SO4 and concentrated in vacuo. Purification of the crude product by silica gel chromatography (20 mm ' 200 mm column, 3:1 hexanes/Et2O as eluent, flash column) afforded a mixture of regioisomers 140 and 141 in 8:1 ratio as an oil in 86% yield (142 mg, 0.173 mmol) over two steps. 1) TFA (1.0 equiv.)HOAc (0.5 equiv.)CH2Cl2, rt. 48 h2) NaOH, EtOH/H2ONC15H31BUDAMHNOBu(2S,3R)-126gC15H31NHOHHNBUDAMOBu+C15H31NHNHOHOBuBUDAM140141!',*!Spectral data for 140: Rf = 0.20 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.86 (t, 3H, J = 7.0 Hz), 0.92 (t, 3H, J = 7.2 Hz), 1.16-1.31 (m, 28H), 1.36 (s, 18H), 1.38 (s, 18H), 1.42-1.54 (m, 5H), 2.83-2.90 (m, 1H), 3.02 (d, 1H, J = 5.5 Hz), 3.16-3.26 (m, 1H), 3.27-3.36 (m, 2H), 3.65 (d, 6H, J = 3.0 Hz), 3.74-3.83 (m, 1H), 4.65 (s, 1H), 6.81 (t, 1H, J = 5.8 Hz), 7.15 (s, 2H), 7.20 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 13.74, 14.12, 20.16, 22.68, 26.00, 29.35, 29.59, 29.63, 29.67, 29.68, 30.29, 31.72, 31.91, 32.04, 32.08, 32.10, 3376, 35.72, 35.76, 38.84, 63.92, 64.07, 64.14, 65.60, 72.99, 125.64, 125.70, 126.49, 137.29, 143.28, 143.49, 158.41, 158.54, 173.20 (two sp3 carbon not located); IR (thin film) 3354s, 2958vs, 2854s, 1655vs, 1529s, 1465s, 1412vs, 1222vs, 1115s, 1014s cmÐ1; HRMS (ESI-TOF) m/z 821.7109 [(M+H+); calcd. for C53H93N2O4: 821.7135]; !!!!!" +2.1¡ (c 1.0, EtOAc) on 94% ee material (HPLC). General Procedure B Ring-Opening of trans-Aziridine Carboxylate 143 and 143Õ  Methyl (2R,3R)-2-((bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)amino)-3-(2,2,2-trifluoroacetoxy)octadecanoate 144: To a 10 mL flame-dried round-bottom flask equipped with a nitrogen balloon was added trans-aziridine 143 (207 mg, 0.270 mmol) and dry CH2Cl2 (5.4 mL). The solution was cooled in the ice bath. Thereafter, trifluoroacetic acid (21 µL, 0.27 mmol) was added to the solution. The resulting reaction mixture was stirred at room temperature for 48 h (monitored by TLC). The reaction mixture was concentrated in vacuo to afford a mixture of regioisomers 144 and 145 in 6:1 ratio as an oily material. Purification of the crude product by silica gel chromatography TFA (1.0 equiv.)NC15H31BUDAMOMeOC15H31OHNOMeOBUDAMNHOOMeOBUDAM+OF3COCF3CH2Cl2, rt. 48 hC15H31143144145!',+!(20 mm ' 200 mm column, 50:1 hexanes/EtOAc as eluent, flash column) afforded a mixture of regioisomers 144 and 145 as an oil in 61% yield (145 mg, 0.166 mmol) over two steps. Spectral data for 144: Rf = 0.80 (10:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.86 (t, 3H, J = 6.8 Hz), 1.16-1.34 (m, 26H), 1.37 (d, 36H, J = 7.0 Hz), 1.64-1.76 (m, 1H), 1.93-2.06 (m, 1H), 2.25-2.37 (m, 1H), 3.37 (d, 1H, J = 7.0 Hz), 3.65 (d, 6H, J = 5.5 Hz), 3.71 (s, 3H), 4.61 (s, 1H), 5.10-5.19 (m, 1H), 7.13 (s, 2H), 7.20 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 14.12, 22.69, 25.08, 27.88, 29.21, 29.34, 29.37, 29.51, 29.60, 29.64, 29.67, 29.68, 29.70, 31.35, 31.93, 32.02, 32.09, 35.74, 35.75, 52.13, 61.55, 64.09, 64.10, 65.60, 79.67, 111.12, 113.39, 115.67, 117.94, 125.51, 126.07, 135.74, 137.34, 143.26, 143.40, 156.37, 156.71, 157.05, 157.38, 158.48, 158.57, 172.59; IR (thin film) 3447s, 2960vs, 2924vs, 2854s, 1739vs, 1457s, 1413s, 1261vs, 1222s, 1202s, 1094s, 1016vs cmÐ1; HRMS (ESI-TOF) m/z 876.6345 [(M+H+); calcd. for C52H85F3NO6: 876.6329]; !!!!!" +4.7¡ (c 1.0, EtOAc) on 96% ee material (HPLC).  Ethyl (2R,3R)-2-((bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)amino)-3-(2,2,2-trifluoroacetoxy)octadecanoate 144Õ: The ring-opening of aziridine 143Õ (192 mg, 0.250 mmol) followed the general procedure B with trifluoroacetic acid (19 µL, 0.25 mmol) in CH2Cl2 (2.50 mL). The resulting reaction mixture was stirred at room temperature for 48 h (monitored by TLC). The reaction mixture was concentrated in vacuo to afford a mixture of regioisomers 144Õ and 145Õ in 5:1 ratio as an oily material. Purification of the TFA (1.0 equiv.)NC15H31BUDAMOEtOC15H31OHNOEtOBUDAMNHOOEtOBUDAM+OF3COCF3CH2Cl2, rt. 48 hC15H31143'144'145'!',,!crude product by silica gel chromatography (20 mm ' 200 mm column, 50:1 hexanes/EtOAc as eluent, flash column) afforded a mixture of regioisomers 144Õ and 145Õ as an oil in 49% yield (110 mg, 0.123 mmol) over two steps. Spectral data for 144Õ: Rf = 0.83 (10:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.86 (t, 3H J = 6.8 Hz), 1.16-1.33 (m, 26H), 1.36 (d, 36H, J = 9.0 Hz), 1.64-1.75 (m, 1H), 1.92-2.06 (m, 1H), 2.29 (d, 1H, J = 10.0 Hz), 3.35 (dd, 1H, J = 10.0, 7.0 Hz), 3.65 (d, 6H, J = 6.5 Hz), 4.12-4.24 (m, 2H), 4.62 (s, 1H), 5.12-5.20 (m, 1H), 7.12 (s, 2H), 7.20 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 14.12, 14.18, 22.69, 25.08, 27.88, 29.22, 29.33, 29.37, 29.51, 29.60, 29.64, 29.66, 29.68, 29.90, 31.39, 31.93, 32.02, 32.10, 35.74, 35.75, 61.32, 61.56, 64.08, 64.10, 65.51, 79.76, 111.13, 113.40, 115.68, 117.95, 125.51, 126.09, 135.74, 137.39, 143.25, 143.39, 156.35, 156.68, 157.03, 157.36, 158.48, 158.57, 172.04; IR (thin film) 3439s, 2958s, 2925vs, 2854s, 1735vs, 1465s, 1413vs, 1361s, 1261s, 1222s, 1200s, 1115s, 1015s cmÐ1; HRMS (ESI-TOF) m/z 890.6507 [(M+H+); calcd. for C53H87F3NO6: 890.6485]; !!!!!" +5.8¡ (c 1.0, EtOAc) on 96% ee material (HPLC). 6.3.6 Synthesis of erythro-Sphinganine   (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-pentadecylaziridine-2-carboxamide 126g: Palmitaldehyde 33h (793 mg, 3.30 mmol, 1.10 equiv) was reacted according to the General Procedure A of multi-component trans-aziridination of aliphatic BUDAMNH2(S)-VANOL BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNn-C15H31BUDAMHNOBu+N2+Bu33h101b122b126gn-C15H31HOBUDAMNH2(R)-VANOL BOROX(10 mol%)4 † MSNHOtolueneÐ10 ¡C, 24 hNn-C15H31BUDAMHNOBu+N2+Bu33h101b122bent-126gn-C15H31HO!',-!aldehydes with BUDAM amine 101b (1.40 g, 3.0 mmol), (S)-VANOL (132 mg, 0.300 mmol, 0.100 equiv), triphenylborate (261 mg, 0.900 mmol, 0.300 equiv.) and N-butyl diazoacetamide (508 mg, 3.60 mmol, 1.20 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 6:1 hexanes/Et2O as eluent, flash column) afforded aziridine (2R,3S)-126g as an off-white solid in 96% ee and 88% yield (2.12 g, 2.64 mmol); trans/cis 28:1. The aziridination of 126g in the presence of (R)-VANOL BOROX catalyst afforded (2S,3R)-ent-126g in 96% ee and 86% yield (2.07 g, 2.58 mmol); trans/cis 30:1.  Methyl (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-pentadecylaziridine-2-carboxylate (2R,3S)-143: n-BuLi (1.6 M in hexanes, 1.50 mL, 2.40 mmol) was added into the solution of aziridine (2R,3S)-126g (1.92 g, 2.4 mmol) in THF (17 mL) at 0 ¡C. The resulting solution was stirred for 10 min and a solution of Boc2O (1.57 g, 7.20 mmol, 3.00 equiv) in THF (7 mL) was added via cannula. The reaction mixture was warmed up to room temperature, stirred for 36 h and refluxed for another 8 h to complete the conversion of the starting material. The reaction was cooled down to room temperature and quenched by saturated NH4Cl aq. (12 mL). The mixture was diluted by Et2O (20 mL) and the organic phase was separated. The aqueous phase was extracted by Et2O (3 ' 10 Nn-C15H31BUDAMHNOBu126g1) n-BuLi, Boc2O2) NaOMeNn-C15H31BUDAMOMeO143Nn-C15H31BUDAMHNOBuent-126g1) n-BuLi, Boc2O2) NaOMeNn-C15H31BUDAMOMeOent-14376%91%!',.!mL). The combined organic phase was dried with Na2SO4 and the solvent was removed in vacuo.  The residue was dissolved in THF (10 mL) and was added to a solution of sodium methoxide (25%wt in MeOH, 0.82 mL, 3.6 mmol). Additional THF (2 mL) was used to rinse the Boc-protected 126g and combined with the reaction mixture. The reaction was stirred for 16 h at room temperature and was diluted with H2O (10 mL) and saturated KH2PO4 aq. (10 mL). The organic phase was separated and the aqueous phase was extracted by EtOAc (4 ' 10 mL). The combined organic phase was dried by Na2SO4 and concentrated in vacuo. Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 25:1 hexanes/Et2O as eluent, flash column) afforded aziridine 143 as an oil in 76% yield (1.39 g, 1.82 mmol) over two steps. The Boc-protection and methanolysis of (2S,3R)-ent-126g (1.69 g, 2.10 mmol) reacted with n-BuLi (1.6 M in hexanes, 1.31 mL, 2.10 mmol), Boc2O (1.37 g, 6.30 mmol, 3.00 equiv) and sodium methoxide (25%wt in MeOH, 1.06 mL, 4.62 mmol, 2.20 equiv), afforded ent-143 in 91% yield (1.46 g, 1.91 mmol) over two steps. Spectral data for 143: Rf = 0.66 (10:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.86 (t, 3H, J = 6.8 Hz), 1.01-1.31 (m, 28H), 1.37 (d, 36H, J = 8.5 Hz), 2.38-2.40 (m, 1H), 2.53 (d, 1H, J = 2.5 Hz), 3.44 (s, 3H), 3.60 (s, 3H), 3.64 (s, 3H), 4.65 (s, 1H), 7.17 (s, 2H), 7.26 (s, 2H); 13C-NMR (125 MHz, CDCl3) & 14.13, 22.68, 26.90, 29.25, 29.36, 29.52, 29.56, 29.62, 29.65, 29.68, 31.92, 31.12, 32.42, 35.69, 35.72, 41.42, 48.08, 51.68, 64.06, 64.09, 68.07, 125.88, 126.31, 136.90, 137.55, 142.47, 142.81, 157.97, 158.38, 170.29 (three sp3 carbon not located); IR (thin film) 3320s, 2959vs, 2872s, 1740vs, 1656vs, 1534s, 1446s, 1413s, 1361s, 1221vs, 1115s, 1013s cmÐ1; HRMS (ESI-TOF) m/z !'-/!784.6254 [(M+Na+); calcd. for C50H83NO4Na: 784.6220]; !!!!!" +8.6¡ (c 1.0, EtOAc) on Ð96% ee material (HPLC).  (2S,3R)-2-(N-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)amino)octadecane-1,3-diol (2S,3R)-142: The ring-opening of aziridine 143 (1.52 g, 1.99 mmol) followed the general procedure B in section 6.3.5 with trifluoroacetic acid (152 µL, 1.99 mmol) in CH2Cl2 (40 mL). The resulting reaction mixture was stirred at room temperature for 48 h (monitored by TLC). The reaction mixture was concentrated in vacuo to afford an oil.  The residue was dissolved in dry THF (4.0 mL). In another flame-dried 100 mL round bottom flask equipped with a nitrogen balloon was containing LiAlH4 (1 M in THF, 8.0 mL, 8.0 mmol) in THF (14 mL). The solution of LiAlH4 was cooled in the ice-bath for 5 min. The solution of crude product was then transferred into the solution of LiAlH4 in dropwise. The crude product was rinsed with addition THF (2.0 mL) and the washing was transferred into the solution of LiAlH4 as well. The resulting solution was then stirred at room temperature for 16 h. The reaction mixture was then cooled in the ice-bath and carefully quenched by slow addition of H2O (10 mL), and then NaOH aq. (1 M, 20 mL) and finally H2O (10 mL). The white slurry was filtered and washed with Et2O (4 ' 10 mL). The organic phase was separated from the filtrate and the aqueous phase was extracted with Et2O (3 ' 20 mL). The combined organic phase was dried by Na2SO4 and Nn-C15H31BUDAMOMeO1431) TFA, CH2Cl2n-C15H31OHHNOHNn-C15H31BUDAMOMeOent-143n-C15H31OHHNOH2) LiAlH4, THFBUDAMBUDAM142ent-1421) TFA, CH2Cl22) LiAlH4, THF+n-C15H31NHOHOH146BUDAM+n-C15H31NHOHOHent-146BUDAM!'-&!concentrated under reduced pressure to afford a mixture of regioselectivity 142 and 146 with 1.5:1 ratio. Purification of the crude aziridine by silica gel chromatography (20 mm ' 200 mm column, 5:1 hexanes/Et2O as eluent, flash column) afforded compound 142 as an oil in 62% yield (928 mg, 1.23 mmol) and the regioisomer 146 as a semi-solid in 37% (558 mg, 0.740 mmol) over two steps. The ring-opening and reduction of ent-143 (1.41 g, 1.85 mmol) reacted with TFA (142 µL, 1.85 mmol) and LiAlH4 (1 M in THF, 7.4 mL, 7.4 mmol), afforded crude ent-142 in 58% yield (807 mg, 1.07 mmol) and ent-146 in 23% (323 mg, 0.429 mmol) over two steps. Spectral data for 142: Rf = 0.41 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.86 (t, 3H, J = 6.8 Hz), 1.19-1.30 (m, 28 H), 1.38 (d, 36H, J = 3.0 Hz), 2.52 (q, 1H, J = 4.2 Hz), 3.65 (d, 6H, J = 1.5 Hz), 3.68-3.70 (m, 1H), 3.73 (dd, 2H, J = 11.0, 5.0 Hz), 4.83 (s, 1H), 7.20 (d, 4H, J = 5.5 Hz) (two OH and one NH not located); 13C-NMR (125 MHz, CDCl3) & 14.12, 22.68, 26.36, 29.35, 29.60, 29.65, 29.69, 31.91, 32.06, 32.09, 32.10, 33.82, 35.75, 59.18, 60.81, 64.10, 64.56, 72.36, 125.74, 125.75, 137.41, 137.66, 143.20, 143.26, 158.31, 158.35 (six sp3 carbon not located). IR (thin film) 3340s, 2924s, 2854s, 1465s, 1413s, 1362s, 1261s, 1223vs, 1115s, 1012s cmÐ1; HRMS (ESI-TOF) m/z 752.6556 [(M+H+); calcd. for C49H86NO4: 752.6557]; !!!!!" Ð3.7¡ (c 1.0, CH) on 96% ee material (HPLC). Spectral data for (2S,3S)-3-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methylamino)octadecane-1,2-diol 146: Rf = 0.32 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.87 (t, 3H, J = 7.0 Hz), 1.17-1.33 (m, 28H), 1.40 (d, 36H, J = 4.0 Hz), 1.52-1.66 (m, 1H), 2.67 (q, 1H, J = 5.7 Hz), 3.59-3.68 (m, 2H), 3.66 (d, 6H, J !'-'!= 2.5 Hz), 4.82 (s, 1H), 7.17 (s, 2H), 7.22 (s, 2H) (two OH and one NH not located); 13C-NMR (125 MHz, CDCl3) & 22.67, 25.72, 29.34, 29.57, 29.60, 29.64, 29.67, 29.88, 30.23, 31.90, 32.05, 32.08, 35.74, 58.28, 64.08, 64.10, 64.60, 65.00, 71.23, 125.56, 125.90, 136.77, 137.63, 143.32, 143.38, 158.39, 158.41 (five sp3 carbon not located); IR (thin film) 3374s, 2958s, 2925vs, 2854s, 1466s, 1413s, 1362s, 1309s, 1262s, 1224vs, 1115s, 1012s cmÐ1; HRMS (ESI-TOF) m/z 752.6561 [(M+H+); calcd. for C49H86NO4: 752.6557]; !!!!!" +58.4¡ (c 2.0, CHCl3) on 96% ee material (HPLC).  (2S,3R)-2-aminooctadecane-1,3-diol D-erythro-sphinganine 135: To a 25 mL flame-dried round-bottom was added BUDAM-protected sphinganine 142 (533 mg, 0.709 mmol), PearlmanÕs catalyst (20% Pd(OH)2 on carbon, moisture 53%, 530 mg, 0.354 mmol, 0.500 equiv) and MeOH (7.1 mL). The flask was sealed by a septum and applied to freeze-pump-thaw cycling. The reaction mixture was flash-freezed in liquid nitrogen and a vacuum (0.05 mmHg) was applied. The mixture was then disconnected from vacuum line and thawed at room temperature. This process was repeated three times and a hydrogen balloon was placed to the septum. The reaction mixture was stirred at room temperature for 48 h. The solid was filtered and washed with EtOAc (3 ' 10 mL). The organic phase was dried with Na2SO4 and concentrated. To the residue was added hexanes (10 mL). The white slurry was separated from centrifugation to afford a white n-C15H31OHHNOH(2S,3R)-135D-erythro-sphinganinen-C15H31OHHNOHBUDAMBUDAM142ent-142H2, Pd(OH)2/CMeOHn-C15H31OHNH2OH(2R,3S)-135L-erythro-sphinganineH2, Pd(OH)2/CMeOHn-C15H31OHNH2OH+MeOt-But-But-BuOMet-Bu+MeOt-But-But-BuOMet-Bu147147!'-(!solid. Purification of the crude sphingaine by silica gel chromatography (20 mm ' 200 mm column, 8:1:0.1 CH2Cl2/MeOH/Et3N as eluent, flash column) afforded D-erythro-sphinganine 135 as a white solid (mp 80-82 ¡C) in 91% yield (195 mg, 0.645 mmol). The supernatant liquor from centrifugation was concentrated under reduced pressure to afford BUDAM hydrocarbon 147 as a white solid (mp 148-150 ¡C) in 100% yield (321 mg, 0.709 mmol). The hydrogenolysis of ent-142 (745 mg, 0.990 mmol) with PearlmanÕs catalyst (20% Pd(OH)2 on carbon, moisture 53%, 739 mg, 0.495 mmol, 0.500 equiv) afforded L-erythro-sphinganine ent-135 in 85% yield (254 mg, 0.842 mmol) and 147 in 100% yield (448 mg, 0.990 mmol). Spectral data for 135: Rf = 0.29 (EtOAc); 1H-NMR (500 MHz, d4-MeOH) & 0.90 (t, 3H, J = 6.8 Hz), 1.22-1.42 (m, 26 H), 1.44-1.59 (m, 3H), 3.20 (dt, 1H, J = 8.5, 4.1 Hz), 3.70 (dd, 1H, J = 11.5, 8.5 Hz), 3.78 (pent, 1H, J = 4.2 Hz), 3.83 (dd, 1H, J = 11.2, 4.2 Hz) (one OH and one NH not located); 13C-NMR (125 MHz, d4-MeOH) & 14.60, 23.89, 27.18, 30.63, 30.73, 30.85, 30.89, 30.92, 30.95, 33.22, 34.33, 58.59, 59.05, 70.45 (four sp3 carbon not located); !!!!!" Ð5.4¡ (c 1.0, MeOH) on 96% ee material (HPLC). For ent-135 !!!!!" +10.8¡ (c 3.0, MeOH) on 96% ee material (HPLC). Lit21 !!!!!" Ð1.9¡ (c 1.0, pyridine, D-erythro-sphinganine), !!!!!" +2.1¡ (c 1.0, pyridine, L-erythro-sphinganine). Spectral data for bis(3,5-di-tert-butyl-4-methoxyphenyl)methane 147: Rf = 0.78 (10:1 hexanes/CH2Cl2); 1H-NMR (500 MHz, CDCl3) & 1.39 (s, 36H),  3.67 (s, 6H), 3.86 (s, 1H), 7.03 (s, 4H); 13C-NMR (125 MHz, CDCl3) & 32.10, 35.67, 41.29, 64.17, 127.04, 134.96, 143.18, 157.57.  !'-)!6.3.7. Experimental Details of BUDAM Amine 101c Recycling   Bis(3,5-di-tert-butyl-4-methoxyphenyl)methanone 148:27 A mixture of hydrocarbon 147 (782 mg, 1.73 mol) and CAN (3.79 g, 6.92 mol, 4.00 equiv) in glacial acetic acid (17 mL) was heated to 95 ¡C. After 3 h, the mixture was poured onto ice and extracted with Et2O. The combined extracts were neutralized, dried, and reduced to a pale yellow solid (mp 157-158 ¡C) in 85% yield (685 mg, 1.47 mmol) without further purification. Spectral data for 147: Rf = 0.64 (10:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.43 (s, 36H), 3.73 (s, 6H), 7.72 (s, 4H); 13C-NMR (125 MHz, CDCl3) & 31.98, 35.92, 64.38, 129.02, 132.29, 143.66, 163.24, 196.23.  Bis(3,5-di-tert-butyl-4-methoxyphenyl)methanamine BUDAM amine 101c:28 To a 10 mL flame-dried round bottom flask was added a solution of ketone 148 (138 mg, 0.300 mmol) in THF (1.5 mL). The resulting mixture was cooled down to 0 ¡C. Then TiCl4 (53 µL, 0.48 mmol) was quickly added to the cold solution and an orange slurry was formed. The orange slurry then turned dark green after gaseous ammonia was bubbled into the stirred mixture for 5 min. With a continuous supply of gaseous ammonia, the dark green slurry turned orange and NH3 (g) was kept for another 20 min and then the NH3 flow was CAN, HOAc95 ¡C, 3 h147148MeOt-But-But-BuOMet-BuMeOt-But-But-BuOMet-BuO1) NH3 (g), TiCl42) LiAlH4, THF148101cMeOt-But-But-BuOMet-BuNH2MeOt-But-But-BuOMet-BuO!'-*!stopped. The resulting mixture was warmed up to room temperature and then slowly heated to reflux for 24 h. The resulting reaction mixture was cooled down to the room temperature and then placed in the ice bath. A solution of LiAlH4 (2.40 mL, 1 M in THF, 2.40 mmol) was added in dropwise at 0 ¡C to give a dark blue solution. The reaction mixture was then heated to reflux for 12 h until it gave a pale green slurry. The slurry was carefully quenched by conc. ammonium hydroxide at 0 ¡C and then extracted by Et2O. The combined organic phase was washed by brine, dried with Na2SO4 and concentrated by reduced pressure to afford a yellow oil. Purification of the crude amine by silica gel chromatography (20 mm ' 200 mm column, 5:1:0.1 hexanes/EtOAc/Et3N as eluent, flash column) afforded aziridine 101c as a white solid (mp 175-178 ¡C) in 89% yield (125mg g, 0.267 mmol). Spectral data for 147: Rf = 0.21 (3:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDCl3) & 1.42 (s, 36H), 1.77 (s, 2H), 3.69 (s, 6H), 5.10 (s, 1H), 7.28 (s, 4H); 13C-NMR (125 MHz, CDCl3) & 32.09, 35.78, 59.81, 64.12, 125.17, 139.55, 143.14, 158.17. These spectral data match those previous reported for this compound.2 6.4 Experimental Information for Chapter 4 6.4.1 trans-Aziridination/Ring-Opening Cascade Reaction with Phenol  (2S,3S)-2-((bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)amino)-3-phenoxy-N-phenyl-3-(p-tolyl)propanamide 218a: To a 10 mL flame-dried home-made Schlenk flask, prepared from a 10 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added BUDAMNH2NHON2Phtoluene, 0 ¡C, 48 h221aOPhHNNHOPhBUDAM33c122a101c218aHO+++OH(R)-VANOL BOROX(10 mol%)4 † MS!'-+!(R)-VANOL 68a (8.8 mg, 0.020 mmol), B(OPh)3 (17 mg, 0.060 mmol) and BUDAM amine 101c (94 mg, 0.200 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (1.0 mL) was added. The flask was sealed by closing the Teflon valve and the mixture was stirred at 80 ¡C for 0.5 h. To the flask containing the catalyst was added the 4† Molecular Sieves (60 mg, freshly flame-dried) and 4-tolualdehyde 33c (28 µL, 0.24 mmol, 1.2 equiv). The reaction mixture was allowed to stirred at room temperature for 20 min that the corresponding imine was formed completely. This solution was then allowed to cool to 0 ¡C and rapidly added phenol 221a (28 mg, 0.3 mmol, 1.5 equiv) N-phenyl diazoacetamide 122a (45 mg, 0.28 mmoL, 1.4 equiv). The resulting mixture was stirred for 48 h at Ð20 ¡C. The reaction was dilluted by addition of pre-cooled hexane (3 mL) under 0 ¡C before the reaction mixture was filtered through a silica gel plug to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL ' 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude product as a yellow-colored viscous oil. Purification of the crude aziridine by silica gel chromatography (20 mm ' 150 mm column, 15:1 hexanes/Et2O as eluent, flash column) afforded amino amide 218a as a white foam (mp 77-79 ¡C on 94% ee material) in 94% yield (149 mg, 0.187 mmol). The enantiomeric purity of 218a was determined to be 94% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 95:5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 19.46 min (minor enantiomer, ent-218a) and Rt = 22.93 min (major enantiomer, 218). The reaction in the presence of (R)-VAPOL BOROX afforded 218a in 28% ee and 26% yield (41 mg, 0.051 mmol). The reaction in the !'-,!presence of (R)-tBu2VANOL BOROX afforded 218a in 26% ee and 59% yield (94 mg, 0.12 mmol). Spectral data for 218a: Rf = 0.48 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.31 (s, 18H), 1.39 (s, 18H), 2.28 (s, 3H), 2.36 (d, 1H, J = 6.5 Hz), 3.60 (s, 3H), 3.69 (s, 3H), 3.98-4.05 (m ,1H), 5.20 (s, 1H), 6.09 (d, 1H, J = 3.0 Hz), 6.90 (t, 1H, J = 7.2 Hz), 6.94 (d, 2H, J = 8.0 Hz), 7.08 (t, 1H, J = 7.5 Hz), 7.09 (d, 2H, J = 8.0 Hz), 7.13 (s, 2H), 7.18 (s, 2H), 7.21 (t, 2H, J = 7.5 Hz), 7.28 (t, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0 Hz), 7.40 (d, 2H, J = 8.0 Hz), 9.14 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 21.10, 32.02, 32.05, 35.64, 35.80, 64.08, 64.13, 64.35, 66.09, 80.29, 115.70, 119.68, 121.20, 124.25, 126.05, 126.27, 126.27, 126.56, 128.85, 129.41, 129.49, 133.59, 135.59, 135.44, 137.07, 137.32, 137.81, 143.36, 143.50, 157.25, 158.49, 158.68, 169.80; IR (thin film) 3314s, 2961vs, 1688vs, 1600vs, 1519vs, 1494vs, 1442vs, 1412vs, 1393s, 1224vs, 1115s, 1012s cmÐ1; HRMS (ESI-TOF) m/z 797.5275 [(M+H+); calcd. for C53H69N2O4: 797.5257]; !!!!!" Ð61.6¡ (c 1.0, CHCl3) on 94% ee material (HPLC). 6.4.2 trans-Aziridination/Ring-Opening Cascade Reaction with 4-Methoxyphenol  (2S,3S)-2-((bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)amino)-3-(4-methoxyphenoxy)-N-phenyl-3-(p-tolyl)propanamide 218b: To a 10 mL flame-dried home-made Schlenk flask, prepared from a 10 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (R)-VANOL 68a (8.8 mg, 0.020 mmol), B(OPh)3 (17 mg, 0.060 mmol) and BUDAMNH2NHON2Phtoluene, Ð20 ¡C, 48 h221bOHNNHOPhBUDAM33c122a101c218bHO+++OH(R)-VANOL BOROX(10 mol%)4 † MSMeOMeO!'--!BUDAM amine 101c (94 mg, 0.200 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (1.0 mL) was added. The flask was sealed by closing the Teflon valve and the mixture was stirred at 80 ¡C for 0.5 h. The pre-catalyst was subjected to high vacuum (0.05 mmHg) at 80 ¡C for 30 min to remove all the volatile substances. The flask was then allowed to cool to room temperature and open to argon through side arm of the Schlenk flask. To the flask containing the catalyst was added dry toluene (1.0 mL) to dissolve all the materials, followed by addition of the 4† Molecular Sieves (60 mg, freshly flame-dried) and 4-tolualdehyde 33c (28 µL, 0.24 mmol, 1.2 equiv). The reaction mixture was allowed to stirred at room temperature for 20 min that the corresponding imine was formed completely. This solution was then allowed to cool to Ð20 ¡C and rapidly added 4-methoxyphenol 221b (37 mg, 0.3 mmol, 1.5 equiv) N-phenyl diazoacetamide 122a (45 mg, 0.28 mmoL, 1.4 equiv). The resulting mixture was stirred for 48 h at Ð20 ¡C. The reaction was dilluted by addition of pre-cooled hexane (3 mL) under Ð20 ¡C before the reaction mixture was filtered through a silica gel plug to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL ' 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude product as a yellow-colored viscous oil. Purification of the crude aziridine by silica gel chromatography (20 mm ' 150 mm column, 10:1 hexanes/Et2O as eluent, flash column) afforded amino amide 218b as a white foam (mp 63-64 ¡C on 93% ee material) in 85% yield (141 mg, 0.170 mmol). The enantiomeric purity of 218b was determined to be 93% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 95:5 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = !'-.!27.54 min (minor enantiomer, ent-128b) and Rt = 35.79 min (major enantiomer, 128b). Spectral data for 218b: Rf = 0.30 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.30 (s, 18H), 1.38 (s, 18H), 2.28 (s, 3H), 2.31-2.41 (m, 1H), 3.59 (s, 3H), 3.68 (s, 3H), 3.71 (s, 3H), 3.99 (d, 1H, J = 3.5 Hz), 5.14 (s, 1H), 5.95 (d, 1H, J = 3.5 Hz), 6.74 (d, 2H, J = 9.0 Hz), 6.85 (d, 2H, J = 8.5 Hz), 7.07 (t, 1H, J = 7.5 Hz), 7.09 (d, 2H, J = 8.0 Hz), 7.12 (s, 2H), 7.16 (s, 2H), 7.27 (t, 2H, J = 7.8 Hz), 7.31 (d, 2H, J = 7.5 Hz), 7.38 (d, 2H, J = 8.0 Hz), 9.08 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 21.10, 32.00, 32.05, 35.63, 35.79, 55.54, 64.06, 64.12, 64.31, 66.01, 80.97, 114.59, 116.73, 119.68, 124.23, 126.05, 126.25, 126.63, 128.83, 129.34, 133.80, 135.54, 137.02, 137.31, 137.76, 143.32, 143.48, 151.29, 154.04, 158.48, 158.64, 169.94; IR (thin film) 3315s, 2961vs, 2869s, 1685vs, 1601vs, 1506s, 1443s, 1412s, 1394s, 1361s, 1224vs, 1115vs, 1042s, 1012s cmÐ1; HRMS (ESI-TOF) m/z 827.5358 [(M+H+); calcd. for C54H71N2O5: 827.5363]; !!!!!" Ð54.5¡ (c 1.0, CHCl3) on 93% ee material (HPLC). 6.4.3 trans-Aziridination/Ring-Opening Cascade Reaction with Benzoic Acid  (1S,2S)-2-((bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)amino)-3-oxo-3-(phenylamino)-1-(p-tolyl)propyl benzoate 223a: To a 10 mL flame-dried home-made Schlenk flask, prepared from a 10 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (R)-VANOL 68a (8.8 mg, 0.020 mmol), B(OPh)3 (17 mg, 0.060 mmol) and BUDAM amine 101c (94 mg, 0.200 mmol). Under an argon flow through the side arm of BUDAMNH2NHON2Phtoluene, Ð20 ¡C, 48 h222OHNNHOPhBUDAM33c122a101c223aHO+++(R)-VANOL BOROX(10 mol%)4 † MSOHOOPh!'./!the Schlenk flask, dry toluene (1.0 mL) was added. The flask was sealed by closing the Teflon valve and the mixture was stirred at 80 ¡C for 0.5 h. The pre-catalyst was subjected to high vacuum (0.05 mmHg) at 80 ¡C for 30 min to remove all the volatile substances. The flask was then allowed to cool to room temperature and open to argon through side arm of the Schlenk flask. To the flask containing the catalyst was added dry toluene (1.0 mL) to dissolve all the materials, followed by addition of the 4† Molecular Sieves (60 mg, freshly flame-dried) and 4-tolualdehyde 33c (28 µL, 0.24 mmol, 1.2 equiv). The reaction mixture was allowed to stirred at room temperature for 20 min that the corresponding imine was formed completely. This solution was then allowed to cool to Ð20 ¡C and rapidly added N-phenyl diazoacetamide 122a (45 mg, 0.28 mmoL, 1.4 equiv). The resulting mixture was stirred for 24 h at Ð20 ¡C. Benzoic acid 222 (49 mg, 0.40 mmol, 2.0 equiv) was added and the reaction was kept for another 24 h. The mixture was then dilluted by addition of pre-cooled hexane (3 mL) under Ð20 ¡C before the reaction mixture was filtered through a silica gel plug to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL ' 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude product as a yellow-colored viscous oil. Purification of the crude aziridine by silica gel chromatography (20 mm ' 150 mm column, 10:1 hexanes/Et2O as eluent, flash column) afforded amino amide 223a as a white foam (mp 62-64 ¡C on 68% ee material) in 81% yield (133 mg, 0.161 mmol). The enantiomeric purity of 223a was determined to be 68% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 22.66 min !'.&!(minor enantiomer, ent-223a) and Rt = 39.77 min (major enantiomer, 223a). Spectral data for 223a: Rf = 0.30 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.28 (s, 18H), 1.36 (s, 18H), 2.29 (s, 3H), 2.30-2.36 (m, 1H), 3.60 (s, 3H), 3.67 (s, 3H), 3.91-3.98 (m, 1H), 5.14 (s, 1H), 6.76 (d, 1H, J = 3.5 Hz), 7.07 (t, 1H, J = 7.0 Hz), 7.08 (s, 2H), 7.12 (d, 2H, J = 7.5 Hz), 7.17 (s, 2H), 7.28 (t, 2H, J = 7.8 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.42 (d, 2H, J = 8.0 Hz), 7.46 (t, 2H, J = 7.5 Hz), 7.58 (t, 1H, J = 7.5 Hz), 8.14 (d, 2H, J = 8.0 Hz), 9.08 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 21.13, 31.96, 32.01, 32.04, 35.63, 35.78, 64.09, 64.14, 64.38, 65.97, 119.66, 124.27, 125.86, 126.02, 126.33, 128.92, 129.54, 129.80, 129.98, 133.31, 133.42, 135.34, 136.82, 137.39, 138.14, 143.58, 143.68, 158.62, 158.78, 165.20, 168.79; IR (thin film) 3316s, 2960vs, 2869s, 1727vs, 1693vs, 1602vs, 1523s, 1444vs, 1412s, 1394s, 1362s, 1314s, 1266vs, 1224vs, 1115s, 1012s cmÐ1; HRMS (ESI-TOF) m/z 825.5200 [(M+H+); calcd. for C54H69N2O5: 825.5206]; !!!!" Ð30.9¡ (c 1.0, CHCl3) on 54% ee material (HPLC). 6.4.4 Controlled Experiments  The catalytic trans-aziridination/ring-opening reaction was set up by the general procedure in 6.4.1 with BUDAM amine 101c (94 mg, 0.200 mmol), 4-tolualdehyde 33c (28 µL, 0.24 mmol, 1.2 equiv), phenol 221a (28 mg, 0.3 mmol, 1.5 equiv) N-phenyl diazoacetamide 122a (45 mg, 0.28 mmoL, 1.4 equiv). After 48 h, trans-aziridine ent-125c (141 mg, 0.200 mmol, 76% ee) obtained from trans-azidiridination of 4-NBUDAMOHNPhNHOPhHNOPhent-125c0.200 mmol, 76% eePhOH 221a (1.2 equiv.)0 ¡C, 28 hBUDAM0.292 mmol, 91% eeBUDAMNH24 † MS(R)-VANOL BOROX (10 mol%)p-TolCHO 33c (1.2 equiv.)NHON2Ph122a(1.4 equiv.)0 ¡C, 48 hrt. 20 minPhOH 221a (1.4 equiv.)101c0.200 mmol218a!'.'!tolualdehyde 33c was added and the reaction mixture was stirred for another 28 h. Purification of the crude mixture afforded amino amide 218a (209 mg, 0.292 mmol) in 91% ee. 6.4.5 Reaction Monitoring  The catalytic trans-aziridination/ring-opening reaction was set up by the general procedure in 6.4.1 with BUDAM amine 101c (94 mg, 0.200 mmol), 4-tolualdehyde 33c (28 µL, 0.24 mmol, 1.2 equiv), phenol 221a (28 mg, 0.3 mmol, 1.5 equiv) N-phenyl diazoacetamide 122a (45 mg, 0.28 mmoL, 1.4 equiv). Triphenylmethane (6.4 mg) was added in the reaction mixture as the internal standard. A small portion of reaction mixture was analyzed by 1H-NMR at specific reaction. The yields of each component of the reaction mixture are listed in Table 6.1. Table 6.1  Reaction tracking  Reaction Time/h aminophenoxy amide/% trans-azidirine/% imine/% 0.5 0 25.4 28.4 1 4.2 31.7 8.3 1.5 9.3 29.0 1.7 2 14.4 21.9 0 2.5 19.6 19.6 0 3 22.8 16.1 0 4 27.9 12.5 0 5 30.8 11.6 0 6 32.4 10.2 0 8 35.0 8.1 0 10 36.7 5.8 0 12 38.3 5.5 0 24 47.3 3.3 0 48 62.1 2.9 0  BUDAMNH2NHON2Phtoluene, 0 ¡C, 48 h221aOPhHNNHOPhBUDAM33c122a101c218aHO+++OH(R)-VANOL BOROX(10 mol%)4 † MSBUDAMNH2NHON2Phtoluene, 0 ¡C, 48 h221aOPhHNNHOPhBUDAM33c122a101c218aHO+++OH(R)-VANOL BOROX(10 mol%)4 † MS+NBUDAMOHNPhent-125c+HNBUDAM220!'.(!6.4.6 Absolute Stereochemistry of Aminohydroxy Amide  (2S,3S)-2-((bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)amino)-3-hydroxy-N-phenyl-3-(p-tolyl)propanamide ent-226: Aminobenzoyloxy amide ent-223a (240 mg, 0.29 mmol) was dissolved in ethanol (1.0 mL). NaOH aq. (0.3 mL, 2 M) was added and the resulting mixture was stirred at room temperature for 20 min before it was diluted with ethanol (1.5 mL) to dissolved all the suspension. The mixture was extracted with Et2O and the organic phase was dried with Na2SO4 and concentrated to afford an oil. Purification of the crude aminohydroxy amide by silica gel chromatography (20 mm ' 150 mm column, 5:1 hexanes/Et2O as eluent, flash column) afforded amino amide ent-226 as a white foam (mp 80-81 ¡C on 74% ee material) in 79% yield (166 mg, 0.230 mmol). The reaction with aminobenzoyloxy amide 223a (38 mg, 0.047 mmol, 54% ee) afforded amino amide 226 in 98% yield (33 mg, 0.046 mmol).  Spectral data for ent-226: Rf = 0.31 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.33 (s, 18H), 1.37 (s, 18H), 1.96-2.09 (m, 1H), 2.39 (s, 3H), 3.39 (d, 1H, J = 7.5 Hz), 3.61 (s, 3H), 3.66 (s, 3H), 4.07 (s, 1H), 4.54 (s, 1H), 4.89 (d, 1H, J = 8.0 Hz), 6.94 (s, 2H), 7.09 (s, 2H), 7.13 (t, 1H, J = 7.5 Hz), 7.23 (t, 2H, J = 7.0 Hz), 7.31 (d, 2H, J 7.5 Hz), 7.32 (d, 2H, J = 8.0 Hz), 7.46 (d, 2H, J = 8.0 Hz), 9.53 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 21.24, 29.68, 32.01, 35.66, 35.73, 64.00, 64.03, 64.10, 54.77, 76.23, 119.58, 124.54, 125.59, 125.91, 127.09, 129.01, 129.32, 135.42, 136.66, 137.04, 137.35, 138.18, 143.42, 143.51, 158.56, 158.68, 172.42; IR (thin film) 3145s, 2960vs, 2925s, OHNNHOPhBUDAMent-223aOPh72% eeNaOH, EtOH/H2Ort. 20 minOHHNNHOPhBUDAMent-226!'.)!2868s, 1666vs, 1601s, 1527vs, 1444vs, 1412vs, 1361s, 1222vs, 1115s, 1013s cmÐ1; HRMS (ESI-TOF) m/z 721.4940 [(M+H+); calcd. for C47H65N2O4: 721.4944]; !!!!!" +33.9¡ (c 1.0, CHCl3) on 74% ee material (HPLC); !!!!!" Ð28.6¡ (c 1.0, CHCl3) on 52% ee material of 126 (HPLC).  (2S,3S)-2-((bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)amino)-3-hydroxy-N-phenyl-3-(p-tolyl)propanamide 226: trans-Aziridine ent-125c (141 mg, 0.200 mmol, 80% ee) was reacted according the general procedure of ring-opening a1 with trifluoroacetic acid (15 µL, 0.20 mmol) and acetic acid (57 µL, 1.0 mmol) in dry CH2Cl2 (2 mL). Purification of the crude aminohydroxy amide by silica gel chromatography (20 mm ' 150 mm column, 5:1 hexanes/Et2O as eluent, flash column) afforded amino amide 226 as a white foam in 55% yield (79 mg, 0.11 mmol). !!!!!" Ð33.6¡ (c 1.0, CHCl3) on 80% ee material of 126 (HPLC). 6.5 Experimental Information for Chapter 5 6.5.1 General Procedure for Preparation of !-Iminols 286b-e  To a 25 mL clean and dry Schlenk flask was added a solution of alkylmagnesium chloride (7.5 mmol, 1.5 equiv) in THF. The flask was tightly sealed and the solution was cool down to 0 ¡C for 10 min. A solution of 2,2-Diethoxyacetopheone 334 (1.01 mL in 2 NBUDAMOHNPhent-125c1) TFA (1 equiv)HOAc (5 equiv)CH2Cl2, rt. 48 h2) NaOH (1.5 equiv) EtOH/H2O/Et2O, rt. 6 hOHHNNHOPhBUDAM22680% eePhEtOOEtO1) RMgCl, THFrt. 30 min2) 5% HCl, acetone70 ¡C, 1 hHOOHPhR334292anisidinepyrrolidinetoluene, rt. 12 hHNOHPhR286MeO!'.*!mL THF, 5.00 mmol, 1.00 equiv.) was added in dropwise and slowly via a syringe. The resulting mixture was stirred for another 30 min at room temperature then quenched with 5 mL saturated NH4Cl solution. The two layers were separated and the aqueous layer was extracted with ether (5 mL ' 3). The combined organic layer was concentrated under rotary evaporation and the crude residue was subjected to hydrolysis without purification.  The crude acetal intermediate was transferred to a 25 mL Schlenk flask with 0.5 mL 5% HCl (that is 1.7 M HCl) and enough acetone (usually it took 10 mL) to obtain a single layer homogenous solution. Thereafter, the flask was sealed and heated to 70 ¡C for 1 h. After being cooled to room temperature, the solution was diluted with CH2Cl2 (10 mL). The organic layer was separated and washed with NaHCO3 solution and brine, dried over MgSO4 and concentrated by rotary evaporation. The crude residue was purified by silica gel column chromatography with 20:1 hexanes/EtOAc as eluent to afford an !-hydroxyl aldehyde 292 as a white solid without further purification. To a 20 mL vial was added the !-hydroxyl aldehyde 292 (1.0 equiv), p-anisidine (1.1 equiv), pyrrolidine (20 mol%) in toluene. The vial was capped and the mixture was stirred at room temperature for 12 h. Upon completion, the reaction mixture was neutralized with Et3N and dried over Na2SO4, then it was concentrated under rotary evaporation to afford crude iminol as an oil. Purification by a short flash column chromatography with hexanes/EtOAc/Et3N as eluent.   !'.+! 1-Cyclohexyl-2-((4-methoxyphenyl)imino)-1-phenylethan-1-ol 286b: Cyclohexylmagnesium chloride (3.8 mL, 2 M in THF, 7.5 mmol, 1.5 equiv) was reacted according to the general procedure. Purification by a short flash column chromatography with 15:1:0.1 hexanes/EtOAc/Et3N as eluent afforded !-iminol 286b as an off-white solid (mp 103-105 ¡C) in 47% yield (664 mg, 2.05 mmol) over two steps. Spectral data for 286b: Rf = 0.45 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.11-1.29 (m, 4H), 1.33-1.42 (m, 2H), 1.54 (d, 1H, J = 17.5 Hz), 1.65 (dd, 2H, J = 27.2, 6.2 Hz), 1.77 (d, 1H, J = 11.0 Hz), 2.02 (tt, 1H, J = 12.5, 3.2 Hz), 3.78 (s, 3H), 4.91 (s, 1H), 6.84 (dd, 2H, J = 7.0, 2.0 Hz), 7.06 (dd, 2H, J = 7.0, 2.0 Hz), 7.24 (t, 1H, J = 7.5 Hz), 7.36 (t, 2H, J = 7.5 Hz), 7.53 (d, 2H, J = 7.0 Hz), 8.08 (s, 1H); 13C-NMR (125 MHz, CDCl3) & 25.85, 26.28, 26.42, 26.56, 26.96, 45.93, 55.48, 79.08, 114.23, 122.30, 125.60, 126.80, 128.38, 141.76, 142.88, 158.44, 164.86; IR (thin film) 3410s, 2930vs, 2852s, 1646s, 1506vs, 1447s, 1388s, 1248vs, 1033s cmÐ1; HRMS (ESI-TOF) m/z 324.1930 [(M+H+); calcd. for C21H26NO2: 324.1964].  1-((4-Methoxyphenyl)imino)-2-phenylpropan-2-ol 286c: Methylmagnesium bromide (10 mL, 3 M in THF, 30 mmol, 1.5 equiv) was reacted according to the general procedure. Purification by a short flash column chromatography with 6:1:0.1 hexanes/EtOAc/Et3N PhEtOOEtO1) CyMgCl, THFrt. 30 min2) 5% HCl, acetone70 ¡C, 1 hHOPhOH334292banisidinepyrrolidinetoluene, rt. 12 hHNPhOH286bMeOPhEtOOEtO1) MeMgBr, THFrt. 30 min2) 5% HCl, acetone70 ¡C, 1 hHOPhOH334292canisidinepyrrolidinetoluene, rt. 12 hHNPhOH286cMeO!'.,!as eluent afforded !-iminol 286c as a colorless oil in 67% yield (2.63 g, 10.3 mmol) over two steps. Spectral data for 286c: Rf = 0.37 (2:1 hexane/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.74 (s, 3H), 3.78 (s, 3H), 5.20 (d, 1H, J = 1.0 Hz), 6.85 (dd, 2H, J = 6.2, 2.2 Hz), 7.10 (dd, 2H, J = 7.0, 2.2 Hz), 7.26 (t, 1H, J = 6.8 Hz), 7.36 (t, 2H, J = 7.5 Hz), 7.52 (dd, 2H, J = 8.2, 1.2 Hz), 8.01 (d, 1H, J = 1.0 Hz); 13C-NMR (125 MHz, CDCl3) & 26.90, 55.45, 74.32, 114.26, 122.39, 125.46, 127.32, 128.52, 141.47, 143.69, 158.56, 164.08; IR (thin film) 3416vs, 2977vs, 2835s, 1646vs, 1603vs, 1581s, 1505vs, 1446vs, 1370s, 1247s, 1106s, 1068s, 1030s cmÐ1; HRMS (ESI-TOF) m/z 256.1337 [(M+H+); calcd. for C16H18NO2: 256.1338].  1-((4-methoxyphenyl)imino)-2-phenylbutan-2-ol 286d: Ethylmagnesium bromide (10 mL, 3 M in THF, 30 mmol, 1.5 equiv) was reacted according to the general procedure. Purification by a short flash column chromatography with 6:1:0.1 hexanes/EtOAc/Et3N as eluent afforded !-iminol 286d (2.78 g, 10.3 mmol) as an off-white solid (mp 66-68 ¡C) in 53% yield over two steps. Spectral data for 286d: Rf = 0.48 (2:1 hexane/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.93 (t, 3H, J = 7.5 Hz), 2.00-2.14 (m, 2H), 3.78 (s, 3H), 5.06 (s, 1H), 6.85 (d, 2H, J = 8.5 Hz), 7.09 (d, 2H, J = 8.5 Hz), 7.27 (t, 1H, J = 7.2 Hz), 7.38 (t, 2H, J = 8.0 Hz), 7.55 (d, 2H, J = 8.5 Hz), 8.04 (d, 1H); 13C-NMR (125 MHz, CDCl3) & 7.53, 32.71, 55.43, 76.97, 114.23, 122.32, 125.53, 127.07, 128.45, 141.63, 143.00, 158.49, 164.17; IR (thin film) 3418vs, 2966s, 2935s, 1645vs, 1603s, 1505s, 1463s, PhEtOOEtO1) EtMgCl, THFrt. 30 min2) 5% HCl, acetone70 ¡C, 1 hHOPhOH334292danisidinepyrrolidinetoluene, rt. 12 hHNPhOH286dMeO!'.-!1447s, 1247vs, 1033s cmÐ1; HRMS (ESI-TOF) m/z 270.1496 [(M+H+); calcd. for C17H20NO2: 270.1494].  1-((4-methoxyphenyl)imino)-2-phenylhexan-2-ol 286e: n-BuLi (1.88 mL, 2 M in THF, 3.75 mmol, 1.50 equiv) was reacted according to the general procedure. Purification by a short flash column chromatography with 9:1:0.1 hexanes/EtOAc/Et3N as eluent afforded !-iminol 286e (461 mg, 1.55 mmol) as an off-white solid (mp 55-58 ¡C) in 65% yield over two steps. Spectral data for 286e: Rf = 0.59 (2:1 hexane/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.86 (t, 3H, J = 7.0 Hz), 1.22-1.40 (m, 4H), 1.91-2.01 (m, 1H), 2.02-2.13 (m, 1H), 3.78 (s, 3H), 5.07 (s, 1H), 6.84 (d, 2H, J = 8.5 Hz), 7.08 (d, 2H, J = 8.5 Hz), 7.25 (t, 1H, J = 7.0 Hz), 7.36 (t, 2H, J = 7.8 Hz), 7.53 (d, 2H, J = 7.0 Hz), 8.04 (d, 1H, J = 1.0 Hz); 13C-NMR (125 MHz, CDCl3) & 14.02, 23.00, 25.33, 39.79, 55.48, 76.78, 114.26, 122.36, 125.48, 127.07, 128.48, 141.64, 143.26, 158.52, 164.26; IR (thin film) 3412s, 2955s, 2870s, 1645vs, 1603s, 1506vs, 1465s, 1447s, 1390s, 1291s, 1247vs, 1033s cmÐ1; HRMS (ESI-TOF) m/z 298.1806 [(M+H+); calcd. for C19H24NO2: 298.1807]. 6.5.2 Kinetic resolution of !-Iminols General Procedure of Zirconium-Catalyzed !-Iminol Rearrangement29  Preparation of zirconium complex catalyst solution: (R)-VANOL (44 mg, 0.10 mmol, 2.0 equiv), zirconium(IV) isopropoxide isopropanol complex (19 mg, 0.050 mmol, 1.0 equiv) PhEtOOEtO1) n-BuLi, THFrt. 30 min2) 5% HCl, acetone70 ¡C, 1 hHOPhOH334292eanisidinepyrrolidinetoluene, rt. 12 hHNPhOH286eMeO(S)-VANOL+Zr(Oi-Pr)4¥i-PrOH+NNtoluenert. 30 min2 equiv1 equiv1 equivZr(S-VANOL)2(NMI)!'..!and toluene (1.0 mL) were mixed at room temperature in a 4 mL vial, then N-methylimidazole (4.0 µL, 0.050 mmol, 1.0 equiv) was added via a syringe. Soon after addition of N-methylimidazole, a white solid precipitate started to form. The resulting slurry was stirred at room temperature under air for 30 min before being used in the following asymmetric catalytic rearrangement of !-iminols. This catalyst solution can be stored in toluene for extended periods, with no compromise to the yield or ee of the rearranged product. The solution of zirconium complex catalyst with a different ligand could all be prepared by this method with an appropriate ligand.  "-Iminol rearrangement: To a 20 mL clean and dry Schlenk flask under air was added appropriate !-iminol 286 (0.20 mmol) and dry toluene (0.30 mL). The Zr(S-VANOL)2(NMI) complex catalyst solution (0.05 M in toluene, 0.20 mL, 0.010 mmol, 5.0 mol%, this white slurry was vigorously swirled and agitated while being drawn by a syringe). The Schlenk flask was sealed and applied to freeze-pump-thaw cycling three times. After the reaction mixture was warmed to room temperature and then heated up to 40 ¡C for 24 h. Upon completion, the solution was cooled to room temperature and diluted with hexanes (1.0 mL). The white precipitate was filtered and the crude product purified by flash column chromatography on silica gel.  HNOHPhRMeO5% Zr(S-VANOL)2(NMI)toluene, 40 ¡C, 24 hRPhONHMeO+PhRONHMeO286287287'!(//! (S)-2-cyclohexyl-2-hydroxy-2-phenylacetaldehyde (S)-292b: !-Iminol 286b (65 mg, 0.20 mmol) was reacted according to general procedure. The reaction was monitored by the 1H-NMR spectrum of a small portion from the mixture with an internal standard and quenched at the 49% conversion of substrate. Amino ketone 287b was detected in 39% yield and amino ketone 287bÕ was detected in 7.5% by the 1H-NMR spectrum of crude reaction mixture. The residue was concentrated in high vavuo and dissolved in THF (1.0 mL). Diluted HCl (0.20 mL, 1 M) was added and the resulting solution was stirred at room temperature for 20 min. The reaction mixture was neutralized by saturated Na2CO3 and then extracted by Et2O (5 mL ' 3). The combined organic phase was dried with Na2SO4 and concentrated to afford a yellow oil. Purification by silica gel chromatography (20 mm ' 150 mm column, 15:1 hexanes/Et2O as eluent, flash column) afforded !-hydroxyaldehyde (S)-292b as a white solid (mp 59-60 ¡C on 60% ee material) in 37% yield (16 mg, 0.074 mmol). The enantiomeric purity of 223a was determined to be 60% ee by HPLC analysis (CHIRALCEL AS column, 99:1 hexane/2-propanol at 280 nm, flow-rate: 0.5 mL/min): retention times; Rt = 13.46 min (minor enantiomer, (R)-292b) and Rt = 27.17 min (major enantiomer, (S)-292b).  Spectral data for (S)-292b: Rf = 0.41 (5:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.12-1.18 (m, 3H), 1.25-1.41 (m, 4H), 1.63-1.70 (m, 2H), 1.76-1.79 (m, 1H), 2.17-2.21 (m, 1H), 3.70 (d, 1H, J = 1.0 Hz), 7.29 (t, 1H, J = 7.5 Hz), 7.39 (t, 2H, J = 7.8 Hz), 7.49 (d, 2H, J = 8.0 Hz), 9.62 (d, 1H, J = 1.5 Hz); 13C-NMR (125 MHz, CDCl3) & 24.98, HNPhOH286bMeO1) 5 mol% Zr(S-VANOL)2(NMI)toluene, 40 ¡C, 7 h2) HCl, THFrt. 20 minPhONHMeO+PhONHMeO287b287b'HOPhOH(S)-292b+!(/&!26.10, 26.16, 26.37, 26.76, 43.45, 84.35, 125.85, 127.60, 128.75, 138.04, 201.14; IR (thin film) 3421s, 2921vs, 2854vs, 1716vs, 1445s, 1328s, 1191s, 1133s, 1073s cmÐ1; HRMS (ESI-TOF) m/z 219.1384 [(M+H+); calcd. for C14H19O2: 219.1385]; !!!!!" +64.1¡ (c 1.0, EtOAc) on 63% ee material (HPLC).  (R)-2-((4-methoxyphenyl)amino)-1-phenylpropan-1-one 287c: !-Iminol 286c (51 mg, 0.20 mmol) was reacted according to general procedure to afford a mixture of amino ketone regioisomers 287c and 287cÕ. Purification by silica gel chromatography (20 mm ' 150 mm column, 3:1 hexanes/Et2O as eluent, flash column) afforded amino ketone 287c as a yellow oil in 33% yield (17 mg, 0.066 mmol). The enantiomeric purity of 287c was determined to be 98.5:1.5 er by HPLC analysis (CHIRALCEL AS column, 80:20 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 32.24 min (minor enantiomer, ent-287c) and Rt = 45.41 min (major enantiomer, 287c). The reaction with zirconium-Cy2VANOL complex catalyst afforded amino ketone 287c in 99:1 er and 30% yield (15 mg, 0.060 mmol). Spectral data for 287c: Rf = 0.41 (1:1 hexane/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.44 (d, 3H, J = 6.5 Hz), 3.71 (s, 3H), 4.08-4.69 (br, 1H), 5.04 (q, 1H, J = 6.8 Hz), 6.63 (d, 2H, J = 9.0 Hz), 6.75 (d, 2H, J = 9.0 Hz), 7.49 (t, 2H, J = 7.5 Hz), 7.59 (t, 1H, J = 8.0 Hz), 7.98 (d, 2H, J = 8.0 Hz); 13C-NMR (125 MHz, CDCl3) & 19.66, 54.45, 55.70, 114.93, 115.18, 128.38, 128.83, 133.56, 134.79, 140.77, 152.48, 201.24; IR (thin film) 3368s, 2930vs, 2833s, 1686vs, 1596s, 1513s, 1448s, HNPhOH286cMeO5% Zr(S-VANOL)2(NMI)toluene, 40 ¡C, 24 hPhONHMeO+PhONHMeO287c287c'!(/'!1239vs, 1166s, 1035s cmÐ1; HRMS (ESI-TOF) m/z 256.1338 [(M+H+); calcd. for C16H18NO2: 256.1338]; !!!!!" +32.9¡ (c 1.0, EtOAc) on 97% ee material (HPLC). (R)-1-((4-methoxyphenyl)amino)-1-phenylpropan-2-one 287cÕ: Purification by silica gel chromatography (20 mm ' 150 mm column, 3:1 hexanes/Et2O as eluent, flash column) afforded amino ketone 287cÕ as an off-white solid (mp 93-95 ¡C on 91% ee material) in 48% yield (25 mg, 0.096 mmol). The enantiomeric purity of 287c was determined to be 75.5:24.5 er by HPLC analysis (CHIRALCEL AS column, 85:15 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 25.52 min (major enantiomer, 287cÕ) and Rt = 41.34 min (minor enantiomer, ent-287cÕ). The reaction with zirconium-Cy2VANOL complex catalyst afforded amino ketone 287c in 65.5:34.5 er and 51% yield (26 mg, 0.10 mmol). Spectral data for 287cÕ: Rf = 0.48 (1:1 hexane/Et2O); 1H-NMR (500 MHz, CDCl3) & 2.10 (s, 3H), 3.67 (s, 3H), 4.92 (s, 1H), 5.14 (s, 1H), 6.48 (d, J = 9.0 Hz), 6.67 (d, J = 8.5 Hz), 7.29 (t, 1H, J = 7.5 Hz), 7.36 (t, 2H, J = 7.5 Hz), 7.43 (d, 2H, J = 7.5 Hz); 13C-NMR (125 MHz, CDCl3) & 26.71, 55.67, 69.04, 114.40, 114.78, 127.80, 128.32, 129.19, 138.28, 140.28, 152.10, 204.35; IR (thin film) 3372s, 2961s, 2834s, 1686vs, 1603s, 1512vs, 1448s, 1245vs, 1171s, 1106s, 1034s cmÐ1; HRMS (ESI-TOF) m/z 256.1343 [(M+H+); calcd. for C16H18NO2: 256.1338]; !!!!!" Ð58.3¡ (c 1.0, EtOAc) on 51% ee material (HPLC).  (R)-2-((4-methoxyphenyl)amino)-1-phenylbutan-1-one 287d: !-Iminol 286d (54 mg, 0.20 mmol) was reacted according to general procedure to afford a mixture of amino ketone HNPhOH286dMeO5% Zr(S-VANOL)2(NMI)toluene, 40 ¡C, 24 hPhONHMeO+PhONHMeO287d287d'!(/(!regioisomers 287d and 287dÕ. Purification by silica gel chromatography (20 mm ' 150 mm column, 6:1 hexanes/Et2O as eluent, flash column) afforded amino ketone 287d as a yellow oil in 48% yield (26 mg, 0.096 mmol). The enantiomeric purity of 287d was determined to be 96.5:3.5 er by HPLC analysis (CHIRALCEL OD column, 90:10 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 18.02 min (minor enantiomer, ent-287d) and Rt = 21.94 min (major enantiomer, 287d). The reaction with zirconium-Cy2VANOL complex catalyst afforded amino ketone 287d in 96:4 er and 33% yield (18 mg, 0.066 mmol). Spectral data for 287d: Rf = 0.32 (2:1 hexane/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.91 (t, 3H, J = 7.5 Hz), 1.66-1.73 (m, 1H), 1.97-2.04 (m, 1H), 3.71 (s, 3H), 4.40 (s, 1H), 4.91-4.99 (m, 1H), 6.65 (d, 2H, J = 9.0 Hz), 6.74 (d, 2H, J = 9.0 Hz), 7.48 (t, 2H, J = 7.8 Hz), 7.58 (t, 1H, J = 7.2 Hz), 7.97 (d, 2H, J = 7.0 Hz); 13C-NMR (125 MHz, CDCl3) & 9.42, 26.08, 55.72, 60.01, 114.91, 115.24, 128.28, 128.80, 133.47, 135.34, 141.28, 152.41, 201.02; IR (thin film) 3404s, 2965s, 1684vs, 1512vs, 1448s, 1382s, 1241vs, 1040s cmÐ1; HRMS (ESI-TOF) m/z 270.1495 [(M+H+); calcd. for C17H20NO2: 270.1494]; !!!!!" +2.2¡ (c 1.0, CH2Cl2) on 93% ee material (HPLC). (R)-1-((4-methoxyphenyl)amino)-1-phenylbutan-2-one 287dÕ: Purification by silica gel chromatography (20 mm ' 150 mm column, 6:1 hexanes/Et2O as eluent, flash column) afforded amino ketone 287dÕ as an off-white solid (mp 51-53 ¡C on 94% ee material) in 47% yield (25 mg, 0.094 mmol). The enantiomeric purity of 287dÕ was determined to be 97:3 er by HPLC analysis (CHIRALCEL OD column, 90:10 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 17.65 min (major enantiomer, 287dÕ) and Rt = 21.43 min (minor enantiomer, ent-287dÕ). The reaction with zirconium-Cy2VANOL complex catalyst afforded amino ketone 287d in 90:10 er and 35% yield (19 !(/)!mg, 0.070 mmol). Spectral data for 287dÕ: Rf = 0.40 (2:1 hexane/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.96 (t, 3H, J = 7.5 Hz), 2.38-2.48 (m, 2H), 3.66 (s, 3H), 4.92 (d, 1H, J = 3.5 Hz), 5.17 (s, 1H), 6.48 (d, 2H, J = 9.0 Hz), 6.66 (d, 2H, J = 8.5 Hz), 7.28 (t, 1H, J = 7.2 Hz), 7.34 (t, 2H, J = 7.5 Hz), 7.42 (d, 2H, J = 7.0 Hz); 13C-NMR (125 MHz, CDCl3) & 7.90, 32.54, 55.72, 68.37, 114.46, 114.81, 127.84, 128.27, 129.16, 138.62, 140.42, 152.10, 207.35; IR (thin film) 3423s, 1653vs, 1512vs, 1244vs, 1179s, 1108s, 1034s cmÐ1; HRMS (ESI-TOF) m/z 270.1498 [(M+H+); calcd. for C17H20NO2: 270.1494]; !!!!!" Ð127.7¡ (c 0.93, EtOAc) on 94% ee material (HPLC).  (R)-2-((4-methoxyphenyl)amino)-1-phenylhexan-1-one 287e: !-Iminol 286e (59 mg, 0.20 mmol) was reacted according to general procedure to afford a mixture of amino ketone regioisomers 287e and 287eÕ. Purification by silica gel chromatography (20 mm ' 150 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded amino ketone 287e as a yellow oil in 46% yield (27 mg, 0.092 mmol). The enantiomeric purity of 287e was determined to be 96.5:3.5 er by HPLC analysis (CHIRALCEL OD column, 90:10 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 16.60 min (minor enantiomer, ent-287e) and Rt = 20.39 min (major enantiomer, 287e). Spectral data for 287e: Rf = 0.32 (3:1 hexane/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.83 (t, 3H, J = 7.0 Hz), 1.18-1.49 (m, 4H), 1.55-1.67 (m, 1H), 1.86-1.98 (m, 1H), 3.70 (s, 3H), 4.44 (s, 1H), 4.95 (dd, 1H, J = 7.8, 4.8 Hz), 6.63 (d, 2H, J = 9.0 Hz), 6.73 (d, 2H, J = 9.0 Hz), 7.48 (t, 2H, J = 7.5 Hz), 7.58 (t, 1H, J = 7.2 Hz), 7.97 (d, 2H, J = 7.5 Hz); 13C-NMR (125 MHz, HNPhOH286eMeO5% Zr(S-VANOL)2(NMI)toluene, 40 ¡C, 24 hPhONHMeO+PhONHMeO287e287e'!(/*!CDCl3) & 13.88, 22.62, 27.56, 33.14, 55.71, 59.26, 114.90, 115.31, 128.26, 128.82, 133.46, 135.36, 141.48, 152.48, 201.41; IR (thin film) 3387s, 2957s, 2931s, 2871s, 1685vs, 1603s, 1513vs, 1465s, 1448s, 1244vs, 1178s, 1036s cmÐ1; HRMS (ESI-TOF) m/z 298.1807 [(M+H+); calcd. for C19H24NO2: 298.1807]; !!!!!" +1.6¡ (c 0.93, EtOAc) on 93% ee material (HPLC). (R)-1-((4-methoxyphenyl)amino)-1-phenylhexan-2-one 287eÕ: Purification by silica gel chromatography (20 mm ' 150 mm column, 8:1 hexanes/Et2O as eluent, flash column) afforded amino ketone 287eÕ as a colorless oil in 46% yield (27 mg, 0.092 mmol). The enantiomeric purity of 287eÕ was determined to be 98:2 er by HPLC analysis (CHIRALCEL OD column, 90:10 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 17.06 min (major enantiomer, 287eÕ) and Rt = 22.54 min (minor enantiomer, ent-287eÕ). Spectral data for 287eÕ: Rf = 0.41 (3:1 hexane/Et2O); 1H-NMR (500 MHz, CDCl3) & 0.77 (t, 3H, J = 7.8 Hz), 1.08-1.20 (m, 2H), 1.35-1.53 (m, 2H), 2.31-2.47 (m, 2H), 3.66 (s, 3H), 4.91 (s, 1H), 5.18 (s, 1H), 6.48 (d, 2H, J = 8.5 Hz), 6.66 (d, 2H, J = 9.0 Hz), 7.27 (t, 1H, J = 7.2 Hz), 7.34 (t, 2H, J = 7.5 Hz), 7.41 (d, 2H, J = 7.0 Hz); 13C-NMR (125 MHz, CDCl3) & 13.67, 22.04, 25.89, 38.85, 55.70, 68.52, 114.41, 114.78, 127.88, 128.23, 129.10, 138.38, 140.37, 152.04, 206.74; IR (thin film) 3390s, 2957vs, 2932s, 2872s, 1714vs, 1513s, 1464s, 1444s, 1242vs, 1179s, 1037s cmÐ1; HRMS (ESI-TOF) m/z 298.1809 [(M+H+); calcd. for C19H24NO2: 298.1807]; !!!!!" Ð84.6¡ (c 0.93, EtOAc) on 96% ee material (HPLC).    !(/+! (R)-2-cyclohexyl-2-((4-methoxyphenyl)amino)-1-phenylethan-1-one 287b: !-Iminol 286b (65 mg, 0.20 mmol) was reacted according to general procedure. Amino ketone 287b was detected in 53% yield and amino ketone 287bÕ was detected in 44% yield by the crude 1H-NMR spectrum. Purification by silica gel chromatography (20 mm ' 150 mm column, 5:1 hexanes/Et2O as eluent, flash column) afforded a mixture of amino ketones 287b and 287bÕ as a yellow oil. The enantiomeric purity of 287b was determined to be 94:6 er by HPLC analysis (CHIRALCEL OD column, 99:1 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 26.76 min (minor enantiomer, ent-287b) and Rt = 39.73 min (major enantiomer, 287b). The enantiomeric purity of 287bÕ was determined to be 99:1 er by HPLC analysis (CHIRALCEL OD column, 99:1 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 31.10 min (major enantiomer, 287bÕ) and Rt = 44.25 min (minor enantiomer, ent-287bÕ). The reaction with zirconium-Cy2VANOL complex catalyst afforded amino ketones 287b and 287bÕ both in 99.5:0.5 er and 42% yield. To a 4 mL vial was added the mixture of amino ketones 287b and 287bÕ, FmocCl (103 mg, 0.400 mmol, 2.00 equiv) and NaHCO3 (50 mg, 0.60 mmol, 3.0 equiv) in THF (1.0 mL). The resulting mixture was stirred for 60 h at room temperature, filtered to remove the precipitate and concentrated. A mixture of N-Fmoc amino ketone regioismers 296 and 296Õ with unconverted amino ketone 287b was detected in the residue. Purification by HNPhOH286bMeO1) 5 mol% Zr(S-VANOL)2(NMI)toluene, 40 ¡C, 24 h2) FmocCl, NaHCO3THF, rt. 60 hCyPhONFmocMeO+PhONFmocMeO296296'PhONHMeO287b+Cy!(/,!silica gel chromatography (20 mm ' 150 mm column, 5:1 hexanes/Et2O as eluent, flash column) afforded amino ketone 287b as a yellow oil in 9% yield (5.8 mg, 0.018 mmol). Spectral data for 287b: Rf = 0.44 (2:1 hexanes/Et2O); 1H-NMR (500 MHz, CDCl3) & 1.07-1.15 (m, 3H), 1.17-1.28 (m, 2H), 1.37 (qd, 1H, J = 12.3, 3.6 Hz), 1.50-1.65 (m, 2H), 1.69-1.82 (m, 3H), 3.69 (s, 3H), 4.37 (s, 1H), 4.75 (d, 1H, J = 4.5 Hz), 6.65 (d, 2H, J = 9.0 Hz), 6.71 (d, 2H, J = 9.0 Hz), 7.46 (t, 2H, J = 8.0 Hz), 7.57 (t, 1H, J = 7.5 Hz), 7.93 (dd, 2H, J = 8.2, 1.2 Hz); 13C-NMR (125 MHz, CDCl3) & 26.01, 26.13, 26.38, 27.66, 30.89, 41.81, 55.72, 64.72, 128.27, 128.79, 133.39, 136.12, 142.44, 152.51, 201.83; IR (thin film) 3371s, 2928vs, 2852s, 1681s, 1512vs, 1448s, 1242vs, 1037s cmÐ1; HRMS (ESI-TOF) m/z 324.1932 [(M+H+); calcd. for C21H26NO2: 324.1964]; !!!!!" Ð65.0¡ (c 1.2, EtOAc) on 99% ee material (HPLC). (9H-fluoren-9-yl)methyl (R)-(1-cyclohexyl-2-oxo-2-phenylethyl)(4-methoxyphenyl)carbamate 296: Purification by silica gel chromatography (20 mm ' 150 mm column, 2.5:1 benzene/CHCl3 as eluent, flash column) afforded amino ketone 296 as an off-white solid (mp 75-77 ¡C on 88% ee material) in 36% yield (40 mg, 0.073 mmol). The enantiomeric purity of 296 was determined to be 94:6 er by HPLC analysis (CHIRALCEL OD column, 85:15 hexane/2-propanol at 240 nm, flow-rate: 0.7 mL/min): retention times; Rt = 21.06 min (minor enantiomer, ent-296) and Rt = 23.93 min (major enantiomer, 296). Spectral data for 296: Rf = 0.40 (1:1 benzene/CHCl3); 1H-NMR (500 MHz, CDCl3) & 0.86-0.93 (m, 1H), 1.09-1.38 (m, 4H), 1.56-1.77 (m, 3H), 1.80-1.90 (m, 1H), 1.98-2.05 (m, 2H), 3.81 (s, 3H), 3.95 (t, 1H, J = 7.2 Hz), 4.24 (dd, 1H, J = 10.5, 7.5 Hz), 4.39 (dd, 1H, J = 10.5, 7.5 Hz), 5.76 (d, 1H, J = 10.5 Hz), 6.73 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = !(/-!9.5 Hz), 7.00 (d, 1H, J = 8.0 Hz), 7.04 (d, 1H, J = 7.0 Hz), 7.10 (dt, 2H, J = 10.3, 7.6 Hz), 7.29 (t, 2H, J = 7.2 Hz), 7.48 (t, 2H, J = 7.8 Hz), 7.58 (t, 1H, J = 7.2 Hz), 7.64 (d, 2H, J = 8.0 Hz), 8.08 (d, 2H, J = 7.5 Hz); 13C-NMR (125 MHz, CDCl3) & 25.71, 25.82, 26.47, 29.54, 30.11, 36.56, 46.91, 55.36, 63.90, 67.82, 113.96, 119.75, 119.77, 125.09, 125.20, 126.77, 126.78, 127.50, 128.32, 128.60, 128.89, 130.31, 133.42, 136.80, 141.17, 141.15, 143.50, 143.60, 156.41, 158.94, 196.36; IR (thin film) 2929.2s, 1685s, 1647vs, 1511s, 1449s, 1396s, 1290s, 1248s cmÐ1; HRMS (ESI-TOF) m/z 546.2647 [(M+H+); calcd. for C36H36NO4: 546.2644]; !!!!!" +47.0¡ (c 1.0, EtOAc) on 88% ee material (HPLC). (9H-fluoren-9-yl)methyl (R)-(2-cyclohexyl-2-oxo-1-phenylethyl)(4-methoxyphenyl)carbamate 296Õ: Purification by silica gel chromatography (20 mm ' 150 mm column, 2.5:1 benzene/CHCl3 as eluent, flash column) afforded amino ketone 296Õ as an off-white solid (mp 70-71 on 90% ee material) in 46% yield (37 mg, 0.067 mmol). The enantiomeric purity of 296Õ was determined to be 95:5 er by HPLC analysis (CHIRALCEL OD column, 85:15 hexane/2-propanol at 240 nm, flow-rate: 0.7 mL/min): retention times; Rt = 40.60 min (minor enantiomer, ent-296Õ) and Rt = 44.35 min (major enantiomer, 296Õ). Spectral data for 296Õ: Rf = 0.25 (1:1 benzene/CHCl3); 1H-NMR (500 MHz, CDCl3) & 0.81-0.88 (m, 3H), 1.06-1.76 (m, 6H), 2.13 (d, 1H, J = 13.0 Hz), 2.32-2.45 (m, 1H), 3.74 (s, 3H), 4.00 (t, 1H, J = 7.8 Hz), 4.17 (t, 1H, J = 9.2 Hz), 4.35 (t, 1H, J = 9.0 Hz), 6.16 (s, 1H), 6.66 (d, 2H, J = 8.0 Hz), 6.94 (d, 2H, J = 6.5 Hz), 6.98-7.06 (m, 3H), 7.07 (t, 1H, J = 7.2 Hz), 7.12-7.19 (m, 4H), 7.27-7.32 (m, 3H), 7.65 (t, 2H, J = 6.0 Hz); 13C-NMR (125 MHz, CDCl3) & 25.18, 25.70, 25.84, 27.95, 29.90, 46.83, 48.38, 55.32, 67.75, 69.72, 113.35, 119.71, 119.74, 125.27, 125.44, 126.72, 126.81, 127.44, 127.50, 128.32, 128.51, !(/.!131.03, 131.97, 132.49, 141.10, 141.17, 143.56, 143.82, 156.13, 158.46, 210.45; IR (thin film) 2930s, 1682s, 1646vs, 1511s, 1450s, 1396s, 1247s cmÐ1; HRMS (ESI-TOF) m/z 546.2647 [(M+H+); calcd. for C36H36NO4: 546.2644]; !!!!!" Ð43.4¡ (c 1.0, EtOAc) on 90% ee material (HPLC). 6.5.3 Preparation of Enantiometic Pure !-Iminol  (R)-286c  (R)-2-phenylpropane-1,2-diol (R)-303:30 To a 250 mL round-bottomed flask, AD-mix " (14.0 g, 10 mmol), tert-butyl alcohol (50 mL) and water (50 mL). Stirring a t room temperature produced two clear phases; the lower aqueous phase appears bright yellow. The mixture was cooled to 0 ¡C where upon some of the dissolved salts precipitated. !-Methylstyrene was added at once, and the heterogeneous slurry was stirred vigorously at 0 ¡C for 12 h (progress was monitored by TLC or GLC). While the mixture was stirred at 0 ¡C, Na2SO3 (1.5 g) was added and the mixture was allowed to warm to room temperature with stirring for 30 min. CH2Cl2 (10 mL) was added to the reaction mixture, and after separation of the layers, the aqueous phase was further extracted with the CH2Cl2 (5 mL ' 3). The combined organic extracts were dried over MgSO4 and concentrated to give the diol (R)-303 and the ligand. This crude product was purified by silica gel chromatography (2:1 hexanes/EtOAc as eluent, flash column) to afford the 1,2-diol (R)-303 as a colorless liquid in 40% yield (603 mg, 3.96 mmol). The enantiomeric purity of (R)-303 was determined to be 97% ee by HPLC analysis (CHIRALCEL AS column, 95:5 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 7.76 min (minor enantiomer, (S)-303) and Rt = 10.43 min (major enantiomer, (R)-303). OHOHMePhAD-mix !t-BuOH/H2Ort. 15 h302(R)-303!(&/!Spectral data for (R)-303: Rf = 0.27 (1:1 hexane/EtOAc); 1H-NMR (500 MHz, CDCl3) & 1.51 (s, 3H), 1.88-1.91 (br, 1H), 2.63 (s, 1H), 3.61 (dd, 1H, J = 11.2, 8.2 Hz), 3.77 (dd, 1H, J = 10.8, 4.8 Hz), 7.26 (t, 1H, J = 7.0 Hz), 7.35 (t, 2H, J = 7.5 Hz), 7.43 (d, 2H, J = 8.0 Hz); 13C-NMR (125 MHz, CDCl3) & 26.00, 71.06, 74.81, 125.04, 127.18, 128.42, 144.90; !!!!!" Ð3.2¡ (c 1.0, EtOH) on 97% ee material (HPLC).  (R)-2-hydroxy-2-phenylpropanal (R)-304:31  To a solution of 1,2-diol (R)-303 (484 mg, 3.18 mmol) in CH2Cl2 (16 mL) was added IBX (2.67 g, 9.54 mmol, 3.00 equiv). After stirring at 40 ¡C for 8 h, the reaction mixture was filtered off under reduced pressure and the filtrate was concentrated in vacuo. The residue was purified by silica chromatography (5:1 hexanes/EtOAc as eluent, flash column) to give hydroxyl aldehyde (R)-304 as a colorless oil in 66% yield (315 mg, 2.10 mmol). Spectral data for (R)-304: Rf = 0.53 (2:1 hexane/EtOAc); 1H-NMR (500 MHz, CDCl3) & 1.69 (s, 3H), 3.84 (s, 1H), 7.32 (t, 1H, J = 7.2 Hz), 7.39 (t, 2H, J = 7.0 Hz), 7.45 (d, 2H, J = 7.5 Hz), 9.54 (d, 1H, J = 1.0 Hz); 13C-NMR (125 MHz, CDCl3) & 23.8, 78.9, 125.5, 128.1, 128.8, 139.4, 200.1; !!!!!" Ð152.3¡ (c 0.5, CHCl3) on 97% ee material (HPLC).  (R)-1-((4-methoxyphenyl)imino)-2-phenylpropan-2-ol (R)-286c: Hydroxy aldehyde (R)-304 (310 mg, 2.06 mmol) was reacted with p-anisidine (279 mg, 2.27 mmol, 1.10 equiv) and pyrrolidine (34 µL, 0.41 mmol, 20 mol%) in toluene (6.0 mL) according to the IBX (3 equiv)CH2Cl2, rt. 5 hOHOHMePhOHOHMePh(R)-303(R)-304OHOHMePh(R)-304NHOHMePhtoluene, rt. 12 h(R)-286cp-anisidinepyrrolidineMeO!(&&!second step of general procedure in section 6.5.1. Purification by a short flash column chromatography with 6:1:0.1 hexanes/EtOAc/Et3N as eluent afforded !-iminol (R)-286c as an off-white solid (mp 61-65 ¡C on 95% ee material) in 71% yield (373 mg, 1.46 mmol). The enantiomeric purity of (R)-286c was determined to be 95% ee by HPLC analysis (CHIRALCEL AS column, 95:5 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 25.57 min (minor enantiomer, (S)-286c) and Rt = 34.84 min (major enantiomer, (R)-286c). !!!!!" Ð63.8¡ (c 1.0, EtOAc) on 95% ee material (HPLC). 6.5.4 Preparation of Enantiometic Pure Amino ketones (R)-287c and (R)-287cÕ  (1S,2R)-2-((4-methoxyphenyl)amino)-1-phenylpropan-1-ol 301: The ligand 2-(N-(2,6-dimethylphenyl)amino)-2-oxoacetic acid 300 was prepared according to the procedure reported in the literature.31 An oven-dried Schlenk tube was charged with CuI (19 mg, 0.10 mmol), DMPAO (39 mg, 0.20 mmol), (+)-norephedrine 299 (151 mg, 1.00 mmol), 4-bromoanisole (188 µL, 1.50 mmol) and K3PO4 (425 mg, 2.00 mmol) in DMSO (1.0 mL). After the tube was evacuated and backfilled with argon, the reaction mixture was stirred at 90 ¡C for 48 h. When amino alcohol 299 was consumed, water was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography (5:1 hexanes/EtOAc PhOHNH2+BrOMe(1.5 equiv.)CuI (10 mol%)DMPAO (20 mol%)K3PO4 (2 equiv.)DMSO, 90 ¡C, 48 hPhOHHNHNHOOODMPAOOMe299301300!(&'!as eluent, flash column) to give the desired product 301 as an off-white solid (mp 62-63 ¡C on 99% ee material) in 59% yield (151 mg, 0.587 mmol). Spectral data for 301: Rf = 0.44 (2:1 hexane/EtOAc); 1H-NMR (500 MHz, CDCl3) & 0.97 (d, 3H, J = 7.0 Hz), 2.50 (s, 1H), 3.35-3.47 (br, 1H), 3.60-3.70 (m, 1H), 3.74 (s, 3H), 4.94 (d, 2H, J = 2.5 Hz), 6.68 (d, 2H, J = 8.5 Hz), 6.79 (d, 2H, J = 9.5 Hz), 7.27 (hex, 1H, J = 4.3 Hz), 7.36 (d, 4H, J = 4.5 Hz); 13C-NMR (125 MHz, CDCl3) & 14.20, 55.67, 55.75, 74.12, 114.96, 115.84, 125.93, 127.34, 128.27, 141.04, 141.40, 152.68; !!!!!" Ð74.5¡ (c 1.0, CH2Cl2) on >99% ee material (HPLC).  (R)-2-((4-methoxyphenyl)amino)-1-phenylpropan-1-one 287c: To a solution of oxalyl chloride (126 µL, 1.46 mmol, 5.00 equiv) and 3 † MS in CH2Cl2 (0.30 mL) at Ð78 ¡C under N2 was added dropwise a solution of DMSO (210 µL, 2.93 mmol, 10.0 equiv) in CH2Cl2 (0.30 mL). After 15 min a solution of the alcohol 301 (76 mg, 0.30 mmol) in CH2Cl2 (0.90 mL) was slowly added dropwise. The resulting solution was warmed up to Ð40 ¡C and stirred for 30 min. Et3N (0.61 mL, 4.4 mmol, 15 equiv) was then added dropwise at Ð78 ¡C. The reaction was stirred 30 min and then slowly allowed to warm to room temperature. Saturated NaHCO3 aq. was added and the mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography (6:1 hexanes/EtOAc as eluent, flash column) to give the desired product (R)-287c as a yellow oil in 100% yield (75 mg, 0.29 mmol). !!!!!" +39.4¡ (c 1.0, EtOAc) on >99% ee material (HPLC). (COCl)2 (5 equiv.)DMSO (10 equiv.)Et3N (15 equiv.)CH2Cl2Ð78 to Ð40 ¡C, 5 hPhONH(R)-287cPhOHNHMeO301MeO!(&(! Methyl (R)-2-((4-methoxyphenyl)amino)-2-phenylacetate 298:32 To a solution of (R)-2-phenylglycine methyl ester hydrochloride 297 (2.02 g, 10.0 mmol) in Et2O was added Na2CO3 aq. (5.0 mL, 2 M, 15 mmol) with vigorous stirring for 15 min. The organic layer was separated and the aqueous layer was extracted with Et2O. The combined organic phase was dried over MgSO4 and concentrated in vacuo to afford a colorless liquid as the free amino ester. A slurry of (R)-2-phenylglycine methyl ester, 4-methoxyphenylboronic acid (4.56 g, 30 mmol) and anhydrous Cu(OAc)2 (2.00 g, 10.0 mmol) [addition of a tertiary amine such as triethylamine or pyridine (2-3 equiv) is likely to increase the yield] in CH2Cl2 (50 mL) was stirred at room temperature for 24-48 h. The progress of the reaction was monitored by TLC. The products were isolated by direct flash column chromatography of the crude reaction mixture with pre-absorption on silica gel with 4:1 hexanes/Et2O as the eluent. The coupling product 298 was obtained as a yellowish liquid in 26% yield (714 mg, 2.63 mmol). Spectral data for 298: Rf = 0.59 (1:1 hexane/Et2O); 1H-NMR (500 MHz, CDCl3) & 3.69 (s, 3H), 3.71 (s, 3H), 4.60-4.72 (br, 1H), 5.01 (s, 1H), 6.52 (d, 2H, J = 9.0 Hz), 6.71 (d, 2H, J = 9.5 Hz), 7.29 (t, 1H, J = 7.5 Hz), 7.34 (t, 2H, J = 7.2 Hz), 7.47 (d, 2H, J = 7.0 Hz); 13C-NMR (125 MHz, CDCl3) & 52.70, 52.63, 61.58, 114.70, 114.78, 127.23, 128.23, 128.82, 137.72, 140.12, 152.44, 172.52; IR (thin film) 3387s, 2952s, 2835s, 1736vs, 1606s, 1513vs, 1505vs, 1450s, 1245vs, 1177s, 1033s, 1013s cmÐ1; HRMS (ESI-TOF) m/z PhNH2 ¥ HClOMeOPMP-B(OH)2 (2 equiv.)Cu(OAc)¥H2O (1 equiv.)4 † MS, CH2Cl240 ¡C, 24 hPhNHOMeO26%Na2CO3 aq.Et2O, rt. 15 minMeO297298!(&)!272.1287 [(M+H+); calcd. for C16H18NO3: 272.1291]; !!!!!" Ð3.0¡ (c 1.0, CH2Cl2) on >99% ee material (HPLC).  (R)-1-((4-methoxyphenyl)amino)-1-phenylpropan-2-one 287cÕ:29 To a 25 mL flame dried Schleck flask was added N,O-dimethylhydroxyamine hydrochloride (200 mg, 2.06 mmol, 2.50 equiv) and THF (4.0 mL) at Ð45 ¡C for 5 min in N2 atmosphere. Methylmagnesium bromide (1.37 mL, 3 M, 4.11 mmol, 5.00 equiv) was added in dropwise and the resulting solution was stirred at the same temperature for another 10 min. A solution of amino ester 298 (223 mg, 0.822 mmol) in THF (1.60 mL) was added in dropwise and the mixture was stirred at the same temperature for another 1 h before being quenched by saturated NH4Cl aq. The reaction mixture was warmed up to room temperature and extracted with EtOAc. The combined organic phase was dried over Na2SO4 and purified by chromatography with a short column on silica gel, 2:1 hexanes/EtOAc as the eluent to remove the excess N,O-dimethylhydroxyamine hydrochloride. The crude Weireb amide was afforded as a pale yellow solid and used in the next step without further purification. To a 25 mL flame dried Schleck flask was added the Weireb amide (159 mg, 0.529 mmol) in THF (2.50 mL). The solution was cool down to 0 ¡C for 5 min and methylmagnesium bromide (0.53 mL, 3 M, 1.59 mmol, 3.00 equiv) was added in dropwise. The resulting solution was stirred at 0 ¡C for 15 min before being quenched by saturated NH4Cl aq. The reaction mixture was warmed up to room temperature and extracted with EtOAc. The combined organic phase was dried over Na2SO4. Purification NHOMe¥HCl(2.5 equiv.)1)MeMgBr (5 equiv.)THF, Ð45 ¡C, 1 h2) MeMgBr (3 equiv.)THF, 0 ¡C, 15 minPhNHO(R)-287c'PhNHOMeOMeO298MeO!(&*!by a silica gel column chromatography with 5:1 hexanes/Et2OAc as eluent afforded amino ketone (R)-287cÕ as a white solid in 41% yield (86 mg, 0.36 mmol). The enantiomeric purity of (R)-287cÕ was determined to be 91% ee by HPLC analysis (CHIRALCEL AS column, 80:20 hexane/2-propanol at 240 nm, flow-rate: 0.5 mL/min): retention times; Rt = 26.65 min (minor enantiomer, (S)-287cÕ) and Rt = 37.28 min (major enantiomer, (R)-287cÕ). !!!!!" Ð194.3¡ (c 1.0, EtOAc) on 91% ee material (HPLC).   !(&+!       REFERENCES   !(&,!REFERENCES  1. a) For VANOL and VAPOL: Ding, Z.; Osminski, W. E. G.; Ren, H.; Wulff, W. D. Org. Process Res. & Dev. 2011, 15, 1089; b) For 7,7Õ-disubsituted VANOL direvatives: Guan, Y.; Ding, Z.; Wulff, W. D. Chem. Eur. J. 2013, 19, 15565. 2. Zhang, Y.; Lu, Z.; Desai, A. Wulff, W. D. Org. Lett. 2008, 10, 5429. 3. Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100. 4. Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13, 5866-5869. 5. Taber, D. F.; Amedio, J. C.; Jung, K. Y. J. Org. Chem. 1987, 52, 5621-5622. 6. Lee, J. C.; Choi, Y. Synthetic Commun 1998, 28, 2021. 7. Shi, B.; Merten, S.; Wong, D. K. 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