CATALYTIC ASYMMETRIC AZIRIDINATIONS AND THEIR APPLICATIONS By Li Huang A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chemistry 2011 ABSTRACT CATALYTIC ASYMMETRIC AZIRIDINATIONS AND THEIR APPLICATIONS By Li Huang The catalytic asymmetric aziridination of imines and diazo compounds mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from α-methylbenzyl amine and various aldehydes. The matched case for cis-aziridines from ethyl α-diazo acetate involves the (R)-imine with the (S)-ligand whereas the matched case for trans-aziridines from N-phenyl α-diazo acetamide involves the (R)-imines with the (R)-ligand for imines from benzaldehyde and butyraldehyde, and the (R)-imines with the (S)-ligand for imines derived from the bulkier aliphatic aldehydes, pivaldehyde and cyclohexane carboxaldehyde. Optically pure aziridines could be obtained in good yields and with high diastereoselectivity, which could be converted to α- or β-amino ester derivatives via hydrogenolysis. Extension of our protocol for di-substituted aziridine synthesis to tri-substituted aziridine proved to be challenging. However, it was realized by employing N-Boc imines and α-diazo carbonyl compounds in which the diazo carbon was disubstituted. The highly reactive α-diazo esters give only moderate yields, but the more slowly reacting α-diazo-N-acyloxazolidinones give much higher yields. The optimal ligand is VANOL that can provide a catalyst for the stereocomplimentary approaches to tri-substituted aziridines: trans-isomers via aziridination and cis-isomers via aziridination/alkylation. Having established a very efficient catalytic asymmetric synthesis of aziridines, the next logical step would be to develop its potential in organic synthesis. The ring expansion of aziridine-2-carboxylic acids has significant potential for the synthesis of hetereocycles and the type of heterocycles proved to be dependent on the structure of the aziridine-2-carboxylic acids. When there is alkyl group on the C2 position and an aromatic group on the C3 position, the reaction of aziridine-2-carboxylic acids with (COCl)2 provides N-carboxyanhydrides whereas morpholine-2,3,5-triones are formed if there is an aromatic group on the C3 position with a hydrogen on C2. Curiously, β-lactams are formed in a stereoselective manner when aziridine-2-carboxylic acids with an alkyl group present on the C3 position is treated with (COCl)2. Finally, it proved possible to convert the aziridine-2-carboxylic acids with an aromatic group on the C3 position to β-lactams with a Vilsmeier reagent. To my parents and my husband iv ACKNOWLEDGMENTS First and foremost, I would like to express my deepest gratitude to my advisor, Professor William D. Wulff for his support, encouragement and trust during my research. He provides us with the freedom to pursue our own ideas, yet at the same time, steered us in the right direction at some critical points. His enthusiasms for Chemistry, extensive knowledge in Organic Chemistry and specificity in details in supplementary information have had a profound influence on me and will definitely benefit my future career. I am grateful to Professor Babak Borhan, Robert Maleczka and Milton Smith for being in my committee. In particular, I would like to deliver my special thanks to Babak for his encouragement during these five years. Without him, I would have quit in my first semester. Without him, I would have never done what I did. I also thank Dr Richard Staples at Center for Crystallographic Research for his efforts in solving my crystal structures. Dr Daniel Holmes and other NMR staff are extremely helpful in training and problem solving. I also thank Ms Chen Lijun, Prof. Daniel Jones at Mass facility in biochemistry at Michigan State University for the training they offered and the service they provided. The retired technician Huang Rui should be thanked for his help in CHN analysis. I would also like to thank our former group members. In particular, I am indebted to Ms Zhenjie Lu who helped tremendously in the early stage of my PhD v study. The friendship with Dr Aman Desai has been appreciated a lot. His insightful comments and constructive criticisms were thought provoking and helped me stay focused on my research. I have been fortunate to be part of the Wulff group. Ren Hong and Zhao Wenjun have been great friends to me for years. We went shopping a lot and even did our ear-piercing together. I am the only child from my family. And they make me feel like sisters together. We also talk about Chemistry and help each other in our research. Life would be a lot harder without them aside along the way. I also thank Anil K. Gupta and Munmun Mukherjee for their help in life and research. Anil is a fun person to talk to. In the party, he is the entertaining star for every one of us most of the time. In the lab, he is the one to make you laugh out loud. Munmun is always the one to go to when you have questions. She knows a lot about Chemistry, especially Physical Organic Chemistry and always kind to help. She is the treasure in our group in this sense. Dima Berbasov is also very helpful. He is always considerate and will be ready whenever you need his help. Guan Yong is also a good friend. He brought back some snacks that we really enjoyed every time he went back to China. Zhang Xin is the one who got me to emergency center when I had my tip of the finger cut. He stayed there with me for a couple of hours. I am really thankful for him doing that. And the postdoc Mattew Vetticatt. He is energetic and smiling all the time. He is also enthusiastic about what he is doing in Chemistry, which motivated me to pursue what I am really interested in. I also vi thank other group members, Wynter D. Osminiski, Victor for the help. I have also made many good friends from other groups. Zhang Quanxuan, Hu Heyi, Yuan Wen and Zhao Hui are all great to me. They will stop their work to help find chemicals and answer my questions whenever I am there asking for the help. And it has been fun to have road trips with them as a group. Luis Mori-Quiroz is very first few friends I have made here. We had the summer English programme together. He is always so patient to talk to you. When he is drunk in the party, you will get to know another funny Luis. I am also very grateful to Roozbeh Yousefi. Instead of saying ʻI am sorryʼ to me when my paper first got rejected, he talked to me for a long while and told me how I could get the paper to another level. Thanks to him, I could focus on my work soon. I would express my apology that I could not mention all the names personally one by one. But I truly thank them for the help that made this thesis possible. Last I would like to thank my parents, Huang Linnan and Xia Shuidi for their faith in me and their unconditional support and love. I know words will never be enough here. Also I owe my thanks to my husband, Xu Zhe. His tolerance of my occasional moodiness, his trust in my ability and his endless love has made my days. Good and bad time we have been through all the past five years, I believe everything in the future is going to get better. vii TABLE OF CONTENTS LIST OF TABLES……………………………………………………………………….x LIST OF FIGURES……………………………………………………………………xii LIST OF SCHEMES………………………………………………………………….xiii CHAPTER ONE CHIRAL AZIRIDINES IN ORGANIC CHEMISTRY 1.1 Introduction………………………………………………………………………1 1.2 Main approaches towards the synthesis of chiral aziridines………………..1 1.2.1 Lewis acid catalyzed catalytic asymmetric aziridination……………..4 1.2.2 Brønsted acid catalyzed asymmetric aziridination……………………5 1.2.3 The catalytic asymmetric Wulff aziridination reaction………………11 1.3 Conclusion……………………………………………………………………..19 CHAPTER TWO DOUBLE STEREODIFFERENTIATION IN THE CATALYTIC ASYMMETRIC AZIRIDINATION OF IMINES PREPARED FROM α-CHIRAL AMINES 2.1 Introduction…………………………………………………………………….20 2.2 Double stereo-differentiation with chiral imines…………………………….23 2.2.1 Double stereo-differentiation with the chiral imine (S)-52a………...24 2.2.2 Double stereo-differentiation with the chiral imine (R)-55a………...25 2.2.3 Double stereo-differentiation with the chiral imine (S)-60a………...26 2.2.4 Double stereo-differentiation with the chiral imine (R)-45a………...28 2.3 Substrate scope of cis-aziridinations with α-methylbenzyl imines………..30 2.4 trans-Aziridines from α-methylbenzyl imines and diazoacetamide 19…...39 2.5 Synthesis of α- and β-amino acid derivatives………………………………45 2.6 Conclusion……………………………………………………………………..49 CHAPTER THREE CATALYTIC ASYMMETRIC TRI-SUBSTITUTED AZIRIDINES 3.1 Introduction…………………………………………………………………….51 3.2 Catalytic asymmetric aziridination of imine 18 and diazo ester 88………52 3.3 Catalytic asymmetric synthesis of tri-substituted aziridines from N-Boc imines and α-diazo-N-acyloxazolidinone…………………………………..56 3.3.1 Optimization of the tri-substituted aziridine synthesis from 18 and 26a………………………………………………………………………56 viii 3.3.2 Substrate scope for the catalytic asymmetric synthesis of tri-substituted azirididnes……………………………………….......60 3.4 Stereo-complimentary access to both cis- and trans-tri-substituted aziridines……………………………………………………………………...64 3.5 Attempts towards the direct catalytic asymmetric synthesis of cis-tri-substituted aziridines………………………………………………...66 3.6 Synthesis of protected form of L-methylDOPA………………………….....69 3.7 Brief study on the nature of the catalyst in the tri-substituted aziridination reaction………………………………………………………………………...71 3.7.1 Effects of different species on the reaction system………………...71 3.7.2 Aziridination reaction of imine 18 with different diazo compounds..73 3.8 Maruoka’s system……………………………………………………………..75 3.9 Conclusion……………………………………………………………………..76 CHAPTER FOUR RING EXPANSION OF AZIRIDINE-2-CARBOXYLIC ACIDS 4.1 N-Carboxyanhydride formation………………………………………………77 4.2 Formation of morpholine-2,3,5-trione……………………………………….81 4.3 Rapid access to β-lactams via ring expansion of aziridine-2-carboxylic acids……………………………………………………………………………84 4.4 Conclusion……………………………………………………………………100 CHAPTER FIVE BOROXINATE CATALYSTS BASED ON BINOL DERIVATIVES 5.1 Introduction…………………………………………………………………...102 5.2 Preparation of the BINOL derivatives………………………………………106 5.3 Substrate induced assembly of borate species from BINOL derivatives.109 5.4 Reactivity of B3 boroxinate based catalysts of BINOL derivatives in the catalytic asymmetric aziridination reaction………………………………..113 5.5 Different boron sources in the aziridination reaction……………………...116 5.6 Conclusion…………………………………………………………………….118 CHAPTER SIX CATALYTIC ASYMMETRIC UGI-TYPE REACTION 6.1 Introduction…………………………………………………………………...120 6.2 Development of catalytic asymmetric 3-component Ugi reaction…..…..124 6.3 Proposed mechanism……………………………………………………….135 6.4 Conclusion……………………………………………………………………136 CHAPTER SEVEN EXPERIMENTAL SECTION…………………………………………………………137 REFERENCES……………………………………………………………………….364 ix LIST OF TABLES Table 1.1 Averaged ligand and N-substituent effects over nine imines with aromatic and aliphatic substituents R………………………………….13 Table 2.1 Matched and mismatched aziridinations of the cyclohexylethyl imine (R)-55a……………………………………………………………………..26 Table 2.2 Matched and mismatched aziridinations of the phenylneopentyl imine (S)-60a……………………………………………………………………..27 Table 2.3 Matched and mismatched aziridinations of the phenylethyl imine (R)-45a……………………………………………………………………..28 Table 2.4 Matched and mismatched aziridination of the phenethyl imine (R)-45 from aryl aldehydes……………………………………………………….32 Table 2.5 Matched and mismatched aziridination of the phenethyl imine (R)-45 from aliphatic aldehydes………………………………………………….34 Table 2.6 Matched and mismatched aziridination of the o-bromo- and o-iodophenyl imines…………………………………………………….37 Table 2.7 Matched and mismatched trans-aziridinations of imine (R)-45a with diazoacetamide 19………………………………………………………..40 Table 2.8 Matched and mismatched trans-aziridinations of diazoacetamide 19 and phenethyl imine (R)-45 from aliphatic aldehydes……………………....43 Table 3.1 Catalytic asymmetric aziridination of α-diazo esters……………………55 Table 3.2 Optimization of the aziridination of α-diazo-N-cycloxazolidinone……..57 Table 3.3 Catalytic asymmetric aziridination with diazo compound 26a…………62 Table 3.4 Catalytic asymmetric aziridination with diazo compound 26b…………64 Table 3.5 Catalytic asymmetric aziridination with different catalyst preparation procedures………………………………………………………………...72 Table 4.1 Conditions for the formation of NCAs…………………………………….79 x Table 4.2 Substrate scope for NCA formation………………………………………81 Table 4.3 The reaction of acid 151g with different chlorination reagent………….87 Table 4.4 Substrate scope of β-lactam formation…………………………………..88 Table 4.5 The reaction of acid 151l with oxalyl chloride……………………………90 Table 4.6 The reaction of acid 151g with (COBr)2………………………………….92 Table 4.7 The formation of β-lactam with in-situ or preformed Vilsmeier reagent.95 Table 4.8 Substrate for the controlled formation of β-lactam……………………..97 Table 5.1 Aziridination reactions with different ligands……………………………115 Table 5.2 Aziridination of imine 31a with catalysts derived from BINOL analog.116 Table 5.3 Aziridination with different boron sources used in the catalyst preparation procedure…………………………………………………..118 Table 6.1 The catalytic asymmetric 3-component Ugi reaction………………….126 Table 6.2 Different ratio of the reactants in the catalytic asymmetric 3-component Ugi reaction……………………………………………………………....128 Table 6.3 The screen of different chiral ligands in the Ugi reaction……………..128 Table 6.4 Solvent screening for the 3-component Ugi reaction………………….133 Table 6.5 Screen of the dibenzylamine derivatives……………………………….134 xi LIST OF FIGURES Figure 3.1 The structure of L-DOPA and L-methylDOPA…………………………..69 Figure 4.1 ORTEP drawing of NCA 140a……………………………………………78 Figure 4.2 ORTEP drawing of morpholine-2,3,5-trione 152a……………………...83 Figure 4.3 ORTEP drawing of cis-lactam 160g……………………………………..88 Figure 5.1 ORTEP drawing of BINOL derivative 93b and of its crystal packing..109 Figure 5.2 List of 11B NMR chemical shift in some known compounds…………110 Figure 5.3 Substrate induced assembly of borate species from BINOL and its analogs…………………………………………………………………..111 xii LIST OF SCHEMES Scheme 1.1 Approaches for catalytic asymmetric aziridination reactions…………3 Scheme 1.2 Lewis acid catalyzed aziridination of imine 1 and diazo 2……………5 Scheme 1.3 Lewis acid catalyzed aziridination reaction…………………………….5 Scheme 1.4 Protonative decomposition of the diazoalkanes……………………….6 Scheme 1.5 Divergent evolution of a diazonium intermediate to aziridines, α-diazo esters and enamine by-products in the addition of diazo compounds to aldimines……………………………………………………………….7 Scheme 1.6 Akiyama’s one pot procedure……………………………………………8 Scheme1.7 Bis(carboxylic acid) catalyzed enantioselective trans-aziridination reaction with α-diazoacetamide………………………………………..9 Scheme 1.8 Bis(carboxylic acid) catalyzed enantioselective Mannich additions of α-diazo esters……………………………………………………………9 Scheme 1.9 Phosphoric acid catalyzed trans-aziridination system developed by Zhong and coworkers………………………………………………….10 Scheme 1.10 Maruoka’s catalytic asymmetric system for tri-substituted aziridines………………………………………………………......11 Scheme 1.11 Catalytic asymmetric aziridination of aldimines with EDA mediated by VANOL and VAPOL derived catalysts………………………......12 Scheme 1.12 Universal catalytic asymmetric aziridinations……………………….15 Scheme 1.13 Catalytic asymmetric synthesis of tri-substituted aziridines developed in our group……………………………………………16 Scheme 1.14 Active catalysts in the catalytic asymmetric aziridination………….17 Scheme 1.15 Proposed catalytic cycle in the catalytic asymmetric aziridination..19 xiii Scheme 2.1 cis-Aziridination protocols with VANOL/VAPOL boroxinate catalysts…………………………………………………………….20 Scheme 2.2 cis-Aziridination reactions with a chiral imine as substrate…………21 Scheme 2.3 Previous examples of aziridination of chiral imines mediated by non-chiral Lewis acids………………………………………………..23 Scheme 2.4 The set of amines chosen in our study……………………………….23 Scheme 2.5 cis-Aziridination reactions of the chiral imines (S)-52a……………..24 Scheme 2.6 The relative rate study of imines (S)-60a, (R)-45a and 31a………..30 Scheme 2.7 Selective removal of bromine via tin hydride reduction……………..38 Scheme 2.8 Determination of the relative stereochemistry………………………..39 Scheme 2.9 Catalytic hydrogenation of 71a to (S)-77a……………………………45 Scheme 2.10 Conversion of cis-aziridine 73a to 43a………………………………45 Scheme 2.11 C2 and C3 cleavage in hydrogenation of aziridines………………..46 Scheme 2.12 Hydrogenation of chiral aziridines in the presence of Boc2O……..46 Scheme 2.13 Hydrogenation of C3-alkyl substituted aziridines…………………..47 Scheme 2.14 Hydrogenation of 43g under conditions that give a mixture……….47 Scheme 2.15 Conversion of an primary amide to an ester………………………..48 Scheme 2.16 Hydrogenation of trans-aziridine ester 67a…………………………48 Scheme 2.17 Hydrogenation of 3-alkyl substituted trans-aziridines to give β-amino acids as the major product…………………………………………...49 Scheme 3.1 aza-Darzens asymmetric synthese of trisubstituted aziridines……..52 Scheme 3.2 Acid-catalyzed aziridination of α-diazocarbonyl compounds and imines…………………………………………………………………..52 xiv Scheme 3.3 Failed attempts towards a tri-substituted aziridine synthesis………53 Scheme 3.4 The proposed mechanism for the formation of 90 and 91………….56 Scheme 3.5 Determination of trans:cis selectivity of the reaction of 18 and 26a..59 Scheme 3.6 General strategy for access to cis and trans-tri-substituted aziridines……………………………………………………………...65 Scheme 3.7 The synthesis of cis and trans-isomers of aziridine 90a…………….66 Scheme 3.8 The preparation of cis-90b and cis-90c……………………………….66 Scheme 3.9 The control of cis:trans selectivity by different diazoacetamides in disubstituted aziridine synthesis…………………………………….67 Scheme 3.10 The attempt towards a direct cis-tri-substituted aziridination……..67 Scheme 3.11 The conversion of oxazolidinone aziridine 90a to its corresponding ester and acid………………………………………………………….68 Scheme 3.12 The configuration of cis and trans-aziridine from the reaction of imine 31b and diazoacetamide 19…………………………………..69 Scheme 3.13 Synthesis of L-DOPA………………………………………………….70 Scheme 3.14 Failed attempts of ethanolysis of aziridine 119……………………..71 Scheme 3.15 Synthesis of the protected form of L-methylDOPA…………………71 Scheme 3.16 The reaction of imine 18 and EDA…………………………………...75 Scheme 3.17 The reaction of imine 18 and diazoacetamide 19………………….75 Scheme 3.18 Catalytic asymmetric synthesis of tri-substituted aziridines developed in Maruoka’s group……………………………………76 Scheme 4.1 Planned synthesis of cis-27a…………………………………………..77 Scheme 4.2 Two conventional methods for access to NCAs……………………..79 Scheme 4.3 Existing examples of N-oxalic anhydrides……………………………83 xv Scheme 4.4 The formation of morpholine-2,3,5-triones……………………………84 Scheme 4.5 Existing examples of lactam formation via ring expansion of aziridines……………………………………………………………….85 Scheme 4.6 Failed attempts towards the ring expansion………………………….93 Scheme 4.7 Proposed mechanism for the formation of different products………94 Scheme 4.8 The transformation of β-lactam 159g…………………...…………...100 Scheme 4.9 Diastereoselective conversion of aziridine-2-carboxylic acids……101 Scheme 5.1 Linear and vaulted biary ligands……………………………………..103 Scheme 5.2 The formation of B3 species………………………………………….104 Scheme 5.3 Reaction of BINOL and its derivatives with boron sources………..105 Scheme 5.4 reaction of BINOL with borane and subsequent transformation….106 Scheme 5.5 Preparation of BINOL derivative 93b………………………………..107 Scheme 5.6 Preparation of BINOL derivative 93c……………………………......108 Scheme 5.7 Preparation of BINOL derivative 93d……………………………......108 Scheme 6.1 Ugi four-component reaction and its mechanism……..…………...120 Scheme 6.2 The three component Ugi reaction of aldehyde 203, dimethylamine 204 and cyclohexyl isocyanide 205 in the presence of acetic acid…………………………………………………………………….121 Scheme 6.3 The three component Ugi reaction of aldehydes, secondary amines and isocyanides catalyzed by Sc(OTf)2 …………………………..121 Scheme 6.4 Other variation of the Ugi reaction of secondary amines………….121 Scheme 6.5 The three component Ugi reaction of aldehydes, secondary amines and isocyanides in the presence of aminoborane 213 or B(OMe)3………………………………………………………………122 xvi Scheme 6.6 Catalytic asymmetric 3-component Ugi reaction reported in List’s group………………………………………………………………….124 Scheme 6.7 Catalytic asymmetric α-addition of α-isocyanoacetamides to imines………………………………………………………………..124 Scheme 6.8 Screen of alcohols and phenol derivatives………………………….130 Scheme 6.9 Proposed mechanism for the Ugi-type reaction…………………….136 xvii CHAPTER ONE CHIRAL AZIRIDINES IN ORGANIC CHEMISTRY 1.1 Introduction Aziridines are saturated strained three-membered heterocycles containing a nitrogen atom. They have attracted great interest to chemists for years because of their easy transformation into pharmacologically and biologically active 1 compounds, their appearance as subunits in naturally occurring substances, their antitumor and antibiotic activities, auxiliaries 5 in asymmetric synthesis 6 3 their use as chiral ligands 4 2 and and their application as chiral building blocks for the construction of various nitrogen-containing compounds, such as chiral amines, amino acids, amino alcohols, alkaloids, β-lactam antibiotics etc. 7 Due to approximate 27 kcal/mol high strain energy, aziridines can undergo ring cleavage reaction with a range of nucleophiles or cycloaddition reactions with dipolarphiles. Aziridines, which are extremely important synthetic building blocks, 8 are the nitrogen equivalent to epoxides. However, they are less widely used in synthesis than their oxygen counterparts, partly because there are fewer efficient methods for aziridinations than epoxidations. This is particularly true when enantioselective methods are considered. 1.2 Main approaches towards the synthesis of chiral aziridines As most optically active aziridines are prepared from ‘chiral pool’, asymmetric synthesis of chiral aziridines can be obtained either based on the use of chiral 1 auxiliaries or by catalytic asymmetric methods. Asymmetric aziridination based 2 on the use of chiral auxiliaries was reviewed by Sweeney in 1997. On the other hand, asymmetric aziridination based on chiral catalysts was previously reviewed 9 by Müller and Fruit in 2003, covering the literature till the end of 2002. The asymmetric synthesis of aziridines based on both methods has been reviewed by Pellissier in 2010, covering the literature till the end of 2009. 10 The main approaches to the synthesis of chiral aziridines can be classified as transfer of nitrogen to olefins, transfer of carbon to imines, cyclization reactions, addition across the carbon-nitrogen double bond of azirines, reactions of ylides, aza-Darzens 10 contraction. approaches and miscellaneous reactions such as ring Among those, catalytic asymmetric aziridination reactions have been developed based on two approaches: transfer of nitrogen to olefins and transfer of carbon to imines (Scheme 1.1). Specifically, transfer of nitrogen to olefins could fall into two categories: the metal nitrene transfer to an olefin (metal nitrene approach) and organocatalyst-mediated addition of nitrene surrogate to an activated olefin. As to the transfer of carbon to imines, the aziridine ring could be constructed from transfer of a metal carbene to an imine and the reaction of a diazo compound with an acid-activated imine. 2 Scheme 1.1 Approaches for catalytic asymmetric aziridination reactions Transfer of nitrogen to olefins Transfer of carbon to imines R1 R LnM N N R1 R2 R Nitrene transfer R Carbene transfer M R2 N R R1 R2 N X R1 N2 R2 H H Organocatalyst A R2 Acid catalyst N R R1 The publication of successful efforts of finding catalytic asymmetric nitrene transfer methods by using different organometallic catalysts for the enantioselective synthesis of aziridines began in the 1990s. Evans, Jacobsen 11b and Katsuki, 11c 11a and their coworkers reported the catalytic asymmetric aziridination of olefins with [N-4-toluenesulfonyl)imino]phenyliodinane as a nitrene source. The second approach involves the chiral organocatalystmediated addition of a nitrene surrogate to electron-deficient olefins (α,β12 unsaturated carbonyl compounds) and has just appeared in the literature. The asymmetric transfer of a metal carbene to an imine has not been fully developed yet. The only real success with this approach involves the Rh-catalyzed asymmetric generation of aziridine from chiral in situ generated sulfur ylides and imines by diazo decomposition developed by Aggarwal and coworkers. 13 In this method, however, the stereogenic step does not involve the transfer of carbon to the imine from a metal carbene complex, but rather from a chiral sulfur ylide. The final approach involves the activation of an imine by a chiral Lewis or Brønsted 3 acid towards reaction with a diazo compound. It has been an active field in recent years and the focus of our studies in our research group. The following will provide an overview of catalytic asymmetric reactions of imines with diazo compounds catalyzed by Lewis or Brønsted acids. 1.2.1 Lewis acid catalyzed catalytic asymmetric aziridinations Since the pioneering work of Brookhart and Templeton 14a and of Jørgensen 14b and their co-workers who reported that simple non-chiral Lewis acids such as BF3•OEt2 and Yb(OTf)3 could catalyze the formation of aziridines from imines and ethyl diazoacetate (EDA), the asymmetric catalytic version has been developed. The reaction of EDA with imines mediated by a Lewis acid is normally selective for cis-aziridines. Jørgensen’s group reported in 1999 the first catalytic diastereo- and enantioselective aziridination of imine 1 derived from α-ethyl glyoxylate with trimethylsilyldiazomethane 2 in which the imine is activated by a chiral Lewis acid complex (Scheme 1.2). Chiral Tol-BINAP in combination with CuClO4 in particular can catalyze the reaction, leading to the cis-aziridine 3 with up to 72% ee, the highest asymmetric induction so far obtained in the Lewis acid catalyzed aziridination. 4 Scheme 1.2 Lewis acid catalyzed aziridination of imine 1 and diazo 2 Ts (R)-TolBINAP-CuClO Ts 4 (10 mol%) N PAr EtOOC + 1 PAr THF, –78 °C EtOOC 3 TMS TMS overnight 55% yield trans: cis 19:1 N2 2 72% ee (R)-TolBINAP: Ar = Tol N In 2004, Hossain et al reported the enantioselective reaction of EDA 5 with N15 aryl imine 4 catalyzed by iron-pybox complexes as Lewis acids. When AgSbF6 was used as initiator, the reaction afforded the corresponding cis-aziridine 6 in enantioselectivity of up to 49% ee in the presence of iron-pybox depicted in + Scheme1.3. The role of Ag ion was assumed to create an open site for the coordination of the imine to the Lewis acid. Scheme 1.3 Lewis acid catalyzed aziridination reaction Ph Iron-pybox complex (5 mol%) AgBF4 (5 mol%) Ph 2h N N 4 + O COOEt CH2Cl2, rt, 48 h OEt N2 5 O 6 up to 49% ee N t-Bu O N Fe N t-Bu Cl Cl Iron-pybox complex 1.2.2 Brønsted acid catalyzed asymmetric aziridinations Chiral Brønsted acids, such as dicarboxylic acids and phosphoric acid derivatives, have recently been employed as catalysts for the reactions of imines and diazo compounds. A diazo compound is considered to be an unlikely candidate for the development as a donor in transformations promoted or catalyzed by a Brønsted acid. Compared with Lewis acid activation, a Brønsted 5 acid activation mode in the formation of aziridines has the additional challenge of avoiding competitive protonative decomposition of a diazo compound that leads 16 to alkylation (Scheme1.4) or diazo coupling. Scheme 1.4 Protonative decomposition of the diazoalkane. O O OH H + H O H N2 N H2 O N O N2 The mechanism for the reaction of imine 7 and diazo compound 8 involves the addition of the diazo ‘ylide’ to the catalyst bound imine, thus leading to a discrete diazonium intermediate 9 (Scheme 1.5). Subsequent nucleophilic substitution and loss of N2 furnishes the aziridine 10. Use of some catalysts, for reasons that are not clear, leads to proton loss to reform the diazo functionality. A 1,2-shift of an alkyl group or a hydride gives rise to the formation of some enamine by16 products 12 and 13. Aziridine formation will be the focus of the following discussions. 6 Scheme 1.5 Divergent evolution of a diazonium intermediate to aziridines, αdiazo esters and enamine by-products in the addition of diazo compounds to aldimines PG R 10 7 + O B*H PG Brønsted H N O R X acid H N2 (B*H) X N2 X R PG N Aziridination N SN2 proton transfer HN H R O PG O Diazo X reformation N2 11 9 8 H X = OR1 or NR2R3 1,2-hydride or alkyl shift R N PG O H or X N PG O H X R H 13 12 enamines formation In 2009, Akiyama et al. reported the aziridination reaction using EDA 5 and 417 methoxyphenyl(PMP)-protected imine. The addition of EDA to the electron- deficient aldimine generated in situ from p-methoxyaniline 15 and phenyl glyoxal hydrate 14 was catalyzed by a chiral phosphoric acid (R)-17a and gave aziridine 16 in a good yield with high diastereo- and enantio-selection. It is also interesting to note that the structure of the chiral phosphoric acid affected not only the degree but also the sense of enantioselectivity. Introduction of a bulky substituent to the 4-position of aryl groups in the 3,3’-position of the BINOL ligand significantly improved the enantioselectivity. Optimization of the reaction provided a two-step, one-pot method (Scheme 1.6). Although the reaction shows a good 7 tolerance towards electron-rich and electron-poor aryl groups of 14, the substrate is still limited to aryl glyoxal. Scheme 1.6 Akiyama’s one pot procedure O OH Ar OH O 14 + NH2 MeO 15 (R)-17a (2.5 mol%) MgSO4 toluene, rt, 1 h Ar OEt N2 5 PMP N Ar toluene –30 °C O O P O OH COOEt O 16 Ar = Ph 84% yield 96% ee Ar (R)-17a Ar = Si(4-(t-Bu)C6H4)3 Unlike the proceeding aziridinations, which are cis-selective, Maruoka’s group reported, in 2008, a trans-selective asymmetric aziridination of diazoacetamide 19 and N-Boc imine 18 mediated by an axially chiral dicarboxylic acid. 18 3,3’- dimesityl substituted dicarboxylic acid (R)-21a depicted in Scheme 1.7 was identified as the optimal catalyst and provided the corresponding trans-aziridine 20 exclusively in 61% yield and 97% ee. A proposed explanation of the trans selectivity involves hydrogen bonding between the amide N-H and Boc carbonyl group as indicated in the Newmann projection in Scheme 1.7. In contrast to this trans-aziridination with diazoacetamide 19 with catalyst 21a, the closely related catalyst 21b does not give aziridine products with diazoacetates (Scheme 1.8). Instead, this reaction leads to the α-diazo ester 19 23. Good enantioselection is observed within a range of electronically varied 8 aryl aldimines. They further extended this Mannich reaction of N-Boc imines to dimethyl diazomethylphosphonate 24, as a means of creating the optically enriched β-aminophosphonate derivative 25. Based solely on the general mechanism presented in Scheme 1.5, it is still not clear why the putative diazonium intermediate 9 evolves to the trans-aziridine product 10 instead of the diazo compound 11 when a diazoacetamide is used. Scheme 1.7 Bis(carboxylic acid) catalyzed enantioselective trans-aziridination reaction with α-diazoacetamide N Ph O Boc + NHPh N2 18 Boc (R)-21a (5 mol%) toluene, 0 °C, 2-8 h 19 H-bonding Ot-Bu Favored O H O2CR* H N N H Ph O H N Ph 2 trans: cis >20:1 Ot-Bu O H N H O2CR* CONHPh H N Ph 2 Steric repulsion Disfavored trans Ph N H H CONHPh 20 61% yield 97% ee Ar COOH COOH Ar (R)-21a Ar = 2,4,6-Me3C6H2 cis Scheme 1.8 Bis(carboxylic acid) catalyzed enantioselective Mannich additions of α-diazo esters NHBoc (R)-21b Ar CO2t-Bu (5 mol%) Ph O 23 N2 80% yield COOH Ph 18 N2 22 95% ee COOH (R)-21b Boc NHBoc PO(OMe)2 (5 mol%) N Ar + PO(OMe)2 (R)-21b Ph N2 Ph 24 18 25 N2 68% yield Ar = 2,6-Me2-4-t-BuC6H2 96% ee Boc O N + 9 After the report of Maruoka’s trans-aziridination system, a clean and fast transaziridination of diazoacetamides with N-Boc-imines, catalyzed by chiral phosphoric acid (R)-17b in dichoromethane (DCM) at room temperature was developed by Zhong’s group (Scheme 20 1.9). Excellent yields, diastereoselectivities, chemoselectivities and enantioselectivities were achieved in the reaction. N-Cbz protected imines could also be employed in this aziridination reaction, affording trans-aziridines in high yield and excellent enantioselectivity. Scheme 1.9 Phosphoric acid catalyzed trans-aziridination system developed by Zhong and coworkers. N Ar Boc (R)-17b (5 mol%) Ph 18 O + 0.0125 M in DCM, rt NHPh trans: cis >50:1 N2 19 Boc H N CONHPh Ph H ent-20 95% yield 92% ee O O P O OH Ar (R)-17b Ar = 9-anthryl The significant extension of the Brønsted acid catalyzed reaction of diazoacetates and imines to give aziridines was the extension of this reaction to trisubstituted aziridines by Maruoka in 2011. 21 One year after their discovery of the synthesis of trisubstituted aziridines based on a chiral auxiliary, 22 Maruoka’s group has reported the general procedure for the catalytic asymmetric synthesis of trisubstituted aziridines in the presence of the strong chiral Brønsted acid, Ntriflyl phosphoramide (S)-30. 10 Scheme 1.10 Maruoka’s catalytic asymmetric system for trisubstituted aziridines (S)-30 (S)-30 O O Boc O (5 mol%) (5 mol%) R1 O N H t-BuO2C N O N O 26c R1 = H N 26a R1 = CH3 N N O Ph 2 Boc Ph Boc O 29 O 26a R1 = CH3 N 27a N 89% yield 1 86% yield Ph CO2t-Bu 26c R = H Ph 18 95% ee 83% ee 28 Ph Boc O O P O NHTf Ph (S)-30 Two possible substrate combinations: α-substituted α-diazocarbonyl compound 26a / aldimine 18 and α-unsbstituted α-diazocarbonyl compound 26c / ketimine 28 serve the goal of providing a catalytic asymmetric synthesis of trisubstituted aziridines as shown in Scheme 1.10. Noteworthy is the observation that in contrast to the Brønsted acid catalyzed asymmetric synthesis of disubstituted aziridines, wherein an axially chiral dicarboxylic acid and an axially chiral monophosphoric acid worked efficiently, the reaction of N-Boc imines and α-substituted diazocarbonyls could not be facilitated by these catalysts even at room temperature. 1.2.3 The catalytic asymmetric Wulff aziridination reaction The research in our group is based on the use of vaulted chiral biaryl ligands, VANOL 33 and VAPOL 34. Catalysts derived from these ligands have provided some of the most successful contributions to date for the enantioselective 10 aziridination of imines with diazo compounds. 1.2.3.1 Protocols for cis- and trans-aziridination in our group 11 In 2000, we reported the very first general catalytic asymmetric aziridination that gave good yields and ee’s of cis-aziridines 32 from the reaction of imine 31 with a benzhydryl group as the N-protecting group and EDA 5 with a catalyst 23 prepared from either the VANOL or VAPOL ligand and B(OPh)3 (Scheme1.11). The detailed discovery of the original catalytic system can be found in a review. 24 Scheme 1.11 Catalytic asymmetric aziridination of aldimines with EDA mediated by VANOL and VAPOL ligands. R N 31 Ar Ph Ph O Ar OH OH 33: (S)-VANOL + N2 or Ph Ph precatalyst Ar Ar N OEt 5 R OH OH 32 COOEt Diffrerent catalyst preparation procedure precatalyst 34: (S)-VAPOL The vaulted chiral biaryls, VANOL and VAPOL have both proven to be superior ligands for the reaction. In contrast, the linear chiral biaryls, BINOL and its derivatives give poor to moderate inductions. 12 25 Table 1.1 Averaged ligand and N-substituent effects over nine imines with aromatic and aliphatic substituents R N R 31 O Ar + Ar Ar precatalyst N OEt R N2 5 MeO Benzhydryl t-Bu t-Bu BUDAM N-substituent Benzhydryl Ligand VAPOL VANOL VAPOL VANOL VAPOL VANOL VAPOL VANOL DAM BUDAM MEDAM COOEt OMe OMe MeO OMe t-Bu 32 DAM t-Bu MeO Ar MEDAM Average % yield 70 77 73 78 88 90 92 91 Average % ee 88 88 88 85 95 94 97 96 Over the years, we have focused on the optimization of the yields and asymmetric inductions in this reaction. Higher yields and enantioselectivities have been realized by the fine-tuning of the nitrogen substituent of the imine. The catalytic asymmetric AZ reaction with imines derived from the dianisylmethyl (DAM) amine 26b is as effective as that with benzyhydryl imines tert-butyldianisylmethyl (BUDAM) N-substituent gives 26a . The 3,5-di- exceptionally high asymmetric inductions in the asymmetric aziridinations for imines from aryl aldehydes. 26c Imines derived from tetra-methyldianisylmethyl (MEDAM) amine were found to be superior to the benzyhydryl and BUDAM imines especially for 13 imines derived from aliphatic aldehydes. 26d Comparative data for the VAPOL and VANOL ligands over nine imine substrates with four different nitrogen protecting groups on the imines is listed in Table 1.1. The DAM, BUDAM and MEDAM group have the advantage that they can be cleaved from the aziridines with a strong Brønsted acid without ring opening. Triflic acid can cleave all three under conditions that are milder than that required for cleavage of the benzyhydryl group and this is presumably due to the greater stabilization of the resulting dianisylmethyl cation. 26b This highly efficient asymmetric methodology can be successfully applied to other diazo compounds, such as diazomethyl vinyl ketones27a and functionalized diazomethyl ketones. 27b 18 Inspired by the report on trans-aziridination by Maruoka , we have shown recently that the chiral catalysts derived from VANOL/VANOL can also give trans-aziridines 35 in the reaction of imine 31 and diazoacetamide 19 with high yields and asymmetric inductions. Our protocol thus represents the only universal catalytic asymmetric aziridination reaction where either cis or trans-aziridines can be prepared from the same imine substrate 31 and the same catalyst (Scheme 28a 1.12). 14 Scheme 1.12 Universal catalytic asymmetric aziridinations. precatalyst (5 mol%) precatalyst (2.5-10 mol%) (S)-VAPOL (S)-VANOL BH3.SMe2 Ar Ar PhOH B(OPh)3 CONHPh 35 trans-aziridines R O NHPh N2 19 H2O Ar H2O N R ( or VANOL) N 31 Ar O Ar Ar N R COOEt OEt 32 N2 5 cis-aziridines The origin of the cis-selectivity in the reactions of EDA 5 can be understood on the basis of the difference in specific noncovalent interactions in the stereochemistry-determining step. A hydrogen bonding interaction between the amidic hydrogen and an oxygen atom of the chiral counterion in the catalyst has been identified as the key interaction responsible for the trans-selectivity. 28b Independently from Maruoka, we found that our VANOL borate precatalyst can catalyze the reaction of N-Boc imine 18 and diazo compound 26a to give 29 trisubstituted aziridines (Scheme 1.13). While a strong Brønsted acid (S)-30 was used as the catalyst by Maruoka in the synthesis of tri-substituted 21 aziridines , we were surprised by the fact that the reaction with the VANOL catalyst afforded a good yield of 27a even at –78 °C. This reaction will be the subject of Chapter Three. 15 Scheme 1.13 Catalytic asymmetric synthesis of trisubstituted aziridines developed in our group. N Ph O Boc + O N N2 Boc O O N N O (R)-VANOL-precatalyst O CH2Cl2, –78 °C 72% yield 94% ee Ph 27a 26a 1.2.3.2 Active catalyst and catalytic cycle in the aziridination system 18 In the course of the development of an asymmetric catalytic method for the synthesis of cis-aziridines, we also devoted efforts to the identification of the active catalyst in the system. Mass spectral analysis and the 11 B NMR spectrum of the catalyst mixture suggested the presence of two species: one derived from one of one molecule of the ligand and one boron atom (B1) and the second from one molecule of the ligand and two boron atoms (B2). These species have been 26a tentatively identified as those shown in Scheme 1.13. Studies with catalysts enriched in either the B1 or B2 species reveal that precatalyst enriched in the B2 species gives higher asymmetric induction and higher rates in the asymmetric aziridination reaction than the precatalyst enriched in the B1 species. It was not until 2009 that we came to know that the catalyst for this system was actually a species derived from one molecule of the ligand and three borons (B3). This was a surprise since the catalyst is a chiral Brønsted acid (B3) and not a chiral Lewis acid as we had long thought. 30a The mixture of the B1 and B2 species is converted under reaction conditions to the boroxinate (B3), the actual catalyst in these reactions. More recently, the crystal structures of the catalyst/substrate complex were obtained. 30b We have not yet confirmed the existence of the 16 protonated boroxinate as B3-H species, but instead we have observed ion-pairs in which a basic substrate abstracts the proton and the resulting protonated substrate is hydrogen bonded to the anionic core. These new chiral Brønsted acids are chiral polyborates, which contain a boroxinate core that incorporate the biaryl ligands VANOL and VAPOL and have the general structure shown in Scheme 1.14. Scheme 1.14 Active catalysts in the catalytic asymmetric aziridination. Ph Ph O B OPh O R1 R2 R2 O R3 O O B B O O O B O R3 Ph Ph OPh O B O B O OPh B2 B1 R1 H R2 R2 R3OH (2.0 equiv) OH + OH H2O (3.0 equiv) BH3•SMe2 (3.0 equiv) R1 In-situ generated B3 catalyst R1 The discovery of this new class of strong chiral Brønsted acids not only provides critical insights into the binding of the substrates with the boroxinate catalyst in the aziridination reaction but also opens up new opportunities in asymmetric catalysis. In the long run, this new class of the catalyst will actually stand out as being one of great diversity. As in the BINOL phosphoric acids and derivatives, diversity can be achieved by preparing the catalysts from substituted 17 VANOL and VAPOL ligands. Another dimension to diversity could be attained by variation of the alcohol or phenol that makes up the boroxinate core. In addition, the catalyst can be quickly generated from 1.0 equivof the ligand, 2.0 equiv of alcohol or phenol, 3.0 equiv of H2O and 3.0 equiv of BH3•SMe2. As illuminated by the crystal structure of polyborate-imine complex, the variety and diversity of noncovalent interactions that are involved in the binding of the substrate and the catalyst is particularly appealing in thinking about and designing asymmetric catalyst systems. The fact it has been used in other reactions31 will make it more appealing to the scientific community. The catalytic cycle for the cis-aziridination has been proposed 30b as that in Scheme 1.14. Several protocols for catalyst preparation allows for the generation of mixtures of B1 and B2, which, along with a basic imine substrate 31, could be converted to boroxinate B3 with hydrogen bonding to a protonated imine. Once the boroxinate B3 catalyst is assembled, the next step involves the reaction with EDA 5 to give a boroxinate-H-aziridine complex. The loss of aziridine and incorporation of another molecule of imine 31 regenerate the boroxinate-imine complex and continues the catalytic cycle. 18 Scheme 1.15 Proposed catalytic cycle in the catalytic asymmetric aziridination. Ar N R VAPOL or VANOL B1 + B2 B(OPh)3 Ar Ar 31 Ar N H-aziridine OPh O O B * B O O O B OPh B3-H-aziridine complex N Ar R 32 H-imine COOEt R Ar 31 OPh O B * B O O O B OPh B3-H-imine complex O O OEt N2 5 1.3 Conclusion The understanding of the mechanistic basis of action of the catalyst in the asymmetric aziridination of imines with diazo compounds should widen its employment in organocatalysis. The discovery of chiral boroxinate structures not only provides new insights into molecular recognition between a catalyst and its substrate that would be important in the design of function of catalyst in existing reactions, but also should stimulate new applications of this catalyst in new catalytic asymmetric reactions. Our unique polyborate template for which new applications in enantioselective synthesis of chiral molecular frameworks will undoubtedly emerge in the years to come. 19 CHAPTER TWO DOUBLE STEREODIFFERENTIATION IN THE CATALYTIC ASYMMETRIC AZIRIDINATION OF IMINES PREPARED FROM α-CHIRAL AMINES 2.1 Introduction A general method has been developed in our group for the asymmetric catalytic synthesis of both cis- and trans-aziridines that involves the reaction of imines and diazo compounds with catalysts prepared from either VANOL or 23, 28 VAPOL ligand and B(OPh)3 or BH3•SMe2. The actual catalyst in the reaction is an ion pair consisting of a boroxinate anion and an iminium cation as 30 shown in Scheme 2.1. Scheme 2.1 cis-Aziridination protocols with VANOL/VAPOL boroxinate catalysts Ar Ar N R Boroxinate catalyst (5 mol%) CONHPh R NHPh N2 19 35 Ph Ph O OH OH or 33: (S)-VANOL Ph Ph Ar N Boroxinate catalyst Ar (2.5-10 mol%) Ar 31 OH OH 34: (S)-VAPOL O N R COOEt OEt N2 5 Ph Ph Ar 32 O Ph O B O B O O O B O Ph H-imine In-situ generated boroxinate catalyst (B3) Over the years we have focused on the identification on the optimal aryl 26 substituents for the diarylmethyl group on the nitrogen in imine 31. 20 Over all of the imines 31 of the type that we have examined, the optical purity of cisaziridines 32 range from 77-99% ee and that of trans-aziridines 35 from 81-98% ee which includes imines derived from electron-rich and electron-poor aromatic aldehydes as well as primary, secondary and tertiary aliphatic aldehydes. Since many reactions gave 98-99% ee, those substrates that give less than ideal asymmetric inductions usually require an upgrade of the optical purity of the product by any number of procedures. 26a When a chiral imine 36 prepared from a chiral amine is employed, two diastereomeric aziridines could be formed, for example 37 and 38 in the cis-aziridination reaction (Scheme 2.2). Once one diastereomer is separated from the other, the optical purity of this particular diastereomer would be 100% ee. Given a good yield, the strategy may prove to be ideal for many synthetic applications. Therefore, we decided to investigate the aziridination of imines of type 36 prepared from chiral amines. Scheme 2.2 cis-Aziridination reactions with a chiral imine as substrate 2 R1 VANOL/VAPOL R boroxinate catalyst N + 1 R ? R COOEt 37 R2 R N 36 R2 R1 N R 38 COOEt Although the cis-aziridination of chiral imines of type 36 with diazo compounds have not been previously investigated with chiral catalysts, three reports have appeared that describes these reactions with non-chiral Lewis acids as shown in Scheme 2.3. The synthesis of aziridine-2-carboxylates from the reaction of hexahydro-1,3,5-triazine (R)-39 with EDA in the presence of SnCl4 as a catalyst has been reported. 32a An N-methyleneamine equivalent could be generated in 21 situ from hexahydro-1,3,5-triazine prepared from α-methylbenzylamine. The overall yield of the reaction was 67-76% with the diastereomeric ratio ranging from 64:36 to 67:33. Ha and coworkers generated imines (R)-45 in situ during Lewis acid mediated aziridination of α-aminonitriles (R)-42 derived from αmethylbenzylamine with EDA. 32b The optimal condition involved the reaction with 0.5-1.0 equivalent of SnCl4, affording a mixture of diastereomers 43 and 44 in ratios from 58:42 to 75:25 with 43 being the major one. Both aryl and alkyl substituents could be introduced into the aziridine in the 3-position with the yield of the major diastereomer being 25-71%. In another example, Lee and coworkers found that the reaction of chiral imines (S)-45 with 3.0 equivalent EDA gave the diastereomeric aziridines 46 and 47 with dr of 57:43 to 73:27 and an overall yield of 34-89%. chiral 32c amine While a range of imines prepared from aryl aldehydes and the afforded good yields of the aziridines, imine from p- methoxybenzaldehyde gave no reaction. To summarize, the reaction of imines prepared from aldehydes and α-methylbenzylamine with EDA in the presence of non-chiral Lewis acids give a slight diastereomeric preference for a particular diastereomer. But the degree of stereoinduction is generally low and the yields of aziridine products are not practically useful. 22 Scheme 2.3 Previous examples of aziridination of chiral imines mediated by nonchiral Lewis acids Ph O N N N +N 2 Ph (R)-39 Ph NH CH2Cl2 5 Ph NC OEt SnCl4 Ph (0.2-1.0 equiv) SnCl4 (0.5-1.0 equiv) O + R (R)-42 OEt N2 5 CH2Cl2, 25 °C R 6h CoCl2/AgBF4 (0.2 equiv) + OEt N Acetone, 25 °C N2 R 10h 5 R (S)-45 O Ph Ph 1 examples Yield: 67-76% + N N dr: 67:33 to 64:36 COOEt COOEt 41 40 5 examples Ph Ph R = aryl,alkyl Yield(43): 25-71% + N N dr: 58:42 to 75:25 COOEt R COOEt 43 44 12 examples Ph Ph R = aryl Yield: 34-89% + N N dr: 57:43 to 73:27 COOEt COOEt R 46 47 2.2 Double stereo-differentiation with chiral imines The set of amines that we chose to examine in the double stereodifferentiation study are the four amines shown in Scheme 2.4. These were chosen to examine the effect of the competition between the aryl and alkyl groups, between aryl groups of different electron density and between alkyl groups of different sizes. We decided to first screen chiral imines prepared from benzaldehyde and chiral amine 48-51 in the cis-aziridination reaction. Scheme 2.4 The set of amines chosen in our study R2 R R N R1 36 R2 + OH N 2 R1 H2N (S)-48 H2N Br (R)-49 23 H2N (S)-50 H2N (R)-51 2.2.1 Double stereo-differentiation with the chiral imine (S)-52a Yu Zhang, our former group member, conducted the reactions of the unsymmetrical chiral benzhydryl imine (S)-52a prepared from benzaldehyde and 33 the chiral amine (S)-48 with EDA. The imine (S)-52a was chosen such that the two phenyl rings are nearly sterically identical but electronically distinct. It was observed in the X-ray analysis of a boroxinate-iminium complex (Scheme 2.1) that the binding of the protonated imine 31 in the VAPOL boroxinate catalyst results from several different types of non-covalent interactions of the two phenyl groups with the boroxinate catalyst. This includes a CH-π interaction of one of phenyl rings of MEDAM group to one of the phenyl rings on the back end of the 30b VAPOL ligand. Scheme 2.5 cis-Azirdination reactions of the chiral imine (S)-52a Br Br VAPOL borate catalyst (10 mol%) Ph N (S)-52a CCl4, 25 °C, 24 h O Br OEt N2 5 + N Ph 53a Ligand COOEt (S)-VAPOL % yield 75 N Ph COOEt 54a 53a:54a 97:3 74 3:97 (R)-VAPOL With all the efforts that it took to resolve the amine (S)-48, it was thus disappointing to find that in the reaction of chiral imine (S)-52a with a phenyl and p-bromophenyl substituent, aziridine 53a and 54a were obtained in a 97:3 mixture in favor of 53a with the (S)-VAPOL catalyst and in a 3:97 mixture in favor of 54a with the (R)-VAPOL catalyst (Scheme 2.5). Both enantiomers of the VAPOL-borate catalyst gave a 30:1 mixture of products with no evidence for a 24 matched/mismatched pair of the substrate. It is clear that the cis-aziridination reactions of imine (S)-52a with chiral benzhydryl substituents were dominated by catalyst control. 2.2.2 Double stereo-differentiation with the chiral imine (R)-55a The catalytic aziridination reaction of chiral imine (R)-55a pits the effects of a cyclohexyl group against a methyl group in the control of diastereoselectivity in competition with VAPOL and VANOL catalyst. As indicated in Table 2.1, these effects turn out to be very small as there is only a slight difference in the selectivity with the (R) and (S)-isomers of the ligands. With the non-chiral catalyst B(OPh)3, nearly a 1:1 mixture of 56a and 57a was obtained. It was also noted that the reaction of cyclohexylethyl imine (R)-55a was not complete even after 24 h with the VAPOL catalyst. This is actually consistent with the fact that the aziridination with imine derived from dicyclohexylmethanamine and benzaldehyde is 25 times slower than the corresponding imine derived from 26c benzhydryl amine and benzaldehyde. 25 Table 2.1 Matched and mismatched aziridinations of the cyclohexylethyl imine (R)-55a a Cy VAPOL/VANOL Cy Cy borate catalyst NH (10 mol%) N Ph N Cy N COOEt + + O (H)Ph toluene Ph COOEt COOEt Ph H(Ph) (R)-55a OEt 25 °C 56a 57a 58a (59a) 24 h N2 5 cis:trans: >50:1 b 83:17 % yield c 56a 35 % yield d 57a 6 % yield d 58a/59a 3/7 66 20:80 7 28 3/5 (S)-VANOL 64 83:17 32 5 2/4 4 (R)-VANOL 100 25:75 15 45 4/9 5 B(OPh)3 only 38 56:44 nd nd nd entry ligand % conv 56a:57a 1 (S)-VAPOL 90 2 (R)-VAPOL 3 a Unless otherwise specified all reactions were run at 0.5 M in imine with 1.2 equiv EDA (5) and 10 mol% catalyst in toluene at rt for 24 h. The catalyst was prepared from 1.0 equiv of the ligand, 4.0 equiv of B(OPh)3 and 1.0 equiv of H2O according to general procedure (Method A) in the experimental section. nd = not b 1 c determined. Determined from the H NMR spectrum of the crude mixture. d 1 Isolated yield after chromatography on silica gel. Yield from H NMR spectrum of the crude mixture and based on the isolated yield of 56a. 2.2.3 Double stereo-differentiation with the chiral imine (S)-60a The aziridination of the chiral imine 60a pits a t-butyl versus a phenyl group in vying for the diastereoselection in competition with the VAPOL and VANOL derived catalysts. As can be observed from the data in Table 2.2 obtained by Yu 33 Zhang , there is a strong matched and mismatched relationship between the chiral imine substrate (S)-60a and the chiral catalyst. The matched case results from the reaction of (S)-60a and the catalyst prepared from (R)-enantiomer of the 26 ligand, affording the major diastereomer 62a in 80-85% yield. No detectable amount of the diastereomers 61a was formed in the matched reaction. In the mismatched case, the reaction of (S)-60a and EDA gave a 69:31 and 52:48 mixtures of 61a and 62a with (S)-VAPOL and (S)-VANOL catalysts, respectively. Even the reaction with the non-chiral catalyst B(OPh)3 gives a strong preference for the matched diastereomers 62a. Table 2.2 Matched and mismatched aziridinations of the phenylneopentyl imine (S)-60a a Ph VAPOL/VANOL t-Bu Ph t-Bu borate catalyst t-Bu Ph t-Bu NH (10 mol%) N + COOEt + N Ph N Ph O CCl4 (H)Ph COOEt (S)-60a Ph COOEt Ph H(Ph) 61a 62a OEt 25 °C 63a (64a) cis:trans: >50:1 N2 5 24 h b % yield c 61a % yield d 62a % yield 63a/64ad 69:31 56 25 nd (R)-VAPOL <2:98 <2 80 <2 3 (S)-VANOL 52:48 36 33 11/2 4 (R)-VANOL <2:98 <2 85 <2 5 B(OPh)3 only 8:92 nd nd nd entry 61a:62a 1 (S)-VAPOL 2 a ligand Unless otherwise specified all reactions were run at 0.5 M in imine with 1.2 equiv EDA (5) and 10 mol% catalyst in CCl4 at rt for 24 h. The catalyst was prepared from 1.0 equiv of the ligand, 3.0 equiv of B(OPh)3 according to general procedure. nd = not determined. All the reaction went to completion. All data in 33 b 1 this Table comes from the thesis of Yu Zhang. Determined from the H NMR spectrum of the crude mixture. c Isolated yield after chromatography on silica gel. d 1 Yield from H NMR spectrum of the crude mixture and based on the isolated yield of 62a. 27 2.2.4 Double stereo-differentiation with the chiral imine (R)-45a The results in Table 2.3 definitely show that there is a synergism between the chiral centers in the imine (R)-45a and in the catalyst with the matched case from the reaction of (R)-45a and the (S)-enantiomer of the catalyst. Table 2.3 Matched and mismatched aziridinations of the phenylethyl imine (R)45a a VAPOL/VANOL borate catalyst Ph Ph Ph (10 mol%) NH N + + N Ph N Ph O Toluene COOEt COOEt (H)Ph 25 °C Ph COOEt Ph OEt (R)-45a 44a 43a 65a (66a) H(Ph) N2 5 cis:trans: >50:1 b % yield c 43a % yield d 44a % yield d 65a/66a 96:4 74 3 1/7 100 33:67 17 33 7/11 1 87 97:3 51 2 4/6 (R)-VAPOL 1 82 41:59 18 26 3/8 5 (S)-VANOL 24 100 >97:3 69 <2 3/3 6 (R)-VANOL 24 100 31:69 22 48 9/15 7 B(OPh)3 24 66 75:25 31 10 7/8 entry ligand time % con 43a:44a 1 (S)-VAPOL 24 100 2 (R)-VAPOL 24 3 (S)-VAPOL 4 a Unless otherwise stated all reactions were run at 0.5 M in imine with 1.2 equiv only EDA (5) and 10 mol% catalyst in toluene at rt for the specified time. The catalyst was prepared from 1.0 equiv of the ligand, 4.0 equiv of B(OPh)3 and 1.0 equiv H2O according to the general procedure (Method A). nd = not determined. 1 Determined from the H NMR spectrum of the crude reaction mixture. d 1 c b Isolated yield after chromatography on silica gel. Yield from H NMR spectrum of the crude reaction mixture based on the isolated yield of 43a. This is a slightly weaker matched/mismatched pair than seen in the reaction of t-butylbenzyl imine (S)-60a. This is also reflected in the fact that the nonchiral 28 catalyst B(OPh)3 gives a 3:1 selectivity of the two diastereomers 43a and 44a (92:8 in case of (R)-60a). The selectivity flips over for the mismatched case with the (R)-VAPOL catalyst giving a 33:67 mixture of 43a and 44a, but the (R)VANOL catalyst gives nearly a 1:1 mixture of the two. Fewer amounts of the enamines were detected in the matched case than in the mismatched one. No effort was made to determine the minimum reaction time which are definitely less than 24 h since the reaction stopped after 1 h went to 87% and 82% conversion for the VAPOL catalyst. With the finding that both α-methylbenzylamine and α-t-butylbenzylamine have a strong matched and mismatched relationship with the VAPOL and VANOL cataysts, it was then decided to investigate how the rates of these reactions compare with the corresponding benzhydryl imine 31a. The relative rates of the chiral imines were measured in a pair-wise reaction with equimolar amounts of the two imine substrates ((S)-60a vs 31a and (R)-45a vs 31a) with 5 mol% catalyst in the presence of a substoichiometric amount (0.2 equivalent) of EDA. It was found that the α-t-butylbenzylimine 60a reacted three times slower than imine 31a in the matched case with VAPOL, while the α-methylbenzylimine 45a reacted three times faster. Surprisingly, the α-methylbenzylimine reacted 1.3 times faster than the benzyhydryl imine 31a even in the mismatched case with VAPOL. 29 Scheme 2.6 The relative rate study of the imines (S)-60a, (R)-45a and 31a VAPOL/VANOL borate catalyst t-Bu Ph Ph Ph t-Bu Ph + (5 mol%) N N Ph N Ph + Ph N Ph CCl4, 25 °C Ph COOEt Ph COOEt O 24 h 61a (S)-60a 31a ent-32a (R)-VAPOL 25:75 OEt N2 5 (0.2 equiv) (R)-VANOL 40:60 VAPOL/VANOL Ph Ph Ph borate catalyst Ph + (5 mol%) N N + Ph N Ph Ph N Ph 5, CCl , 25 °C 4 Ph COOEt Ph COOEt 43a 32a 24 h (R)-45a 31a (S)-VAPOL 75:25 a A 33:67 mixture of 43a and 44a was obtained (R)-VAPOL 57a:43b b ent-32a was formed in this reaction (S)-VANOL 75:25 t-Bu relative rate 3.0 (matched) 1.3 (mismatched) 0.30 (matched) 1.0 Although the imine (S)-60a derived from the chiral amine 50 and benzaldehyde furnished a higher diastereoselectivity and yield in the matched reaction, the α-tbutylbenzylamine 50 is not commercially available. Given the facts that both enantiomers of N-α-methylbenzylamine are commercially available and relatively inexpensive (about the same cost as benzyhydryl amine) and that it has been 34 recognized as a simple, yet powerful chiral adjuvant , it becomes the amine of choice in our study. 2.3 Substrate scope of cis-aziridinations with α-methylbenzyl imines 30 The scope of the aziridination of imines (R)-45 from (R)-N-α- methylbenzylamine was explored with five additional aromatic aldehydes and three aliphatic aldehydes. The results for imines derived from aromatic aldehydes are shown in Table 2.4. In all these reactions, the cis:trans selectivity was >50:1. There is no difference between the VAPOL and VANOL catalyst on the cis:trans selectivity. Chiral imine (R)-45b derived from 4-nitrobenzaldehyde has a relatively higher reaction rate than the rest of the imines. This is reflected in the fact that the reaction of imine (R)-45b and EDA with only B(OPh)3 as catalyst went to completion after 24 h. The optimal ligand for imine (R)-45b is VANOL, giving the major diastereomer cis-43b in 74% yield and the minor diastereomer cis-44b in only 3% yield. A similar situation was found with imine (R)-45c. In this case, (S)-VAPOL gave a higher yield with a slightly reduced diastereoselectivity as compared to (S)-VANOL. In the matched reaction of imine (R)-45d and 45e derived from 4- and 2-tolualdehyde, respectively, >98:2 diastereomeric ratios were observed with both (S)-VAPOL and (S)-VANOL catalysts. In the case of imine (R)-45f derived from 4-methoxybenzaldehyde, a strong electron-donating benzaldehyde, we found that the (S)-VANOL catalyst was much more efficient than that from (S)-VAPOL: the reaction went to completion with excellent diastereoselectivity (98:2) with the (S)-VANOL catalyst whereas only 46% conversion was observed with the (S)-VAPOL catalyst but still with good diastereo-selection (95:5). This is consistent with the fact that the aziridination reaction of the N-benzhydryl imine derived from 4-methoxybenzaldehyde with the VAPOL catalyst is also sluggish, affording 73% conversion after 24 h while that 31 with the VANOL catalyst went to 100% conversion in the same time period, although the same level of the asymmetric induction was observed for both 26a VAPOL and VANOL catalysts. The low reactivity of imine 45f is also manifested by the fact that no reaction of (S)-45f with EDA was observed when 32c 20 mol% CoCl2/AgBF4 was used as catalyst. Table 2.4 Matched and mis-matched aziridinations of the phenethyl imine (R)-45 from aryl aldehydes a VAPOL/VANOL Ph borate catalyst Ph Ph NH (10 mol%) + N + COOEt N N Ph O Ar (H)Ar Toluene COOEt (R)-45 COOEt Ar H(Ar) OEt 25 °C Ar 44 43 65 (66) N2 5 cis:trans: >50:1 substrate ligand % con 43:44 (S)-VAPOL 100 (R)-VAPOL b %yield c 43 %yield d 44 % yield d 65/66 96:4 74 3 1/7 100 33:67 17 33 7/11 (S)-VANOL 100 >97:3 69 <2 3/3 4 (R)-VANOL 100 31:69 22 48 9/15 5 B(OPh)3 only 100 75:25 31 10 7/8 6 (S)-VAPOL 100 94:6 82 5 4/4 (R)-VAPOL 100 38:62 24 40 13/13 (S)-VANOL 100 97:3 77 2 11/9 9 (R)-VANOL 100 31:69 21 46 9/9 10 B(OPh)3 only 94 77:23 35 10 11/8 (S)-VAPOL 100 >98:2 71 <1 0/1 (R)-VAPOL 100 33:67 19 38 3/7 entry 1 2 3 7 8 11 12 O2N (R)-45b Br (R)-45c Me (R)-45d 32 Table 2.4 cont’d 13 (S)-VANOL 100 >98:2 70 <1 3/13 14 (R)-VANOL 100 38:62 21 35 6/8 15 B(OPh)3 only 61 80:20 28 7 4/3 16 (S)-VAPOL 100 >98:2 62 <1 1/0 17 (R)-VAPOL 100 41:59 23 16 15/0 (S)-VANOL 100 >98:2 52 <1 9/6 (R)-VANOL 100 44:56 16 13 11/0 20 B(OPh)3 only 28 75:25 <21 <7 <15/<2 21 (S)-VAPOL 46 95:5 35 2 3/5 (R)-VAPOL 21 47:53 nd nd nd (S)-VANOL 100 98:2 63 1 7/23 24 (R)-VANOL 29 44:56 nd nd nd 25 B(OPh)3 only 8 nd nd nd nd 18 19 22 23 a Me (R)-45e MeO (R)-45f Unless otherwise stated all reactions were run at 0.5 M in imine with 1.2 equiv EDA (5) and 10 mol% catalyst in toluene at rt for 24 h. The catalyst was prepared from 1.0 equiv of the ligand, 4.0 equiv of B(OPh)3 and 1.0 equiv H2O according to general procedure (Method A). nd = not determined. NMR spectrum of the crude reaction mixture. d 1 b 1 Determined from the H c Isolated yield after chromatography on silica gel. Yield from H NMR spectrum of the crude reaction mixture based on the isolated yield of 43. The results of the aziridination of imines (R)-45 derived from three aliphatic aldehydes are summarized in Table 2.5. In the reactions of imine (R)-45g from cyclohexanecarbaldehyde, there is no profound difference in the selectivities seen with the (R)- or (S)-enantiomers of the ligands. This is also true even with the non-chiral catalyst B(OPh)3 which gives nearly a 1:1 ratio of the diastereomers 43g and 44g. The selectivity imparted by the catalysts is 5:1 in favor of cis-43g when the (S)-enantiomers of the VAPOL and VANOL ligands are 33 used and 3:1 in favor of cis-44g when the (R)-enantiomers of the VAPOL and VANOL ligands are used. This is so far the weakest matched and mis-matched relationship found between the chiral imines in the series (R)-45 series with either VAPOL or VANOL catalyst. These reactions are dominated by catalyst control rather than by substrate control. Fortunately, the products 43g and 44g are easy to separate and obtained in good yields with the (S)-catalysts. The optimal ligand for chiral imine (R)-45h is VANOL, with higher diastereoselectivity and isolated yield than observed with the (S)-VAPOL ligand. Table 2.5 Matched and mis-matched aziridinations of the phenethyl imine (R)-45 from aliphatic aldehydes a VAPOL/VANOL Ph borate catalyst Ph Ph (10 mol%) NH + N + N R N Ph O COOEt Toluene (R)-45 R COOEt R 44 COOEt (H)R OEt 25 °C 43 H(R) 65 (66) N2 5 cis:trans: >50:1 b %yield c 43 % yield d 44 % yield d 65/66 83:17 66 13 0/0 100 23:77 14 47 0/0 (S)-VANOL 100 83:17 72 14 0/0 4 (R)-VANOL 100 23:77 23 76 0/0 5 B(OPh)3 only 53 55:45 17 21 0/0 6 (S)-VAPOL 100 91:9 61 6 0/0 (R)-VAPOL 31 38:62 13 22 0/0 8 (S)-VANOL 100 93:7 79 6 0/0 9 (R)-VANOL 100 41:59 22 31 0/0 ligand % con 43:44 1 (S)-VAPOL 100 2 (R)-VAPOL entry 3 7 substrate (R)-45g (R)-45h 34 Table 2.5 cont’d 10 B(OPh)3 only 43 58:42 18 13 0/0 11 (S)-VANOL 100 80:20 28 7 0/0 (R)-VANOL 100 47:53 29 33 0/0 12 (R)-45i a Unless otherwise stated all reactions were run at 0.5 M in imine with 1.2 equiv EDA (5) and 10 mol% catalyst at rt for 24 h. The catalyst was prepared from 1.0 equiv of the ligand, 4.0 equiv of B(OPh)3 and 1.0 equiv H2O according to general procedure (Method A). nd = not determined. spectrum of the crude reaction mixture. d c 1 b 1 Determined from the H NMR Isolated yield after chromatography on silica gel. Yield from H NMR spectrum of the crude reaction mixture and based on the isolated yield of 43. The reaction of chiral imine (R)-45h and EDA with the (S)-VAPOL catalyst gave moderate yield and the mis-matched reaction with the (R)-VAPOL catalyst only went to 31% conversion. These results are consistent with the fact that the reaction of N-benzhydryl imine from trimethylacetaldehyde with the VAPOL catalyst is sluggish and gives a lower yield and asymmetric induction compared 26a with the VANOL catalyst. Although imine (R)-45i prepared from the primary aldehyde n-butanal gives a matched and mis-matched relationship with the VANOL catalysts, the major aziridine 43i from the reaction in the matched case could be isolated in only 28% yield. The low yield might be due to an aldol side product similar to that observed in the aziridination of imines derived from the DAM amine and n-butanal. 26d It is also interesting to note that no enamine by- products were observed in the reaction of any of the imines derived from aliphatic aldehydes. The low migratory aptitudes of aliphatic groups might be responsible 14a for an absence of the enamine byproducts relative to aromatic groups. 35 Unlike the aziridination reactions of chiral imines (R)-45a-i and EDA investigated above, in which a >50:1 cis:trans selectivity was observed, the reaction of chiral imine (R)-45 from o-halobenzaldehydes and EDA afforded all four possible cis- and trans-diastereomers (Table 2.6). A significant amount of the trans-isomers was observed in all the reactions of chiral imine (R)-45j-k. This is consistent with the fact that the reaction of the N-benzhydryl imine derived from o-bromobenzaldehyde and EDA with the VAPOL or VANOL catalysts gave a ~2:1 cis/trans selectivity. 26a For both cis- and trans-isomers of the aziridines from imine (R)-45j, there is a strong matched and mismatched relationship between the chiral imine and one of the enantiomers of the ligands. In the matched cis-aziridination reaction of imine (R)-45j and EDA with (S)-enantiomer of the catalysts, a 91:9 mixture of cis-diastereomers 43j and 44j was obtained using (S)-VAPOL and a 97:3 mixture was obtained using (S)-VANOL. In the mismatched case for the cis-diastereomer, nearly a 1:1 mixture of 43j and 44j was obtained from (R)-enantiomer of both VAPOL and VANOL catalysts. However, the (R)-enantiomer of the catalysts provided the matched reaction for trans-diastereomers, giving a ~12:1 mixture of trans-diastereomers 67j and 68j. The reactions of chiral imine (R)-45j and (S)-enantiomer of the catalysts furnished a 2:1 to 1:1 diastereoselectivity of the trans-aziridines. It is interesting to note that the matched cases for cis-aziridines are the mismatched cases for trans-aziridines. A very similar pattern was seen for imine (R)-45k derived from o-iodobenzaldehyde. The origin of formation of substantial amount of transaziridines from imines (R)-45j-k that bear an ortho-halogen substituent is not 36 understood at this stage but it is clear that it is not due to just the presence of the ortho-substituents since the imine from o-tolualdehyde does not give any detectable amount of the trans-aziridines. In addition, the bromine atom could be removed from the trans-aziridine 67j with tributyltin hydride without ring opening to give the trans-aziridine 67a in 68% yield (Scheme 2.7). Despite the fact that a significant amount of trans-isomers could be obtained in the aziridination reaction and the fact that the halogen could be selectively removed, this does not provide for a practical method for providing access to trans-aziridines due to their low isolated yields in the aziridination reaction. Table 2.6 Matched and mismatched aziridinations of the o-bromo- and oiodophenyl imine a Ph VAPOL/VANOL borate catalyst (10 mol%) X N X N X N 44 Ph X N + COOEt Ph COOEt 43 Ph Toluene O 25 °C 24 h (R)-45j: X = Br OEt (R)-45k: X = I N2 5 + COOEt Ph + (H)Ar Ph X NH CO2Et H(Ar) 65/66 N COOEt 67 68 entry X ligand 43/ 44 67/ 68 cis/ b trans %yield c 43 %yield d 67 % yield d 65/66 1 Br (S)-VAPOL 91:9 67:33 71:29 48 14 10/16 2 Br (R)-VAPOL 50:50 93:7 35:65 10 33 15/21 3 Br (S)-VANOL 97:3 44:56 70:30 43 8 10/12 4 Br (R)-VANOL 55:45 92:8 36:64 10 30 10/13 5 Br B(OPh)3 only 75:25 88:12 23:77 13 50 13/13 37 Table 2.6 cont’d 6 I (S)-VAPOL 94:6 67:33 50:50 21 15 11/17 7 I (R)-VAPOL 50:50 91:9 26:74 8 40 15/21 8 I (S)-VAPOL 96:4 67:33 52:48 23 15 10/12 9 I (R)-VANOL 63:37 91:9 25:75 7 30 10/13 10 I B(OPh)3 only 33:67 85:15 23:77 6 51 11/11 a Unless otherwise stated all reactions were run at 0.5 M in imine with 1.2 equiv EDA (5) and 10 mol% catalyst in toluene at rt for 24 h. The catalyst was prepared from 1.0 equiv of the ligand, 4.0 equiv of B(OPh)3 and 1.0 equiv H2O according to general procedure (Method A). nd = not determined. b NMR spectrum of the crude reaction mixture. d 1 Determined from the H c Isolated yield after 1 chromatography on silica gel. Yield from H NMR spectrum of the crude reaction mixture based on the isolated yield of 43. Scheme 2.7 Selective removal of bromine via tin hydride reduction Ph Br Ph n-Bu3SnH N COOEt AIBN, Benzene trans-67j N COOEt trans-67a 68% The assignment of the relative stereochemistry of the cis-aziridine 43a was made after comparison of its rotation with that reported in the literature for this compound 32b and by its conversion to the (R)-enantiomer of phenylalanine ethyl ester 69 and comparison of its optical rotation with that previously reported for 23a this compound (Scheme 2.8). The relative stereochemistry for aziridines 43b-f with aryl substituents on C-3 position was assumed to be the same as that determined for 43a. The relative stereochemistry of the cyclohexyl aziridine 43g 26b was assigned by a chemical correlation with the known aziridine 80g 38 as outlined in Scheme 2.13. The assignment of the relative stereochemistry of tbutyl aziridine 43h was made by its conversion to the p-bromobenzoate 70, which was a solid that gave crystals suitable for X-ray crystallographic analysis. Hydrodebromination of 43j with tributyltin hydride gives aziridine 43a in 89% yield which was found to be identical with the major aziridine formed from the matched reaction of chiral imine (R)-43a and EDA with (S)-VAPOL. The assignment of the trans-aziridine 67j was made by its conversion to the (S)-enantiomer of 23a phenylalanine ethyl ester 69. In the matched reaction of imine (R)-45j from o- bromobenzaldehyde, the facial selectivity for the imine is the same for both the major cis and trans diastereomers but that for the diazo compound EDA is changed in the trans-aziridine. The relative stereochemistry for o-iodophenyl substituted aziridines was assumed to be the same as aziridine 43j and 67j. Scheme 2.8 Determination of the relative stereochemistry of the α-methylbenzyl aziridines Ph Ph CO2Et H2 (1 atm) Ph N NH2 Pd(OH)2/C (S)-69 57% COOEt 67j Ph Ph 1) LiAlH4 Br N 2) 4-bromobenzoyl N O chloride, DMAP COOEt 70 84% O 43h Ph Ph n-Bu3SnH Br N N COOEt AIBN, Benzene COOEt 43j 43a 89% CO2Et Br H2 (1 atm) Ph N NH2 Pd(OH)2/C (R)-69 41% Ph 43a COOEt 2.4 trans-Aziridines from α-methylbenzyl imines and diazoacetamide 19 39 A substantial proportion of trans-aziridine was observed in the reaction of imine (R)-45j-k and EDA, yet the synthetic utility is limited due to the low isolated yield. A better route to the synthesis of trans-aziridines should be the reaction of imine (R)-45 with diazoacetamide 19 since the reaction of imines of the type 31 and diazoacetamide 19 with either the VAPOL or VANOL catalyst gave high trans/cis selectivity with good isolated yields for trans-aziridines (Scheme 2.1). The question now becomes whether the double differentiation approach that was successful for cis-aziridination of chiral imines (R)-45 and EDA could be extended to the trans-aziridination by simply changing the diazo compound from EDA to diazoacetamide 19. Table 2.7 Matched and mismatched trans-aziridinations of imine (R)-45a with diazoacetamide 19 a Ph Ph N N + VAPOL/VANOL Ph CONHPh Ph CONHPh borate catalyst Ph 72a (10 mol%) 71a NH + CONHPh N Ph Toluene (H)Ph Ph Ph 25 °C H(Ph) (R)-45a O 24 h N N + 75/76 NHPh Ph CONHPh Ph CONHPh N2 19 74a 73a entry ligand 71a/ b 72a 73a/ b 74a trans/ b cis % yield c 71a %yield d 73a % yield d 75/76 1 (S)-VAPOL 60:40 83:17 79:21 25 9 12/19 2 (R)-VAPOL 91:9 50:50 88:12 71 5 6/6 3 (S)-VANOL 62:32 75:25 68:32 28 16 18/16 4 (R)-VANOL 89:11 67:33 89:11 70 6 8/10 40 Table 2.7 e (R)-VANOL 96:4 67:33 96:4 78 2 3/4 f 5 cont’d (R)-VANOL 91:9 60:40 91:9 69 4 6/9 B(OPh)3 only 86:14 75:25 86:14 43 8 4/4 6 7 a Unless otherwise stated all reactions were run at 0.5 M in imine with 1.2 equiv diazoacetamide 19 and 10 mol% catalyst in toluene at rt for a specified time. The catalyst was prepared from 1.0 equiv of the ligand, 3.0 equiv of BH3•SMe2, 2.0 equiv of PhOH and 3.0 equiv H2O according to the general procedure (Method b 1 B). nd = not determined. Determined from the H NMR spectrum of the crude reaction mixture. 1 c Isolated yield after chromatography on silica gel. d Yield from H NMR spectrum of the crude reaction mixture based on the isolated yield of 71a. e f The reaction was run at 0 °C. The catalyst was prepared from 1.0 equiv of the ligand 4.0 equiv of B(OPh)3 and 1.0 equiv of H2O. Fortunately, it was found that the aziridination reaction of chiral imine (R)-45a and diazoacetamide 19 beginning with either the (R) or (S)-enantiomer of the ligand gave good to high trans:cis selectivity ranging from 68:32 to 89:11 at room temperature (Table 2.7). Interestingly, there is a matched relationship found between the chiral imine (R)-45a and the (R)-VAPOL catalyst in the transaziridination with diazoacetamide 19 while a matched relationship was observed between the same chiral imine and (S)-enantiomer of the catalyst in the cisaziridination with EDA. The (R)-VAPOL and (R)-VANOL catalysts are equally effective, affording ~8:1 trans:cis selectivity and isolated yield of the major transdiastereomer 71a in 70-71%. A higher trans:cis selectivity (96:4), a better isolated yield (78%) and reduced amounts of the enamine by-products were obtained in the reaction with the (R)-VANOL catalyst at a lower temperature (0 °C) (entry 5). A different catalyst preparation procedure was proven to be equally effective for the reaction (entry 4 vs entry 6). Generally, a reduced amount of 41 enamine by-products was observed in the matched case than in the mismatched case. Since the asymmetric inductions for the trans-aziridines derived from aliphatic aldehydes and nonchiral amines were not generally as high as they were for those from aromatic aldehydes, we decided to explore the trans-aziridination reactions of the imines (R)-45g-i derived from aliphatic aldehydes. The results for the aziridination reaction of chiral imines from primary, secondary and tertiary aliphatic aldehydes and diazoacetamide 19 are summarized in Table 2.8. Similar to what we found with imine (R)-45a, there is a strong matched relationship between (R)-45i and the (R)-enantiomer of the ligands with high diastereomeric ratios and good yields. The (R)-VAPOL and (R)-VANOL catalysts gave equally good profiles with chiral imine (R)-45i. It is not clear why the trans-aziridination of the imine (R)-45i and diazoacetamide 19 gives the trans-aziridine 71i in excellent yields while the reaction of the same substrate with EDA only gives low yields of cis-aziridine 43i (Table 2.5). It is not surprising to note that matched/mismatched cases were also found with chiral imine (R)-45g and (R)-45h but what is so unexpected is to observe that the matched reaction for (R)-45g or (R)-45h is with the (S)-ligands. A very high diastereomeric ratio (>96:4) for 71g:72g was observed with good isolated yields for the 71g in the reaction of (R)-45g and diazoacetamide 19 with the (S)-catalyst. In addition, no detectable amount of the other diastereomer 72g could be found in these matched reactions. The same situation was found with (R)-45h. All the trans-aziridination reactions with (R)-45h were sluggish, with 64-87% conversion after 24 h at room temperature. A 97:3 42 and a >97:3 mixture of 71h:72h were observed with 61-69% isolated yield in the matched reactions of (R)-45h with the (S)-VAPOL and (S)-VANOL catalysts, respectively. For all the trans-aziridination reactions with imine (R)-45 derived from aliphatic aldehydes and α-methylbenzylamine, there is not a profound difference found between the VAPOL and VANOL catalysts. This is in striking contrast with the reactions of nonchiral imine 31 and diazoacetamide 19 in which VANOL ligand is much more efficient than the VAPOL catalyst in terms of 28a asymmetric induction (Scheme 2.1). Table 2.8 Matched and mismatched trans-azirdinations of diazoacetamide 19 and phenethyl imine (R)-45 from aliphatic aldehydes a VAPOL/VANOL Ph Ph borate catalyst (10 mol%) N N + R N Ph O Toluene, 25 °C R CONHPh R CONHPh 24 h NHPh 72 71 (R)-45 N2 19 b % yield c 71 % yield d 72 52:48 15 14 100 95:5 79 4 (S)-VANOL 100 67:33 40 20 4 (R)-VANOL 100 95:5 80 4 5 B(OPh)3 only 100 83:17 43 9 6 (S)-VAPOL 100 >96:4 78 <3 (R)-VAPOL 100 67:33 59 30 8 (S)-VANOL 100 >96:4 80 <3 9 (R)-VANOL 100 75:25 60 20 ligand % con 71:72 1 (S)-VAPOL 100 2 (R)-VAPOL entry 3 7 substrate (R)-45i (R)-45g 43 Table 2.8 cont’d 10 B(OPh)3 only 100 91:9 42 4 11 (S)-VAPOL 87 97:3 69 2 12 (R)-VAPOL 70 50:50 30 30 (S)-VANOL 81 >97:3 61 <2 14 (R)-VANOL 63 67:33 19 10 15 B(OPh)3 only 64 83:17 42 8 13 (R)-45h a Unless otherwise stated all reactions were run at 0.2 M in imine with 1.2 equiv diazoacetamide 19 and 10 mol% catalyst in toluene at rt for 24 h. The catalyst was prepared from 1.0 equiv of the ligand, 3.0 equiv of BH3•SMe2, 2.0 equiv of PhOH and 3.0 equiv H2O according to the general procedure (Method B). nd = not determined. c b 1 Determined from the H NMR spectrum of the crude reaction d 1 mixture. Isolated yield after chromatography on silica gel. Yield from H NMR spectrum of the crude reaction mixture based on the isolated yield of 71. The assignment of the relative stereochemistry of trans-71a was made by conversion to the phenylalanine derivative 77a of the known optical rotation 28a, 35 (Scheme 2.9). The relative stereochemistry of the cis-aziridine 73a was determined by its conversion to 43a (Scheme 2.10). Comparison of 43a with (2R,3R)-43a obtained from aziridination of (R)-43a and EDA confirmed its stereochemistry. The stereochemistry of trans-71i was assumed to be the same as trans-71a since there are the same matched and mismatched relationships between the chiral imines and the (R)-enantiomer of the ligands. The relative stereochemistry of trans-71h was determined by X-ray analysis which showed trans-71h and 71a gave the same relative stereochemistry in the major diastereomers in the matched cases even though the matched case for (R)-45a is with the (R)-catalyst and for (R)-45h is with the (S)-catalyst. The aziridine trans-71g was assumed to have the same relative stereochemistry as trans-71h. 44 Scheme 2.9 Catalytic hydrogenation of 71a to (S)-77a Ph H2 (1 atm) O Pd(OH)2/C (20 mol%) Ph NHPh NHBoc CONHPh Boc2O, MeOH 71a (S)-77a 40% N Scheme 2.10 Conversion of cis-aziridine 73a to 43a Ph 1) Boc2O, DMAP N 73a CONHPh 2) EtONa, EtOH Ph N COOEt 43a 2.5 Synthesis of α- and β-amino acid derivatives The regio- and stereoselective ring opening reactions of aziridine 2carboxylate esters serve as valuable methods for access to a structurally diverse array of α and β-amino acids. 36 Activation of the aziridine nitrogen by an electron-withdrawing group (acyl, carbamoyl, sulfonyl) or by Brønsted or Lewis acids promotes either C2 cleavage to give β-amino acids or C3 cleavage to give 36 α-amino acids (Scheme 2.11). Since ring opening does not affect the stereochemistry at C2 or C3, the aziridine stereochemistry is maintained in the amino acid product. The ring substituents and the reaction conditions determine stereo- and regioselectivity of the ring opening. With C3 aryl or vinyl substituted aziridines, catalytic hydrogenation regiospecifically cleaves the benzylic/vinyl C-N bond in unactivated and sulfonyl-activated aziridine carboxylates. 37 In the absence of a C3 benzylic or vinyl aziridine substituent, hydrogenation occurs at C2 for mono- and disubstituted aziridine-2-carboxylates to give β-amino esters. 45 38 It is noteworthy in aziridine chemistry that nitrogen activation with an electronwithdrawing group is not always necessary. Scheme 2.11 C2 and C3 cleavage in hydrogenation of aziridines NHZ Z NHZ 3 C2 cleavage C3 cleavage R3 R R2 R2 N R3 R2 CO2R CO2R Hydrogenation 1 CO2R Hydrogenation R1 R R1 !-amino acid ester "-amino acid ester Hydrogenation of cis-aziridines 43a and 43d-e was carried out under 1 atm of hydrogen in methanol at room temperature with 10 mol% Pearlman’s catalyst in the presence of Boc2O to give the Boc-protected phenylalanine derivatives 78 in excellent yields as shown in Scheme 2.12. Boc2O was added simply for the purpose of convenient isolation. Reductive ring opening and removal of the chiral auxiliary occur simultaneously under these reaction conditions. In the case of 43b, the nitro group was also reduced to an alanine to give the bis-Boc protected phenylanaline derivative 79 shown in Scheme 2.12 which was isolated in 66% yield. Scheme 2.12 Hydrogenation of chiral aziridines in the presence of Boc2O CO2Et Ph H2 (1 atm) NHBoc Pd(OH)2/C (10 mol%) N R % yield COOEt Boc2O, MeOH, 6 h (R)-78a 94 43a R = H (R)-78d 99 R 43d R = 4-Me (R)-78e 88 43e R = 2-Me Ph H2 (1 atm) CO2Et Pd(OH)2/C (10 mol%) N NHBoc COOEt Boc2O, MeOH, 6 h BocHN (R)-79 66% 43b O2N 46 In the cases of the alkyl-substituted cis-aziridines 43g-h, deprotection occurred without reductive ring opening to give the N-Boc protected aziridines 80g-h in high yields (Scheme 2.13). Scheme 2.13 Hydrogenation of C3-alkyl substituted aziridines H2 (1 atm) Boc Ph N Pd(OH)2/C (10 mol%) N COOEt Boc2O, MeOH, 6 h R % yield R COOEt 43g R = Cy 80g 91 43h R = t-butyl 80h 81 However, hydrogenation of aziridine 43g with a high catalyst loading and prolonged reaction time did provide some of the C2 cleavage product 81g in 24% yield along with a 70% yield of the N-Boc protected aziridine 80g (Scheme 2.14). This indicated that debenzylation of the chiral auxiliary was occurring faster than the reductive ring cleavage which is consistent with previous results. 38b Scheme 2.14 Hydrogenation of 43g under conditions that give a mixture H2 (1 atm) Ph Boc NHBoc Pd(OH)2/C (20 mol%) N + N COOEt Boc2O, MeOH, 24 h COOEt COOEt (S)-81g 24% 80g 70% 43g The direct reductive ring opening of the trans-aziridine amide 71a to give the phenylalanine derivative 77a suffered a low isolated yield (Scheme 2.9). In order to increase the efficiency of this reaction, the amide group was first converted to an ester group. 39 The treatment of trans-aziridine amides with Boc2O and DMAP, and subsequent alcoholysis with sodium ethoxide afforded the corresponding trans-aziridine esters 67 in good yields as summarized in Scheme 2.15. 47 Scheme 2.15 Conversion of a primary amide to an ester Ph Ph 1) Boc2O, DMAP N N 2) EtONa, EtOH R COOEt % yield R CONHPh 71a R = Ph 96% 67a 71g R = Cy 67g 77% 71h R = t-Butyl 67h 95% 71i R = n-Pr 83% 67i When the trans-ester 67a was subjected to catalytic hydrogenation, the C2 cleavage product was formed as anticipated giving the phenylalanine derivative 78a in a much higher yield (86%) (Scheme 2.16) than was observed for the hydrogenolysis of the corresponding amide (Scheme 2.9). Scheme 2.16 Hydrogenation of trans-aziridine ester 67a Ph N Ph H2 (1 atm) Pd(OH)2/C (20 mol%) COOEt Boc2O, MeOH Ph COOEt NHBoc (S)-78a 86% 67a Unlike 3-alkyl substituted cis-aziridine esters 43g, which gave predominantly the non-ring opened N-Boc protected aziridines (Scheme 2.14), 3-alkyl substituted trans-aziridine esters 67g-i under the same conditions underwent smooth reductive ring opening to give the β-amino acid esters 81g-i in a moderate to high yield with only a small amount of N-Boc protected transaziridines 82g-i. As shown in Scheme 2.17, the yields are highly dependent on the nature of the 3-substituent. In cases of n-propyl and cylohexyl as the 3substituent, β-amino acid esters 81g and 82i were obtained in 77% and 90% yield, respectively. Reductive ring opening of 67h was sluggish: even after 45 h, the β-amino ester was obtained in only 55% yield. A direct comparison of the 48 hydrogenation of the cis and trans-aziridine esters 43g and 67g indicated that the reductive ring opening of trans-aziridine ester 67g occurs with a faster reaction rate. This might be due to the better coordination of the C2-N bond of the transaziridine esters with the heterogeneous catalyst. Scheme 2.17 Hydrogenation of 3-alkyl substituted trans-aziridines to give βamino acids as the major product Ph H2 (1 atm) Pd(OH)2/C (20 mol%) N R Boc N NHBoc COOEt + 67g R = Cy 81g 90% R COOEt % yield 82g 3% 67h R = t-Butyl (45 h) 81h 55% 82h 6% 81i 77% 82i 12% R COOEt Boc2O, MeOH, 24 h 67i R = n-Pr 2.6 Conclusion % yield A significant matched/mismatched relationship has been observed in both cisand trans-aziridination reaction of chiral imines derived from chiral αmethylbenzylamine. This double stereo-differentiation study not only provides an excellent approach to cis- and trans-aziridines but also provides information about the interaction of the substrate and the catalyst. Chromatographic purification allows for easy separation of any minor diastereomers that may have been formed and gives the desired aziridines in good yields and high optical and diastereomeric purity. Reductive ring opening of these aziridines via hydrogenation with Pd(OH)2/C in the presence of Boc2O allows the efficient synthesis of α- and β-amino acids. The attractive features of this protocol lie in the use of commercially available and inexpensive α-methylbenzylamine, the 49 high diastereoselectivities and yields observed in both cis- and trans-aziridination reactions in combination with the perfect optical purity of the final aziridine products. 50 CHAPTER THREE CATALYTIC ASYMMETRIC SYNTHESIS OF TRI-SUBSTITUTED AZIRIDINES 3.1 Introduction Among the various strategies for the preparation of aziridines demonstrated in Chapter 1, the Brookhart-Templeton aziridination, 14a wherein the reaction of aldimines and diazo compounds is catalyzed by a Lewis acid, is considered to be the most elaborated system. Significant advances in the asymmetric catalytic variants of this reaction for the synthesis of cis- and trans-disubstituted aziridines have been made during the last few years. 9,10,16,24,28 When it comes to the catalytic asymmetric synthesis of tri-substituted aziridines, neither this method nor any other methodology of making di-substituted aziridines provides a general solution. The successful methods reported to date for the asymmetric synthesis of tri-substituted aziridines in a straightforward manner are based on the use of chiral 40 auxiliaries. The asymmetric aza-Darzens synthesis of N-(p- toluenesulfinyl)aziridine-2-carboxylate ester 85 from a chiral sulfinimine 83 has 40a,c,d,g been developed in Davis’s group (Scheme 3.1). The one-step aza- Darzens reaction of sulfinimine 83 with lithium α-bromoenolate 84 readily affords diversely substituted tri-substituted aziridine carboxylate esters 85 in good yields and excellent diastereoselectivities. In addition, Maruoka’s group has established a protocol for the asymmetric synthesis of tri-substituted aziridines by use of a 40i,j camphor derived chiral auxiliary (Scheme 3.2). 51 A Brønsted acid-catalyzed reaction of α-substituted α-diazocarbonyl compound 86 bearing camphorsultam as chiral auxiliary with the N-alkoxylcarbonyl imine 18 was implemented as an unprecedented means to provide tri-substituted aziridines 87 in a highly stereodefined manner. In contrast to these methods with chiral auxiliaries, there are only scattered and isolated examples of catalytic asymmetric syntheses of trisubstituted aziridines. 41 A general method for the direct catalytic asymmetric synthesis of tri-substituted aziridines is still lacking. Scheme 3.1 aza-Darzens asymmetric syntheses of trisubstituted aziridines R OMe p-Tolyl O Br S H O 84 OLi Yield: 61-85% Ph N R S p-Tolyl N Ph R = Me, Et, Ph de: 90-95% H CO2Me 83 85 Scheme 3.2 Acid-catalyzed aziridination of α-diazocarbonyl compounds and imines N Ph + Boc 18 O Catalyst (20 mol%) Boc O N Catalyst BF3•Et2O time (h) Yield (%) 1 43 74 Ph CF SO H 0.17 N 3 3 SO2 N 87 68 CH3SO3H 1 SO2 N2 trans/cis !20:1 86 dr ! 20/1 3.2 Catalytic asymmetric aziridination of imine 18 and diazo ester 88 CH2Cl2 –78 °C In this context, we set out to investigate the reaction of imine 31b derived from benzaldehyde and MEDAM amine and ethyl α-diazopropionate 88a with our precatalyst since this is among the best imine substituent we have identified. 26d The aziridination of MEDAM imine 31b and EDA is ten times faster and gives much higher yield and asymmetric induction than the corresponding benzhydryl 52 imine. For example, with 5 mol% VANOL borate catalyst, the reaction of imine 31b and EDA gives aziridine 32b in 94% yield and 97% ee after 24 h at room temperature. Unfortunately, the reaction of imine 31b and α-diazopropionate 88a was tried in vain. Scheme 3.3 clearly shows the ineffectiveness of the synthesis of tri-substituted aziridine 89 from imine 31b and ethyl α-diazopropionate 88a. After 24 h at room temperature, there was no reaction observed for imine 31b and disubstituted diazo 88a. Even with 20 mol% catalyst at 80 °C for 64 h with 5 equivalent of imine 31b, there was no detectable amount of the desired product observed, but rather only a 98% recovery of imine 31b. Scheme 3.3 Failed attempts towards a tri-substituted aziridine synthesis Ph Ph MEDAM MEDAM (R)-VANOL borate catalyst (5 mol%) Ph N CO Et MeO 31b 2 + H H O Toluene, 25 °C 32b 24 h OEt Yield: 94% N2 5 1.2 equiv ee: 97% N OMe MEDAM 88a MEDAM (S)-VANOL borate Conditions (equiv) Result 31b catalyst (20 mol%) MEDAM N CO Et 25 °C, 24 h 1.2 No reaction + O 2 8-Toluene Ph Me d OEt 80 °C, 64 h 5 No reaction 89 N2 88a Recovered 31b: 98% not observed N It was thus clear that a much more reactive imine would be required to effect the union with a diazo ester in which the diazo carbon is disubstituted. According to the scale of the electrophilicity of similar reactions in DMSO, N-tertbutoxycarbonyl-substituted (N-Boc) imines would be much more reactive than 42 imine 31b. To our delight, the introduction of a Boc group on the imine nitrogen was indeed sufficient enough to induce reactivity even at –78 °C as indicated in 53 Table 3.1. It was quickly found that the catalyst prepared from the VAPOL ligand gave very low asymmetric induction whereas the one from VANOL under the same conditions gave the tri-substituted aziridine trans-90a in 83% ee (entry 2 vs entry 3). The yield for the two ligands was about the same but the trans:cis selectivity was higher for the VANOL catalyst. This striking difference between the two ligands was unexpected, since the two give comparable results for cis and trans-disubsituted 28 26 aziridines. With the VANOL catalyst, the yield and asymmetric induction did not increase or decrease with increased time (entry 35). The yield did not depend on the amount of the diazo ester used (entry 6). The asymmetric induction did not change when the temperature was lowered to –100 °C (entry 7). If the catalyst was added as a precooled solution, the asymmetric induction went up to 93% ee with 46% isolated yield (entry 8). Lowering the catalyst loading to 10% or 5% would make the yield and asymmetric induction fall to some extent (entry 9-10). Different catalyst preparation procedures do have an effect on the trans:cis selectivity and the yield but essentially no effect on the asymmetric induction (entry 8 vs entry 10). Tri-substituted aziridines could also be obtained for diazo compounds 88b and 88c, but the more hindered 88d with an iso-propyl group on the diazo carbon failed to give any detectable amount of aziridine under the same reaction conditions. 54 a Table 3.1 Catalytic asymmetric aziridination of α-diazo esters Boc (R)-VANOL/ Ph N Boc Boc Boc (R)-VAPOL NH O 18 catalyst N COOEt N R + O + Ph OEt + Ph R CH2Cl2 Ph COOEt R R OEt – 78 °C trans-(2S,3R)-90 cis-(2R,3R)-90 91 N2 88 entry 88 R ligand mol % time (min) trans b /cis %yield b,c trans % ee d trans % yield b 91 e 88a Me TfOH 20 15 3:1 42 – 25 f 88a Me (R)-VAPOL 20 60 12:1 49 –5 14 88a Me (R)-VANOL 20 15 20:1 48 83 13 4 88a Me (R)-VANOL 20 60 20:1 48 83 13 5 88a Me (R)-VANOL 20 240 20:1 48 84 13 g 88a Me (R)-VANOL 20 15 nd 45 nd 12 h 88a Me (R)-VANOL 20 15 10:1 32 86 9 e,f 88a Me (S)-VANOL 20 15 20:1 (46) –93 12 f 88a Me (R)-VANOL 10 30 25:1 36 84 9 88a Me (R)-VANOL 5 30 25:1 34 83 11 88a Me (R)-VANOL 20 15 14:1 27 88 23 f 88b Et (S)-VANOL 20 60 16:1 (32) –82 nd f 88c n-Pr (S)-VANOL 20 60 5:1 (25) –70 nd f 88d i-Pr (S)-VANOL 20 60 – ≤1 – – 1 2 3 6 7 8 9 10 11 12 13 14 a f e,f,i Unless otherwise specified, all reactions were performed with a solution of 0.10 mmol of the diazo compound 88 with 2.0 equiv of imine 18 in 0.6 mL CH2Cl2 at – 78 °C. A solution of the catalyst in 0.4 mL CH2Cl2 was then added dropwise over a few minutes and then the solution was allowed to stir for the indicated time after which the reaction was quenched by the addition of 0.5 mL of Et3N. The catalyst was prepared by heating 1 equiv of the ligand, 3 equiv BH3•Me2S, 2 equiv PhOH, and 3.0 equiv of H2O in toluene at 100 °C for 1 followed by the removal of volatiles at 100 °C for 0.5 h at 0.1 mmHg. The residue was then taken up in the proper amount of CH2Cl2 to have the desired catalyst in 0.4 mL. b 1 Determined from the H NMR spectrum of the crude reaction mixture with Ph3CH c as internal standard. The yields in parentheses are isolated yields after silica 55 Table 3.1 cont’d d gel chromatography. Determined by HPLC on purified trans-90. When trans-90 is not purified, % ee was determined on the reaction mixture that was passed through silica gel. A minus sign indicated that the (2R,3S)-isomer of trans-90 is e f formed. 3.0 equiv of imine was used. The catalyst was added as a solution precooled to –78 °C. g Reaction was performed with 0.10 mmol imine and 4.0 equiv of diazo ester 88a. h Solvent is 3:2 mixture of Et2O and CH2Cl2 (1.0 mL in i total) and the temperature was –100 °C. Catalyst was prepared as in footnote a except that the ratio of VANOL:PhOH:BH3•Me2S was 1:1:1 and no H2O was used. As also observed in the synthesis of disubstituted aziridines, enamine products are also formed in this reaction 14a , which result from a 1,2-migration of H to the incipient carbocation to yield 92 as the primary product as shown in Scheme 3.4. Scheme 3.4 The proposed mechanism for the formation of 90a and 91 Boc N CO Et 2 Ph Me Boc Ph N 90a 18 Lewis acid Boc N LA + Ph CO2Et O H Boc Me N Boc H N OEt 2 N O CO2Et N2 88a H Ph Ph OEt migration Me Me 3.3 91 Catalytic asymmetric synthesis of tri-substituted aziridines from N- Boc imines and α-diazo-N-acyloxazolidinone 26 3.3.1 Optimization of the tri-substituted aziridine synthesis from 18 and 26a While reactions with diazo ester 88 gave good asymmetric inductions, the yields of the tri-substituted aziridines were moderate. To improve the yields, we turned our attention to the screening of different diazo compounds. As had been demonstrated by Maruoka’s group, the nature of the group attached to the 56 carbonyl carbon of the diazo compound has a drastic influence on the reaction pathway observed in their studies. 18,19,43 We were thus pleased to find that α- diazo carbonyl compound 26a having an oxazolidin-2-one unit as the carbonyl substituent reacted with imine 18 in the presence of the VANOL catalyst to give aziridine 27a in 80% yield and 94% ee with >100:1 selectivity for the transdiastereomer (entry 1, Table 3.2). a Table 3.2 Optimization of the aziridination of α-diazo-N-cycloxazolidinone 33: (R)-VANOL 34: (R)-VAPOL Boc R Ph N Boc (R)-VANOL O O 18 borate catalyst OH N + N O OH O O CH2Cl2, – 78 °C Ph trans-(2S,3R)-27a N O R N2 93a: R = H 26a 93b: R = Ph 93c: R = Br entry ligand mol % solvent time (h) conv b % %yield c trans-27a %ee transd 27a 1 (R)-33 20 CH2Cl2 4 100 80 94 2 (R)-34 20 CH2Cl2 4 66 21 –8 3 (R)-93a 20 CH2Cl2 4 92 56 40 (R)-93a 60 CH2Cl2 4 100 65 –16 5 (R)-93b 20 CH2Cl2 4 100 79 53 6 (R)-93c 20 CH2Cl2 4 65 14 0 7 (R)-33 10 CH2Cl2 4 100 78 90 8 (S)-33 10 toluene 6 96 74 –84 9 (S)-33 10 THF 8 93 67 –77 10 (S)-33 10 Et2O 8 100 83 –79 4 e 57 Table 3.2 11 12 13 14 a cont’d f (S)-33 10 CH2Cl2 4 100 78 –94 f,g (S)-33 10 CH2Cl2 6 98 72 –94 f,h (S)-33 10 CH2Cl2 6 85 58 –94 f,i (S)-33 20 CH2Cl2 4 100 80 –95 Unless otherwise specified, all reactions were performed with a solution of 0.10 mmol of the diazo compound 26a with 3.0 equiv of imine 18 in CH2Cl2 at – 78 ºC at 0.2 M in 26a with 10 mol% catalyst and 0.1 M with 20 mol% catalyst. A solution of the catalyst in a proper amount of CH2Cl2 to give the desired concentration was then added dropwise over a few minutes and then the solution was allowed to stir for the indicated time after which the reaction was quenched by the addition of 0.5 mL of Et3N. The catalyst was prepared as described in Table 3.1. with b 1 Determined from the H NMR spectrum of the crude reaction mixture Ph3CH as chromatography. d internal c standard. Isolated yields after silica gel Determined by HPLC on purified trans-27a. A minus sign indicates that the (2R,3S)-isomer of trans-27a is formed. e Catalyst was prepared by heating 2 equiv BINOL 93a and 1 equiv BH3•Me2S in toluene at 100 °C for 1 f h followed by removal volatiles at 100 °C for 0.5 h at 0.1 mm Hg. The catalyst was added as a solution precooled to the reaction temperature. h i g 2.0 equiv imine was used. 1.5 equiv imine was used. Catalyst was prepared as indicated in footnote i of Table 3.1. Ideally, it would be the most desirable to have an authentic sample of the aziridine cis-27a to determine the trans:cis selectivity. Unfortunately, we were not able to obtain cis-27a with the route that was planned, which will be discussed in detail in Chapter 4. Therefore an alternative strategy was taken to determine the trans:cis selectivity of the reaction of imine 18 and diazo compound 26a (Scheme 3.5). Specifically, the crude reaction mixture was treated with excess sodium ethoxide to generate a mixture of the cis- and trans-ester 90a. Since we have authentic samples of both the cis and trans-isomer 90a, it could be determined 58 1 that the trans/cis selectivity was ≥100:1 by H NMR spectroscopy with the aid of standard solutions varying from 50:1 to 200:1. This in turn suggests that the diastereomeric ratio for trans-27a and cis-27a was ≥100:1 as determined by the 1 H NMR spectrum of the crude reaction mixture. Scheme 3.5 Determination of trans:cis selectivity of the reaction of 18 and 26a Boc Boc Boc N N N Ph Ph (S)-VANOL N O catalyst COOEt Ph 18 EtONa (10 mol%) O + O trans-(2R,3S)-90a trans-(2R,3S)-27a O O + CH2Cl2 + O N Boc Boc –78 oC N N N2 N O 26a Ph COOEt Ph O O cis-90a cis-27a As with diazo ester 88a, the VAPOL catalyst gave very low and reversed asymmetric induction for the α-diazoacyloxazolidinone 26a. The catalyst prepared from the BINOL ligands 93a-c did not give useful stereoselectivities (entry 3-6). Although the reaction with BINOL 93a went to completion, the yield was moderate with low induction. The asymmetric induction did increase to 53% when the 3,3’-diphenyl BINOL ligand 93b was used whereas the 3,3’-dibromo BINOL ligand 93c gave incomplete reaction with no asymmetric induction. Thus, VANOL is still the ligand of choice for this reaction. Different solvents were also examined (entry 7-10). However, it was found that there was not a strong impact of the solvent upon the reaction, although methylene chloride did give the best asymmetric induction. When the catalyst was added as a precooled solution (– 78 °C), the asymmetric induction increased from 90% to 94% ee (entry 7 vs entry 59 11). The yield for trans-27a was highly dependent on how much excess imine 18 was employed (entry 11-13). With 2 equivalents of imine 18 instead of 3 equivalents, the trans-aziridine 27a could be obtained with no loss in the asymmetric induction and only a slight decrease in the isolated yield (entries 11 vs 12). Different catalyst preparation procedures within the same protocol gave comparable results in terms of both yields and asymmetric induction (entry 11 vs entry 14). The optimized protocol was identified as that presented in entry 12 of Table 3.2. 3.3.2 Substrate scope for the catalytic asymmetric synthesis of trisubstituted aziridines With the optimal conditions in hand, the scope of this catalytic asymmetric trisubstituted aziridine synthesis was investigated in detail and the results are summarized in Table 3.3 and 3.4. Irrespective of the substituent pattern and electronic property of the aromatic ring of the N-Boc imines, the reaction generally proceeded smoothly and uniformly excellent asymmetric induction was observed for nearly all substrates. The reaction with electron-withdrawing groups are generally faster and para-substituents give slightly higher inductions. The asymmetric induction falls off a bit with the meta-bromo substituent (entries 1315, Table 3.3). The reaction of the para-methyl aryl imine 100 is slower, requring 27 hours to go to completion with 10 mol% catalyst, but the asymmetric induction was excellent (96% ee) (entries 16-17, Table 3.3). The meta-methyl substituted aryl imine 101 gives good yield with 10 mol% catalyst after 8 hours (entries 1819, Table 3.3). The ortho-methyl substituents is not tolerated and there is 60 essentially no reaction for imine 102 even with 20 mol% VANOL catalyst after 9 hours. Although para-methoxy substituted aryl imine 103 was more reactive than the ortho-methyl imine 102, it only went to 40% conversion in 11 h with 20 mol% catalyst and gave a 15% yield of aziridine. As a surrogate for the p-methoxy imine 103, we were pleased to find that the 4-pivaloyloxybenzaldehyde N-Boc imine 104 provided trans-aziridine 118 in 69% yield and 98% ee (entry 23, Table 3.3). Even 3,4-dioxycarbonyl substituted aryl imines are tolerated in the reaction. The reaction of the imine prepared from 3,4-diacetoxyl benzaldehyde went smoothly to give the desired trans-product 119 in good yield and good asymmetric induction (entry 24-25, Table 3.3). A similar situation was found with the imine from 3,4-dipivaloyoxybenzaldehyde (entry 26-27, Table 3.3). At present, this method is not applicable to the reaction of N-Boc imines derived from aliphatic aldehydes: under the reaction conditions, imine 107 gave no reaction at all. Finally, α-ethyl-substituted diazo compound 26b could also be utilized as well, giving the corresponding trans-aziridines in good yields and excellent asymmetric inductions (Table 3.4). The reaction of imine 18 with 26b was much slower than that with 26a, and it went to only 70% conversion even after 30 h with 10 mol% catalyst. The asymmetric induction also dropped to 85% ee which is to be compared with 90% ee from the reaction of the same imine and 26a (entry 12, Table 3.2). Introduction of an electron-withdrawing group bromo substituent into the imine increased not only the rate of the reaction of imine 96 and diazo 26b but also the asymmetric induction (entry 3-4, Table 3.4). 61 a Table 3.3 Catalytic asymmetric aziridination with diazo compound 26a Boc O O O O (R)-VANOL catalyst Boc N N O N Ar N O + N2 CH2Cl2, – 78 °C Ar 94-107 26a trans-(2S,3R)-108-120 mol % time (h) O 94 (R)-VANOL 20 6 100 62 90 N O 94 (R)-VANOL 10 6 100 62 90 O 95 (R)-VANOL 20 1 100 48 96 N O 95 (R)-VANOL 10 1 100 58 96 96 (S)-VANOL 20 4 100 71 –96 N O 96 (R)-VANOL 10 6 100 78 96 96 (R)-VANOL 10 6 100 62 96 97 (S)-VANOL 20 4 95 71 –93 N O 97 (S)-VANOL 10 6 95 80 –93 97 (S)-VANOL 10 6 88 68 –93 O 98 (S)-VANOL 20 6 100 55 –96 N O 2 O2N 3 98 (S)-VANOL 10 8 81 64 –96 99 (R)-VANOL 20 4 100 48 85 N O 99 99 113 (R)-VANOL 10 4 100 59 85 (R)-VANOL 10 4 100 53 85 100 (S)-VANOL 10 27 100 83 –96 N O 100 (S)-VANOL 10 9 60 42 –95 108 Boc O N 4 F3C 109 Boc O N 5 6 Br 9 Cl 110a 12 F 13 15 16 Br O 111 Boc O N 11 14 O Boc O N 8 10 Yield ee d (%) c (%) ligand Boc O N 1 7 Conv %b imine product entry 112 Boc O N Boc O N 17 114 O O 62 Table 3.3 cont’d 101 (R)-VANOL 20 8 100 83 92 N O 101 (S)-VANOL 10 6 84 71 –92 O N O 102 (R)-VANOL 20 9 -- trace -- O N O 103 (R)-VANOL 20 11 40 15 -- O 104 (R)-VANOL 20 1 100 67 98 N O 104 (R)-VANOL 10 11 87 69 98 O 105 (R)-VANOL 20 11 100 69 88 N O 105 (R)-VANOL 10 11 88 65 88 O 106 (R)-VANOL 20 10 100 63 88 106 (R)-VANOL 10 10 85 46 88 107 (R)-VANOL 20 8 -- Boc O N 18 19 O 115 Boc O N 20 116 Boc N O 21 MeO Boc O N 22 23 PivO 24 AcO 25 AcO 26 PivO 27 PivO 28 117 118 Boc O N 119 Boc O N N O 120 Boc O N O N O nd -- 121 a Unless otherwise specified, all reactions were performed as indicated in footnote a in Table 3.2. b 1 Determined from the H NMR spectrum of the crude c mixture with Ph3CH as internal standard. Isolated yields after silica gel d chromatography. Determined by HPLC on purified trans-aziridine. The absolute configuration was determined for trans-27a and this was assumed for all the other trans-aziridines. A minus sign indicated that the (2R,3S)-isomer of transaziridine is formed. 63 a Table 3.4 Catalytic asymmetric aziridination with diazo compound 26b O Ar N Boc + N N2 18, 96 entry imine product O 18 N O 18 BocO N (R)-VANOL catalyst O O N O Ar CH2Cl2, – 78 °C trans-(2S,3R)-27b, 110b 26b Boc O N 1 O ligand mol % time Conv (h) %b ee Yield (%) c (%) d 10 30 70 60 –85 (R)-VANOL 10 9 35 30 83 96 (S)-VANOL 20 8 100 85 –98 N O 96 2 (S)-VANOL (R)-VANOL 10 6 100 68 98 27b Boc O N 3 4 Br a O 110b Unless otherwise specified, all reactions were performed as indicated in footnote a in Table 3.2. b 1 Determined from the H NMR spectrum of the crude c mixture with Ph3CH as internal standard. Isolated yields after silica gel d chromatography. Determined by HPLC on purified trans-aziridine. The absolute configuration was deterimined for trans-27a and this was assumed for all other trans-aziridines. A minus sign indicated that the (2R,3S)-isomer of trans-aziridine is formed. 3.4 Stereo-complimentary access to both cis- and trans-tri-substituted aziridines The method for the catalytic asymmetric synthesis of tri-substituted transaziridines described herein, and our previously published work 44 on the alkylation of di-substituted cis-aziridines to give tri-substituted cis-aziridines, taken together can provide stereocomplimentary access to cis- and transtrisubstituted aziridines. Specifically, the VANOL catalyst could be used to give either cis or trans-tri-substituted aziridine-2-carboxylates (Scheme 3.6). 64 Scheme 3.6 General strategy for access to cis and trans-tri-substituted aziridines O 2(H) P + R X R1 N N2 VANOL catalyst aziridination/alkylation aziridination P N R2 cis COX P N COX 2 R1 R1 trans R As shown in Scheme 3.7, trans-aziridine ester 90a could be simply obtained from the ethanolysis of aziridine 27a in high yield. Alternatively, trans-90a can be obtained directly from the aziridination of imine 18 with the diazo ester 88a (Table 3.1). The cis-isomer of aziridine 90a could be obtained in three steps starting from the disubstituted aziridine of the cis-32c. The reaction of the BUDAM imine 31c and ethyl diazoacetate 5 with the VANOL catalyst provides the cis-aziridine 32c in 97% yield and 98% ee. It has been reported previously that aziridines of the type 29 can be alkylated with methyl iodide with retention of the stereochemistry. 44 When cis-32c is thus methylated followed by removal of the BUDAM group with triflic acid and by protection of the nitrogen with Boc anhydride, cis-90a was furnished in 81% yield over three steps. It is noteworthy that the (S)-VANOL catalyst gives different facial selectivities with the imine 31c and 18. This indicates that the two aziridinations may occur by different mechanisms. The same chemistry could be applied to the preparation of cisaziridines 90b and 90c which were employed as standards to determine the diastereoselectivities for the aziridination reactions of imine 18 and diazo ester 88b and 88c shown in Table 3.1 (Scheme 3.8). Thus, with the proper choice of 65 the catalytic asymmetric method and the proper choice of the chirality of the ligand, all four possible stereoisomers of tri-substituted aziridine-2-carboxylates can be obtained with high diastereoselectivity and optical purity. Scheme 3.7 The synthesis of cis and trans-isomers of aziridine 90a (S)-VANOL Boc BUDAM catalyst 1 LDA; MeI (2 mol%) BUDAM O N N N OEt toluene Ph + COOEt COOEt 2 triflic acid Ph Ph N2 rt cis-(2R,3R)-32c 31c cis-(2R,3R)-90a 5 97% yield, 98% ee 3 Boc2O 81% yield cis:trans ! 50:1 Scheme 3.8 The preparation of cis-90b and cis-90c DAM Boc yield (%) 1 LDA; RI R 90 N N R cis-90b 64 Et Ph COOEt 2 triflic acid Ph COOEt n-Pr cis-90c 58 32d cis-(2R,3R)-90 3 Boc2O 3.5 Attempts towards the direct catalytic asymmetric synthesis of cis-trisubstituted aziridines Although we have developed the indirect method to make cis-tri-substituted aziridine described above, it would be nice to have a route to cis-trisubstituted aziridine in a straightforward and direct manner from the reaction of the imines and diazo compounds. The possibility for direct access to cis-tri-substituted aziridines is suggested by previous observations made in our laboratory on control of cis and trans stereoselectivity in disubstituted aziridine synthesis. The reaction of the imine 31b with the 3°-diazoacetamide 122 was found to give the cis-aziridine 123b whereas the 2°-diazoacetamide 19 was found to give the trans-aziridine 35b with the same imine 31b (Scheme 3.9). Thus the question becomes whether a secondary diazoacetamide of the type 124 which has two 66 substituents on the diazo carbon also reverse the diastereoselectivity to directly give the cis-tri-substituted aziridines. When diazo acetamide 124 was subjected to the standard reaction conditions, it was disappointing to find that transaziridine 125 was still the major product, abeit in a low yield (Scheme 3.10). There is a large change in the level of the diastereoselectivity for the reaction from greater than 100:1 for diazo compound 26a to 1.5:1 for the diazo compound 124. The low yield and low asymmetric induction for both the cis and trans-trisubstituted aziridines 125 will need to be improved in any future investigation of this approach to cis-tri-substituted aziridines. Scheme 3.9 The control of cis:trans selectivity by different diazoacetamides in disubstituted aziridine synthesis (S)-VANOL catalyst MEDAM MEDAM (S)-VANOL catalyst toluene, 25 °C toluene, –20 °C N Ph N MEDAM N Ph N O O Ph Ph CONHPh 31b O NHPh N 35b 90% yield 32% yield 123b N2 N2 Ph 93% ee 96% ee 19 122 trans:cis 21:1 cis:trans !50:1 Scheme 3.10 The attempt towards a direct cis-tri-substituted aziridination Boc Boc (S)-VANOL catalyst O Boc (10 mol%) N N + Ph N NHBn CH Cl , –78 °C + CONHBn Ph CONHBn 2 2 Ph N2 cis-(2R,3R)-125 trans-(2R,3S)-125 18 124 12% yield, 20% ee 18% yield, 37% ee The synthetic utility of the N-oxazolidinone function group 45 of the tri- substituted aziridines is illustrated in the facile conversion of 27a to the corresponding ester and the acid (Scheme 3.11). The treatment of trans-27a with methanolic sodium methoxide at 0 ºC for 10 min led to the formation of ester trans-126 whose absolute configuration has been reported. 67 41i Thus, this conversion established the absolute configuration of trans-27a. Acid 127 could be obtained in 85% yield via the cleavage of oxazolidinone with LiOH at room temperature for 2 hours. The conversion of the resulting acid 127 to the amide 125 serves to identify the absolute configuration of the trans-aziridine 125 obtained from the reaction of the imine 18 and diazoacetamide 124 (Scheme 3.10). It is also interesting to note that the difference in the diastereoselectivity between cis- and trans-125 is the result of the change in the facial selectivity to the imine 18 but not to the diazo compound 124. The same situation was also observed in the catalytic asymmetric synthesis of cis- and trans-disubstituted aziridine 35b from imine 31b and diazoacetamide 19 (Scheme 3.12). Scheme 3.11 The conversion of oxazolidinone aziridine 90a to its corresponding ester and acid NaOMe CH3OH Boc O N Ph O N 0 °C, 10 min O trans-(2S,3R)-27a Boc N CO Me 2 Ph trans-(2S,3R)-126 81% yield HOBt (1.5 equiv) BnNH2 (3.0 equiv) Boc Boc N CONHBn N COOH DIC (1.5 equiv) 25 °C, 2 h Ph Ph trans-(2S,3R)-127 trans-(2S,3R)-125 85% yield 58% yield over 2 steps LiOH, THF 68 Scheme 3.12 The configuration of cis and trans-aziridine from the reaction of imine 31b and diazoacetamide 19 5 mol% MEDAM MEDAM (S)-VANOL catalyst MEDAM N N + Ph N NHPh + toluene (0.2 M) Ph CONHPh Ph CONHPh N2 19 31b 25 °C, 16h trans-(2R,3S)-35b cis-(2R,3R)-35b 100% conversion 71% yield 14% yield 5:1 trans:cis 88% ee 77% ee 3.6 Synthesis of protected form of L-methylDOPA O There has been a large body of work devoted to the synthesis of α,αdisubstituted amino acids but only a few involve aziridines as intermediates. 46 The interest in α,α-disubstituted amino acids has been driven by their properties that differ from α-substituted amino acids including biological properties when incorporated into medicinal agents, structural properties as occurring in natural products and solid state properties when incorporated in new materials. One 47 such example is L-DOPA and L-methylDOPA (Figure 3.1). L-DOPA is used clinically in the treatment of Parkinson’s disease, whereas, L-methylDOPA is an antihypertensive agent used in the treatment of high blood pressure, especially gestational hypertension. Figure 3.1 The structure of L-DOPA and L-methylDOPA COOH HO HO HO NH2 L-DOPA HO COOH NH2 L-methylDOPA We have previously reported that the di-substituted aziridine cis-(2S,3S)-128 23b can be used to access L-DOPA (Scheme 3.13). Ring opening of cis-128 via hydrogenolysis provided α-amino ester 129, which was then treated with HCl in 69 acetone for 20 hours to afford L-DOPA in a moderate yield. Scheme 3.13 Synthesis of L-DOPA Ph Ph N AcO AcO Pd black HCOOH MeOH AcO COOH 3N HCl HO Acetone NH2 90 °C HO 129 20 h 72% yield COOEt 25 °C AcO 128 COOH NH2 L-DOPA 60% yield Herein, we show that the tri-substituted trans-(2S,3R)-aziridines described above can provide access to L-methylDOPA. The attempt at the cleavage of the oxazolidinone group from aziridine 119 failed. The treatment of trans-aziridine 119 with sodium ethoxide led to a messy crude mixture instead of the desired product as determined from the 1 H NMR spectrum (Scheme 3.14). This is probably due to the presence of the acetyl group that is known to be susceptible to strong basic conditions. The pivaloyloxy group has been proven to be more tolerant towards strong bases. The replacement of acetyl with pivaloyl groups did enable methanolysis of 120 with NaOMe in MeOH to give the methyl ester 130 in 41% yield. It was quickly found that the treatment of aziridine 120 with MeOMgBr 45 also allows for the cleavage of oxazolidinone and provideds a much improved yield of 86% (Scheme 3.15). As expected, catalytic hydrogenation of trans-aziridine ester 130 with Pearlman’s catalyst provided the ring opening product, α,α-disubstituted amino ester 131 in 92% yield as a protected form of methyl-DOPA. 70 Scheme 3.14 Failed attempt of ethanolysis of aziridine 119 Boc O N AcO O N NaOEt, EtOH O 119 AcO AcO Boc N COOEt AcO Scheme 3.15 Synthesis of the protected form of L-methylDOPA Boc O N O MeOMgBr PivO PivO N O PivO PivO trans-(2S,3R)-120 Boc N CO MePd(OH) PivO 2 2 H2 PivO 130 MeOH 86% yield CO2Me NHBoc 131 92% yield 3.7 Brief study on the nature of the catalyst in the tri-substituted aziridination reaction 3.7.1 Effect of different species on the reaction system After the development of the catalytic asymmetric tri-subsubstituted aziridination, the next question to be addressed is what is the active catalyst in the reaction. It has been reported that different catalyst preparation procedures allow for the 26a generation of the B1 and B2 species in different ratios (Chapter 1). The reaction was performed with catalysts enriched with either the B1 or B2 species (Table 3.5). With 26a as the reactant, the enantioselectivity showed essentially no difference from the precatalysts having different B1 and B2 ratios. With 88a as the reactant, the reaction went with decreased yield and enantioselectivity if the precatalyst with the least amount of B2 was used. 71 Table 3.5 Catalytic asymmetric aziridination with different catalyst preparation procedures N a O Boc N + Ph 26a 1.0 equiv O Boc OEt + Ph (S)-VANOL-catalyst (20 mol%) O N2 18 3.0 equiv N O CH2Cl2, - 78 (S)-VANOL-catalyst (20 mol%) CH2Cl2, - 78 oC N2 18 3.0 equiv oC 88a 1.0 equiv Boc N Ph N O O O trans-(2S,3R)-27a Boc N Ph CO2Et trans-(2S,3R)-90a b d B2:B1 Diazo Time Yield (%) ee (%) 1:1.9 26a 4h 80 94 2 1:0.4 26a 4h 80 95 3 1:1.9 88a 15 min 46 93 4 1:0.4 88a 15 min 27 Entry 1 e c 88 a General procedure was followed as described in Table 3.1 for 20 mol% catalyst loading with a 1:1.9 B2:B1 ratio. The catalyst preparation procedure given in b footnote i in Table 3.1 gave a 1:0.4 ratio of B2:B1. Isolated yield after silica gel column chromatography; c Determined from 1 H NMR spectra of the crude d reaction mixture with Ph3CH added as internal standard; Determined from chiral HPLC. When the product was not isolated. The crude reaction mixture was e flushed through silica gel before HPLC analysis. The catalyst solution was not precooled before addition to the reaction mixture. It has been previously determined that B1 and B2 species can be assembled into a B3 species (boroxinate) in the presence of a basic component, such as an imine or an amine. 30 We were then wondering whether a similar process could be happening with the N-Boc imine. N-Boc imine 98 (from 4-fluorobenzaldehyde, Table 3.3) was chosen for study because it is a solid and easy to handle. We decided to use VAPOL in this study first because the bay region proton in the 72 VAPOL ligand is a convenient spectroscopic handle for probing the number of catalyst species that are generated as this proton is significantly deshielded relative to the rest of the aromatic protons. The B1 and B2 derivatives of VAPOL were generated in a ratio of 7:1. There is no profound difference observed in the chemical shift of B1 and B2 before and after the addition of the N-Boc imine 98 although the ratio of B2:B1 went up to 13:1 after imine was added. A new peak at ~5.5 ppm in the 11 B NMR spectrum was also found after the imine was added to the B1 and B2 mixture. A very similar situation was found with the VANOL derived catalyst where the ratio of B1 and B2 was 1.0:1.5 and did not change before and after imine 98 was added. There was also a new broad peak observed at 6.5 ppm in the 11 B NMR spectrum. The new peak in the 11 B NMR spectrum could be from a B3 (boroxinate) species or it could result from the imine coordinating B1 and B2 species which are acting as Lewis acids. At this point, it is not known whether the metaborate B1 and pyroborate B2 could function as a mono or bidentate Lewis acid and whether one or another or both could be active catalysts. Further work will be required to determine the structure of the catalyst for this reaction. 3.7.2 Aziridination reaction of imine 18 with different diazo compounds Unlike our cis-aziridination protocol, in which the reaction of imines of type 31 and EDA generally gives cis-aziridines in high yield and good asymmetric induction (Scheme 3.3), the electron poor N-Boc imine 18 reacted with EDA in the presence of our VANOL borate catalyst to afford the Friedel-Crafts adduct 132 in low yield (Scheme 3.16). It was also found that there was no cis-aziridine 73 detected in the reaction and only trans-aziridine 133 was observed (5% yield at – 78 °C). When the reaction was performed at –46 °C, the Friedel-Crafts adduct 132 was obtained in 29% yield along with trans-aziridine 133 in 13% yield. Slightly more enamine products were obtained at –78 °C than at –46 °C. Tentative identification of enamines 134 and 135 was possible on the basis of comparison of their NMR data with similar compounds. 18a They showed a doublet (δ = ~10 ppm) assigned as the NH resonance. This low field shift is compatible with the existence of a hydrogen bond to the carbonyl group. In consideration of the electron density of the N attached to Boc group in intermediate I (Scheme 3.16) that makes the attack of the N to the α-carbon disfavored, it was not a surprise that the adduct 132 was formed as a major product instead of aziridines. Indeed, this result is consistent with what has been reported by Terada’s 48 and Maruoka’s group 19 on the acid catalyzed Frieldel- Craft type reaction of diazo esters with N-Boc imines. At this point, the reason why the trans-aziridine was obtained instead of cis remains unknown. Our trans-aziridination protocol involves electron rich N-alkyl imines. Thus it was interesting to find that the aziridination also proceeded with N-Boc imine 18 and diazoacetamide 19 in the presence of our borate catalyst, albeit in a dimished yield. Scrutiny of the byproducts led to the confirmation of the enamine products 136 and 137 resulting from 1,2-hydride or aryl shift. Again, the identification of the enamines was based on the chemical shift (δ = ~10.5-11.0 ppm) assigned as carbamate NH resonance. Electron deficiency of nitrogen of imine 18 might be responsible for the low yield of trans-aziridine 20. When the 74 reaction was performed at room temperature, no aziridines could be detected because of its instability in the presence of acids (the catalysts). Scheme 3.16 The reactions of imine 18 and EDA N Boc Ph 18 O + N2 PG Ph OEt 5 N HN (S)-VANOL Boc + NH O catalyst Boc NHBoc unreacted (20 mol%) + N CO2Et + CONHPh 5 Ph OEt (H)Ph Ph CH2Cl2 N2 H(Ph) 132 134/135 133 –78 °C, 3 h 12% 5% 2%/2% 73% –46 °C, 3 h O 29% 13% 7%/5% 29% OEt 2 Intermediate I Scheme 3.17 The reactions of imine 18 and diazoacetamide 19 Boc N NHBoc Boc + (S)-VANOL-catalyst Ph N CONHPh unreacted + (H)Ph Ph 18 19 (20 mol%) + CONHPh H(Ph) CH2Cl2 O 20 136/137 58% 12% 11%/6% –78 °C, 3 h NHPh N2 19 –46 °C, 3 h 23 °C, 24 h 3.8 Maruoka’s system 25% 16%/6% 30% 0% 5%/5% 0% Two weeks after we published our method for the catalytic asymmetric trisubstituted aziridine synthesis, another acid catalyzed asymmetric method was reported by Maruoka’s group. 21 The right combination of imine, diazo compound and the catalyst was demonstrated to be essential for their reaction (Scheme 3.18). 75 Scheme 3.18 Catalytic asymmetric synthesis of tri-substituted aziridines developed in Maruoka’s group (S)-30 (S)-30 O O Boc O (5 mol%) (5 mol%) R1 O N H t-BuO2C N O N O 26c R1 = H N 26a R1 = CH3 N N O Ph 2 Boc Ph Boc O 29 O 26a R1 = CH3 N 27a N 89% yield 1 86% yield Ph CO2t-Bu 26c R = H Ph 18 95% ee 83% ee 28 Ph Boc O O P O NHTf (S)-30 Ph 3.9 Conclusion With the development of the catalytic asymmetric synthesis of tri-substituted aziridines described herein, it will be of interest not only to investigate its mechanism but also to compare the mechanistic differences in the reactions of electron-rich N-alkyl imines giving di-substituted aziridines and electron-poor NBoc imines affording tri-substituted aziridines. 76 CHAPTER FOUR RING EXPANSION OF AZIRIDINE-2-CARBOXYLIC ACIDS 4.1 N-carboxyanhydride formation In the course of the catalytic asymmetric synthesis of tri-substituted aziridine, we needed cis-27a to determine the diastereoselectivity of the reaction of imine 18 and diazo compound 26a (Scheme 3.5). We first took steps towards the preparation of cis-139a, a convenient substrate for our planned synthesis of cis27a as shown in Scheme 4.1. To this end, the coupling reaction of acyl chloride generated from acid 138a with oxazolidinone anion was performed, which unfortunately led to another new compound 140a instead of the desired aziridine 139a. Scheme 4.1 Planned synthesis of cis-27a Boc N N O Ph O O cis-27a Ph BUDAM N N O O 139a O 1 (COCl)2 O Ph 2 O 140a 69% yield N BUDAM N OH O 138a 87% yield 1 LDA; MeI 2 KOH, EtOH Ph then H+ BUDAM N OEt 32c O This reaction was examined more closely and it was found that the problem lies in the acyl chloride formation step. The treatment of acid 138a with oxalyl chloride afforded a single major new product whose 77 13 C NMR spectrum indicated one sp 2 carbon more than expected for aziridine acid 138a. The infrared spectrum (carbonyl absorbances at 1847, 1784 cm–1) suggested a new CO unit had been incorporated into the new molecule. After several trials, we were pleased to obtain X-ray quality crystals that revealed a five-membered ring consisting of the N-carboxyanhydride (NCA) structure (Figure 4.1 and Table 4.1). Notably, only a single diastereomer was isolated in the reaction; no other diastereomers could be detected. Figure 4.1 ORTEP drawing of NCA 140a BUDAM N O Ph O Cl O 140a t-Bu MeO t-Bu OMe t-Bu t-Bu BUDAM It is worth noticing that N-carboxyanhydrides (NCAs) 49 have been used extensively as reactive amino acid surrogates in polypeptide synthesis 50a and have served more generally as important synthetic intermediates and pharmaceutical building blocks. 50b-c Currently, NCAs are largely synthesized in two ways: cyclization of α-amino acids with phosgene or its alternatives oxidative ring enlargement of 3-hydroxy-β-lactam 78 52 51 and (Scheme 4.2). Herein, we present an unprecedented method for NCA formation from aziridine-2-carboxylic acids. Scheme 4.2 Two conventional methods for access to NCAs O R1 1 O oxidant R triphosgene O OH N 2 NH R2 R O N-carboxyanhydride NCA HO O R1 N 2 R We then set out to investigate different conditions for this transformation. The reactions of acid 141a or its sodium salt with oxalyl chloride for 2 hours at room temperature provided the corresponding product 142a in comparable yields (entries 1-2). Decreasing the reaction time to 1 hour did not change the yield (entry 3). Table 4.1 Conditions for the formation of NCAs Ar Ar Conditions a Ar Ph N Cl Ph COOH 138a, 141a entry Substrate 1 2 c O N O O 140a, 142a Conditions Prod 141a 1) NaOH; 2) (COCl)2 (2.0 equiv), 23 °C for 2h 142a t-Bu (COCl)2 (2.0 equiv), 0-23 °C for 1 h b 56% 54% (COCl)2 (2.0 equiv), 0-23 °C for 1 h 138a Yield 51% (COCl)2 (2.0 equiv), 23 °C for 2 h 3 4 Ar 140a 69% MeO a t-Bu General procedure: A 25 mL round bottom flask was flame-dried and cooled under N2. Then the starting material (0.20 mmol, 1.0 equiv) was added to the flask under N2. The vacuum adapter was quickly replaced with a septum to 79 Table 4.1 cont’d which a N2 balloon was attached via a needle. Dry CH2Cl2 (2 mL) was added via syringe. The flask was then cooled to 0 ºC, and then (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) was added via syringe. After it was stirred at 0 ºC for 5 min, the ice bath was removed and the resulting mixture was stirred at rt for another 1-2 hour. After the solvent was evaporated, the product was purified by column b c chromatography. Isolated yield after column chromatography. To the mixture of acid 141a (69 mg, 0.20 mmol, 1.0 equiv) in acetone (1 mL) and CH2Cl2 (1 mL) was added a solution of NaOH (8 mg, 0.2 mmol, 1 equiv) in H2O (0.17 mL). The resulting mixture was stirred at rt for 2 h. Then it was evaporated to dryness. And the step was carried out according to the procedure in footnote a. It was quickly found that this transformation was highly dependent on the structure of the starting acid. When acid 138a with BUDAM as protecting group on nitrogen was employed, the NCA product 140a was obtained in 69% yield. The product was found to be stable even to silica gel chromatography. This is actually consistent with the fact that N-trityl-NCAs (TNCAs) and the Nphenylfluorenyl-NCAs (PFNCAs) are relatively stable (several months at room temperature) and overcome the tendency of NCAs to polymerize. 51a Having identified that a better yield can be obtained from the N-BUDAM acid 138a than the N-benzhydryl analog 141a, we turned our efforts to exploring the substrate scope of the reaction. The results of the reactions of an additional six acids with oxalyl chloride are summarized in Table 4.2. The scope was found to be very broad with C2 methylated aziridine-2-carboxylic acids. The ortho- and para-substituted aryl groups on the C3 position, as well as aryl electron donating and withdrawing groups were well tolerated (entries 2-6). The reactions produced the corresponding NCAs smoothly in good yields. When it came to the C2 ethylated aziridine carboxylic acid 143c, the yield of NCA 144c dropped 80 significantly (20%). However, only a single diastereomer was observed in all cases. Table 4.2 Substrate scope for NCA formation BUDAM N R a Ar COOH 138a-f, 143c Ar R BUDAM N O Cl (COCl)2, DCM O O 140a-f, 144c b Entry Ar R NCA Yield (%) 1 138a Ph H 140a 69 2 138b 4-MeC6H4 H 140b 75 3 138c 4-BrC6H4 H 140c 71 4 138d 2-MeC6H4 H 140d 78 5 138e 2-BrC6H4 H 140e 73 6 138f 1-naphthyl H 140f 79 7 a Acid 143c 4-BrC6H4 CH3 144c 20 General procedure: A 25 mL round bottom flask was flame-dried and cooled under N2. Then the starting material (0.20 mmol, 1.0 equiv) was added to the flask under N2. The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (2 mL) was added via syringe. The flask was then cooled to 0 ºC, and then (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) was added via syringe. After the reaction mixture was stirred at 0 ºC for 5 min, the ice bath was removed and the resulting mixture was stirred at rt for another 1 hour. After the solvent was evaporated, the product was purified b by column chromatography. Isolated yield after column chromatography. 4.2 Formation of morpholine-2,3,5-trione As is evident from entries 3 and 7 in Table 4.2, the steric effect of substituents at C2 has a dramatic influence on the reaction yield, with the larger ethyl substituent giving a much lower yield than methyl (20% vs 71%). We then became interested in testing the reaction of acid 151a with a H substituent next 81 to the acid with oxalyl chloride (Scheme 4.4). Surprisingly, it was found that no NCA structure could be observed at all upon exposure of 151a to oxalyl chloride. Again, a single isomer of a single product was isolated in 74% yield and found to be unable to survive column chromatography on silica gel. The spectrum showed two sp 2 13 C NMR carbons more than expected for the starting acid 151a. And the infrared spectrum showed three carbonyl absorbances at 1832, –1 1782 and 1705 cm . This suggests the incorporation of both of the carbonyl groups of oxalyl chloride into the new product. These data prompted the assignment of the structure as the morpholine-2,3,5-trione 152a (Scheme 4.4). Only three examples of this ring system have been previously reported (Scheme 53 4.3). The reaction of 4-carbomethoxy-5,5-dimethylthiazolidine-2-carboxylic acid 53a 145 and oxalyl chloride led to the N-oxalic anhydride 146. The cyclic N-oxalic anhydride of L-proline 147 was obtained via treatment of the amino acid in dioxane with excess oxalyl chloride. It is noteworthy that when amino acids with primary α-amino groups were treated with oxalyl chloride under conditions successful for L-proline, no anhydride could be isolated. 53b-c Another example is that of the N-oxalic anhydride 150 which was proposed be formed as an intermediate during the preparation of an aspartic acid side chain. 53d The presence of an α- or β-amino acid in the starting material is a common feature of these three examples. The formation of an N-oxalic anhydride is unprecedented from aziridine-2-carboxylic acids. 82 Scheme 4.3 Existing examples of N-oxalic anhydrides. S (COCl)2 S MeO2C N COOH H 145 COOH O N MeO HOOC O NH Dioxane (COCl)2 DCM O N O O 146 O 47% yield O Dioxane (COCl)2 N H 147 MeO2C N O O 148 O 74% yield O N O 150 O No yield reported 149 O N MeO O O Luckily, we were able to obtain X-ray quality crystals of 152a that confirmed our assignment. The ORTEP drawing is shown in Figure 4.2. Figure 4.2 ORTEP drawing of morpholine-2,3,5-trione 152a. Cl Ph Bh H N O O O O 152a As can be seen from Scheme 4.4, the success of the formation of morpholine2,3,5-triones is susceptible to structural changes in the starting acids: the protecting group on nitrogen and the substituent on C3. When the N-protecting group was changed from benzhydryl to benzyl, the reaction yield increased from 83 74% to 82% (acid 151a vs 153a). It was clear that the presence of an electronwithdrawing group on C3 position (acid 151c) caused the yield to fall to 42% whereas the electron-donating group (acid 151b) gave rise to a higher yield. Scheme 4.4 The formation of morpholine-2,3,5-triones. Ph Bh H Ph Ph N O (COCl)2, DCM Cl N O O O Ph COOH 152a 74% 151a Cl Bh Ph Ph H (COCl)2, DCM N O N COOH 151b Ph Ph N Br (COCl)2, DCM COOH 151c Ph N Ph 153a O O O 152b 82% Cl Bh H N O Br (COCl)2, DCM Cl O O O 152c 42% Ph Ph H N O O O O 154a 82% COOH 4.3 Rapid access to β-lactams via ring expansion of aziridine-2-carboxylic acids A substrate with an aliphatic group on the C3-position was also tested in the reaction with oxalyl chloride. To our surprise, the reaction of acid 151g with oxalyl chloride furnished, in a quantitative yield, cis-β-lactam 159g in high stereoselectivity and as the only detected diastereomer (Table 4.3, entry 1). The 1 relative cis-configuration of β-lactam was determined on the basis of the H NMR coupling constant between the hydrogen atoms at the C3 and C4 positions. 84 Surveying the literature, we found that this transformation is not without precendent. The first example as shown in Scheme 4.5 appeared in 1969. Deyrup and Clough reported that entry into functionally substituted β-lactams can be achieved by ring expansion of the aziridine ring. 54a,b For example, reaction of sodium salt 155 with oxalyl chloride yielded β-lactam 156 stereoselectively in good yields. In the only other report of this reaction, Sharma and coworkers expanded the substrate scope of the reaction. A variety of cis-α-chloro-βalkyl/aryl azetidine-2-ones 158 were reported by ring enlargement of cis54c aziridine-2-carboxylates 157. We have been unable to reproduce the chemistry in this report by Sharma and coworkers and this will be discussed in Scheme 4.6. Scheme 4.5 Existing examples of lactam formation via ring expansion of aziridines. t-Bu O 2N R R1 156 Cl 79% 63% R2 O (COCl)2 N t-Bu (COCl)2 2 N R R1 155 COONa R1 = CH3, R2 = H R1 = H, R2 = CH3 R2 N COONa R1 157 1 = H, CH , Ar R 3 R1 158 Cl 55-68% As we have established a catalytic asymmetric method for access to both cisand trans-aziridines (see Chapter 1 for details), we were keen to further develop 85 their potential in synthesis. And the coupling of these methods with ring expansion to β-lactams was particularly attractive. The β-lactam skeleton is a key structural motif of several classes of antibiotics, 55a such as penicillin, cephalosporin, thienamycin and various monobactams. Unfortunately, the longstanding use and abuse of these antibiotics have led to the emergence of bacterial strains resistant to these drugs so that the design and synthesis of new families of β-lactam containing molecules are constantly being pursued. Another aspect underlying the importance of β-lactams in the realm of organic synthesis and medicinal chemistry is their application to the synthesis of other classes of biologically active compounds, especially densely functionalized β-amino acids, via the so-called β-lactam synthon methodology (β-LSM). 55b We found that it is unnecessary to employ the sodium salt of the aziridine carboxylic acid as reported by both Deyrup and Clough coworkers 54c 54a,b and by Sharma and . The acid can be directly converted to 3-chloro-4-alkyl substituted β-lactams in a highly stereoselective manner. The treatment of acid 151g and oxalyl chloride gave the β-lactam 159g in an excellent yield whereas the reaction with thionyl chloride furnished the product 159g in a moderate yield. As expected, the enantiomeric and diastereomeric purity is preserved during this transformation. 86 a Table 4.3 The reaction of acid 151g with different chlorination reagents Ph Ph Ph O Ph (COCl)2, DCM N N Cl COOH 151g 159g entry Yield (%) 1 (COCl)2 SOCl2 b 100% 2 a Reagent 62% General procedure: A 25 mL round bottom flask was flame-dried and cooled under N2. Then the starting acid (0.10 mmol, 1.0 equiv) was added to the flask under N2. The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (1 mL) was added via syringe. The flask was then cooled to 0 ºC, and then (COCl)2 (0.020 mL, 2.0 equiv) or SOCl2 (0.020 mL, 2.0 equiv) was added via syringe. After it was stirred at 0 ºC for 5 min, the ice bath was removed and the resulting mixture was stirred at rt for another 1 hour. After the solvent was evaporated, the product was purified by b column chromatography. Isolated yield after column chromatography. We decided to explore the substrate scope of the ring expansion of aziridine-2carboxylic acids to β-lactams, and the results are summarized in Table 4.4. We were also pleased to find that a range of aziridine-2-carboxylic acids reacted with oxalyl chloride to afford an array of β-lactams not only with generally good yields but also with excellent diastereoselectivity (Table 4.4). The nature of the Nprotecting group has only a small impact on the yield. Although aziridine carboxylic acids with a benzhydryl protecting group produced the lactam in a quantitative yield (Table 4.3), both the benzyl and MEDAM protected acids 153g and 161g gave good yields (entries 1-2, Table 4.4). The cis-configuration of the β-lactam was also confirmed by X-ray diffraction analysis of β-lactam 160g, the ORTEP of which is shown in Figure 4.3. 87 Figure 4.3 ORTEP drawing of cis-lactam 160g Ph N O Cl 160g The reaction of acid 151h with an isopropyl group on the C3 position under the same conditions gave an excellent yield. Acid 151i with an n-propyl group on the C3 position yielded the β-lactam 159i in 81% yield. While aziridine with both 1° and 2° aliphatic group on the C3 position gave excellent yields of β-lactam, the presence of a tert-butyl group on the C3 position also allowed the transformation, albeit in a low yield (entry 7). The treatment of the tri-substituted aziridine 163 with oxalyl chloride gave the corresponding lactam 164 in 39% yield. When trans-acid 153g was employed, the trans-lactam 160g was formed in 85% yield as the only detectable diastereomers (entry 9). a Table 4.4 Substrate scope of β-lactam formation R2 (COCl)2, DCM N entry 1 R1 Substrate N R1 COOH Product 153g Ph R2 N Ph N O Cl COOH 88 160g O Cl Yield (%) 83 b Table 4.4 cont’d 2 c 3 Ph Ph N COOH 4 7 8 9 161g 151h e 162g 89 159h 96 159i 81 159j 75 159k 75 159l O N Ph Ph N O 38 164 39 85 Cl 151i Ph Ph N Ph COOH d MEDAM Cl Ph Ph N COOH 5 6 MEDAM N COOH 151j Ph Ph N COOH 151k Ph Ph N O Cl Ph Ph N O Cl Ph Ph Ph N O Cl Ph Ph N COOH 151l BUDAM N COOH 163 Ph Ph N O Cl BUDAM O N Cl trans- Ph N COOH Ph N O trans- 153g Cl 160g 89 Table 4.4 cont’d a General procedure: A 25 mL round bottom flask was flame-dried and cooled under N2. Then the starting acid (0.10 or 0.20 mmol, 1.0 equiv) was added to the flask under N2. The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via needle. Dry CH2Cl2 (1 or 2 mL) was added via syringe. The flask was then cooled to 0 ºC, and then (COCl)2 (0.020 or 0.040 mL, 2.0 equiv) was added via syringe. After the reaction mixture was stirred at 0 ºC for 5 min, the ice bath was removed and the resulting mixture was stirred at rt for another 1 hour. After the solvent was evaporated, the product was purified by b c column chromatography. Isolated yield after column chromatography. After the addition of oxalyl chloride, the reaction mixture was stirred at 0 ºC for 10 min, d and the reaction was stopped. After it was stirred at 0 °C for 5 min, the reaction e mixture was stirred at rt for 30 min. After it was stirred at 0 °C for 5 min, the reaction mixture was stirred at rt for 24 hours. In order to improve the yield of β-lactam 159l bearing a tert-butyl group on the C3 position, the reaction of aziridine 151l with oxalyl chloride was further studied under different conditions. It was found that despite the fact that the complete conversion of the starting acid was always observed, there are three species observed in the reaction under all the conditions we investigated. The results are shown in Table 4.5. The ratio of cis- and trans-159l does not change a lot with the reaction time (entries 1-2). An increased excess of oxalyl chloride favored the formation of the acid chloride 165l and suppressed the formation of cis-155l (entry 5). Solvent also plays a role in the reaction since the formation of acyl chloride 165l is dominant in benzene (entry 6). a Table 4.5 The reactions of acid 151l with oxalyl chloride Ph Ph (COCl)2 Ph Ph Ph Ph O Ph Ph (x equiv) N N N N + + Solvent Cl COOH time COCl 151l 165l 90 cis-159l O Cl trans-159l Table 4.5 cont’d cis-159l/ b trans-159l Yield of cisc 159l (%) 49:51 76:24 ND 5 43:57 77:23 ND 2.0 24 55:45 90:10 38 0-23 5.0 1 40:60 66:34 (21) CH2Cl2 0-23 10.0 1 75:25 90:10 ND Benzene 23 2.0 1 94:6 83:17 ND entry Solvent Temp (°C) X 1 CH2Cl2 0-23 2.0 1 2 CH2Cl2 23 2.0 CH2Cl2 23 4 CH2Cl2 5 6 3 a d Time 165l/159l (h) General procedure: A 25 mL round bottom flask was flame-dried and cooled under N2. Then the starting acid (0.10 mmol, 1.0 equiv) was added to the flask under N2. The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (1 mL) was added via syringe. Then (COCl)2 (x equiv) was added via syringe at 0 °C or rt, and the resulting mixture was stirred at 0 ºC or rt for a specified time. After the solvent was b evaporated, the product was purified by column chromatography. Determined 1 from the H NMR spectrum of the crude reaction mixture. c Isolated yield. The yield in parentheses refers to the isolated yield of 159l ND = not determined. d The reaction was quenched by the addition of aqueous aq sat NaHCO3 solution. Similarly, oxalyl bromide can effect the same transformation. Unlike the reaction with oxalyl chloride, which gave exclusively cis-product, the reaction of acid 151g with oxalyl bromide proceeded with unsatisfactory stereoselectivity, affording 166g as a 1:2 mixture of cis:trans 91iastereomers. It is possible to improve the cis:trans ratio. When the reaction was quenched at 0 °C, the cislactam 166g became the dominate diastereomers in the reaction (entry 2). Neither increasing the temperature nor changing the solvent would drive the cis:trans ratio to a further extent (entry 3, Table 4.6). It seems that the cis:trans 91 mixture is in an equilibrium at room temperature and trans-166g is thermodynamically more stable than its cis-isomer. a Table 4.6 The reaction of acid 151g with (COBr)2 Ph Ph Ph Ph (COBr)2, DCM N N COOH Ph O + Br 151g N O Br cis-166g b Ph c trans-166g d entry workup procedure 1 Concentration 1:2 28(63) 2 Aqueous workup 7:1 83 cis:trans % Yield cis-166g e Concentration 1:2 (56) 3 a General procedure: A 25 mL round bottom flask was flame-dried and cooled under N2. Then the starting acid (0.10 mmol, 1.0 equiv) was added to the flask under N2. The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (1 mL) was added via syringe. The flask was then cooled to 0 ºC, and then (COBr)2 (0.020 mL, 2.0 equiv) was added via syringe. The reaction mixture was stirred at 0 ºC for 15 min. After the b solvent was evaporated, the product was purified by column chromatography. Concentration means that the reaction mixture was stripped of volatiles to give the crude product. Aqueous workup means the reaction was quenched by the c 1 addition of aq sat NaHCO3 (1 mL) at 0 °C. Determined from the H NMR d spectrum of the reaction crude mixture. Isolated yield after column chromatography. The yield in parenthesis refers to the NMR yield, determined on the crude reaction mixture with the aid of triphenylmethane as internal standard. e The reaction was performed in benzene (1 mL). After the addition of (COBr)2 at rt, the reaction mixture was refluxed for 1 h. We were not able to obtain the cis-lactam 160a from acid 153a under conditions identical to those that have been reported by Sharma and 54c coworkers. Hydrolysis of ester 167a with 1.0 equivalent NaOH in H2O at room temperature only led to the complete recovery of the starting material. It was 92 found that the acid 153a could be obtained in 99% yield after reflux in aqueous KOH solution for 1 hour. The conversion of acid to sodium salt was achieved by treatment with aqueous NaOH at room temperature for 1 hour. Under the reported conditions, β-lactam 160a could not be observed at all by treatment of sodium salt 168a with (COCl)2 and Et3N. Instead, the six-membered ring morpholine-2,3,5-trione 154a was obtained in 34% yield (Scheme 4.6). Scheme 4.6 Failed attempts towards the ring expansion Sharma and coworker (COCl)2 (1.2 equiv) Ph Ph aq NaOH Ph O Et3N (1.2 equiv) (1.0 equiv) N N N Benzene, 45 min Ph COOEt rt Ph Cl Ph COONa 167a overnight 160a 62% yield 168a Our work Ph aq KOH (5.0 equiv) Ph aq NaOH (1.0 equiv) Ph N N EtOH, reflux Ph COOH acetone, 1h Ph COONa Ph COOEt 1h, then H+ 168a 153a 167a 99% yield Benzene (COCl)2 (1.2 equiv) 45 min Et3N (1.2 equiv) Ph Ph Ph O H N O N + Cl Ph Cl O O O 160a 154a 34% not observed N In the proposed mechanism shown in Scheme 4.7, the treatment of an aziridine-2-carboxylic acid with oxalyl chloride gives intermediate I whose carbonyls will be attacked by aziridine nitrogen to furnish the morpholine trione via intermediate II and the NCA via intermediate III. As to the formation of βlactams, it is unlikely that the free carbonium ions are involved in the expansion 93 process since it is a highly stereospecific process. The proposed bicyclic structure 54 shown in Scheme 4.7 is indeed in agreement with the observed stereochemistry. Scheme 4.7 Proposed mechanism for the formation of different products Ar Ar O O N R' O O Ar Ar Ar (COCl)2 N R' Ar N R' R COOH H R Cl Cl O N O O Cl O Cl morpholine-2,3,5-trione Intermediate II Ar Ar Ar R: Ar Ar R' Me, Et N R' O N R R' O O Cl O O O H R NCA Cl R R Aliphatic Ar N N O H Intermediate V Ar H Ar Cl O Ar R H Intermediate III Ar N R' O O O Intermediate I N Cl Ar R O R: Ar R': H R' O Cl H R Intermediate IV Ar Ar N R O R' Cl lactam Based on the mechanism in Scheme 4.7, it is clear that the intermediate I can suffer several different fates and lead to several different products depending on which carbonyl is attacked. It was envisioned that β-lactam formation could be enhanced by removing the options for formation of the other products. This can be simply done by treating the aziridine carboxylic acid with a Vilsmeier reagent which is expected to give intermediate V. This species has a single carbonyl group, the attack on which should lead to a β-lactam. We therefore subjected 94 acid 151a with Vilsmeier reagent and were immediately rewarded with success. With 2.3 equivalent Vilsmeier reagent (preformed), cis-β-Lactam 155a was obtained in 57% yield (entry 5, Table 4.7). The equivalents of the Vilsmeier reagent did not have a big effect on the yield of the lactam. Although five equivalents of Vilsmeier reagent increased the yield slightly to 61% (entry 6), we decided to employ 2.3 equivalents in our standard conditions. The Vilsmeier reagent is generated from oxalyl chloride and DMF. This can also be done in-situ as indicated by the data in Table 4.7. There is a competition between the reaction of oxalyl chloride with acid 151a and the reaction of oxalyl chloride with DMF to give an in-situ generated Vilsmeier reagent. There is no β-lactam if no DMF is added, only a 74% yield of the morpholine-2,3,5-trione (entry 1). With pre-generated Vilsmeier reagent in absence of oxalyl chloride, no morpholine trione is observed and only β-lactam is produced. Table 4.7 The formation of β-lactam with in-situ or preformed Vilsmeier reagent. Ph Vilsmeier reagent Ph Ph Ph Ph H (in-situ generated O Ph N O or preformed) N Cl + N O O O Ph Cl Ph COOH 152a 151a 159a entry Formation DMF % yield % yield (COCl)2 c c (equiv) 159a 152a (equiv) a 1 2.0 0 0 74 In-situ 2 2.0 1.0 7.5 11 3 2.0 2.0 5 0 4 2.0 4.0 46 46 2.3 (57) 0 5.0 61 0 5 6 Preformed b 95 a Table 4.7 cont’d Procedure for in-situ generated Vilsmeier reagent: A 25 mL round bottom flask was flame-dried and cooled under N2. Then the starting acid 151a (0.10 mmol, 1.0 equiv) was added to the flask under N2. The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (1 mL) was added via syringe. Dry DMF was added via syringe. The flask was then cooled to 0 ºC, and then (COCl)2 (0.020 mL, 2.0 equiv) was added via syringe. The reaction mixture was stirred at 0 ºC for 15 min. After the solvent was b evaporated, the crude reaction mixture was obtained. Procedure for preformed Vilsmeier reagent. A 25 mL round bottom flask was flame-dried and cooled under N2. Then the starting acid 151a (0.10 mmol, 1.0 equiv) was added to the flask under N2. The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. The flask was then cooled to 0 ºC, and then Vilsmeier reagent (0.23M in CH2Cl2) was added via syringe. The reaction mixture was stirred at 0 ºC for 15 min. After the solvent was evaporated, the c 1 crude reaction mixture was obtained. The yield was determined on the H NMR spectrum of the crude reaction mixture with the aid of triphenylmethane as internal standard. The one in parentheses is the isolated yield. The substrate scope for this controlled β-lactam formation was then investigated and the results are shown in Table 4.8. Both electron-donating and electron-withdrawing groups on the para-position of the phenyl group on the C3 position of the aziridine-2-carboxylic acid causes a low reaction yield (entries 2-3), as well as the trisubstituted aziridine-2-carboxylic acid 141a (entry 4). It is clear that the N-protecting group has a significant impact on the yield of the reaction. The reaction of the N-benzyl protected aziridine acid 153a gave a 74% yield of βlactam 160a. Unfortunately, we still have not been able to prepare ester 167a in a direct and high enantioselective fashion. The aziridination reaction with Nbenzyl imine with 10 mol% VAPOL catalyst gave the aziridine 167a in only 51% 26c yield and 43% ee in CH2Cl2 at room temperature at 24 hours. From the results shown in entries 1 and 5 in Table 4.8, we then reasoned that aziridine acids with 96 an N-α-methylbenzyl protecting group might be sterically more similar to the benzyl group, hence affording the lactam in a better yield. Indeed, a good yield was obtained when acid 170a was treated with Vilsmeier reagent (76% yield, entry 6). The presence of the para-bromo substituent of the phenyl did not change the yield significantly (entry 7). It was important to find that good reaction yields could be obtained from aziridines with N-α-methylbenzyl protecting groups since we have developed an efficient catalytic asymmetric synthesis of N-αmethylbenzyl aziridine ester (Chapter 2). As expected from the data in Table 4.3 and 4.4, when an aliphatic group is present on the C3 position of the aziridine acid such as 151g, Vilsmeier reagent can also effect this transformation in excellent yield (entry 8). Table 4.8 Substrate scope for the controlled formation of β-lactam R2 R2 O Vilsmeier reagent N N R1 entry Substrate 1 2 3 Ph Ph N Ph COOH c Ph Ph N COOH c Ph Ph N COOH Br R1 COOH Product 151a 151b Cl Yield (%) 159a 57 159b Ph Ph N O Ph a 36 159c 33 Cl Ph Ph N O Cl 151c Ph Ph N O Cl Br 97 b Table 4.8 cont’d 4 c 5 Ph Ph N Ph COOH 141a Ph 153a Ph N Ph 6 170a Ph N Ph 7 170c Ph N a 171a 76 171c 69 159g 100 Cl Ph N O Cl Br c 74 Cl COOH 8 160a Ph N O Ph COOH 22 Cl Ph N O Ph COOH 169a Ph Ph N O Br Ph Ph N COOH 151g Ph Ph N O Cl General procedure: A 25 mL round bottom flask was flame-dried and cooled under N2. Then the starting acid (0.10 mmol, 1.0 equiv) was added to the flask under N2. The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. The flask was placed in the ice bath. A solution of Vilsmeier reagent (0.23M, 1.0 mL, 0.23 mmol, 2.3 equiv) generated from 1:1 ratio of dry DMF (0.1 mL) and oxalyl chloride (0.1 mL) in dry CH2Cl2 (5 mL) was added via syringe. The reaction mixture was stirred at 0 ºC for 15 min. After the solvent was evaporated, the product was purified by column b c chromatography. Isolated yield after column chromatography. The reaction mixture was stirred at 0 °C for 1 hour. The synthetic utility of 3-chloro-β-lactam is illustrated by its facile conversion to a variety of highly functionalized compounds (Scheme 4.8). The nucleophilic substitution of a chlorine atom by an azido group opens a new route for the preparation of β-lactam bearing nitrogen at the same position. 98 56 The β-lactam 159g was employed as a test substrate. Treatment of 159g with excess sodium azide in DMSO gives trans-3-azido-β-lactam 172 in 86% yield. It was delightful to find that this substitution reaction underwent a clean inversion by a SN2 mechanism, furnishing the β-lactam with trans stereochemistry. A similar situation was found with the nucleophilic substitution of chloride of β-lactam 159g with sodium iodide. The trans-3-iodo-β-lactam 173 was produced in a high diastereoselective manner. This high inversion of configuration is not surprising since the carbonyl group might be playing a role. Treatment of β−lactam 159g with LiAlH4 in THF at 0 °C for 2 hours afforded ring-opened product 3-amino alcohol 174 in 91% yield. This transformation proceeded with retention of stereochemistry at C4. The chlorine can be removed from the β-lactam 159g by means of tin hydride reduction without causing disruption to the β-lactam ring. Treatment of the α-haloazetidinone 159g in benzene with n-Bu3SnH in the presence of AIBN furnished the 3-unsubstituted azetidinone 175 in an excellent yield. Encouraged by this result, we turned our attention to diastereoslective 57 allylation under free radical conditions. The reaction of β-lactam 159g with allyltributyltin in the presence of AIBN upon heating provided the substituted trans-lactam 176 as a sole product in 89% yield. Although this radical condition is usually not conducive to high diastereoselectivity 57b , we were surprised that the stereoselection was excellent here. This might be due to presence of the stereocenter adjacent to the reacting radical carbon center. Attempted Suzuki coupling 99 of 159g with phenlboronic acid under the conditions reported by Fu’s group 58 did not lead to the desired product product, but trans-159g was obtained instead. Scheme 4.8 The transformation of β-lactam 159g Ph O N 76% 173 Ph Ph NH 174 Ph NaI, DMSO 100 °C, 66h I Ph Ph NaN3, DMSO Ph 80 °C, 48h N 100 °C, 12h Ph N O LiAlH4 rt, 2h 91% N3 86% Cl 159g AllyBu3Sn AIBN Bu3SnH 80 °C, 17h 80 °C, 19h 89% OH 97% Ph Ph O O Ph Ph N N AIBN O 172 NiCl2•glyme, (S)-prolinol phenyl boronic acid KHMDS, i-PrOH, 80 °C, 24h Ph Conversion: 95% Ph N O Cl trans-159g 175 176 4.4 Conclusion The rapid increase in molecular complexity from simple precursors is a major goal in organic synthesis. 59 This chapter has described the diastereoselective conversion of aziridine-2-carboxylic acids to N-carboxy anhydride, morpholine2,3,5-triones or β-lactams — depending on the starting material or reagents as summarized in Scheme 4.10. From consideration of the likely mechanism, a controlled formation of β-lactams was also realized. Hence a variety of β-lactams can be conveniently synthesized from aziridine-2-carboxylic acids in a stereospecific manner. Since aziridine-2-carboxylic acids are readily available with high enantiomeric purity from our catalytic asymmetric aziridination reaction, this combined methodology has significant potential. The 3-chloro-β-lactam products 100 are synthetic intermediates with significant utility since they can be converted into various functionalized compounds. Scheme 4.9 Diastereoselective conversion of aziridine-2-carboxylic acids Ar Cl H N Cl Ar Ar N R' R Ar O Ar Ar Ar N O H R' R Cl !"lactam R: Aliphatic Cl a Ar c N R' (COCl)2 O N R' b O R COOH R a Cl O O R: Aromatic b R': Me or Et O N Ar R' R Cl O c R: Aromatic R': H Cl Ar N O NCAs Ar R H O Ar N O O O O morpholine-2,3,5-trione 101 CHAPTER FIVE BOROXINATE CATALYSTS BASED ON BINOL DERIVATIVES 5.1 Introduction BINOL is a classical C2-symmetric biaryl ligand that has been widely used in 60 asymmetric reactionS since 1981. The biaryl unit is both an important structural feature of many natural products and the conformationally stable backbone of many highly effective chiral catalysts and reagents in asymmetric synthesis. However, BINOL is considered to be an inefficient chiral ligand because its chiral pocket is positioned on the opposite side of the active site. In order to achieve a better-defined chiral pocket around the active site, two general strategies have been applied: introducing substituents at the 3- and 3’-positions 60a and re- orientating the chiral pocket towards the active site by changing the naphthalenenaphthalene bond from the 1,1’-positions to the 2,2’-positions. Originated from the latter strategy, a new class of biaryl ligands VANOL and VAPOL 61 has been developed in our group. Based on the orientation of the naphthalene rings, VANOL and VAPOL are termed vaulted biaryl ligands while those BINOL type 61a ligands are called linear biaryl ligands (Scheme 5.1). Both types of ligands have found wide applications in asymmetric synthesis. In the course of exploring the application of the vaulted biaryl ligands, we became interested in the borate complexes derived from those ligands that proved to be successful in the 102 26 catalytic asymmetric aziridination , aza-Diels-Alder reactions 62 and amino 31 allylation of aldehydes . Scheme 5.1 Linear and vaulted biaryl ligands R 93a R = H 93b R = Ph OH 93c R = Br OH 93d R = SiPh 3 93e R = 9-anthracenyl R 93f R = SiMe3 OH Linear biary ligands OH 93a: BINOL Vaulted biaryl ligands OH Ph OH Ph OH OH Ph Ph OH OH 33: VANOL 34: VAPOL As outlined in Scheme 5.2, we have recently identified the B1 and B2 26a derivatives of VAPOL in the precatalyst for the aziridination reaction. It was later found that the active catalyst for this catalyst is a boroxinate species containing three boron atoms (B3) which is only formed in the presence of the imine substrate. 30 103 Scheme 5.2 The formation of B3 species Ph Ph O B OPh O B(OPh)3, H2O Ph Ph OH OH B1 Imine + or BH3•SMe2, PhOH,H2O Ph Ph OPh O B O B O OPh Ph Ph H-imine O Ph O B O B O O O B O Ph B3 boroxinate catalyst B2 It has also been demonstrated that the reaction of biaryl bis-phenols with boron compounds is complicated and dependent on both the boron source and 63 the substitution pattern of the biaryl bis-phenols. When BINOL is reacted with borane, hydrohaloboranes or boric acid, the bicyclic homochiral bisborate propeller compound 177 with axially chiral 1,1’-binaphthyl groups as ‘blades’ is formed exclusively in very good yield. 63 Introduction of either a bromo or trimethylsilyl substituent in the 3,3’-positions of BINOL exclusively leads to the formation of the seven membered dioxadihydroborepin system 178 to avoid 63 additional steric strain (Scheme 5.3). It was then postulated that the steric hinderance around the active site of the ligands plays the role in which boron species to be favored. 63 Previous work in our group suggested that BINOL dioxadihydroborepin 178 with Y = OPh could not be obtained cleanly. 104 64 Scheme 5.3 Reaction of BINOL and its derivatives with boron sources O O R B B O O R O O boron source H BH3, BH2Hal, H3BO3 OH OH R 93 + boron source 177 Kaufmann's propeller R boron source Y TMS BHal3 Hal Br BHal3 Hal H B(OPh)3 OPh H PhB(OH)2 Ph R O B Y O R 178 Dioxadihydroborepin Hu Gang, one of our former group members, devoted his efforts to the identification of the boron complexes formed in the reaction of BINOL with 64 different boron sources under varying conditions. The optimized procedure to prepare VAPOL B1 was indentified to be from 1:1 ratio of VAPOL and B(OPh)3 at 80 °C. When this procedure was used with BINOL, it produced a complex mixture in which Kaufmann’s propeller 177 and BINOL B2 180 can be readily observed. However, when 2/3 equivalent of BH3•SMe2 based on 1.0 equivalent of BINOL was employed, the reaction gave a nearly exclusively Kaufmann’s propeller 177 with a small amount of unreacted BINOL. When an imine was mixed with 2 equivalent BINOL and 1 equivalent of B(OPh)3 at room temperature, the clean production of the spiro-borate imine complex 181 was 105 observed to form immediately (Scheme 5.4). The structure of the spiro-borateimine complex 181 from BINOL has been confirmed by X-ray analysis. 64 Scheme 5.4 Reaction of BINOL with borane and subsequent transformation BINOL BH3•Me2S PhOH H-imine H2O O B OPh + O OPh O B O B O OPh or 179 B1 OPh O B O O B OPh + 177 Kaufmann's Propeller O O B O O Imine 181 spiro-borate-imine complex + OPh O B O B O O O B H-imine OPh 182 B3-boroxinate-imine complex 180 B2 Based on the discovery that in the presence of imine, BINOL and VAPOL borate species self-assemble to a spiro-borate species and a B3 boroxinate structure, respectively, we then became interested in whether borate complexes of the 3,3’-disubstituted derivatives of BINOL would favor the formation of a spiro-borate species or a B3 boroxinate structure upon addition of the imine. 5.2 Preparation of the BINOL derivatives A number of BINOL derivatives with substituents on the 3,3’-positions have been reported. 60a The three BINOL analogs 93b-d were chosen in our study to provide a range of substituents with different sizes. The synthetic routes are 65 outlined in Scheme 5.5, 5.6 and 5.7 and all follow published procedures . In the preparation of 93b, the BINOL was first protected with MOMCl using NaH as 106 deprotonation reagent to afford the key intermediate 183 in a high yield. The MOM group serves as both a protecting group and a strong ortho-metalation directing group. The treatment of the key intermediate 183 with n-BuLi led to an 65a ortho-metalated intermediate that can react with a variety of electrophiles: I2, Br2 65b and SiPh3Cl 65c to give 184, 186 and 187, respectively. Suzuki coupling of 184 with phenyl boronic acid in the presence of Pd(PPh3)4 furnished the 3,3’65a diphenyl BINOL derivative 185. Finally, deprotection of the MOM group by aq HCl in THF was successfully carried out to give 93b-d in good isolated yields. 65a Scheme 5.5 Preparation of BINOL derivative 93b I OH NaH, MOMCl OH BINOL OMOM OMOM n-BuLi, I2 183 53% yield Ph OH OH Ph 93b 84% yield 107 HCl, THF OMOM OMOM 184 I 45% yield Pd(PPh3)4 PhB(OH)2 Ph OMOM OMOM Ph 185 93% yield Scheme 5.6 Preparation of BINOL derivative 93c Br OMOM OMOM n-BuLi, Br2 183 65b Br OMOM OMOM HCl, THF Br 91% yield 186 OH OH Br 93c 76% yield 65c Scheme 5.7 Preparation of BINOL derivative 93d SiPh3 n-BuLi HCl, THF OMOM SiPh3Cl OMOM OMOM SiPh3 OH OH OMOM SiPh3 187 47% yield 183 93d SiPh3 68% yield Because oxygen atoms are strong hydrogen bond acceptors, these chiral BINOL derivatives are typically involved in both intramolecular and intermolecular O-H-O hydrogen bonding. Therefore, the investigation of hydrogen bonding in these chiral BINOL derivatives is essential for understanding the role these ligands may play in catalytic process. 66 While the 3,3’-diphenyl BINOL derivative 93b is known, its solid state structure has not previously been reported. The structure of 3,3’-diphenyl BINOL 93b in the solid state was studied by Xray crystallography and the ORTEP diagram is shown in Figure 5.1. The dihedral angle between the naphthalenes of the BINOL derivative 93b in its solid-state form is 86.99 º. Therefore, this BINOL derivative, along with VAPOL 67 whose dihedral angle between the phenanthrenes is <90 º varying from 80.1 to 88.5 º, is 68 described as transoid . In contrast, dihedral angle between the naphthalenes of all of the known solid-state forms of BINOL itself is >90 º. Hence, BINOL itself is 108 described as cisoid. 68 67 As has been reported , the non-solvated forms of VAPOL in the solid state lack the classic hydrogen-bonding that is otherwise common in solid state of BINOL. As can be observed from the crystal packing of 93b in Figure 5.1, there is indeed intermolecular hydrogen bonding. These structural differences between BINOL derivative 93b and VAPOL or BINOL might be expected to impact BINOL derivativesʼs reactivity in catalysis. Figure 5.1 ORTEP drawing of BINOL derivative 93b and of its crystal packing A. ORTEP drawing of 93b B. ORTEP drawing of crystal packing of 93b 5.3 Substrate induced assembly of borate species from BINOL derivatives By simply mixing B(OPh)3 with imine 197 in CDCl3, a peak at 1.9 ppm in 11 B NMR was observed (entry 1, Figure 5.3). It is evident that this is an achiral boron species. Comparing its 11 B NMR chemical shift with those of known compounds 69 (Figure 5.2) , species 196 most likely contains a 4-coordinate boroxinate species considering its low chemical shift in the 11 B NMR spectrum (Figure 5.3). It was found by another group member Anil K. Gupta that this achiral species has the structure shown in Figure 5.2. 69f 109 11 Figure 5.2 List of B NMR chemical shifts in some known compounds. OPh PhO OPh PhO OPh B B B O O OPh OPh B B PhO O OPh 189 + PhOH69b 69a (br, 18 ppm) 18969b (br, 16.5 ppm) 188 (br, 14.5 ppm) H-imine HO OH Ar Ar B(OPh)4 B O O B B O O B LiB(OPh)4 B O O B O O 19669f 19269b (s, 3 ppm) B O O B B O O B (s, 1.9 ppm) HO OH Ar Ar 19069d (s, 4.7 ppm) 19169d-e (s, 1-2 ppm) H-amine O O B O O H 19369b (br, 10 ppm) O O B O O 19469c (s, 9 ppm) 110 Ph Ph H-imine O Ph O B O B O O O B O Ph 19530 (s, 5.7 ppm) Figure 5.3 Substrate induced assembly of borate species from BINOL and its analogs R R OH OH 93a R = H R MEDAM N N 197 boron source CDCl3 OPh O B O B O O O B OPh R 198 B3 boroxinate R +R O O B O O H-imine H-imine 93b R = Ph R R 199 spiro-borate + Achiral boron-imine complex 196 93c R = Br 93d R = SiPh3 Sipro-borate B3 198 199 (7) 93d, imine 197 (6) 93b, imine 197 (5) 93b, imine 197 (4) 93c, imine 197 (3) BINOL, imine 197 (2) BINOL, imine 197 (1) No ligand, imine 197 (1) 7 111 Achiral species 196 Figure 5.3 cont’d (1) Imine 197 plus B(OPh)3 (1:1); (2) Treatment of BINOL, B(OPh)3 and imine 197 (2:1:1) at room temperature; (3) The catalyst was prepared by the general procedure from BINOL, B(OPh)3 and H2O (1:4:1). Then imine 197 was added; (4) The catalyst was prepared by the general procedure from 93c, B(OPh)3 and H2O (1:4:1). Then imine 197 was added; (5) The catalyst was prepared from the general procedure from 93b, B(OPh)3 and H2O (1:4:1). Then imine 197 was added; (6) The catalyst was prepared by the general procedure from 93b, BH3•SMe2, PhOH and H2O (1:3:2:3). Then imine 197 was added; (7) The catalyst was prepared by the general procedure from 93d, B(OPh)3 and H2O (1:4:1). Then imine 197 was added. It has been well established that the catalyst prepared from triphenyl borate and the BINOL ligand can have two equivalents of BINOL per boron (a spiro64,69c borate structure). It was found that the reaction of the BINOL ligand 93a and triphenyl borate in the presence of imine favored the formation of the spiroborate iminium species and that the amount of this species would depend on the ratio of the BINOL ligand and triphenyl borate and how the catalyst was prepared. Treatment of BINOL 93a, B(OPh)3 and imine 197 in a ratio of 2:1:1 at room temperature generated 94:6 mixture of the spiro-borate iminium species 199a and the boroxinate B3 imimium species 198a (entry 2, Figure 5.3). The catalysts in entries 3-7 in Figure 5.3 were prepared from a procedure that involves heating the mixture of the proper BINOL ligand 93a-d, triphenyl borate and H2O (1:4:1) in THF at 80 °C for 1 h and then removing the volatiles under high vacuum at 80 °C for 30 min. When the catalyst was prepared from 1:4:1 ratio of BINOL, triphenyl borate and H2O, the spiro-borate iminium complex 199a was still the dominant species as a 3:1 mixture with the boroxinate B3-iminium 112 complex 198a upon addition of imine 197. Upon introduction of substituents on the 3,3’ position, it was anticipated that the formation of catalysts composed of two equivalents of BINOL derivative per boron should be less favorable. An examination of ligands 93b-d proved that this is indeed the case. With R being Br, it is apparent that the preference is largely biased to the boroxinate B3-imine complex 198c with only a small smount of the spiro-borate-imine species 199c (entry 4); with a sterically bulkier phenyl group, it is observed that the spiroborate-imine complex 199b disappears whereas the B3-imine boroxinate 198b is the only chiral species (entry 5); with the extremely bulky SiPh3 group, both the spiro-borate-imine 199d and the B3-imine boroxinate complex 198d disappear while the achiral boron species 196 has become the only 4-coordinate boron species (entry 7). These observations imply that the nature of the boron species induced by the imine substrate is intrinsically dominated by the steric hindrance imposed in the chiral pocket, indicating a clear trend from the spiro-borate-imine complex 199, B3-imine boroxinate complex 198 and further to the non-chiral species 196 not containing a BINOL ligand with increasing steric bulkiness of the substituent on the 3,3’-positions. Although the catalyst prepared from BH3•SMe2 gave a cleaner 11 B NMR spectrum, we decided to use B(OPh)3 in the other catalyst preparations due to its greater stability (entry 5 vs 6). 5.4 Reactivity of B3 boroxinate based catalysts of BINOL derivatives in the catalytic asymmetric aziridination reaction 113 The catalytic asymmetric aziridination reactions with catalysts generated from BINOL and BINOL derivatives with different catalyst preparation procedures were examined and the results are shown in Table 5.1. Since as discussed above it was found that the catalyst prepared from 1:4:1 of BINOL, B(OPh)3 and H2O generated a mixture of spiro-borate-imine complex and B3-imine boroxinate complex (entry 3, Figure 5.3) upon addition of the imine, it was not surprising that the aziridination reaction with this catalyst gave very low asymmetric induction (entry 2, Table 5.1). When spiro-borate-imine complex was cleanly generated from BINOL (entry 2, Figure 5.3), an increase in the enantioselectivity was noted, but the sign of asymmetric induction was reversed (entry 3, Table 5.1). This indicated that both the spiro-borate-imine complex 199 and the B3-boroxinateimine complex 198 from BINOL could catalyze the reaction but give different senses of asymmetric induction. The catalyst prepared from the BINOL derivative 93b gave an increased enantioselectivity. Although different procedures from for catalyst preparation 93b generated different percentages of the B3-boroxinateimine complex 198 (entries 5-6, Figure 5.3), we were surprised to find that there is no significant difference seen in either the yield or asymmetric induction (entries 4-5, Table 5.1), indicating that the B3-boroxinate-imine complex is more reactive than achiral species in catalyzing a background reaction. Lowering the temperature from ambient to 0 °C did not give an increase in the enantioselectivity (entry 6). Changing the substrate to imine 31b provided the corresponding aziridine in a slightly increased enantioselectivity (entry 7). 114 Table 5.1 Aziridination reactions with different ligands a R Ligand B(OPh)3 PG NHPG N COOEt COOEt Ph PG + (H)Ph Ph N EDA H H H(Ph) 31a: PG = Benzhydryl toluene cis-32 200/201 25 °C 31b: PG = MEDAM 24 h entry Sub 1 b OH OH R 93a R = H 93b R = Ph Ligand T (°C) cis/ d trans %yield e cis-32 %ee f cis-32 % yield d 200/201 31a A (R)-BINOL 23 >50:1 66 13 10/7 2 31a C (R)-BINOL 23 17:1 61 20 13/9 3 31a D (R)-BINOL 23 8:1 47 -40 24/23 4 31a A 93b 23 >50:1 88 75 4/5 5 31a B 93b 23 >50:1 91 78 3/5 6 31a A 93b 0 >50:1 91 76 1/5 7 a Cat c prep 31b A 93b 23 >50:1 88 80 3/4 The reaction was run with the imine 31 (0.5 mmol) in dry toluene (1 mL) with 10 mol% catalyst. b Substrate 31a and 31b. c Different catalyst preparation procedure. A: To a flame-dried Schlenk flask filled with N2 was added the ligand, B(OPh)3 (1:3) and toluene (1 mL). The flask was sealed and heated at 80 °C for 1 h. Then the volatiles were removed by slightly cracking the Teflon valve. The resulting mixture was heated at 80 °C for 30 min. B: The same as A except that the ligand, BH3•SMe2, PhOH and H2O (1:3:2:3) were used. C: The same as A except that the ligand, B(OPh)3 and H2O (1:4:1) were added. 1 the H NMR spectrum of the crude reaction mixture. f e d Determined from Isolated yield from column chromatography. Determined from HPLC on purified cis-32. Other BINOL derivatives were also tested in the catalytic asymmetric aziridination reaction and the results are shown in Table 5.2. Interestingly, the aziridination reaction is catalyzed by the achiral species 196 shown in Figure 5.1, giving 100% conversion, >50:1 cis:trans ratio and good isolated yield. Ligand 93c 115 that gives mostly B3 species afforded moderate enantioselectivity (entry 1). Ligands 93d-e with more steric bulk at the 3,3’-positions of BINOL produce essentially no asymmetric induction. This is actually consistent with the fact neither the spiro-borate-imine species nor the B3-boroxinate-imine species were generated from ligand 93d (entry 7, Figure 5.3). Table 5.2 Aziridination of imine 31a with catalysts derived from BINOL analog Ligand (10 mol%) B(OPh)3 (40 mol%) Ph H O (10 mol%) 2 Ph N Ph EDA, toluene 25 °C, 24h 31a R OH OH R Ph Ph a NHBh COOEt Ph N COOEt (H)Ph + H(Ph) H H cis-32a 200/201 93a R = H 93b R = Ph 93c R = Br 93d R = SiPh3 93e R = 9-anthracenyl entry Ligand Conv b (%) cis/ b trans % Yield c cis-32a % ee d cis-32a % Yield b 200/201 1 No 100 >50:1 78 -- 8/2 2 93b 100 >50:1 88 76 4/6 3 93c 100 >50:1 89 55 4/3 4 93d 100 >50:1 80 1 2/2 5 93e 80 20:1 65 3 12/8 a The reaction was run with imine 31a (0.5 mmol) in dry toluene (1 mL) with 10 mol% catalyst. The catalyst was prepared from the ligand, B(OPh)3 and H2O b 1 (1:4:1) according to the general procedure C. Determined from the H NMR spectrum of the crude reaction mixture. chromatography. d c Isolated yield from column Determined by HPLC on the purified cis-32a. 5.5 Different boron sources in the aziridination reaction 116 During this study, we also observed that boron sources other than triphenyl borate and borane could also be used to prepare the catalyst. We decide to use VAPOL as our model ligand since it gave high yield and asymmetric induction. When phenylvinyl boronic acid 202 was used to prepare the catalyst, a 12% decrease in enantioselectivity was observed (entry 1 vs 2, Table 5.3). Decreasing the amount of the boronic acid 202 from 30 to 10 mol% did not result in any significant changes in the reaction (entries 3-4). With the catalyst prepared from boric acid, the reaction did not go to completion and the asymmetric induction dropped to 85% (entry 5). We assumed that the solubility of boric acid in toluene might be responsible for the less effective catalyst in this reaction system. Upon addition of PhOH along with boric acid to prepare the catalyst (entry 1 vs 6, Table 5.3), we were delighted to find that the reaction gave essentially the same result as the catalyst derived from triphenyl borate. From a consideration of the cost and stability, boric acid could be an alternative boron source for the aziridination reaction. The NMR spectra of the catalyst used in entries 2 and 5 were studied (see experimental part for the spectra). For the catalysts from entries 2 and 6, the B3-boroxinate-imine complexes could only be observed in a small amount (<5%) upon addition of the imine 197 (Figure 5.3), and a large amount of VAPOL remained unreacted. Therefore, if a B3 boroxinate catalyst is operating in the catalyst prepared from boric acid and phenol as the data shown in entry 6 suggests, then it can be very effective even at low catalyst loadings. 117 Table 5.3 Aziridination with different boron sources used in the catalyst preparation procedure a (R)-VAPOL (10 mol%) NHBh Boron source Ph Ph Ph COOEt (x mol%) Ph Ph N COOEt (H)Ph N Ph EDA, toluene + H(Ph) H H 31a 200/201 25 °C, 24h cis-32a Ph OH B OH 202 entry Boron source x (mol%) Conv b (%) cis/ b trans % yield c 32a % ee d 32a % yield b 200/201 1 B(OPh)3 30 100 >50:1 83 91 -- 2 202 30 100 >50:1 76 79 4/7 3 202 10 100 >50:1 81 80 2/6 e 202 20 100 >50:1 84 88 3/9 B(OH)3 30 54 >50:1 25 85 0/0 B(OH)3 30 100 >50:1 85 90 3/6 4 5 6 f a The reaction was run with imine 31a (0.5 mmol) in dry toluene (1 mL) with 10 mol% catalyst. The catalyst preparation procedure: To a flame-dried Schlenk flask filled with N2 was added the (R)-VAPOL (10 mol%), boron source (x mol%) and toluene (1 mL). The flask was sealed and heated at 80 °C for 1 h. Then the volatiles were removed by slightly cracking the Teflon valve. The resulting b mixture was heated at 80 °C for 30 min. Determined from the 1H NMR spectrum of the crude reaction mixture. d c Isolated from column chromatography. Determined by HPLC on the purified cis-32a. added to prepare the catalyst. catalyst. f e 10 mol% of B(OPh)3 was also PhOH (30 mol%) was added to prepare the 5.6 Conclusion We have explored the formation and reactivity of borate complexes derived from BINOL and BINOL derivatives. Boroxinate structures represent a new and unique template in asymmetric synthesis. Although the boroxinate catalysts 118 derived from BINOL analogs only show moderate asymmetric induction in the catalytic asymmetric aziridination reactions, they might prove to be useful in other reactions. 119 CHAPTER SIX CATALYTIC ASYMMETRIC 3-COMPONENT UGI REACTION 6.1 Introduction Multicomponent reactions (MCRs) are convergent reactions, in which three or more starting materials react to form a product. 70 The Ugi four component reaction (Ugi-4CR) is one of the most intensively studied and widely used 71 multicomponent reactions. The reaction involves aldehydes, primary amines, isocyanides and carboxylic acids and affords α-amino amides as the product. From the mechanism shown in Scheme 6.1, the carboxylic acid plays a dual role in the reaction, serving as a Brønsted acid to activate the imine to form an iminium ion intermediate and as a donor to trap a nitrilium ion thus enabling the Mumm rearrangement. Scheme 6.1 Ugi four-component reaction and its mechanism O O R2 H CHO 2 N 3 R R1 OH + R R1 N NH2 4 O R R4 R3 NC Mechanism CHO R2 + NH2 R4 O H2O N R4 R1 O OH R1 H R2 R2 H O N R4 R3 R2 NC N R4 N O O R1 O 4 R R4 O R1 R1 proton transfer N R1 NH Mumm H O O O R2 R2 rearrangement R2 NH N N R3 R3 R3 R4 N O 120 R3 Based on the mechanism in Scheme 6.1, the Ugi reaction can not be carried out with secondary amines. However, the use of secondary amine in the Ugi reaction has been achieved by some groups in a three component (Ugi-3CR) 70 version of the reaction. Scheme 6.2 The three component Ugi reaction of aldehyde 203, dimethylamine 204 and cyclohexyl isocyanide 205 in the presence of acetic acid O + + N H 203 204 0.01 mol 0.02 mol N MeOH NC H N + O 205 206 HOAc 0.02 mol 94% yield 0.01 mol HOAc 0.01 mol 35% yield 70a OAc H N O 207 6% yield 41% yield Scheme 6.3 The three component Ugi reaction of aldehydes, secondary amines and isocyanides catalyzed by Sc(OTf)2 2 NHR1R2 + R3CHO + R4NC 70b R1 R2 1 N R N 2 46-98% yield R R3 N 208 R4 Sc(OTf)2 25 mol% MeOH, rt overnight Scheme 6.4 Other variations of the Ugi reaction with secondary amines R NH R1 R2 + + R3 NC + R4 Alk O NH R 209 N O + R4 NC + R5 R3 2 R1 R 211 O 70c,d R4 O OH TsOH (10 mol%) O R N Alk 210 R N O 35-95% yield R1 3 R2 HN R 3 R O R5 N R1 R2 O R4HN OH 121 O 212 20-80% yield Scheme 6.5 The three component Ugi reaction of aldehydes, secondary amines and isocyanides in the presence of aminoborane 213 or B(OMe)3 O R1 70e,f R2 3 N RH N 4 R R1 O N(Pr-i)2 O 214 B O THF, rt 53-96% yield 213 B(OMe)3 DCE, 80 °C 71-91% yield 2 3 + R N R + R4 NC H H In 1963, McFarland reported a 3-component Ugi reaction in which aldehyde 72a 203, secondary amine 204 and isocyanide 205 were involved (Scheme 6.2). It should be noted that the Passerini product 207 was also detected under these reaction conditions. Although an excellent yield of 2-amino amide 206 could be obtained with 2.0 equivalents of acetic acid, the yield was much lower with 1.0 equivalent of acetic acid and a significant amount of the Passerini product was obtained. A similar reaction could also be achieved with a catalytic amount of the 72b Lewis acid Sc(OTf)2 (Scheme 6.3). In both cases, excess amine (2.0 equiv) has to be used. Secondary amines 209 and 211 that have additional functional groups, such as NHR 72c and OH 72d groups can also be employed to effect the coupling of these reagents in variants of the Ugi reaction. In fact, the additional OH and NHR group serve as the receptor of the acyl group (Scheme 6.4). In another example, aminoborane 213 has been used as an iminium ion generator in a 3-component Ugi reaction in which a variety of secondary amines have been 122 utilized. 72e Later on, they found this Ugi reaction can also be mediated by 72f B(OMe)3 (Scheme 6.5). Although diastereoselective 3- or 4-component Ugi reactions using chiral substrates 73 or chiral auxiliaries 74 have been reported, the progress on the development of a catalytic asymmetric version has been limited. In one example, in the development of a non-asymmetric catalytic version of a 3-component Ugi reaction, a single example with the chiral catalyst 17c was reported to give an 75 asymmetric induction of 18% ee (Scheme 6.6). Another example is the three- component reaction of an aldehyde, an aniline and an α-isocyanoacetamide of the type 220 in the presence of a catalytic amount of chiral phosphoric acid 17d afforded the 5-aminooxazole 221 in excellent yield and moderate to good 76 enantiomeric excess. The asymmetric induction is strongly substrate- dependent. This three-component coupling is not exactly a Ugi reaction but it is the closest example so far to a catalytic asymmetric Ugi reaction. 123 Scheme 6.6 Catalytic asymmetric 3-component Ugi reaction reported in List’s group 75 O + PMPNH2 + t-BuNC Ph H 217 216 215 Ar Catalyst 17c or 219 (10 mol%) H N PMP NHt-Bu Ph O 218 O O P OH O O O P H O Ar 219 17c: Ar = 2,4,6-(iPr)3C6H2 Yield: 90% Yield: 15% ee: 4% ee: 18% Scheme 6.7 Catalytic asymmetric α-addition of α-isocyanoacetamides to imines 76 O NHAr O CN Catalyst 17d NR3R4 (20 mol%) 1 O R NR3R4 + R2 R1 N 220 toluene, –20 °C R2 X H2N 221 Ar O O P OH O Ar 17d: Ar = 2,4,6-(CH3)3C6H2 To the best of our knowledge, there is no successful chiral catalyst that has been reported for either the 3- or 4-component Ugi reaction. Given the potential of products in the synthesis of α-amino acids, we decided to put our efforts into developing a catalytic asymmetric Ugi reaction. 6.2 Development of catalytic asymmetric 3-component Ugi reaction The study was commenced by investigating whether a Ugi-type reaction of benzaldehyde 215, dibenzylamine 222a and t-butyl isocyanide 217 could be catalyzed by a Brønsted or Lewis acid. As it has been shown by Suginome’s 124 group that a 3-component Ugi reaction could be mediated by B(OMe)3 (Scheme 72f 6.5), it was found that B(OPh)3 could also be effective in the coupling of benzaldehyde, dibenzylamine and t-butyl isocyanide giving a 47% yield of the 2amino amide 223a in toluene at 80 °C (entry 2, Table 6.1). A catalytic amount of the strong Brønsted acid, TfOH (20 mol%) can furnish the product 223a in toluene at room temperature in 45% yield (entry 3). Encouraged by these results with non-chiral Brønsted and Lewis acid, attention was turned to the broroxinate catalyst prepared from VAPOL, B(OPh)3 and H2O in the reaction. It was delightful to find that the reaction went smooth in toluene at 80 °C to give the product 223a in 74% yield and with low but non-negligible enantiomeric excess (entry 4). The additives MgSO4, 3Å MS and benzoic acid all had a bigger effect on the yield than on the asymmetric induction, whereas, the additive Mg(ClO4)2 affected both reaction yield and enantiomeric excess (entries 5-8). The catalyst prepared from VAPOL, BH3•Me2S, PhOH and H2O gave results to those with the catalyst derived from VAPOL, B(OPh)3 and H2O (entry 9 vs 4). It was quickly found that the reaction performed at room temperature gave results similar to one at 80 °C (entry 9 vs 10). Lowering the temperature to 0 °C did improve the ee to 23%, however the reaction yield dropped significantly (entry 11). Although the reaction with 10 mol% catalyst gave the same asymmetric induction as the reaction with 20 mol% catalyst, the yield of the reaction dropped from 76% to 61% (entry 10 vs 12). 125 Table 6.1 The catalytic asymmetric 3-component Ugi reaction O + Ph H 215 1.0 equiv entry e 1 2 3 4 5 6 7 8 9 10 11 Bn Bn N + NC H 222a 217 2.0 equiv 1.5 equiv b Catalyst Bn Ph a N Bn H N O 223a f % ee d 223a -- f -- f -- Additive T °C Time (h) % yield c 223a -- 23 30 31 B(OPh)3 (200 mol%) TfOH (20 mol%) -- 80 17 47 -- 23 36 (S)-VAPOL (20 mol%) B(OPh)3 (80 mol%) -- 80 24 45 74 17 MgSO4 (4.0 equiv) 80 22 65 19 3Å MS (150 mg) 80 24 44 19 Benzoic acid (10 mol%) 80 24 52 17 Mg(ClO4)2 (20 mol%) 80 24 44 24 -- 80 24 68 19 -- 23 24 76 18 -- 0 24 21 23 Catalyst B(OPh)3 (150 mol%) H2O (20 mol%) (S)-VAPOL (20 mol%) B(OPh)3 (80 mol%) H2O (20 mol%) (S)-VAPOL (20 mol%) B(OPh)3 (80 mol%) H2O (20 mol%) (S)-VAPOL (20 mol%) B(OPh)3 (80 mol%) H2O (20 mol%) (S)-VAPOL (20 mol%) B(OPh)3 (80 mol%) H2O (20 mol%) (S)-VAPOL (20 mol%) BH3•Me2S (60 mol%) PhOH (40 mol%) H2O (60 mol%) (S)-VAPOL (20 mol%) BH3•Me2S (60 mol%) PhOH (40 mol%) H2O (60 mol%) (S)-VAPOL (20 mol%) BH3•Me2S (60 mol%) PhOH (40 mol%) H2O (60 mol%) 126 Table 6.1 cont’d 12 a (S)-VAPOL (20 mol%) BH3•Me2S (60 mol%) PhOH (40 mol%) H2O (60 mol%) -- 23 24 61 18 The reaction was run with benzaldehyde (0.25 mmol, 1.0 equiv), dibenzylamine (0.10 mL, 2.0 equiv) and t-butyl isocyanide (45 µL, 1.5 equiv) in toluene (1 mL). The catalyst was prepared according to the general procedure. after column chromatography. d f c b Isolated yield Determined from HPLC on purified 223a. e The reaction was run in THF. The NMR yield was determined from the crude reaction mixture with the aid of triphenylmethane as internal standard. Although there were no remarkable differences found in the formation of 223a with different equivalents of the reagents, the reagent ratio of 1:2:1.5 for benzaldehyde, dibenzyl amine and t-butyl isocyanide of gave the product 223a was chosen for continued study of this reaction (Table 6.2). Table 6.2 Screen of different ratios of the reactants in the catalytic asymmetric 3CR Ugi reaction a (S)-VAPOL (20 mol%) BH3•Me2S (60 mol%) O + Bn N Bn + H Ph H 215 222a NC 217 PhOH (40 mol%) H2O (40 mol%) Toluene, rt, 24 h Bn N Bn H N Ph 223a O b entry 215 (equiv) 222a (equiv) 217 (equiv) % yield 223a 1 1.0 2.0 1.5 76 2 1.0 1.0 1.0 60 15 3 3.0 1.0 1.5 79 c 18 12 a % ee 223a The reaction was run with benzaldehyde (0.25 mmol, 1.0 equiv), dibenzylamine (0.10 mL, 2.0 equiv) and t-butyl isocyanide (45 µL, 1.5 equiv) in toluene (1 mL). 127 Table 6.2 cont’d The catalyst was prepared from (S)-VAPOL, BH3•Me2S, PhOH and H2O in toluene according to the general procedure. c b Isolated yield after column chromatography. Determined from HPLC on purified 223a. As has been discussed in Chapter 1 and Chapter 5, the boroxinate catalyst can be prepared from different ligands and different alcohol or phenol derivatives. It was thus decided to investigate the effects of different ligands and alcohol or phenol derivatives. The results of catalysts derived from different ligands are summarized in Table 6.3. It was surprising to find that the catalyst derived from the VANOL ligand gave lower asymmetric induction than the VAPOL catalyst (entry 1 vs 2). This is in striking contrast with the catalytic asymmetric aziridination of imines with EDA in which there is no siginificant difference seen 26 with VAPOL and VANOL catalysts. Although it was previously shown (Chapter 5) that the catalysts derived from BINOL derivatives 93b-d formed predominantly B3 boroxinate catalyst in the presence of an imine, ligands gave catalysts that were less effective than the VAPOL catalyst. Table 6.3 The screen of different chiral ligands in the Ugi reaction R Ligand (20 mol%) BH3•Me2S (60 mol%) Bn Bn O N H Bn Bn + NC PhOH (40 mol%) + N N Ph H H2O (40 mol%) Ph H 217 215 222a Toluene, rt O 1.0 equiv 2.0 equiv 1.5 equiv 223a entry Ligand Time (h) 128 a % yield 223a OH OH R 93b R = Ph 93c R = Br 93d R = SiPh3 b % ee 223a c Table 6.3 cont’d 1 (R)-VAPOL 24 76 -18 2 (S)-VANOL 36 60 6 3 (R)-93b 24 37 -11 4 (R)-93c 43 30 -11 5 (R)-93d 24 trace -- a The reaction was run with benzaldehyde (0.25 mmol, 1.0 equiv), dibenzylamine (0.10 mL, 2.0 equiv) and t-butyl isocyanide (45 µL, 1.5 equiv) in toluene (1 mL). The catalyst was prepared from chiral ligand (20 mol%), BH3•Me2S (60 mol%), PhOH (40 mol%) and H2O (60 mol%) in toluene according to the general b c procedure. Isolated yield after column chromatography. Determined from HPLC on purified 223a. The minus sign means the other enantiomer of 223a was obtained. After identifying that VAPOL is the ligand of choice, the optimization effort was then focused on screening different alcohol and phenol derivatives that are incorporated into the boroxinate core of the catalyst and the results are given in Scheme 6.8. Catalysts from primary alcohols, such as ethanol and benzyl acohol, were found to be ineffective and only give traces of product. The reaction gave good yields and low ee’s with catalysts derived from more sterically hindered secondary ((+), (-)-menthol) or tertiary (adamantanol) alcohols. Monosubstituted phenols with strong electron-withdrawing group on the para-position diminished the asymmetric induction of the reaction. Phenols with aliphatic groups in the 2- and 6-positions seems to give a slight increase in the asymmetric induction, whereas 2,6-diphenylphenol gave a catalyst that behaved 129 essentially the same as that from phenol. When it came to tri-substituted phenols, there was no clear relationship between the substitution pattern and the asymmetric induction. However, the catalyst derived from 2,4,6-trimethylphenol afforded the α-amino amide 223a in 72% yield and with 40% ee. Catalysts derived from the phenols with sterically more hindered groups on the para position of 2,6-dimethylphenol such as diphenylmethyl and admantyl resulted in a lower ee of the product. The best enantioselectivity came from the catalyst prepared from 2,4,6-tri-t-butylphenol, which gave 223a with 58% ee. Variation of the group in the 4-position of 2,6-di-t-butylphenol resulted in a lower ee of the product. VANOL and VAPOL monomers were also examined but gave the same %ee simple phenol. Scheme 6.8 Screen of alcohol and phenol derivatives a (S)-VAPOL catalyst Bn N Bn H Bn Bn + (20 mol%) + N N NC Ph H Ph H Toluene, rt 217 215 222a O 223a 1.0 equiv 2.0 equiv 1.5 equiv O ROH (40 mol%) Ph Ph OH + H O (60 mol%) 2 OH BH3•SMe2 (60 mol%) O R O B O B O O O B O R H Ph Ph In-situ generated B3 catalyst (20 mol%) 130 Scheme 6.8 cont’d Alcohols Br OH HO OH HO OMe trace trace (+)-menthol Purificationb: I Purification: II 24 h 73% yield 17% ee Purification: III Monosubstituted phenols OH OH Ph Ph 24 h 36 h 76% yield 70% yield 17% ee 18% ee Purification: III Purification: III Disubstituted phenols OH (–)-menthol 24 h 91% yield 16% ee Purification: III OH NO2 36 h 64% yield 13% ee Purification: III 39 h 86% yield 15% ee Purification: III OH OH OMe 36 h 75% yield 18% ee Purification: III 24 h 89% yield 22% ee Purification: III OH OH OH 37 h 82% yield 19% ee Purification: III 39 h 70% yield 26% ee Purification: III 37 h 82% yield 26% ee Purification: III OH OH OH 24 h 56% yield 17% ee Purification: III OH 24 h 71% yield 17% ee Purification: III OH OH Ph F3C CF3 37 h 77% yield 31% ee Purification: I 37 h 76% yield 19% ee Purification: III 131 Ph 42 h 87% yield 19% ee Purification: III 37 h 69% yield 24% ee Purification: III Scheme 6.8 cont’d Trisubstituted phenols OH OH Br 24 h 83% yield 27% ee Purification: III OH 39 h 76% yield 24% ee Purification: II OH Ph 39 h 73% yield 40% ee Purification: II OH Br 36 h 92% yield 26% ee Purification: III OH 38 h 82% yield 58% ee Purification: III OH 42 h 72% yield 40% ee Purification: III OH OMe 41 h 68% yield 36% ee Purification: III OH 39 h 73% yield 40% ee OH OH Ph Ph 43 h 80% yield 25% ee Purification: II OH 41 h 76% yield 35% ee Purification: II OH Br 36 h 60% yield 36% ee Purification: III 36 h 61% yield 46% ee Purification: III OH 39 h 44 h 59% yield 42% yield 33% ee 20% ee Purification: II F3C CF3 Purification: II Purification: II Miscellaneous OH OH F Ph OH Ph 36 h 77% yield 19% ee Purification: II OH 36 h 70% yield 19% ee Purification: II MeO OMe OMe 36 h 76% yield 14% ee Purification: III F F F 37 h F 65% yield 19% ee Purification: I a The reaction was run with benzaldehyde (0.25 mmol, 1.0 equiv), dibenzylamine (0.10 mL, 2.0 equiv) and t-butyl isocyanide (45 µL, 1.5 equiv) in toluene (1 mL). The catalyst was prepared from chiral ligand (20 mol%), BH3•Me2S (60 mol%), alcohol or phenol derivatives (40 mol%) and H2O (60 mol%) in toluene according to the general procedure. Isolated yield after column chromatography. ee was 132 Scheme 6.8 cont’d b determined from HPLC on purified 223a. Purification means purification method of the alcohol or phenol derivatives. I: used as received; II: Purified by column chromatography on silica gel; III: Purified by sublimation. With the 2,4,6-tri-t-butylphenol and VAPOL derived catalyst identified as giving the best asymmetric induction, a screen of different solvents was undertaken to achieve further optimization. From Table 6.4, it is clear that in polar solvents, such as acetonitrile and ether, the reaction went with a reduced asymmetric induction, with CH3CN affording the racemic product. In nonpolar solvents, the asymmetric induction improved, with the best 66% ee observed in mesitylene. Table 6.4 Solvent screening for the 3-component Ugi reaction a (S)-VAPOL (20 mol%) BH3•Me2S (60 mol%) Bn Bn 2,4,6-tri-t-butylphenol (40 mol%) N H Bn Bn + + N NC N H2O (40 mol%) H Ph H Ph 217 222a 215 223a O Solvent, rt 1.0 equiv 2.0 equiv 1.5 equiv O entry Solvent % yield b 223a % ee c 223a entry Solvent % yield b 223a % ee c 223a 1 mesitylene 85 66 4 m-xylene 77 57 2 CCl4 86 62 5 CH3CN 43 0 3 toluene 82 58 6 Et2O 91 30 a The reaction was run with benzaldehyde (0.25 mmol, 1.0 equiv), dibenzylamine (0.10 mL, 2.0 equiv) and t-butyl isocyanide (45 µL, 1.5 equiv) in the specified solvent (1 mL). The catalyst was prepared from (R)-VAPOL (20 mol%), BH3•Me2S (60 mol%), PhOH (40 mol%) and H2O (60 mol%) in toluene according b to the general procedure. Isolated yield after column chromatography. Determined from HPLC on purified 223a. 133 c It was surprising to find that dibenzylamine is the only secondary amine that works in the reaction. There is essentially no reaction with pyrrolidine, diethylamine, phenylbenzylamine and diphenylamine. Fortunately, a series of dibenzylamine derivatives could be employed in the reaction (Table 6.5). When the catalyst was prepared from VAPOL, BH3•Me2S, PhOH and H2O, the asymmetric induction seems to change with the dibenzylamine derivative, with bis-(4-fluorobenzyl)amine giving the highest induction of 27% ee (entry 6). It was then disappointing to observe that with the catalyst prepared from tri-tbutylphenol, the reaction of bis-(4-fluorobenzyl)amine provided the same level of asymmetric induction as that of dibenzylamine (Table 6.5, entry 7 vs Table 6.4, entry 3). Table 6.5 Screen of the dibenzylamine derivatives a (R)-VAPOL (20 mol%) Ar O + Ph H 215 Ar BH3•Me2S (60 mol%) + N NC H 217 222 2.0 equiv 1.5 equiv Ar PhOH (40 mol%) Ar N H2O (40 mol%) Toluene, rt Ph 223 O b H N entry Ar Product T (h) % yield 223 1 Phenyl (222a) 223a 24 76 2 2-naphthyl (222b) 223b 48 76 8 3 4-methoxylphenyl (222c) 223c 48 82 15 4 4-bromophenyl (222d) 223d 24 72 19 5 4-chlorophenyl (222e) 223e 24 72 24 6 4-fluorophenyl (222f) 223f 48 68 27 d 4-fluorophenyl (222f) 223f 39 88 c 18 56 a 7 % ee 223 The reaction was run with benzaldehyde (0.25 mmol, 1.0 equiv), dibenzylamine 134 Table 6.5 cont’d (0.10 mL, 2.0 equiv) and t-butyl isocyanide (45 µL, 1.5 equiv) in toluene (1 mL) in the specified time. The catalyst was prepared from (R)-VAPOL (20 mol%), BH3•Me2S (60 mol%), PhOH (40 mol%) and H2O (60 mol%) in toluene according to the general procedure. b Isolated yield after column chromatography. c d Determined from HPLC on the purified material 223. 2,4,6-tri-t-butylphenol was used instead of phenol in the preparation of the catalyst. This project has been taken over by Wenjun Zhao, one of our group members. She found that the reaction with the catalyst prepared from the VAPOL and tri-tbutylphenol that gave 58% ee in toluene was not reproducible. After a lot of efforts on her part, it was found that the reason appears to be closely related to impurities present in the 2,4,6-tri-t-butylphenol and this is now under investigation. 6.3 Proposed mechanism Athough no detailed mechanistic study has been carried out at this point, a catalytic cycle leading to α-amino amides can be proposed (Scheme 6.9). The reaction of benzaldehyde and dibenzylamine provides an hemiaminal that is in equilibrium with the starting materials. In the presence of the catalyst, the hemi-aminal may form an ion pair consisting of the VAPOL-B3 boroxinate anion and an iminium ion. Subsequent reaction with isocyanide generates the nitrilium ion as an ion pair with the VAPOL-B3 boroxinate anion.Then, abstraction of the hydroxyl group from the hemi-aminal by the nitrilium ion gives a tautomer of the final product. As can be seen from the mechanism in Scheme 6.9, the VAPOL boroxinate catalyst is not acting as a Brønsted acid as in the aziridination reaction but rather as a chiral counter anion catalyst. This is actually consistent with the above observed solvent effect (Table 6.4). 135 Scheme 6.9 Proposed mechanism for the Ugi-type reaction O Ph Bn Ph N Bn + Bn N Bn H H Bn H N N Bn Ph OH hemi-aminal Bn N Bn Chiral Brønsted acid Bn H2O N Ph N Ph Bn * H O Ph O B O B O O O B O Ph OH O NC Bn N Bn Bn Ph Ph OH hemi-aminal N Bn N * O Ph O B O B O O O B O Ph 6.4 Conclusion A catalytic asymmetric 3-component Ugi reaction has been described. Although the best enantiomeric excess acheieved so far is 66% in our study, it is still by far the best enantioselectivity reported for this reaction. In addition, from consideration of the mechanism, the boroxinate catalyst developed in our group is apparently serving as a chiral counter anion catalyst. This was anticipated as it was expected that it would serve as a chiral Brøsted acid as it does in the aziridination reaction. This new chiral counteranion may very well provide for new options in future catalyst development. 136 CHAPTER SEVEN EXPERIMENTAL SECTION General information: Dichloromethane and acetonitrile were distilled from calcium hydride under nitrogen. Toluene, THF and benzene were distilled from sodium under nitrogen. Hexanes and ethyl acetate were ACS grade and used as purchased. Other reagents were used as purchased from Aldrich. VANOL and VAPOL were prepared according to a literature procedure and were determined 61 to be at least 99% optical purity. 307 26a , 312 26a , 317 26a , 32d 26b Preparation of aziridine ester 32a , 32c 26c , 300-304 26c , 167a 26c 26a , 32b previously reported. The preparation of 308 and 318 could be found. , 305- 26d are 33,77 Melting points were determined on a Thomas Hoover capillary melting point apparatus and were uncorrected. IR spectra were taken on a Galaxy series 1 FTIR-3000 spectrometer. H NMR and 13 C NMR were recorded on a Varian Inova-300 MHz, Varian UnityPlus-500 MHz or Varian Inova-600 MHz instrument in CDCl3 unless otherwise noted. CDCl3 was used as the internal standard for 1 both H NMR (δ = 7.24) and 13 C NMR (δ = 77.0). HR-MS was performed in the department of Biochemistry at Michigan State University. Analytical thin-layer chromatography (TLC) was performed on 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. Column chromatography was performed with silica gel 60 (230 – 450 mesh). HPLC 137 analyses were carried out using a Varian Prostar 210 Solvent Delivery Module with a Prostar 330 PDA Detector and a Prostar Workstation. 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. Although we have not experienced any problems with either the preparation or use of diazo compounds herein, we note that diazo compounds in general are heat sensitive and potentially explosive and should be handled with due care. 7.1 Experimental for Chapter Two 7.1.1 General procedure for the preparation of aldimines R + H N Ph O 2 (R)-51 MgSO4, CH2Cl2 R N Ph (R)-45a-k The mixture of the corresponding aldehyde (1.01-1.20 equiv), (R)-51 (1.00 equiv) and MgSO4 (4.00 equiv) in dry CH2Cl2 (2-4 mL/mmol) was stirred at room temperature for the specified time. After it was filtered over a Celite pad on a sintered glass funnel, the filtrate was concentrated by rotary evaporation to give the crude product. (R)-N-Benzylidene-1-methylbenzylamine (45a): Ph N Ph (R)-45a The general procedure was followed with 2.76 g benzaldehyde (26.0 mmol, 1.05 equiv), (R)-(+)-α-methylbenzylamine 51 (3.00 g, 24.8 mmol, 1.00 equiv), dry CH2Cl2 (50 mL) and a reaction time of 6 hours. The crude product was purified 138 by vacuum distillation (119 °C/6 mmHg) to give the pure imine 45a (2.658 g, 1 12.72 mmol, 51%) as a colorless oil. H NMR (300 MHz, CDCl3) δ 1.44 (d, 3H, J = 6.6 Hz), 4.38 (q, 1H, J = 6.6 Hz), 7.04-7.30 (m, 8H), 7.58-7.66 (m, 2H), 8.20 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 24.89, 69.70, 126.60, 126.79, 128.23, 128.38, 128.49, 130.52, 136.40, 145.18, 159.39. (R)-N-(4-Nitrobenzylidene)-1-methylbenzylamine (45b): N O2N Ph (R)-45b The general procedure was followed with 1.284 g 4-nitrobenzaldehyde (8.500 mmol, 1.030 equiv), (R)-51 (1.00 g, 8.25 mmol, 1.00 equiv), dry CH2Cl2 (25 mL) and a reaction time of 24 hours. The crude product was placed at rt under high vacuum (0.1 mmHg) for at least 4 hours to give the imine 45b (2.09 g, 8.23 mmol, 100%) as a pale yellow oil which was used in the aziridination reaction 1 without further purification. H NMR (300 MHz, CDCl3) δ 1.50 (d, 3H, J = 5.7 Hz), 4.49 (q, 1H, J = 5.7 Hz), 7.12-7.32 (m, 5H), 7.80-7.84 (m, 2H), 8.12-8.16 (m, 2H), 8.31 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 24.79, 70.08, 123.79, 126.59, 127.15, 128.57, 128.91, 141.87, 144.29, 148.99, 157.05. (R)-N-(4-Bromobenzylidene)-1-methylbenzylamine (45c): Br N Ph (R)-45c 139 The general procedure was followed with 3.084 g 4-bromobenzaldehyde (16.67 mmol, 1.010 equiv), (R)-51 (2.00 g, 16.5 mmol, 1.00 equiv), dry CH2Cl2 (50 mL) and a reaction time of 24 hours. The crude product was purified by recrystallization (CH2Cl2/hexane 1:10) to afford imine 45c (3.879 g, 13.47 mmol, 1 82%) as white crystals; mp 88-89 °C. H NMR (300 MHz, CDCl3) δ 1.57 (d, 3H, J = 6.9 Hz), 4.52 (q, 1H, J = 6.9 Hz), 7.10-7.60 (m, 9H), 8.21 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 24.80, 69.75, 124.91, 126.60, 126.92, 128.46, 129.67, 131.74, –1 135.31, 144.92, 158.14; IR (thin film) 2974(w), 2853(w), 1587(m), 831(m) cm ; Anal calcd for C15H14NBr: C, 62.52; H, 4.90; N, 4.86. Found: C, 62.05; H, 5.02; 20 N, 4.81; [α] D –87.9° (c 1.0, CH2Cl2). (R)-N-(4-Tolylbenzylidene)-1-methylbenzylamine (45d): N Ph (R)-45d The general procedure was followed with 3.12 g 4-tolualdehyde (26.0 mmol, 1.05 equiv), (R)-51 (3.00 g, 24.8 mmol, 1.00 equiv), dry CH2Cl2 (50 mL) and a reaction time of 24 hours. The crude product was purified by recrystallization (CH2Cl2/hexane 1:10) to afford imine 45d (4.14 g, 18.57 mmol, 75%) as white 1 needle-like crystals; mp 97-98 °C. H NMR (300 MHz, CDCl3) δ 1.58 (d, 3H, J = 6.5 Hz), 2.36 (s, 3H), 4.51 (q, 1H, J = 6.5 Hz), 7.17-7.45 (m, 7H), 7.64-7.69 (m, 140 2H), 8.33 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 21.49, 24.85, 69.65, 126.61, 126.74, 128.21, 128.37, 129.22, 133.79, 140.78, 145.31, 159.37; IR (thin film) –1 2976(m), 1741(s), 1178(s) cm ; Anal calcd for C16H17N: C, 86.05; H, 7.67; N, 20 6.27. Found: C, 85.47; H, 7.87; N, 6.22; [α] D –92.3° (c 1.0, CH2Cl2). (R)-N-(2-Tolylbenzylidene)-1-methylbenzylamine (45e): N Ph (R)-45e The general procedure was followed with 3.123 g 2-tolualdehyde (25.99 mmol, 1.05 equiv), (R)-51 (3.00 g, 24.8 mmol, 1.00 equiv), dry CH2Cl2 (50 mL) and a reaction time of 24 hours. The crude product was placed at rt under high vacuum (0.1 mmHg) for at least 4 hours to give the imine 45e (5.53 g, 24.80 mmol, 102%) as a colorless oil which was used in the aziridination reaction without further 1 purification. H NMR (300 MHz, CDCl3) δ 1.58 (d, 3H, J = 6.6 Hz), 2.48 (s, 3H), 4.45 (q, 1H, J = 6.6 Hz), 7.10-7.44 (m, 8H), 7.83 (d, 1H, J = 3.6 Hz), 8.64-8.70 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 19.44, 25.22, 70.39, 126.09, 126.57, 126.74, 127.86, 128.38, 130.08, 130.73, 134.30, 137.55, 145.38, 158.09. (R)-N-(4-Methoxybenzylidene)-1-methylbenzyllamine (45f): MeO N Ph (R)-45f The general procedure was followed with 3.539 g 4-methoxybenzaldehyde (25.99 mmol, 1.050 equiv), (R)-51 (3.00 g, 24.8 mmol, 1.00 equiv), dry CH2Cl2 141 (50 mL) and a reaction time of 120 hours. The crude product was placed at 80 °C under high vacuum (0.1 mmHg) for 24 hours to give the imine 45f (5.92 g, 24.8 mmol, 100%) as a colorless oil which was used in the aziridination reaction 1 without further purification. H NMR (300 MHz, CDCl3) δ 1.58 (d, 3H, J = 6.9 Hz), 3.82 (s, 3H), 4.49 (q, 1H, J = 6.6 Hz), 6.86-6.96 (m, 2H), 7.18-7.46 (m, 5H), 7.687.76 (m, 2H), 8.29 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 24.87, 55.33, 69.57, 113.89, 126.61, 126.71, 128.36, 129.42, 129.77, 145.44, 158.73, 161.54. (R)-N-(Cyclohexymethylidene)-1-methylbenzylamine (45g): N Ph (R)-45g The general procedure was followed with 2.916 g cyclohexanecarboxaldehyde (25.99 mmol, 1.05 equiv), (R)-51 (3.00 g, 24.8 mmol, 1.00 equiv), dry CH2Cl2 (50 mL) and a reaction time of 4 hours. The crude product was placed at rt under high vacuum (0.1 mmHg) for at least 4 hours to give the imine 45g (5.286 g, 24.59 mmol, 99%) as a colorless oil which was used in the aziridination reaction 1 without further purification. H NMR (300 MHz, CDCl3) δ 1.14-1.38 (m, 5H), 1.50 (d, 3H, J = 4.2 Hz), 1.62-1.90 (m, 5H), 2.16-2.26 (m, 1H), 4.25 (q, 1H, J = 4.2 Hz), 7.18-7.36 (m, 5H), 7.57 (d, 1H, J = 7.0 Hz); 13 C NMR (75 MHz, CDCl3) δ 24.67, 25.33, 25.93, 29.71, 29.73, 43.40, 69.39, 126.42, 126.58, 128.27, 145.22, 3 167.60 (One sp carbon not located). (R)-N-(t-Butylmethylidene)-1-methylbenzylamine (45h): 142 N Ph (R)-45h The general procedure was followed with 1.62 g trimethylacetaldehyde (18.2 mmol, 1.10 equiv), (R)-51 (2.00 g, 16.5 mmol, 1.00 equiv), dry CH2Cl2 (50 mL) and a reaction time of 25 hours. The crude product was purified by vacuum distillation (98 °C/7 mmHg) to give imine 45h (1.421 g, 7.52 mmol, 46%) as a 1 colorless oil. H NMR (300 MHz, CDCl3) δ 1.00 (s, 9H), 1.36 (d, 3H, J = 6.6 Hz), 4.18 (q, 1H, J = 6.6 Hz), 7.10-7.30 (m, 5H), 7.52 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 24.96, 26.98, 36.00, 69.00, 126.40, 126.48, 128.21, 145.60, 170.26. (R)-N-(n-Propylmethylidene)-1-methylbenzylamine (45i): N Ph (R)-45i The general procedure was followed with 86 mg butyraldehyde (1.2 mmol, 1.2 equiv), (R)-51 (121 mg, 1.00 mmol, 1.00 equiv), dry CH2Cl2 (10 mL) and a reaction time of 1.5 hours. The crude product was placed at rt under high vacuum (0.1 mmHg) for 5 minutes to give the imine 45i (180 mg, 1.03 mmol, 103%) as a colorless oil which was used immediately in the aziridination reaction 1 without further purification. H NMR (500 MHz, CDCl3) δ 0.93 (t, 3H, J = 7.5 Hz), 1.48 (d, 3H, J = 6.5 Hz), 1.60-1.50 (m, 2H), 2.28-2.20 (m, 2H), 4.25 (q, 1H, J = 6.5 Hz), 7.36-7.18 (m, 5H), 7.73 (t, 1H, J = 5.0 Hz); 143 13 C NMR (75 MHz, CDCl3) δ 2 13.78, 19.57, 24.65, 37.79, 69.77, 126.56, 126.78, 128.42, 163.89 (One sp C not located). (R)-N-(2-Bromobenzylidene)-1-methylbenzylamine (45j): Br N Ph (R)-45j The general procedure was followed with 2.36 g 2-bromobenzaldehyde (12.5 mmol, 1.01 equiv), (R)-51 (1.50 g, 12.4 mmol, 1.00 equiv), dry CH2Cl2 (50 mL) and a reaction time of 24 hours. The crude product was placed at rt under high vacuum (0.1 mmHg) for at least 4 hours to give the imine 45j (3.56 g, 12.38 mmol, 100%) as a colorless oil which was used in the aziridination reaction 1 without further purification. H NMR (300 MHz, CDCl3) δ 1.60 (d, 3H, J = 6.6 Hz), 4.64 (q, 1H, J = 6.6 Hz), 7.24-7.38 (m, 5H), 7.42-7.47 (m, 2H), 7.52-7.57 (m, 1H), 8.10 (dd, 1H, J = 9.0, 3.0 Hz), 8.74 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 24.86, 69.81, 125.01, 126.58, 126.89, 127.53, 128.44, 129.05, 131.69, 132.90, 134.67, 144.84, 158.47. (R)-N-(2-Iodobenzylidene)-1-methylbenzylamine (45k): I N Ph (R)-45k The general procedure was followed with 2.134 g 2-iodobenzaldehyde (9.200 mmol, 1.020 equiv), (R)-51 (1.10 g, 9.02 mmol, 1.00 equiv), dry CH2Cl2 (30 mL) and a reaction time of 40 hours. The crude product was placed at rt under high 144 vacuum (0.1 mmHg) for at least 4 hours to give the imine 45k (3.03 g, 9.04 mmol, 101%) as a yellow oil which was used in the aziridination reaction without 1 further purification; H NMR (300 MHz, CDCl3) δ 1.50 (d, 3H, J = 6.6 Hz), 4.54 (q, 1H, J = 6.6 Hz), 6.92-7.38 (m, 7H), 7.70-7.76 (m, 1H), 7.92 (dd, 1H, J = 7.8, 1.5 Hz), 8.41 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 24.83, 69.54, 100.07, 126.61, 126.91, 128.35, 128.44, 129.08, 131.91, 137.08, 139.50, 144.79, 162.72. (R)-N-Benzylidene-1-cyclohexylethylamine (55a): Ph O + H2N MgSO4, CH2Cl2 (R)-49 Ph N (R)-55a The general procedure was followed with benzaldehyde (1.686 g, 15.88 mmol, 1.010 equiv), (R)-(-)-1-cyclohexylethylamine 49 (2.00 g, 15.7 mmol, 1.00 equiv), dry CH2Cl2 (25 mL) and a reaction time of 20 hours. The crude product was placed under the vacuum (0.1 mmHg) for at least 4 hours before the aziridination 1 reaction to give the imine 55a (3.377 g, 15.70 mmol, 100%) as a colorless oil. H NMR (300 MHz, CDCl3) δ 0.82-1.00 (m, 2H), 1.06-1.30 (m, 6H), 1.42-1.52 (m, 1H), 1.60-1.84 (m, 5H), 2.96-3.02 (m, 1H), 7.36-7.40 (m, 3H), 7.69-7.74 (m, 2H), 8.20 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 19.92, 26.21, 26.38, 26.57, 29.81, 29.97, 43.68, 71.99, 128.03, 128.48, 130.22, 136.52, 158.59. 7.1.2 Preparation of diazoacetamide 19 145 O p-Ts N N OH H 250 SOCl2 O p-Ts N H N DBU Cl 251 O N2 N H Ph 19 To a suspension of the acid 250 (17.8 g, 0.0740 mol, 1.00 equiv) in dry benzene (80 mL) was added freshly distilled SOCl2 (17.5 g, 10.7 mL, 0.147 mol, 2.00 equiv). The resulting mixture was refluxed for 2 hours during which time the solid was gradually dissolved. Then it was cooled to room temperature and filtered through a Celite pad on a sintered glass funnel. After the filtrate was concentrated, warm benzene (~45 °C, 30 mL) was added and the solid was broken up into small pieces. The suspension was cooled and filtered. The solid product was washed with cold benzene (2 × 10 mL). The filtrate was concentrated to give a solid. To the solid was added warm benzene (~45 °C, 10 mL), filtered and washed with cold benzene. The combined solids from both crops were heated to dissolve in benzene (25 mL) and petroleum ether (bp 35-60 °C, 25 mL) was added. Precipitate came out. After filtration, the product 251 was given as a pale yellow solid (15.56 g, 0.05984 mol, 82%). A 100 mL round bottom flask was flame dried and cooled to rt under N2. It was then charged with acid chloride 251 (3.600 g, 13.85 mmol, 1.000 equiv) and dry CH2Cl2 (30 mL). And the vacuum adapter was quickly replaced with a septum in which a N2 balloon was attached via a needle. Then aniline (1.414 g, 1.400 mL, 15.18 mmol, 1.100 equiv) and DBU (4.217 g, 4.200 mL, 2.000 equiv) were added via syringe sequentially at 0 °C. The resulting mixture was stirred at 0 °C for 2 146 hours during which time the color turned from yellow to dark red. After it was warmed up to rt, aq sat NH4Cl (30 mL) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4) and filtered. After concentration, the residue was loaded onto the column (silica gel, 30 × 270 mm, CH2Cl2:MeOH 50:1). The yellow fractions were collected and concentrated to dryness. After it was put on the high vacuum for 1 hour, the yellow solid was washed with ether (2 × 50 mL + 25 mL) to afford a yellow crystal 1 solid 19 (1.099 g, 6.819 mmol, 49%). H NMR (500 MHz, DMSO-d6) δ 5.48 (s, 1H), 6.95-7.06 (m, 1H), 7.20-7.34 (m, 2H), 7.50-7.52 (m, 2H), 9.69 (s, 1H); 13 C NMR (125 MHz, DMSO-d6) δ 47.97, 118.59, 122.64, 128.72, 139.51, 163.51. 7.1.3 Catalytic asymmetric aziridinations General Procedure for the Catalytic Asymmetric Aziridination of Aldimines with EDA 5 (Method A): For reactions in Table 2.1, Table 2.3-2.6. A 25 mL pearshaped single neck flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it), cooled to rt under N2 and charged with 10 mol% ligand (0.10 mmol, 0.10 equiv) (or no ligand), 40 mol% triphenyl borate (116 mg, 0.400 mmol, 0.400 equiv), H2O (18 mg, 1.8 µL, 0.10 mmol, 0.10 equiv) and dry toluene (2 mL). The Teflon valve was closed and the flask was heated at 80 °C for 1 hour. After the flask was cooled to rt, the 147 toluene was carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon value. After the solvent was removed, the Teflon valve was completely opened and the flask was heated at 80 °C under high vacuum for 30 min. The flask was then allowed to cool to rt. The imine substrate (1.0 mmol, 1.0 equiv) and toluene (2 mL) were added. To this stirred solution was rapidly added EDA 5 (124 µL, 1.20 mmol, 1.20 equiv). The resulting mixture was stirred at rt for 24 h (or 1 h for entries 3 and 4 in Table 2.3). The conversion was 1 determined from the H NMR spectrum of the crude mixture by integration of the aziridine ring methine protons relative to either the imine methine proton or the proton on the imine carbon. The cis/trans ratio was determined on the crude mixture by integration of the ring methine protons for each aziridine. The cis (J = 7-8 Hz) and trans (J = 2-3 Hz) coupling constants were used to differentiate cis and trans diastereomers. The yield of the noncyclic enamine products were determined from the 1 H NMR spectrum of the crude reaction mixture by integration of the NH proton (9-10 ppm) of the enamine by-product and aziridine methine peak of the desired product. Conversion was 100% unless otherwise stated. In some cases, the minor product from the matched case was isolated and fully characterized. In other cases, it was not but assigned as the minor diastereomer based on the coupling constant (6-7 Hz) of the aziridine methine 1 peak from the H NMR spectrum of the crude reaction mixture. After column chromatography, the corresponding product was obtained. 148 General Procedure for the Catalytic Asymmetric Aziridination of Aldimines with Diazoacetamide 19 (Method B): For reactions in Table 2.7 (entries 1-5) and Table 2.8. A 25 mL pear-shaped single neck flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it), cooled to rt under N2 and charged with 10 mol% ligand (0.02 mmol, 0.1 equiv) (or no ligand), borane dimethylsulfide in toluene (2M, 30 µL, 0.060 mmol, 0.30 equiv), sublimed PhOH (5 mg, 0.04 mmol, 0.2 equiv), H2O (1.08 µL, 0.0600 mmol, 0.300 equiv) and dry toluene (2 mL). The Teflon valve was closed and the flask was heated at 100 °C for 1 hour. After the flask was cooled to rt, the toluene was carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon value. After the solvent was removed, the Teflon valve was completely opened and the flask was heated to 100 °C under high vacuum for 30 min. The flask was then cooled to rt, and the substrate (0.20 mmol, 1.0 equiv) and dry toluene (1 mL) were added to the flask under N2 flow. To this stirred solution was added diazoacetamide 19 (39 mg, 0.24 mmol, 1.2 equiv) under N2 flow. Then the Teflon valve was closed and the resulting mixture was stirred at rt for the specified time. The reaction was quenched with n-hexane (5 mL) and concentrated. The crude mixture was analyzed by 1 H NMR spectroscopy to determine the conversion and diastereoselectivity. After column chromatography, the corresponding product was obtained. Synthesis of cis-(2R,3R)-56a from aziridination of the cyclohexylethyl chiral imine (R)-55a derived from benzaldehyde. 149 N COOEt cis-(2R,3R)-56a cis-(2R,3R)-56a: The reaction of imine (R)-55a (215 mg, 1.00 mmol) and (S)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a 90% conversion, >50:1 cis/trans ratio, 3%/7% enamine products 58a/59a and an 83:17 mixture of cis-(2R,3R)-56a and cis-(2S,3S)-57a. Purification of the products by column chromatography (1 nd hexane:CH2Cl2:Et2O 8:1:1; 2 st column, silica gel, 40 × 400 mm, column, silica gel, 15 × 150 mm, hexane:EtOAc 19:1) gave cis-(2R,3R)-56a (98 mg, 0.35 mmol) in 35% isolated yield as a white solid; mp 47-49 °C; Rf = 0.35 (hexane:EtOAc 9:1). Spectral data for cis-(2R,3R)1 56a: H NMR (300 MHz, CDCl3) δ 0.92 (t, 3H, J = 7.2 Hz), 0.97-1.26 (m, 8H), 1.43-1.76 (m, 6H), 1.84-1.95 (m, 1H), 2.36 (d, 1H, J = 6.6 Hz), 2.94 (d, 1H, J = 6.9 Hz), 3.80-4.02 (m, 2H), 7.16-7.30 (m, 3H), 7.36-7.42 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 13.91, 16.47, 26.43, 26.53, 26.66, 28.94, 30.06, 43.55, 44.53, 49.35, 60.47, 70.50, 127.18, 127.75, 127.90, 135.70, 168.69; IR (thin film) -1 2980(m), 2924(s), 2853(m), 1734(s), 1201(s), 698(m) cm ; HRMS (ESI) calcd 150 + 20 for C19H28NO2 m/z 302.2120 ([M+H] ), meas 302.2117; [α] D –22.3° (c 1.0, CH2Cl2). Synthesis of cis-(2R,3R)-43a and cis-(2S,3S)-44a from aziridination of the phenethyl chiral imine (R)-45a derived from benzaldehyde. Ph N COOEt cis-(2R,3R)-43a The reaction of imine (R)-45a (209 mg, 1.00 mmol) and (S)-VAPOL (54 mg, 0.10 1 mmol) was performed according to the General Procedure (Method A). The H NMR spectrum of the crude mixture showed a >50:1 cis/trans ratio, 1%/7% of enamine products 65a/66a and a 96:4 mixture of cis-(2R,3R)-43a and cis(2S,3S)-44a. Purification by column chromatography (silica gel, 40 × 400mm, hexane:CH2Cl2:Et2O 8:1:1) gave pure cis-(2R,3R)-43a in 74% isolated yield (215 mg, 0.74 mmol) as a pale yellow solid; mp 84-85 °C (Lit 32b 87-89 °C); Rf = 0.25 1 (hexane:CH2Cl2:Et2O 8:1:1). Spectral data for cis-(2R,3R)-43a: H NMR (300 MHz, CDCl3) δ 0.96 (t, 3H, J = 7.2 Hz), 1.54 (d, 3H, J = 6.2 Hz), 2.60 (d, 1H, J = 6.9 Hz), 2.85 (q, 1H, J = 6.6 Hz), 2.95 (d, 1H, J = 6.9 Hz), 3.86-4.04 (m, 2H), 7.10-7.34 (m, 8H), 7.40-7.46 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 13.94, 22.92, 46.03, 47.36, 60.65, 69.80, 126.94, 127.18, 127.28, 127.67, 127.76, 128.39, 135.20, 143.28, 168.26; mass spectrum m/z (% rel intensity) 295(4), 105(100); 151 20 [α] D –60.8° (c 1.0, CH2Cl2). The major product from this reaction can be assigned as ethyl (2R,3R)-3-phenyl-1-[(R)-1-phenylethyl]aziridine-2-carboxylate by comparison of its optical rotation with that previously reported for this compound. 32b This assignment was confirmed by reductive ring opening to (R)- phenylalanine ethyl ester 69. Ph N COOEt cis-(2S,3S)-44a cis-(2S,3S)-44a: The reaction of imine (R)-45a (209 mg, 1.00 mmol) and (R)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a >50:1 cis/trans ratio, 7%/11% of enamine products 65a/66a and a 33:67 mixture of cis(2R,3R)-43a and cis-(2S,3S)-44a. Purification of the products by column chromatography (silica gel, 40 × 400 mm, hexane:CH2Cl2:Et2O 8:1:1) gave cis(2R,3R)-43a in 17% isolated yield (52 mg, 0.17 mmol) as a pale yellow solid. The fraction containing 44a was collected and concentrated. It was then further purified by column chromatography (silica gel, 40 × 400 mm, hexane:EtOAc 19:1) to give cis-(2S,3S)-44a as a white solid (98 mg, 0.33 mmol) in 33% yield; mp 87-88 °C (Lit 5b 64-66 °C); Rf = 0.42 (hexane:CH2Cl2:Et2O 8:1:1). Spectral data for cis-(2S,3S)-44a: 1 H NMR (300 MHz, CDCl3) δ 0.92 (t, 3H, J = 6.9 Hz), 1.50 (d, 3H, J = 6.6 Hz), 2.49 (d, 1H, J = 6.9 Hz), 2.90 (q, 1H, J = 6.6 Hz), 3.10 152 (d, 1H, J = 6.6 Hz), 3.86-3.94 (m, 2H), 7.20-7.40 (m, 6H), 7.44-7.47 (m, 4H); 13 C NMR (75 MHz, CDCl3) δ 13.89, 23.90, 45.54, 48.02, 60.45, 69.19, 126.67, 127.09, 127.43, 127.89, 127.90, 128.40, 135.52, 143.70, 167.98; IR (thin film) -1 2963(w), 1738(s), 1201(m) cm ; mass spectrum m/z (% rel intensity) 295(2), 190(63), 117(100); Anal calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: 20 C, 76.74; H, 7.20; N, 4.66; [α] D –32.8° (c 1.0, CH2Cl2). Synthesis of cis-(2R,3R)-43b from aziridination of the phenethyl chiral imine (R)45b derived from 4-nitrobenzaldehyde. Ph N O2N COOEt cis-(2R,3R)-43b cis-(2R,3R)-43b: The reaction of imine (R)-45b (254 mg, 1.00 mmol) and (S)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a >50:1 cis/trans ratio, 4%/5% of enamine products and a 94:6 mixture of cis-(2R,3R)43b and cis-(2S,3S)-44b. Purification of the major product by column chromatography (1 8:1:1; 2 nd st column, silica gel, 40 × 400 mm, hexane:CH2Cl2:Et2O column, silica gel, 25 × 250 mm, hexane:EtOAc 15:1) gave cis- (2R,3R)-24b in 74% isolated yield as a yellow oil (249 mg, 0.732 mmol); Rf = 1 0.10 (hexane:CH2Cl2:Et2O 8:1:1). Spectral data for cis-(2R,3R)-43b: H NMR 153 (300 MHz, CDCl3) δ 1.00 (s, 3H, J = 6.6 Hz), 1.48 (d, 3H, J = 6.9 Hz), 2.68 (d, 1H, J = 6.9 Hz), 2.88 (d, 1H, J = 6.9 Hz), 3.00 (d, 1H, J = 6.6 Hz), 3.84-4.02 (m, 2H), 7.12-7.52 (m, 7H), 8.00 (d, 2H, J = 7.5 Hz); 13 C NMR (75 MHz, CDCl3) δ 13.91, 22.81, 46.34, 60.89, 69.61, 122.82, 126.67, 127.45, 128.43, 128.65, 3 142.74, 142.76, 147.05, 167.39 (One sp carbon not located); 13 C NMR (75 MHz, MeOD) δ 14.35, 22.97, 47.54, 47.66, 62.09, 70.33, 123.81, 128.02, 128.52, 129.51, 129.94, 144.58, 144.71, 148.55, 169.51; IR (thin film) 2978(w), 1747(s), –1 + 1520(s), 1346(s) cm ; HRMS (ESI ) calcd for C19H21N2O4 m/z 341.1501 + 20 ([M+H] ), meas 341.1508; [α] D –118.2° (c 1.0, CH2Cl2). Synthesis of cis-(2R,3R)-43c and cis-(2S,3S)-44c from aziridination of the phenethyl chiral imine (R)-45c derived from 4-bromobenzaldehyde. Ph N COOEt Br cis-(2R,3R)-43c cis-(2R,3R)-43c (Table 4, entry 6): The reaction of imine (R)-45c (289 mg, 1.00 mmol) and (S)-VAPOL (54 mg, 0.10 mmol) was performed according to the 1 General Procedure (Method A). The H NMR spectrum of the crude mixture showed a >50:1 cis/trans ratio, 4%/4% of enamine products and a 94:6 mixture of cis-(2R,3R)-43c and cis-(2S,3S)-44c. Purification of the major product by column chromatography (silica gel, 40 × 400mm, hexane:CH2Cl2:Et2O 8:1:1) gave cis-(2R,3R)-43c in 82% isolated yield as a pale colored crystalline solid 154 (305 mg, 0.820 mmol); mp 80-82 °C; Rf = 0.26 (hexane:CH2Cl2:Et2O 8:1:1). 1 Spectral data for cis-(2R,3R)-43c: H NMR (300 MHz, CDCl3) δ 1.00 (t, 3H, J = 6.9 Hz), 1.50 (d, 3H, J = 6.0 Hz), 2.58 (d, 1H, J = 6.9 Hz), 2.74-2.96 (m, 2H), 13 3.84-4.06 (m, 2H), 7.04-7.52 (m, 9H); C NMR (75 MHz, CDCl3) δ 14.01, 22.89, 46.07, 46.72, 60.81, 69.76, 121.18, 126.83, 127.38, 128.44, 129.53, 130.80, -1 134.25, 143.10, 160.12; IR (thin film) 2978(m), 1747(s), 1197(s) cm ; mass + spectrum m/z (% rel intensity) 375 M (0.5, + 81 + Br), 373 M (0.5, 79 Br), 104(100); + 79 HRMS (ESI ) calcd for C19H21NO2 Br m/z 374.0756 ([M+H] ), meas 374.0773; 20 [α] D –69.8° (c 1.0, CH2Cl2). Ph N COOEt Br cis-(2S,3S)-44c cis-(2S,3S)-44c: The reaction of imine (R)-45c (289 mg, 1.00 mmol) and (R)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a >50:1 cis/trans ratio, 13%/13% of enamine products and a 38:62 mixture of cis(2R,3R)-43c and cis-(2S,3S)-44c. Purification of the products by column chromatography (silica gel, 40 × 400 mm, hexane:CH2Cl2:Et2O 8:1:1) gave cis(2R,3R)-43c in 24% isolated yield (89 mg, 0.24 mmol) as a pale yellow solid. The fraction containing cis-(2S,3S)-44c was collected and concentrated. The aziridine 155 was purified by column chromatography (1 hexane:EtOAc 15:1; 2 nd st column, silica gel, 40 × 400 mm, column, silica gel, 28 × 280 mm, hexane:EtOAc 15:1) to give cis-(2S,3S)-44c as a white crystalline solid (100 mg, 0.267 mmol) in 27% yield; mp 73-74 °C; Rf = 0.33 (hexane:Et2O:CH2Cl2 8:1:1). Spectral data for cis1 (2S,3S)-44c: H NMR (300 MHz, CDCl3) δ 0.96 (t, 3H, J = 6.9 Hz), 1.46 (d, 3H, J = 6.6 Hz), 2.49 (d, 1H, J = 6.9 Hz), 2.90 (q, 1H, J = 6.6 Hz), 3.00 (d, 1H, J = 6.9 13 Hz), 3.84-3.94 (m, 2H, J = 6.9 Hz), 7.20-7.52 (m, 9H); C NMR (75 MHz, CDCl3) δ 13.92, 23.81, 45.59, 47.29, 60.53, 69.05, 121.38, 126.57, 127.13, 128.40, 129.62, 130.95, 134.56, 143.45, 167.58; IR (thin film) 2972(w), 1734(s), -1 + 1197(s) cm ; mass spectrum m/z (% rel intensity) 376 M (0.1, (0.1, 79 + 81 Br), 374 M + 79 Br), 105(100); HRMS (ESI ) calcd for C19H21NO2 Br m/z 374.0756 + 20 ([M+H] ), meas 374.0746; [α] D –61.1° (c 1.0, CH2Cl2). Synthesis of cis-(2R,3R)-43d and cis-(2S,3S)-44d from aziridination of the phenethyl chiral imine (R)-45d derived from 4-tolualdehyde. Ph N COOEt cis-(2R,3R)-43d cis-(2R,3R)-43d: The reaction of imine (R)-45d (223 mg, 1.00 mmol) and (S)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a >50:1 156 cis/trans ratio, 0%/1% of enamine products and a >98:2 mixture of cis-(2R,3R)43d and cis-(2S,3S)-44d. Purification of the major product by column chromatography (silica gel, 40 × 400mm, hexane:CH2Cl2:Et2O 8:1:1) gave cis(2R,3R)-43d in 71% isolated yield (220 mg, 0.710 mmol) as a pale yellow solid; mp 62-64 o C; Rf = 0.28 (hexane:CH2Cl2:Et2O 8:1:1). Spectral data for cis- (2R,3R)-43d: 1 H NMR (300 MHz, CDCl3) δ 1.06 (t, 3H, J = 6.9 Hz), 1.58 (d, 3H, J = 6.6 Hz), 2.30 (s, 3H), 2.62 (d, 1H, J = 6.9 Hz), 2.90 (q, 1H, J = 6.6 Hz), 2.98 (d, 1H, J = 6.9 Hz), 3.92-4.12 (m, 2H), 7.00-7.10 (m, 2H), 7.20-7.40 (m, 5H), 7.42-7.50 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 13.97, 21.08, 22.88, 45.98, 47.33, 60.60, 69.80, 126.90, 127.21, 127.61, 128.33, 128.37, 132.11, 136.72, –1 143.30, 168.30; IR (thin film) 2976(m), 1741(s), 1178(s) cm ; mass spectrum + + m/z (% rel intensity) 309 M (3), 130(100); HRMS (ESI ) calcd for C20H24NO2 + 20 m/z 310.1807 ([M+H] ), meas 310.1784; [α] D –62.4° (c 1.0, CH2Cl2). Ph N COOEt cis-(2S,3S)-44d cis-(2S,3S)-44d: The reaction of imine (R)-45d (223 mg, 1.00 mmol) and (R)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a >50:1 cis/trans ratio, 3%/7% of enamine products and a 33:67 mixture of cis-(2R,3R)- 157 43d and cis-(2S,3S)-44d. Purification of the products by column chromatography (silica gel, 40 × 400 mm, hexane:CH2Cl2:Et2O 8:1:1) gave cis-(2R,3R)-43d in 19% isolated yield (54 mg, 0.19 mmol) as a pale yellow solid. The fraction containing cis-(2S,3S)-44d was collected and concentrated. This isomer was purified by column chromatography (silica gel, 30 × 250 mm, hexane:EtOAc 19:1) to give cis-(2S,3S)-44d as a pale solid (100 mg, 0.32 mmol) in 32% yield; mp 48-50 °C; Rf = 0.40 (hexane:Et2O:CH2Cl2 8:1:1). Spectral data for cis1 (2S,3S)-44d: H NMR (300 MHz, CDCl3) δ 0.96 (t, 3H, J = 6.6 Hz), 1.48 (d, 3H, J = 6.6 Hz), 2.15 (s, 3H), 2.46 (d, 1H, J = 6.9 Hz), 2.90 (q, 1H, J = 6.6 Hz), 3.06 (d, 1H, J = 6.9 Hz), 3.80-3.98 (m, 2H), 7.08-7.14 (m, 2H), 7.20-7.40 (m, 5H), 7.467.52 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 13.95, 21.19, 23.90, 45.56, 48.01, 60.44, 69.26, 126.67, 127.05, 127.76, 128.38, 128.61, 132.48, 137.07, 143.77, –1 168.04; IR (thin film) 2974(m), 1749(s), 1194(s) cm ; mass spectrum m/z (% rel intensity) 309 M + + (67), 236(100); HRMS (ESI ) calcd for C20H24NO2 m/z + 20 310.1807 ([M+H] ), meas 310.1819; [α] D –44.3° (c 1.0, CH2Cl2). Synthesis of cis-(2R,3R)-43e from aziridination of the phenethyl chiral imine (R)44e derived from 2-tolualdehyde. Ph N COOEt cis-(2R,3R)-43e 158 cis-(2R,3R)-43e: The reaction of imine (R)-45e (223 mg, 1.00 mmol) and (S)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a >50:1 cis/trans ratio, 1%/0% of enamine products and a >98:2 mixture of cis-(2R,3R)43e and cis-(2S,3S)-44e. Purification of the major product by column chromatography (silica gel, 40 × 400 mm, hexane:CH2Cl2:Et2O 8:1:1) gave cis(2R,3R)-43e in 62% isolated yield as pale yellow crystals (192 mg, 0.621 mmol); mp 62-64 °C; Rf = 0.25 (hexane:CH2Cl2:Et2O 8:1:1). Spectral data for cis1 (2R,3R)-43e: H NMR (300 MHz, CDCl3) δ 0.92 (t, 3H, J = 7.2 Hz), 1.50 (d, 3H, J = 6.6 Hz), 2.20 (s, 3H), 2.65 (d, 1H, J = 6.9 Hz), 2.85 (q, 1H, J = 6.3 Hz), 2.95 (d, 1H, J = 6.9 Hz), 3.80-4.00 (m, 2H), 6.88-7.32 (m, 9H); 13 C NMR (75 MHz, CDCl3) δ 13.80, 18.72, 22.73, 45.21, 46.19, 60.52, 70.12, 125.28, 127.02, 127.13, 127.44, 128.44, 128.54, 129.02, 133.34, 135.89, 143.17, 168.45; IR (thin –1 film) 2966(m), 1743(s), 1192(m) cm ; mass spectrum m/z (% rel intensity) 309 + + + M (1), 130(100); HRMS (ESI ) calcd for C20H24NO2 m/z 310.1807 ([M+H] ), 20 meas 310.1784; [α] D –69.2° (c 1.0, CH2Cl2). Synthesis of cis-(2R,3R)-43f from aziridination of the phenethyl chiral imine (R)45f derived from 4-methoxybenzaldehyde. 159 Ph N COOEt MeO cis-(2R,3R)-43f cis-(2R,3R)-43f: The reaction of imine (R)-45f (239 mg, 1.00 mmol) and (S)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a 46% conversion, a >50:1 cis/trans ratio, 3%/5% of enamine products and a 95:5 mixture of cis-(2R,3R)-43f and cis-(2S,3S)-44f. Purification of the major product by column chromatography (silica gel, 40 × 400mm, hexane:CH2Cl2:Et2O 8:1:1) gave cis-(2R,3R)-43f in 35% isolated yield as a yellow oil (114 mg, 0.351 mmol); Rf = 0.15 (hexane:CH2Cl2:Et2O). Spectral data for cis-(2R,3R)-43f: 1 H NMR (300 MHz, CDCl3) δ 1.00 (t, 3H, J = 6.6 Hz), 1.50 (d, 3H, J = 6.6 Hz), 2.58 (d, 1H, J = 6.6 Hz), 2.85 (q, 1H, J = 6.6 Hz), 2.90 (d, 1H, J = 6.9 Hz), 3.75 (s, 3H), 3.884.04 (m, 2H), 6.72-6.80 (m, 2H), 7.16-7.34 (m, 5H), 7.40-7.44 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 14.03, 22.87, 45.98, 47.08, 55.14, 60.61, 69.79, 113.14, 126.90, 127.22, 127.28, 128.34, 128.83, 143.35, 158.79, 168.36; IR (thin film) –1 + 2978(m), 1747(s), 1516(s), 1197(s) cm ; HRMS (ESI ) calcd for C20H24NO3 + 20 m/z 326.1756 ([M+H] ), meas 326.1735; [α] D –57.3° (c 1.0, CH2Cl2). Synthesis of cis-(2R,3R)-43g from aziridination of the phenethyl chiral imine (R)45g derived from cyclohexanecarboxaldehyde. 160 Ph N COOEt cis-(2R,3R)-43g cis-(2R,3R)-43g: The reaction of imine (R)-45g (215 mg, 1.00 mmol) and (S)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a >50:1 cis/trans ratio, no enamine products and a 83:17 mixture of cis-(2R,3R)-43g and cis-(2S,3S)-44g. Purification of the major product by column chromatography (silica gel, 40 × 400 mm, hexane:EtOAc 19:1) gave cis-(2R,3R)-44g in 66% isolated yield as yellow crystals (198 mg, 0.658 mmol); mp 60-62 °C; Rf = 0.20 (hexane:EtOAc 9:1). Spectral data for cis-(2R,3R)-44g: 1 H NMR (300 MHz, CDCl3) δ 0.46-0.52 (m, 1H), 0.80-1.60 (m, 17H), 2.18 (d, 1H, J = 6.9 Hz), 2.50 (q, 1H, J = 6.3 Hz), 4.12-4.30 (m, 2H), 7.20-7.40 (m, 5H); 13 C NMR (75 MHz, CDCl3) δ 14.27, 21.84, 25.37, 25.49, 26.11, 30.11, 30.79, 36.01, 42.81, 51.49, 60.76, 70.29, 127.45, 127.62, 128.16, 143.01, 170.13; IR (thin film) 2924(m), -1 + 1734(s), 1192(m) cm ; HRMS (ESI ) calcd for C19H28NO2 m/z 302.2120 + 20 ([M+H] ), meas 302.2099; [α] D 59.2° (c 1.0, CH2Cl2). The relative stereochemistry of 43g was determined by conversion to 80g and comparison of its physical properties with those previously reported for this compound. Synthesis of cis-(2R,3R)-43h and cis-(2S,3S)-44h from aziridination of the phenethyl chiral imine (R)-45h derived from trimethylacetaldehyde. 161 Ph N COOEt cis-(2R,3R)-43h cis-(2R,3R)-43h: The reaction of imine (R)-45h (189 mg, 1.00 mmol) and (S)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a >50:1 cis/trans ratio, no enamine products and a 91:9 mixture of cis-(2R,3R)-43h and cis-(2S,3S)-44h. Purification of the major product by column chromatography (1 column, silica gel, 40 × 400 mm, hexane:CH2Cl2:Et2O 8:1:1; 2 nd st column, silica gel, 25 × 250 mm, hexane:EtOAc 19:1) gave cis-(2R,3R)-43h (167 mg, 0.607) in 61% isolated yield as white crystals; mp 58-59 °C; Rf = 0.40 (hexane:EtOAc 9:1). The relative stereochemistry of 43h was determined by conversion to aziridine 70 1 (see below). Spectral data for cis-(2R,3R)-43h: H NMR (300 MHz, CDCl3) δ 0.60 (s, 9H), 1.26 (t, 3H, J = 6.9 Hz), 1.46 (d, 3H, J = 6.6 Hz), 1.56 (d, 1H, J = 7.5 Hz), 2.06 (d, 1H, J = 7.2 Hz), 2.48 (q, 1H, J = 6.6 Hz), 4.08-4.30 (m, 2H), 7.207.40 (m, 5H); 13 C NMR (75 MHz, CDCl3) δ 14.13, 22.36, 27.41, 31.37, 42.85, 55.78, 60.65, 71.17, 127.28, 127.54, 128.11, 143.94, 170.18; IR (thin film) –1 2955(m), 1734(s), 1142(w) cm ; mass spectrum m/z (% rel intensity) 274 [M-1] + + + (2), 105(100); HRMS (ESI ) calcd for C17H26NO2 m/z 276.1964 ([M+H] ), meas 20 276.1958; [α] D 101.5° (c 1.0, CH2Cl2). 162 Ph N COOEt cis-(2S,3S)-44h cis-(2S,3S)-44h: The reaction of imine (R)-45h (189 mg, 1.00 mmol) and (R)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a 31% conversion, a >50:1 cis/trans ratio and a 38:62 mixture of cis-(2R,3R)-43h and cis-(2S,3S)-44h. Purification of the products by column chromatography (silica gel, 40 × 400 mm, hexane:EtOAc 19:1) gave cis-(2S,3S)-44h in 20% isolated yield (55 mg, 0.20 mmol) as a pale yellow oil; Rf = 0.45 (hexane:EtOAc 9:1). 1 Spectral data for cis-(2S,3S)-44h: H NMR (300 MHz, CDCl3) δ 0.98 (s, 9H), 1.24 (t, 3H, J = 6.9 Hz), 1.42 (d, 3H, J = 6.6 Hz), 1.64 (d, 1H, J = 7.5 Hz), 1.96 (d, 1H, J = 7.2 Hz), 2.58 (q, 1H, J = 6.6 Hz), 3.94-4.20 (m, 2H), 7.18-7.24 (m, 3H), 7.48-7.52 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 14.02, 24.32, 27.79, 31.61, 42.46, 56.84, 60.44, 70.27, 126.80, 126.92, 128.13, 144.19, 169.85; IR (thin film) –1 + 2961(s), 1751(s), 1188(s), 758(m), 702(m) cm ; HRMS (ESI ) calcd for + 20 C17H26NO2 m/z 276.1964 ([M+H] ), meas 276.1945; [α] D –10.5° (c 1.0, CH2Cl2). Synthesis of cis-(2R,3R)-43i from aziridination of the phenethyl chiral imine (R)45i derived from n-butyraldehyde. 163 Ph N COOEt cis-(2R,3R)-43i cis-(2R,3R)-43i: The reaction of imine (R)-45i (88 mg, 0.50 mmol) and (S)VANOL (22 mg, 0.05 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a >50:1 cis/trans ratio, no enamine products and a 80:20 mixture of cis-(2R,3R)-43i and cis-(2S,3S)-44i. Purification of the product by column chromatography (1 column, silica gel, 28 × 280 mm, hexane:EtOAc 9:1; 2 nd st column, silica gel, 28 × 280 mm, benzene:EtOAc 30:1) gave cis-(2R,3R)-43i (38 mg, 0.15) in 28% isolated yield as a pale yellow oil; Rf = 0.30 (benzene:EtOAc 30:1). Spectral data 1 for cis-(2R,3R)-43i: H NMR (300 MHz, CDCl3) δ 0.70 (t, 3H, J = 7.5 Hz), 0.941.06 (m, 1H), 1.08-1.18 (m, 1H), 1.28 (t, 3H, J = 7.0 Hz), 1.34-1.42 (m, 1H), 1.44 (d, 3H, J = 6.5 Hz), 1.48-1.56 (m, 1H), 1.79 (q, 1H, J = 6.5 Hz), 2.21 (d, 1H, J = 7.0 Hz), 2.57 (q, 1H, J = 6.5 Hz), 4.16-4.28 (m, 2H), 7.22-7.26 (m, 1H), 7.28-7.32 (m, 2H), 7.36-7.40 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 13.57, 14.29, 20.32, 22.54, 29.73, 43.02, 45.97, 60.76, 70.00, 127.11, 127.20, 128.20, 143.53, –1 + 169.94; IR (thin film) 2964(m), 1745(s), 1182(s) cm ; HRMS (ESI ) calcd for + 20 C16H24NO2 m/z 262.1807 ([M+H] ), meas 262.1794; [α] D 68.8° (c 1.0, CH2Cl2). 164 Synthesis of cis-(2R,3R)-43j and trans-(2S,3R)-67j from aziridination of the phenethyl chiral imine (R)-45j derived from 2-bromobenzaldehyde. Ph Br N COOEt cis-(2R,3R)-43j cis-(2R,3R)-24j: The reaction of imine (R)-45j (287 mg, 1.00 mmol) and (S)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a 71:29 cis/trans ratio, 10%/16% enamine products, a 91:9 mixture of cis-(2R,3R)-43j and cis-(2S,3S)-44j and a 67:33 mixture of trans-(2S,3R)-67j and trans-(2R,3S)68j. Purification of the product by column chromatography (silica gel, 40 × 400 mm, hexane:CH2Cl2:Et2O 10:1:1) gave cis-(2R,3R)-43j (180 mg, 0.482) in 48% isolated yield as a pale yellow crystalline solid; mp 48-50 °C; Rf = 0.25 (hexane:EtOAc 9:1). The relative stereochemistry of 43j was confirmed by 1 conversion to aziridine 43a (see below). Spectral data for cis-(2R,3R)-43j: H NMR (300 MHz, CDCl3) δ 0.96 (t, 3H, J = 6.9 Hz), 1.56 (d, 3H, J = 6.0 Hz), 2.72 (d, 1H, J = 6.6 Hz), 2.90 (q, 1H, J = 6.6 Hz), 3.06 (d, 1H, J = 6.6 Hz), 3.86-4.04 (m, 2H), 7.00-7.50 (m, 9H); 13 C NMR (75 MHz, CDCl3) δ 13.88, 22.67, 45.39, 48.20, 60.71, 69.95, 103.93, 126.69, 127.10, 127.57, 128.50, 128.70, 130.85, -1 131.52, 134.72, 143.03, 168.17; IR (thin film) 2976(m), 1749(s), 1197(s) cm ; 165 + + 79 HRMS (ESI ) calcd for C19H21NO2 Br m/z 374.0756 ([M+H] ), meas 374.0769; 20 [α] D –41.2° (c 1.0, CH2Cl2). Ph Br N COOEt trans-(2S,3R)-67j trans-(2S,3R)-67j: The reaction of imine (R)-45j (1.50 g, 5.23 mmol, 1.00 equiv), (R)-VAPOL (282 mg, 0.523 mmol, 0.100 equiv), triphenyl borate (607 mg, 2.09 mmol, 0.400 equiv), H2O (9.4 mg, 0.52 mmol, 0.10 equiv), EDA (716 mg, 6.28 mmol, 1.20 equiv) in toluene (10 mL) was performed according to the General Procedure (Method chromatography (1 10:1:1; 2 nd st A). Purification of the major product by column column, silica gel, 40 × 400 mm, hexane:CH2Cl2:Et2O column, silica gel, 40 × 400 mm, hexane:EtOAc 19:1; 3 rd column, silica gel, 40 × 400 mm, hexane:EtOAc 30:1) gave the pure aziridine trans(2S,3R)-67j (613 mg, 1.70 mmol) in 32% isolated yield as a colorless oil; Rf = 0.35 (hexane:EtOAc 9:1). The relative stereochemistry of 67j was confirmed by conversion to (S)-phenylalanine ethyl ester 69. Spectral data for trans-(2S,3R)1 67j: H NMR (300 MHz, CDCl3) δ 1.20-1.34 (m, 6H), 2.59 (d, 1H, J = 2.7 Hz), 3.42 (d, 1H, J = 2.4 Hz), 4.04 (q, 1H, J = 6.6 Hz), 4.25 (q, 2H, J = 7.2 Hz), 6.907.48 (m, 9H); 13 C NMR (300 MHz, CDCl3) δ 14.29, 22.85, 43.82, 48.49, 59.59, 61.32, 123.49, 127.30, 128.00, 128.44, 128.67, 131.90, 137.45, 144.19, 168.72 166 2 (Two sp carbons not located); 13 C NMR (300 MHz, DMSO-d6) δ 14.12, 22.66, 43.48, 47.55, 59.08, 61.20, 122.74, 127.04, 127.37, 127.63, 127.73, 128.46, 129.37, 131.96, 136.73, 143.82, 167.80; IR (thin film) 2976(w), 1728(s), 1188(s) -1 + cm ; mass spectrum m/z (% rel intensity) 376 [M+1] (0.20, (0.20, 79 + 81 Br), 374 [M+1] + 79 Br), 105(100); HRMS (ESI ) calcd for C19H21NO2 Br m/z 374.0756 + 20 ([M+H] ), meas 374.0764; [α] D 39.8° (c 1.0, CH2Cl2). Synthesis of trans-(2S,3R)-67k from aziridination of the phenethyl chiral imine (R)-45k derived from 2-iodobenzaldehyde. Ph I N COOEt trans-(2S,3R)-67k trans-(2S,3R)-67k: The reaction of imine (R)-45k (335 mg, 1.00 mmol) and (S)VAPOL (54 mg, 0.10 mmol) was performed according to the General Procedure (Method A). The 1 H NMR spectrum of the crude mixture showed a 50:50 cis/trans ratio, 11%/17% enamine products, a 94:6 mixture of cis-(2R,3R)-43k and cis-(2S,3S)-44k and a 67:33 mixture of trans-(2S,3R)-67k and trans-(2R,3S)68k. Purification of the major trans aziridine by column chromatography (silica gel, 40 × 400 mm, hexane:CH2Cl2:Et2O 30:1:1) gave trans-(2S,3R)-67k (65 mg, 0.15 mmol) in 15% isolated yield as a colorless oil; Rf = 0.35 (hexane:EtOAc 1 9:1). Spectral data for trans-(2S,3R)-67k: H NMR (300 MHz, CDCl3) δ 1.20-1.40 (m, 6H), 2.75 (d, 1H, J = 2.7 Hz), 3.26 (d, 1H, J = 2.4 Hz), 4.00 (q, 1H, J = 6.6 167 Hz), 4.20-4.30 (m, 2H), 6.76-6.82 (m, 1H), 6.90-7.28 (m, 5H), 7.40-7.48 (m, 2H), 7.58-7.64 (m, 1H); 13 C NMR (300 MHz, CDCl3) δ 14.36, 22.70, 43.96, 53.05, 59.60, 61.31, 98.40, 127.36, 128.05, 128.45, 128.96, 138.30, 140.33, 144.12, 2 168.70 (Two sp carbons not located); 13 C NMR (300 MHz, DMSO-d6) δ 14.18, 22.55, 43.60, 52.30, 59.03, 61.12, 98.80, 127.10, 127.40, 128.16, 128.45, 2 129.45, 138.25, 139.69, 143.81, 167.81 (One sp carbon not located); IR (thin –1 + film) 2976(w), 1728(s), 1188(s) cm ; HRMS (ESI ) calcd for C19H21NO2I m/z + 20 422.0617 ([M+H] ), meas 422.0626; [α] D 59.4° (c 1.0, CH2Cl2). Synthesis of trans-(2S,3R)-71a and trans-(2R,3S)-72a from aziridination of the phenethyl chiral imine (R)-45a Derived from benzaldehyde. Ph N CONHPh trans-(2S,3R)-71a trans-(2S,3R)-71a: The General Procedure (Method B) was followed with imine (R)-45a (42 mg, 0.20 mmol, 1.0 equiv) and (S)-VAPOL (11 mg, 0.020 mmol, 0.10 1 equiv) with a reaction time of 20 hours. Upon workup, the H NMR spectrum of the crude mixture indicated a 79:21 trans:cis ratio and a 60:40 mixture of trans(2S,3R)-71a/trans-(2R,3S)-72a and an 83:17 mixture of cis-(2R,3R)-73a/cis(2S,3S)-74a, along with 11% and 19% enamine products 75/76. The major product was separated by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 9:1) and trans-(2S,3R)-71a was obtained as a white solid (12 mg, 168 o 0.05 mmol, 25%); mp 47-49 C; Rf = 0.30 (hexane:EtOAc 4:1). The relative stereochemistry of 71a was confirmed by conversion to 77a. Spectral data for 1 trans-(2S,3R)-71a: H NMR (500 MHz, CDCl3) δ 1.16 (d, 3H, J = 6.0 Hz), 2.90 (s, 1H), 3.06 (d, 1H, J = 6.5 Hz), 3.62 (s, 1H), 7.00-7.80 (m, 15H), 8.60 (brs, 1H); 1 H NMR (500 MHz, DMSO-d6) δ 1.14 (d, 3H, J = 6.5 Hz), 2.96 (d, 1H, J = 2.5 Hz), 3.26 (d, 1H, J = 2.0 Hz), 4.24 (q, 1H, J = 6.5 Hz), 7.00-7.70 (m, 15H), 10.64 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 22.96, 42.35, 49.80, 59.21, 119.74, 124.40, 126.98, 127.89, 128.71, 128.90, 129.05, 129.27, 130.35, 131.46, 137.82, 143.98, 168.22; 13 C NMR (125 MHz, DMSO-d6) δ 23.50, 45.66, 46.98, 58.08, 119.25, 123.66, 125.85, 126.64, 126.74, 127.08, 128.16, 128.23, 128.79, 138.78, 138.96, 144.87, 165.24; IR (thin film) 3312(m), 3061(m), 2972(m), 1653(s), -1 + 1541(s) cm ; HRMS (ESI ) exact mass calcd for C23H22N2ONa m/z + 20 365.1630([M+Na] ), meas 365.1661; [α] D 72.6° (c 0.5, CH2Cl2). Ph N CONHPh trans-(2R,3S)-72a trans-(2R,3S)-72a: The General Procedure (Method B) was followed with imine (R)-45a (105 mg, 0.500 mmol, 1.00 equiv) and (S)-VAPOL (27 mg, 0.050 mmol, 0.10 equiv) in toluene (2 mL) with a reaction time of 22 hours. The reaction mixture was concentrated and the products were purified by column chromatography (1 st column, silica gel, 20 × 200 mm, hexane:EtOAc 9:1; 2 169 nd column, silica gel, 20 × 180 mm, benzene:EtOAc 15:1) to give trans-(2S,3R)-71a as a white solid (47 mg, 0.054 mmol, 11%). After the first column, the fraction containing the product trans-(2R,3S)-72a was collected and concentrated. This was combined with fractions containing trans-(2R,3S)-72a from two different reactions (0.2 mmol) of imine (R)-45a with (S)-VAPOL and (S)-VANOL borate catalysts and this aziridine was purified by column chromatography (1 silica gel, 20 × 200 mm, benzene:EtOAc 9:1; 2 nd st column, column, silica gel, 18 × 180 mm, benzene:EtOAc 15:1) to give trans-(2R,3S)-72a as a white foamy solid (32 o mg, 0.094 mmol, 11%); mp 130-132 C; Rf = 0.45 (hexane:EtOAc 4:1). Spectral 1 data for trans-(2R,3S)-72a: H NMR (500 MHz, CDCl3) δ 1.50 (d, 3H, J = 6.0 1 Hz), 3.16-2.96 (m, 2H), 3.55 (s, 1H), 6.90-7.80 (m, 15H), 8.80 (brs, 1H); H NMR (600 MHz, DMSO-d6) δ 1.35 (d, 3H, J = 7.0 Hz), 2.82 (s, 1H), 3.45 (s, 1H), 4.29 (q, 1H, J = 7.2 Hz), 7.00-7.50 (m, 15H), 10.21 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 23.90, 42.37, 49.01, 58.86, 119.50, 124.23, 126.54, 126.94, 127.82, 128.03, 128.24, 129.03, 130.13, 131.34, 137.50, 143.57, 168.33; IR (thin film) -1 + 3300(m), 3060(m), 2970(m), 1653(s), 1539(s) cm ; HRMS (ESI ) calcd for + 20 C23H22N2ONa m/z 365.1630 ([M+Na] ), meas 365.1650; [α] D 7.1° (c 1.0, CH2Cl2). Determination of the relative configuration of cis-(2R,3R)-73a and cis-(2S,3S)74a: 170 Ph Ph N N CONHPh 1 DMAP, Boc2O cis-(2R,3R)-73a + Ph 2 NaOEt, EtOH N 5:1 CONHPh cis-(2S,3S)-74a COOEt cis-(2R,3R)-43a + Ph N COOEt cis-(2R,3R)-44a 5:1 The stereochemistry of cis-isomers from the reaction of (R)-45a and diazoacetamide 19 was determined by the following reaction. The General Procedure (Method B) was followed with imine (R)-45a (105 mg, 0.500 mmol, 1.00 equiv) and 10 mol% (S)-VANOL borate catalyst with a reaction time of 20 hours. After concentration, the cis products were purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 4:1) to give a 5:1 mixture (30 mg, 0.090 mmol, 18%) of cis-(2R,3R)-73a and cis-(2S,3S)-74a free of trans-aziridines. To a solution of the above mixture (30 mg, 0.090 mmol, 1.0 equiv) in a mixture of dry CH3CN and CH2Cl2 (v:v 9:1, 2 mL) were added DMAP (22 mg, 0.18 mmol, 2.0 equiv) and Boc2O (59 mg, 0.27 mmol, 3.0 equiv). After the mixture was stirred at rt overnight (~12 hours), it was concentrated and the products were purified by column chromatography (silica gel, 15 × 150 mm, hexane:EtOAc 9:1) to give the activated amide intermediates as a pale yellow oil which was dissolved in absolute ethanol (1 mL). To the mixture was added a solution of NaOEt in ethanol (21% by weight, 62 mg, 70 µL, 0.18 mmol, 2.0 equiv) at 0 °C dropwise under N2. The resulting mixture was stirred at 0 °C for 1 171 hour under N2. The reaction was quenched with aq sat NH4Cl (1 mL). Ethanol was removed by rotary evaporation and H2O (2 mL) was added. The mixture was extracted with CH2Cl2 (3 × 10 mL). The organic extracts were combined and dried (Na2SO4). This mixture was then filtered and concentrated to give the 1 crude product 73a and 74a. The H NMR spectra of this mixture was taken and revealed to be a mixture of cis-(2R,3R)-73a and cis-(2S,3S)-74a in a ratio of 5:1. The major product was then purified by column chromatography (silica gel, 15 × 150 mm, hexane:EtOAc 15:1) to give the cis-(2R,3R)-73a as a white solid (19 mg, 0.078 mmol, 87%) which has spectral data identical to the major product isolated from the reaction of chiral imine (R)-45a with EDA 5 catalyzed by (S)VAPOL borate. Synthesis of trans-(2S,3R)-71g and trans-(2R,3S)-72g from aziridination of the phenethyl chiral imine (R)-45g derived from cyclohexanecarboxaldehyde. Ph N CONHPh trans-(2S,3R)-71g trans-(2S,3R)-71g: The General Procedure (Method B) was followed with imine (R)-45g (44 mg, 0.20 mmol, 1.0 equiv) and (S)-VAPOL (11 mg, 0.020 mmol, 0.10 1 equiv) with a reaction time of 21 hours. Upon workup, the H NMR spectrum of the crude mixture indicated a >96:4 mixture of trans-(2S,3R)-71g/trans-(2R,3S)72g. After purification by column chromatography (1 172 st column, silica gel, 20 × 200 mm, hexane:EtOAc 5:1; 2 nd column, silica gel, 18 × 180 mm, hexane:acetone 9:1), the product trans-(2S,3R)-71g was obtained as a white o solid (54 mg, 0.39 mmol, 78%); mp 125-126 C; Rf = 0.075 (hexane:EtOAc 4:1). 1 Spectral data for trans-(2S,3R)-71g: H NMR (600 MHz, CDCl3) δ 0.40-2.50 (m, 1 16H), 3.40 (q, 1H, J = 5.4 Hz), 7.00-7.64 (m, 10H), 8.38 (brs, 1H); H NMR (500 MHz, DMSO-d6) δ 0.40-1.90 (m, 14H), 2.02 (dd, 1H, J = 7.0, 2.5 Hz), 2.67 (d, 1H, J = 3.0 Hz), 3.82 (q, 1H, J = 6.0 Hz), 6.90-7.80 (m, 10H), 10.53 (brs, 1H); 13 C NMR (150 MHz, CDCl3) δ 24.55, 25.84, 26.07, 26.18, 32.41, 33.32, 34.77, 43.15, 53.74, 59.88, 119.44, 124.02, 126.82, 127.75, 128.95, 129.10, 137.90, 144.33, 168.92; 13 C NMR (150 MHz, DMSO-d6) δ 22.55, 25.02, 25.22, 25.71, 29.43, 29.69, 36.18, 41.18, 49.68, 58.48, 119.10, 123.38, 126.97, 127.35, 128.07, 128.73, 139.01, 144.86, 166.47; IR (thin film) 3372(m), 2905(m), 1686(s), -1 + + 1548(m) cm ; HRMS (ESI ) calcd for C23H29N2O m/z 349.2280 ([M+H] ), meas 20 349.2300; [α] D –98.2° (c 1.0, CH2Cl2). Ph N CONHPh trans-(2R,3S)-72g trans-(2R,3S)-72g: The General Procedure (Method B) was followed with imine (R)-45g (44 mg, 0.20 mmol, 1.0 equiv) and (R)-VAPOL (11 mg, 0.020 mmol, 0.10 1 equiv) with a reaction time of 21 hours. Upon workup, the H NMR spectrum of 173 the crude mixture indicated a 67:33 mixture of trans-(2S,3R)-71g and trans(2R,3S)-72g. After purification by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 5:1), the major product trans-(2S,3R)-71g was obtained as a white solid (40 mg, 0.12 mmol, 59%). The fraction containing trans-(2R,3S)-72g was loaded onto a chromatography column (silica gel, 18 × 180 mm, benzene:EtOAc 30:1) and elution afforded pure trans-(2R,3S)-72g as a white solid (14 mg, 0.040 mmol, 20%); mp 163-165 °C; Rf = 0.28 (hexane:EtOAc 4:1). 1 Spectral data for trans-(2R,3S)-72g: H NMR (500 MHz, CDCl3) δ 0.60-1.90 (m, 14H), 2.06 (dd, 1H, J = 8.3, 2.5 Hz), 2.14 (d, 1H, J = 2.5 Hz), 3.44 (q, 1H, J = 6.0 Hz), 7.56-7.62 (m, 10H), 8.60 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 24.90, 25.31, 25.87, 25.91, 32.00, 32.30, 35.04, 43.61, 52.85, 59.67, 119.28, 123.95, 126.26, 127.20, 128.45, 128.98, 137.70, 144.76, 169.10; IR (thin film) 3328(m), –1 + 2930(m), 1683(s), 1621(m) cm ; HRMS (ESI ) calcd for C23H29N2O m/z + 20 349.2280 ([M+H] ), meas 349.2269; [α] D 62.9° (c 1.0, CH2Cl2). Synthesis of trans-(2S,3R)-71h from aziridination of the phenethyl chiral imine (R)-45h derived from trimethylacetaldehyde. Ph N CONHPh trans-(2S,3R)-71h trans-(2S,3R)-71h: The General Procedure (Method B) was followed with imine (R)-45h (38 mg, 0.20 mmol, 1.0 equiv) and (S)-VAPOL (11 mg, 0.020 mmol, 0.10 174 1 equiv) with a reaction time of 22 hours. Upon workup, the H NMR spectrum of the crude mixture indicated 87% conversion and a 97:3 mixture of trans-(2S,3R)71h/trans-(2R,3S)-72h. After purification by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 9:1), trans-(2S,3R)-71h was obtained as a white foamy solid (45 mg, 0.14 mmol, 69%); mp 54-56 °C; Rf = 0.20 (hexane:EA 4:1). 1 Spectral data for trans-(2S,3R)-71h: H NMR (500 MHz, CDCl3) δ 0.60 (s, 9H), 1.32 (d, 3H, J = 6.0 Hz), 2.27 (d, 1H, J = 3.0 Hz), 2.48 (d, 1H, J = 3.0 Hz), 3.92 (q, 1H, J = 6.0 Hz), 7.15 (t, 1H, J = 7.5 Hz), 7.20-7.28 (m, 1H), 7.32 (t, 2H, J = 8.0 Hz), 7.38 (t, 2H, J = 8.0 Hz), 7.43 (d, 2H, J = 7.5 Hz), 7.58 (d, 2H, J = 8.0 Hz), 7.78 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 22.9, 26.6, 30.4, 40.0, 55.3, 59.8, 119.9, 124.6, 127.1, 127.8, 128.1, 129.1, 137.7, 145.1, 166.8; IR (thin film) –1 + 3298(m), 2961(m), 1653(s), 1558(s) cm ; HRMS (ESI ) calcd for C21H27N2O + 20 m/z 323.2123 ([M+H] ), meas 323.2107; [α] D 94.1° (c 1.0, CH2Cl2); Recrystallization from hexane gave crystals suitable for X-ray analysis, which revealed the relative stereochemistry of trans-71h. Synthesis of trans-(2S,3R)-71i and trans-(2R,3S)-72i from aziridination of the phenethyl chiral imine (R)-45i derived from n-butyraldehyde. Ph N CONHPh trans-(2S,3R)-71i 175 trans-(2S,3R)-71i: The General Procedure (Method B) was followed with imine (R)-45i (35 mg, 0.20 mmol, 1.0 equiv) and (S)-VAPOL (11 mg, 0.020 mmol, 0.10 1 equiv) with a reaction time of 15 hours. Upon workup, the H NMR spectrum of the crude mixture indicated a 52:48 mixture of trans-(2S,3R)-71i/trans-(2R,3S)st 72i. After purification by column chromatography (1 column, silica gel, 20 × 200 mm, hexane:EtOAc 5:1; 2 nd column, silica gel, 18 × 180 mm, hexane:acetone 9:1), the product trans-(2S,3R)-71i was obtained as a white solid (9 mg, 0.03 mmol, 15%) after two columns. The fractions containing trans-(2R,3S)-72i were collected, concentrated and then the aziridine was purified by a separate column chromatography (silica gel, 18 × 180 mm, benzene:EtOAc 30:1 to 20:1) to give pure trans-(2R,3S)-72i as a colorless oil (9 mg, 0.03 mmol, 15%), solidified during storage, mp 57-58 °C; Rf = 0.05 (hexane:EtOAc 5:1); Spectral data for 1 trans-(2S,3R)-71i: H NMR (500 MHz, CDCl3) δ 1.02 (t, 3H, J = 7.5 Hz), 1.46 (d, 3H, J = 6.0 Hz), 1.50-1.70 (m, 3H), 1.90-1.98 (m, 1H), 2.00 (d, 1H, J = 3.0 Hz), 2.32-2.39 (m, 1H), 3.36 (q, 1H, J = 6.5 Hz), 7.04 (t, 1H, J = 7.5 Hz), 7.20-7.40 (m, 7H), 7.46 (d, 2H, J = 7.5 Hz), 8.37 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 13.96, 21.51, 23.79, 27.82, 44.58, 46.83, 60.13, 119.24, 123.84, 126.62, 127.58, 128.73, 128.92, 137.65, 143.93, 168.52; IR (thin film) 3312(m), 2968(m), –1 + 1682(m), 1528(s) cm ; HRMS (ESI ) calcd for C20H25N2O m/z 309.1967 + 20 ([M+H] ), meas 309.1950; [α] D –207.3° (c 0.5, CH2Cl2). 176 Ph N CONHPh trans-(2R,3S)-72i 1 Spectral data for trans-(2R,3S)-72i: Rf = 0.20 (hexane:EtOAc 5:1); H NMR (500 MHz, CDCl3) δ 0.82 (t, 3H, J = 7.5 Hz), 1.14-1.54 (m, 7H), 2.17 (d, 1H, J = 2.5 Hz), 2.22-2.30 (m, 1H), 3.44 (q, 1H, J = 6.5 Hz), 7.08 (t, 1H, J = 7.5 Hz), 7.207.50 (m, 7H), 7.58 (d, 2H, J = 8.0 Hz), 8.61 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 13.72, 21.27, 24.58, 28.11, 44.90, 46.74, 59.56, 119.34, 124.00, 126.27, 127.14, 128.48, 129.00, 137.63, 144.46, 168.96; IR (thin film) 3310(m), -1 + 2963(m), 1683(m), 1525(s) cm ); HRMS (ESI ) calcd for C20H25N2O m/z + 20 309.1967 ([M+H] ), meas 309.1974; [α] D 48.4° (c 0.5, CH2Cl2). Synthesis of trans-(2S,3R)-67a from trans-(2S,3R)-67j via reduction with tin hydride: Ph Br N COOEt n-Bu3SnH AIBN, Benzene trans-67j Ph N COOEt trans-67a 68% To a flame dried 25 mL Schlenk flask was added trans-(2S,3R)-67j (120 mg, 0.320 mmol, 1.00 equiv) in dry benzene (2 mL), followed by the addition of Bu3SnH (280 mg, 0.260 mL, 0.960 mmol, 3.00 equiv) and AIBN (10 mg) under a stream of N2. Then the flask was sealed and stirred at 50 °C for 24 h. aq sat KF 177 (10 mL) was added to the mixture to quench the reaction. The aqueous layer was separated and extracted with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated. After purification by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 9:1), the product trans(2S,3R)-67a (64 mg, 0.22 mmol) was obtained in 68% yield as a colorless oil; Rf 1 = 0.63 (hexane:EtOAc 4:1). Spectral data for trans-(2S,3R)-67a: H NMR (300 MHz, CDCl3) δ 1.24-1.34 (m, 6H), 3.08 (d, 1H, J = 2.1 Hz), 3.28 (d, 1H, J = 2.4 Hz), 4.10-4.40 (m, 3H), 7.20-7.44 (m, 10H); 13 C NMR (300 MHz, CDCl3) δ 14.22, 23.50, 44.62, 47.97, 59.36, 61.23, 126.22, 126.91, 127.29, 128.21, 128.26, 2 138.267, 144.54, 168.88 (One sp carbon not located); IR (thin film) 2976(w), -1 + 1728(s), 1188(s) cm ; HRMS (ESI ) calcd for C19H21NO2 m/z 296.1651 + 20 ([M+H] ), meas 296.1664; [α] D 55.0° (c 1.0, CH2Cl2). Synthesis of trans-(2S,3R)-71a from trans-(2S,3R)-67a via conversion of an amide group to an ester: Ph N 1) Boc2O, DMAP 2) EtONa, EtOH CONHPh trans-(2S,3R)-71a Ph N COOEt trans-(2S,3R)-67a 96% To a 25 mL round bottom flask filled with N2 was added (2S,3R)-71a (146 mg, 0.426 mmol, 1.00 equiv), di-tert-butyl dicarbonate (278 mg, 1.28 mmol, 3.00 equiv), 4-dimethylaminopyridine (DMAP, 104 mg, 0.852 mmol, 2.00 equiv) and a 178 solvent mixture of CH3CN and CH2Cl2 (v:v 9:1, 5 mL). The vacuum adapter was replaced with a rubber septum to which a N2 balloon was attached via a needle. The resulting mixture was stirred at rt overnight (~12 h). After the solution was concentrated, the crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 9:1) to give the activated amide intermediate as a foamy solid. This material was introduced into a 25 mL single neck round bottom flask and a N2 ballon was attached via a rubber septum in the neck of the flask. Absolute EtOH (2 mL) was added via syringe. The resulting solution was cooled to 0 °C. A solution of NaOEt solution (21wt%, 0.32 mL, 0.85 mmol, 2.0 equiv) was added dropwise via syringe at 0 °C. The mixture was stirred at 0 °C for 1 hour, and then aq sat NH4Cl (1 mL), water (1 mL) and CH2Cl2 (10 mL) were added. The aqueous layer was separated and extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and the product was purified by column chromatography (1 column, silica gel, 28 × 200 mm, hexane:EtOAc 15:1; 2 nd st column, silica gel, 28 × 200 mm, hexane:EtOAc 15:1) and (2S,3R)-67a (120 mg, 0.41 mmol, 96%) was obtained as a colorless oil. The spectral data were identical to the compound prepared by reduction of 67j with tin hydride described above. Synthesis of trans-(2R,3S)-71g from trans-(2R,3S)-67g via conversion of an amide group to an ester: 179 Ph Ph 1) Boc2O, DMAP N CONHPh 2) EtONa, EtOH trans-(2S,3R)-71g N COOEt trans-(2S,3R)-67g 77% The procedure described above for the synthesis of trans-(2S,3R)-71g from trans-(2S,3R)-67g was followed. Amide activation proceeded with trans-(2S,3R)71g (100 mg, 0.287 mmol, 1.00 equiv), di-tert-butyl dicarbonate (188 mg, 0.860 mmol, 3.00 equiv), 4-dimethylaminopyridine (DMAP, 70 mg, 0.57 mmol, 2.00 equiv). Ester formation was achieved with a solution of NaOEt (21wt%, 0.22 mL, 0.57 mmol, 2.0 equiv). The product was purified by column chromatography (silica gel, 18 × 300 mm, hexane:EtOAc 15:1) which gave trans-(2S,3R)-67g (66 mg, 0.22 mmol, 77%) as a colorless oil which solidified as a white solid during storage in the refrigerator; mp 36-37 °C; Rf = 0.45 (hexane:EtOAc 4:1). Spectral 1 data for trans-(2S,3R)-67g: H NMR (500 MHz, CDCl3) δ 0.40-0.56 (m, 1H), 0.80-1.10 (m, 6H), 1.26 (d, 3H, J = 6.5 Hz), 1.31 (t, 3H, J = 7.5 Hz), 1.34-1.64 (m, 4H), 1.99 (dd, 1H, J = 7.5, 3.0 Hz), 2.53 (d, 1H, J = 3.0 Hz), 3.73 (q, 1H, J = 6.5 Hz), 4.14-4.30 (m, 2H), 7.20-7.26 (m, 1H), 7.26-7.32 (t, 2H, J = 8.0 Hz), 7.37 (d, 2H, J = 8.5 Hz); 13 C NMR (125 MHz, CDCl3) δ 14.25, 22.10, 25.49, 25.68, 26.10, 29.85, 30.15, 39.84, 40.59, 52.15, 59.60, 60.99, 127.27, 127.66, 128.24, 144.28, –1 + 169.97; IR (thin film) 2926(m), 1720(s), 1190(s) cm ; HRMS (ESI ) calcd for + 20 C19H28NO2 m/z 302.2120 ([M+H] ), meas 302.2129; [α] D 64.6° (c 1.0, CH2Cl2). 180 Synthesis of trans-(2R,3S)-71h from trans-(2R,3S)-67h via conversion of an amide group to an ester: Ph N 1) Boc2O, DMAP 2) EtONa, EtOH CONHPh trans-(2S,3R)-71h Ph N COOEt trans-(2S,3R)-67h 95% The procedure described above for the synthesis of trans-(2S,3R)-71a from trans-(2S,3R)-67a was followed. Amide activation was performed on trans(2S,3R)-71h (198 mg, 0.615 mmol, 1.00 equiv), di-tert-butyl dicarbonate (404 mg, 1.85 mmol, 3.00 equiv) and 4-dimethylaminopyridine (DMAP, 150 mg, 1.23 mmol, 2.00 equiv). Ester formation resulted upon treatment with a NaOEt solution (21wt%, 0.46 mL, 1.2 mmol, 2.0 equiv). The product trans-(2S,3R)-67h (160 mg, 0.582 mmol, 95%) was obtained as a colorless oil; Rf = 0.57 1 (hexane:EtOAc 4:1). Spectral data for trans-(2S,3R)-67h: H NMR (500 MHz, CDCl3) δ 0.57 (s, 9H), 1.24 (d, 3H, J = 6.5 Hz), 1.32 (t, 3H, J = 7.5 Hz), 2.05 (d, 1H, J = 3.0 Hz), 2.55 (d, 1H, J = 3.0 Hz), 3.75 (q, 1H, J = 6.5 Hz), 4.14-4.30 (m, 2H), 7.18-7.23 (m, 1H), 7.26-7.32 (m, 2H), 7.36-7.40 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 14.27, 22.71, 26.45, 30.44, 36.80, 56.58, 60.12, 60.91, 127.15, -1 127.79, 128.14, 145.05, 170.34; IR (thin film) 2961(m), 1728(s), 1186(s) cm ; + + HRMS (ESI ) calcd for C17H26NO2 m/z 276.1964 ([M+H] ), meas 276.1956; 20 [α] D 93.5° (c 1.0, CH2Cl2). 181 Synthesis of trans-(2R,3S)-71i from trans-(2R,3S)-67i via conversion of an amide group to an ester: Ph N 1) Boc2O, DMAP 2) EtONa, EtOH CONHPh trans-(2S,3R)-71i Ph N COOEt trans-(2S,3R)-67i 83% The procedure described above for the synthesis of trans-(2S,3R)-71a from trans-(2S,3R)-67a was followed. The activated amide was prepared from trans(2S,3R)-71i (170 mg, 0.550 mmol, 1.00 equiv), di-tert-butyl dicarbonate (362 mg, 1.66 mmol, 3.00 equiv) and 4-dimethylaminopyridine (DMAP, 134 mg, 1.10 mmol, 2.00 equiv). The ester was prepared by subsequent treatment with a NaOEt solution (21wt%, 0.41 mL, 1.1 mmol, 2.0 equiv). The product was partially purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 15:1) to give a material that was contamined with Boc protected aniline (PhNHBoc). This was removed by dissolving the crude product in hexanes and filtering off the white solid. The procedure was repeated several times until no solids could be observed. The pure product trans-(2S,3R)-67i (120 mg, 0.460 mmol, 83%) was obtained as a colorless oil; Rf = 0.40 (hexane:EtOAc 4:1). 1 Spectral data for trans-(2S,3R)-67i: H NMR (500 MHz, CDCl3) δ 0.67 (t, 3H, J = 6.0 Hz), 0.82-1.16 (m, 2H), 1.14-1.36 (m, 7H), 1.42 (d, 1H, J = 7.5 Hz), 2.16 (td, 1H, J = 5.0, 2.5 Hz), 2.51 (d, 1H, J = 2.5 Hz), 3.78 (q, 1H, J = 5.5 Hz), 4.18-4.28 (m, 2H), 7.18-7.44 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 13.57, 14.28, 20.00, 22.68, 34.61, 40.96, 46.52, 59.32, 61.03, 127.13, 127.30, 128.28, 144.57, 182 -1 + 169.87; IR (thin film) 2964(m), 1728(s), 1188(s) cm ; HRMS (ESI ) calcd for + 20 C16H24NO2 m/z 262.1807 ([M+H] ), meas 262.1806; [α] D 51.2° (c 1.0, CH2Cl2). 7.1.4 Catalytic hydrogenolysis of aziridines General Procedure for the Synthesis of N-Boc Alanine Derivatives via Hydrogenolysis: To a flame-dried 25 mL round bottom flask filled with N2 was added the aziridine (0.50 mmol, 1.00 equiv), MeOH (5 mL), Pearlman’s catalyst (20% Pd(OH)2 on carbon, moisture ca 60%, 85 mg, 0.050 mmol, 0.10 equiv) and (Boc)2O (220 mg, 1.00 mmol, 2.00 equiv). The flask was equipped with a vacuum transfer adapter connected with vacuum and a H2 balloon. The valve to vacuum was opened for a few seconds and then switched to the H2 balloon. This process was repeated for 3 additional times. The suspension was stirred at rt under a H2 balloon for 6 hours. Then the mixture was filtered through a Celite pad on a sintered glass funnel and washed well with MeOH. The filtrate was concentrated by rotary evaporation, followed by purification of the product by column chromatography on silica gel. Synthesis of N-Boc phenylalanine derivative 78a via reductive ring opening of aziridine 43a: 183 Ph N H2 (1 atm) CO2Et Pd(OH)2/C (10 mol%) NHBoc Boc2O, MeOH, 6 h COOEt cis-(2R,3R)-43a (R)-78a 94% The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with cis-(2R,3R)-43a (149 mg, 0.500 mmol, 1.00 equiv). Purification of the product by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 15:1) provided (R)-78a (140 mg, 0.476 mmol, 94%) as a colorless oil. The optical purity was determined to be >99% ee by HPLC analysis (Chiralpak AS column, 85:15 hexane/2-propanol at 222 nm, flow rate 0.2 mL/min); Retention times: Rt = 25.12 min and Rt = 30.07 min for its enantiomer; 1 Rf = 0.35 (hexane:EtOAc 4:1). Spectral data for (R)-78a: H NMR (500 MHz, CDCl3) δ 1.20 (t, 3H, J = 7.0 Hz), 1.30 (s, 9H), 2.84-3.10 (m, 2H), 4.10 (q, 2H, J = 7.0 Hz), 4.50 (q, 1H, J = 12.5, 5.5 Hz), 4.96 (d, 1H, J = 7.0 Hz), 7.10 (d, 2H, J = 1 6.5 Hz), 7.18-7.28 (m, 3H); H NMR (500 MHz, toluene-d6) δ 0.90 (t, 3H, J = 7.0 Hz), 1.35 (s, 9H), 2.83 (dd, 1H, J = 13.5, 6.0 Hz), 2.96 (dd, 1H, J = 14.0, 6.0 Hz), 3.60-3.90 (m, 2H), 4.62 (dd, 1H, J = 7.5, 5.0 Hz), 4.96 (d, 1H, J = 6.5 Hz), 6.801 o 7.20 (m, 5H); H NMR (500 MHz, toluene-d6, 80 C) δ 0.90 (t, 3H, J = 7.0 Hz), 1.35 (s, 9H), 2.83 (dd, 1H, J = 14.0, 6.5 Hz), 2.96 (dd, 1H, J = 13.5, 6.0 Hz), 3.80-3.90 (m, 2H), 4.56 (dd, 1H, J = 7.5, 5.0 Hz), 4.83 (d, 1H, J = 6.5 Hz), 6.807.20 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 14.04, 28.24, 38.34, 54.41, 61.23, 79.77, 126.89, 128.41, 129.30, 136.06, 155.03, 171.81; IR (thin film) 3364(m), 184 –1 2980(m), 1734(s), 1716(s), 1701(s) cm ; mass spectrum m/z (% rel intensity) + 20 20 237 [M-57] (20), 176(100), 120(88); [α] D –37.6° (c 1.0, CH2Cl2), [α] D 4.5° (c 20 1.0, MeOH) (Lit: [α] D –3.7° (c 1.0, MeOH)). 28a The sign of the optical rotation of 78a in MeOH allows for the assignment of the relative stereochemistry of 43a as R. Synthesis of N-Boc 4-methylphenylalanine derivative 43d via reductive ring opening of aziridine 78d: H2 (1 atm) Ph CO2Et Pd(OH)2/C (10 mol%) N COOEt NHBoc Boc2O, MeOH, 6 h (R)-78d cis-(2R,3R)-43d 99% The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with cis-(2R,3R)-43d (155 mg, 0.500 mmol, 1.00 equiv). Purification of the product by column chromatography (silica gel, 25 × 200 mm, hexane:EtOAc 15:1) provided (R)-78d (154 mg, 0.50 mmol, 99%) as a colorless oil. The optical purity was determined to be >99% ee by HPLC analysis (Chiralcel OD-H column, 99:1 hexane/2-propanol at 222 nm, flow-rate 0.25 mL/min); Retention times Rt = 26.18 min and Rt = 29.45 min for its enantiomer. 1 Spectral data for (R)-78d: H NMR (500 MHz, CDCl3) δ 1.20 (t, 3H, J = 7.5 Hz), 1.42 (s, 9H), 2.30 (s, 3H), 2.90-3.10 (m, 2H), 4.14 (dd, 2H, J = 10.5, 7.5 Hz), 4.50 (dd, 1H, J = 8.0, 5.0 Hz), 4.94 (d, 1H, J = 6.0 Hz), 6.99 (d, 2H, J = 7.5 Hz), 7.06 (d, 2H, J = 7.5 Hz); 13 C NMR (125 MHz, CDCl3) δ 14.00, 20.91, 28.17, 37.71, 185 54.37, 61.11, 79.58, 129.04, 129.09, 132.80, 136.33, 154.99, 171.80; IR (thin -1 film) 3443(m), 3370(m), 2980(m), 1740(s), 1716(s), 1169(s) cm ; mass + spectrum m/z (% rel intensity) 307 M (0.1), 251(1), 190(87), 106(48), 57(100); + + HRMS (ESI ) calcd for C17H26NO4 m/z 308.1862 ([M+H] ), meas 308.1864; 20 [α] D –38.1° (c 1.0, CH2Cl2). Synthesis of N-Boc 2-methylphenylalanine derivative 78e via reductive ring opening of aziridine 43e: H2 (1 atm) Ph Pd(OH)2/C (10 mol%) CO2Et COOEt Boc2O, MeOH, 6 h cis-(2R,3R)-43e NHBoc (R)-78e 94% N The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with cis-(2R,3R)-43e (155 mg, 0.500 mmol, 1.00 equiv). Purification of the product by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 19:1) provided the product (R)-78e (136 mg, 0.440 mmol, 88%) as a colorless oil; The optical purity was determined to be >99% ee by HPLC analysis (Chiralcel OD-H column, 98:2 hexane/2-propanol at 222 nm, flowrate 1.0 mL/min); Retention times Rt = 5.81 min and Rt = 6.46 min for its 1 enantiomer; Rf = 0.35 (Hexane:EtOAc 4:1). Spectral data for (R)-78e: H NMR (300 MHz, CDCl3) δ 1.15 (t, 3H, J = 7.2 Hz), 1.37 (s, 9H), 2.33 (s, 3H), 2.84-3.10 (m, 2H), 4.10-4.22 (m, 2H), 4.52 (dd, 1H, J = 15.0, 7.5 Hz), 5.05 (d, 1H, 1H, J = 7.8 Hz), 6.97-7.20 (m, 4H); 13 C NMR (75 MHz, CDCl3) δ 13.90, 19.28, 28.17, 186 36.15, 53.63, 61.14, 79.64, 125.77, 126.91, 129.83, 130.34, 134.50, 136.65, -1 154.95, 172.25; IR (thin film) 3237(m), 2932(m), 1716(s), 1701(s) cm ; mass + + spectrum m/z (% rel intensity) 307 M (0.3), 251 [M-56] (5), 190(82), 57(100); + + HRMS (ESI ) calcd for C17H26NO4 m/z 308.1862 ([M+H] ), meas 308.1859; 20 [α] D –16.7° (c 1.0, CH2Cl2). Synthesis of N-Boc 4-aminophenylalanine derivative 79 via reductive ring opening of aziridine 43b: Ph N O2N H2 (1 atm) Pd(OH)2/C (10 mol%) COOEt Boc2O, MeOH, 6 h BocHN 43b CO2Et NHBoc (R)-79 66% The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with cis-(2R,3R)-43b (170 mg, 0.500 mmol, 1.00 equiv) and (Boc)2O (440 mg, 2.00 mmol, 4.00 equiv). Purification of the product by column chromatography (silica gel, 25 × 200 mm, hexane:EtOAc 9:1 to 5:1) provided the product (R)-79 (130 mg, 0.330 mmol, 66%) as a white solid; mp 81o 83 C; The optical purity was determined to be >99% ee by HPLC analysis (Chiralpak AS column, 95:5 hexane/2-propanol at 222 nm, flow-rate 1.0 mL/min); Retention times Rt = 21.68 min and Rt = 35.68 min for its enantiomer; Rf = 0.20 1 (hexane:EtOAc 5:1). Spectral data for (R)-79: H NMR (300 MHz, CDCl3) δ 1.22 (t, 3H, J = 7.0 Hz), 1.42 (s, 9H), 1.52 (s, 9H), 2.84-3.10 (m, 2H), 4.10-4.22 (q, 2H, 187 J = 7.2 Hz), 4.50 (q, 1H, J = 7.5 Hz), 4.93 (d, 1H, J = 8.1 Hz), 6.42 (brs, 1H), 7.02 (d, 2H, J = 7.5 Hz), 7.24 (d, 2H, J = 7.5 Hz); 13 C NMR (125 MHz, CDCl3) δ 14.12, 28.28, 37.49, 54.41, 61.29, 79.79, 80.46, 118.50, 129.85, 130.47, 137.25, 3 152.71, 155.08, 171.80 (One sp carbon not located); IR (thin film) 3240(m), -1 2978(m), 1716(s), 1701(s), 1163(s) cm ; mass spectrum m/z (% rel intensity) + + + + 408 M (0.05), 352 [M-56] (0.07), 235 [M-117] (8), 106(100); HRMS (ESI ) + 20 calcd for C21H32N2O6Na m/z 431.2046 ([M+Na] ), meas 431.2049; [α] D – 34.7° (c 1.0, CH2Cl2). Synthesis of N-Boc aziridine 80g via hydrogenolysis of aziridine 43g: Ph N H2 (1 atm) Pd(OH)2/C (10 mol%) COOEt Boc2O, MeOH, 6 h cis-(2R,3R)-43g Boc N COOEt cis-(2R,3R)-80g 91% The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with the aziridine cis-(2R,3R)-43g (145 mg, 0.500 mmol, 1.00 equiv). Purification of the product by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 19:1) provided the product cis-(2R,3R)-80g (135 mg, 0.496 mmol, 91%) as a colorless oil; Rf = 0.50 (hexane:EtOAc 9:1). 1 Spectral data for cis-(2R,3R)-80g: H NMR (300 MHz, CDCl3) δ 0.94-1.80 (m, 22H), 2.03 (d, 1H, J = 10.5 Hz), 2.32 (dd, 1H, J = 9.3, 6.6 Hz), 3.09 (d, 1H, J = 6.9 Hz), 4.14-4.32 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 14.23, 25.28, 25.33, 188 26.10, 27.82, 29.49, 31.01, 36.31, 39.38, 48.45, 61.34, 81.79, 160.76, 167.77; + 20 mass spectrum m/z (% rel intensity) 224 [M-73] (1), 124 (56), 57 (100); [α] D 23.2 (c 2.0, EtOAc). The optical purity was calculated to be >99% ee based on the optical rotation given in the literature. The sign of the optical rotation of 80g thus allows for the assignment of the relative stereochemistry of 43g as 2R, 26b 3R. Synthesis of N-Boc aziridine 80h via hydrogenolysis of aziridine 43h: Ph H2 (1 atm) Boc N Pd(OH)2/C (10 mol%) N Boc2O, MeOH, 6 h COOEt cis-(2R,3R)-43h COOEt cis-(2R,3R)-80h 81% The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with the aziridine cis-(2R,3R)-43h (138 mg, 0.500 mmol, 1.00 equiv). Purification of the product by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 19:1) provided cis-(2R,3R)-80h (105 mg, 0.41 mmol, 81%) as a colorless oil; Rf = 0.50 (hexane:EtOAc 9:1). Spectral data for 1 cis-(2R,3R)-80h: H NMR (500 MHz, CDCl3) δ 0.98 (s, 9H), 1.25 (t, 3H, J = 7.5 Hz), 1.40 (s, 9H), 2.35 (d, 1H, J = 7.5 Hz), 3.02 (d, 1H, J = 7.5 Hz), 4.12-4.26 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 14.02, 26.82, 27.82, 31.78, 40.40, 52.89, -1 61.32, 81.68, 161.57, 167.85; IR (thin film, cm ) 2976(m), 1759(s), 1728(s), + 1159(s); mass spectrum m/z (% rel intensity) 198 [M-73] (2), 156(44), 82(80), 189 + + 57(100); HRMS (ESI ) calcd for C14H25NO4Na m/z 294.1681 ([M+Na] ), meas 20 294.1685; [α] D 70.3° (c 1.0, EtOAc). Synthesis of N-Boc phenylalanine derivative 78a via reductive ring opening of aziridine 67a: Ph N Ph 67a H2 (1 atm) Pd(OH)2/C (20 mol%) COOEt Boc2O, MeOH Ph COOEt NHBoc (S)-78a 86% The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with the aziridine (2S,3R)-67a (30 mg, 0.10 mmol, 1.0 equiv), MeOH (2 mL), Pearlman’s catalyst (20% Pd(OH)2 on carbon, moisture ca 60%, 36 mg, 0.02 mmol, 0.20 equiv), Boc2O (64 mg, 0.30 mmol, 3.0 equiv) and a reaction time of 24 h. After purification by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 9:1), the product (S)-78a was obtained as a colorless oil (25 mg, 0.086 mmol, 86%). The spectral data for the product of this reaction was identical with N-Boc phenylalanine derivative 78a prepared from reductive ring opening of aziridine 43a. The product has the optical rotation 20 [α] D 37.8 (c 1.0, CH2Cl2) which indicates an S configuration based on the optical rotation for compound (R)-78a prepared from reductive ring opening of aziridine 43a (see above). Synthesis of N-Boc alanine derivative 81g via reductive ring opening of aziridine 67g: 190 H2 (1 atm) Ph N NHBoc COOEt + Pd(OH)2/C (10 mol%) COOEt Boc2O, MeOH, 6 h (S)-81g 90% trans-(2S,3R)-67g Boc N COOEt trans-(2S,3R)-82g 3% The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with the aziridine (2S,3R)-67g (31 mg, 0.10 mmol, 1.0 equiv), MeOH (2 mL), Pearlman’s catalyst (20% Pd(OH)2 on carbon, moisture ca 60%, 36 mg, 0.02 mmol, 0.20 equiv), Boc2O (64 mg, 0.30 mmol, 3.0 equiv) and a reaction time of 24 h. The crude reaction mixture was a 13:1 mixture 1 of 81g and 82g as determined from the H NMR spectrum. After purification of the major product by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 15:1), the pure major product (S)-81g was obtained as a colorless oil (27 mg, 0.0903 mmol, 90%) which solidified as a white solid during storage in the refrigerator; mp 43-44 °C; Rf = 0.40 (hexane:EtOAc 4:1). Spectral data for 1 (S)-81g: H NMR (500 MHz, CDCl3) δ 0.84-1.02 (m, 2H), 1.04-1.30 (m, 6H), 1.42 (s, 9H), 1.56-1.80 (m, 6H), 2.36-2.54 (m, 2H), 3.66-3.76 (m, 1H), 4.10 (t, 2H, J = 7.0 Hz), 4.88 (d, 1H, J = 9.5 Hz); 13 C NMR (125 MHz, CDCl3) δ 14.15, 26.00, 26.04, 26.20, 28.36, 28.95, 29.74, 37.05, 41.49, 52.23, 60.45, 78.98, 155.50, –1 + 172.03; IR (thin film) 3360(m), 2928(s), 1718(s), 1172(s) cm ; HRMS (ESI ) + 20 calcd for C16H30NO4 m/z 300.2175 ([M+H] ), meas 300.2188; [α] D 11.6° (c 1.0, CH2Cl2). The structure of the minor product was tentatively assigned as 82g 191 1 based on the following peaks from the H NMR spectrum of the crude mixture in CDCl3: 4.14-4.25 (m, 2H), 2.81 (d, 1H, J = 2.7 Hz). Synthesis of N-Boc alanine derivative 81h via reductive ring opening of aziridine 67h: H2 (1 atm) Ph N COOEt Boc2O, MeOH, 6 h trans-(2S,3R)-67h Boc N NHBoc COOEt + Pd(OH)2/C (10 mol%) COOEt (S)-81h 55% trans-(2S,3R)-82h 6% The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with the aziridine (2S,3R)-67h (28 mg, 0.10 mmol, 1.0 equiv), MeOH (2 mL), Pearlman’s catalyst (20 % Pd(OH)2 on carbon, moisture ca 60%, 36 mg, 0.02 mmol, 0.20 equiv), Boc2O (64 mg, 0.30 mmol, 3.0 equiv) and a reaction time of 45 h. The crude reaction mixture was determined to 1 be a 10:1 mixture of 81h and 82h by its H NMR spectrum. After purification by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 15:1), the pure major product (S)-81h was obtained as a colorless oil (15 mg, 0.055 mmol, 55%) which solidified as a white solid during storage in the refrigerator; mp 41-42 °C; 1 Rf = 0.30 (hexane:EtOAc 4:1). Spectral data for (S)-81h: H NMR (500 MHz, CDCl3) δ 0.88 (s, 9H), 1.23 (t, 3H, J = 7.0 Hz), 1.39 (s, 9H), 2.19 (dd, 1H, J = 14.0, 10.0 Hz), 2.55 (dd, 1H, J = 14.0, 3.5 Hz), 3.86 (td, 1H, J = 10.0, 4.0 Hz), 4.02-4.18 (m, 2H), 4.60 (d, 1H, J = 9.5 Hz); 192 13 C NMR (125 MHz, CDCl3) δ 14.11, 26.20, 28.32, 34.92, 36.46, 55.98, 60.65, 78.98, 155.47, 172.12; IR (thin film) –1 + 3358(m), 2968(s), 1734(s), 1701(s), 1172(s) cm ; HRMS (ESI ) calcd for + 20 C14H27NO4Na m/z 296.1838 ([M+Na] ), meas 296.1816; [α] D 10.5° (c 1.0, CH2Cl2). The minor product was tentatively assigned as 82h based on the 1 following peaks from the H NMR of the crude mixture in CDCl3: 0.90 (s, 9H), 2.61 (d, 1H, J = 2.7 Hz), 2.85 (d, 1H, J = 2.7 Hz). Synthesis of N-Boc alanine derivative 81i via reductive ring opening of aziridine 67i: Ph N H2 (1 atm) Pd(OH)2/C (10 mol%) COOEt trans-(2S,3R)-67i NHBoc COOEt + Boc2O, MeOH, 6 h (R)-81i 77% Boc N COOEt trans-(2S,3R)-82i 12% The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with the aziridine (2S,3R)-67i (27 mg, 0.10 mmol, 1.0 equiv), MeOH (2 mL), Pearlman’s catalyst (20% Pd(OH)2 on carbon, moisture ca 60%, 36 mg, 0.02 mmol, 0.20 equiv), Boc2O (64 mg, 0.30 mmol, 3.0 equiv) and a reaction time of 24 h. The crude reaction mixture was determined to 1 be a 5.26:1 mixture of 81i and 82i by its the H NMR spectrum. After purification by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 15:1), the pure major product was obtained as a colorless oil (20 mg, 0.077 mmol, 77%). 1 Spectral data for (R)-81i: H NMR (500 MHz, CDCl3) δ 0.88 (t, 3H, J = 7.0 Hz), 193 1.23 (t, 3H, J = 7.0 Hz), 1.26-1.40 (m, 4H), 1.40 (s, 9H), 2.40-2.52 (m, 2H), 3.703.92 (m, 1H), 4.10 (t, 2H, J = 7.0 Hz), 4.88 (d, 1H, J = 8.0 Hz); 13 C NMR (125 MHz, CDCl3) δ 13.80, 14.17, 19.33, 28.35, 36.79, 39.33, 47.36, 60.44, 79.08, –1 155.35, 171.75; IR (thin film) 3358(m), 2976(m), 1738(s), 1714(s), 1172(s) cm ; + + HRMS (ESI ) calcd for C13H26NO4 m/z 260.1862 ([M+H] ), meas 260.1857; 20 [α] D 23.5° (c 1.0, CH2Cl2). The identity of the minor product was tentatively 1 assigned as 82i based on the following peaks from the H NMR of the crude mixture in CDCl3: 0.91 (t, 3H, J = 6.6 Hz), 2.61 (td, 1H, J = 7.5 2.4 Hz), 2.72 (d, 1H, J = 2.4 Hz), 4.10-4.14 (m, 1H), 4.15-4.22 (m, 1H). 7.1.5 Determination of Stereochemistry. Determination of the relative configuration for cis-(2R,3R)-43h by conversion to the 4-bromobenzoate 70: Ph Ph 1) LiAlH4 2) 4-bromobenzoyl N chloride, DMAP COOEt 43h Br N O 70 84% O To a flame-dried 25 mL round bottom flask filled with N2 was added LiAlH4 (80 mg, 2.0 mmol, 4.0 equiv) and Et2O (3 mL). Then the vacuum adapter was replaced with a septum to which a N2 ballon was attached via a needle. The flask o was cooled to 0 C. A solution of aziridine cis-(2R,3R)-43h (138 mg, 0.500 mmol, 194 1.00 equiv) in Et2O (2 mL) was added via syringe dropwise to the flask. After it o was stirred at 0 C for 15 min, the ice bath was removed. The mixture was stirred o at rt for 6 hours. After cooling to 0 C, H2O (0.5 mL) was added slowly to quench the reaction. The resulting suspension was stirred at 0 o C for 30 min. The reaction was filtered through a pad of Celite on a sintered glass funnel and washed well with Et2O. The filtrate was dried (Na2SO4), filtered and concentrated to give the aziridinyl methanol as a white solid (115 mg, 0.493 o 1 mmol, 98%); mp 72-73 C. Spectral data for aziridinyl methanol: H NMR (300 MHz, CDCl3) δ 0.68 (s, 9H), 1.34 (d, 1H, J = 7.2 Hz), 1.47 (d, 3H, J = 6.6 Hz), 1.66-1.78 (m, 1H), 2.34 (brs, 1H), 2.46 (q, 1H, J = 6.6 Hz), 3.70-3.90 (m, 2H), 7.20-7.40 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 23.11, 28.80, 30.84, 46.17, 54.45, 61.06, 71.53, 127.07, 127.39, 128.10, 144.85; IR (thin film) 3277(m), -1 + 2988(s), 1037(s) cm ; HRMS (ESI ) calcd for C15H23NONa m/z 256.1677 + 20 ([M+H] ), meas 256.1671; [α] D 66.1° (c 0.5, CH2Cl2). A mixture of the above aziridinyl methanol (47 mg, 0.20 mmol, 1.0 equiv), 4bromobenzoyl chloride (97 mg, 0.44 mmol, 2.2 equiv) and DMAP (74 mg, 0.60 mmol, 3.0 equiv) in dry CH2Cl2 (1 mL) was stirred at rt for 2 hours. Then the reaction mixture was diluted with CH2Cl2 (10 mL). The solution was washed with HCl (2N, 2 × 3 mL) and sat aq Na2CO3 (2 mL). The organic layer was then dried 195 (Na2SO4), filtered and concentrated to give the crude product which was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 15:1) to give the ester 70 as a white solid (71 mg, 0.17 mmol, 86%); mp 66-67 °C. Spectral 1 data for 70: H NMR (300 MHz, CDCl3) δ 0.68 (s, 9H), 1.35 (d, 1H, J = 7.0 Hz), 1.43 (d, 3H, J = 6.5 Hz), 1.74-1.82 (m, 1H), 2.45 (q, 1H, J = 6.5 Hz), 4.44 (dd, 1H, J = 11.5, 8.5 Hz), 4.56 (dd, 1H, J = 11.5, 4.0 Hz), 7.18-7.38 (m, 5H), 7.487.52 (m, 2H), 7.92-7.98 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 23.04, 28.74, 30.93, 42.37, 53.86, 65.31, 71.53, 127.15, 127.45, 128.09, 128.14, 129.25, 131.14, 131.79, 144.77, 165.82; IR (thin film) 2961(s), 1751(s), 1188(s), 758(m), -1 79 + + 702(m) cm ; HRMS (ESI ) calcd for C22H27NO2 Br m/z 416.1225 ([M+H] ), 20 meas 416.1194; [α] D –10.6° (c 0.5, CH2Cl2). Recrystallization of 70 from hexane gave X-ray quality crystals the X-ray diffraction analysis of which confirmed the relative configuration of cis-(2R,3R)-43h. Determination of the relative configuration of cis-(2R,3R)-43j via reduction with tin hydride: Ph Br N 43j n-Bu3SnH COOEt AIBN, Benzene Ph N COOEt 43a 89% The procedure for the synthesis of trans-(2S,3R)-67a from trans-(2S,3R)-67j via selective reductive removal of bromine was followed with cis-(2R,3R)-43j (110 mg, 0.290 mmol, 1.00 equiv), dry benzene (2 mL), Bu3SnH (0.26 mL, 0.88 mmol, 196 3.00 equiv) and AIBN (10 mg) with a reaction time of 15 h at 60 °C. The product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 9:1) to give cis-(2R,3R)-43a (77 mg, 0.26 mmol) in 89% yield as a white solid. The spectral data of the reduced product was found to be identical with the major product cis-(2R,3R)-43a obtained from the aziridination of (R)-45a in the matched case with the (S)-VAPOL catalyst. Determination of the relative configuration of cis-(2R,3R)-43a via reductive ring opening: Ph N H2 (1 atm) Ph CO2Et NH2 Pd(OH)2/C (R)-69 41% Ph 43a COOEt To a flame dried 100 mL round bottom flask filled with N2 was added a sample of cis-(2R,3R)-43a prepared from imine (R)-45a (149 mg, 0.500 mmol, 1.00 equiv), Pearlman’s catalyst (20% Pd(OH)2 on carbon, moisture ca 60%, 85 mg, 0.050 mmol, 0.10 mmol) and MeOH (30 mL). The flask was equipped with a 3-way valve connected with vacuum and a H2 balloon. The valve to vacuum was opened for a few seconds and switched to the H2 balloon. This process was repeated for 3 additional times. The suspension was stirred under a H2 ballon for 3 hours. Then the mixture was filtered through a Celite pad on a sintered glass funnel and washed well with MeOH. The filtrate was concentrated by rotary evaporation, followed by loading onto a chromatography column (silica gel, 20 × 200 mm, hexane:EtOAc 1:1) and elution to give the product (R)-69 as a pale 197 yellow oil (39 mg, 0.21 mmol) in 41% isolated yield; [α]D (Lit 23a 20 –18.9° (c 3.2, EtOH) [α]D –23.0° (c 3.2, EtOH, 23°C); The product can be assigned as (R)-D1 phenylalanine ethyl ester). Spectral data for (R)-69: H NMR (300 MHz, CDCl3) δ 1.28 (t, 3H, J = 7.5 Hz), 1.60 (brs, 2H), 2.90 (dd, 1H, J = 13.5, 7.8 Hz), 3.10 (dd, 1H, J = 13.5, 5.4 Hz), 3.74 (dd, 1H, J = 7.8, 5.4 Hz), 4.20 (q, 2H, J = 7.2 Hz), 7.20-7.40 (m, 5H); 13 C NMR (75 MHz, CDCl3) δ 14.10, 41.08, 55.79, 60.84, 126.71, 128.45, 129.23, 137.23, 174.97. Determination of the relative configuration of trans-(2S,3R)-67j via reductive ring opening: Ph Br CO2Et H2 (1 atm) Ph N NH2 Pd(OH)2/C (S)-69 57% COOEt 67j To a flame dried 100 mL round bottom flask filled with N2 was added trans(2S,3R)-67j (266 mg, 0.710 mmol, 1.0 equiv), Pearlman’s catalyst (20% Pd(OH)2 on carbon, moisture ca 60%, 85 mg, 0.050 mmol, 0.10 mmol), MeOH (30 mL). The flask was equipped with a 3-way valve connected to vacuum and a H2 balloon. The valve was opened to vacuum for a few seconds and then switched to the H2 balloon. This process was repeated for 3 additional times. The suspension was stirred under a H2 ballon for 5 hours. The mixture was filtered through a Celite pad on a sintered glass funnel, washed well with MeOH and 198 concentrated. The residue was treated with aq sat NaHCO3 (2 mL) and extracted with Et2O (2 × 10 mL + 5 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated by rotary evaporation, followed by loading onto a chromatography column (silica gel, 20 × 200 mm, Hexane:EtOAc 1:1) and elution gave the product 69 (78 mg, 0.36 mmol) as a pale oil in 57% isolated yield. The optical rotation of this material ([α]D 20 19.8° (c 3.2, EtOH)) indicated that it is the (S)-enantiomer of phenylalanine ethyl ester based on the published optical rotation for this compound. 23a Determination of the relative configuration of trans-(2S,3R)-71a via reductive ring opening: Ph H2 (1 atm) O Pd(OH)2/C (20 mol%) Ph NHPh NHBoc CONHPh Boc2O, MeOH 71a (S)-77a 40% N The general procedure for the synthesis of N-Boc alanine derivatives via hydrogenolysis was followed with the aziridine trans-(2S,3R)-71a (45 mg, 0.13 mmol, 1.0 equiv), MeOH (2 mL), Pearlman’s catalyst (20% Pd(OH)2 on carbon, moisture ca 60%, 25 mg, 0.013 mmol, 0.10 equiv), Boc2O (58 mg, 0.26 mmol, 2.0 equiv) and a reaction time of 6 h. After purification by column chromatography (silica gel, 18 × 180 mm, Hexane:EtOAc 5:1), the product (S)77a was obtained as a white solid (17 mg, 0.040 mmol, 40%). Spectral data for 1 (S)-77a: H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 3.23 (d, 2H, J = 6.5 Hz), 4.47 199 (brs, 1H), 5.20 (brs, 1H), 7.06 (t, 1H, J = 7.5 Hz), 7.20-7.38 (m, 9H), 7.82 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 28.50, 38.59, 56.91, 80.78, 120.27, 124.73, 2 127.30, 129.04, 129.14, 129.55, 136.87, 137.49, 169.75 (One sp carbon not 20 25 28a,78 located); [α] D –22.7° (c 1.0, CH2Cl2) (Lit: [α] D –37° (c 2.0, CH2Cl2). Rate Competition Study of Chiral α-alkyl benzylimines with VAPOL(VANOL)borate Catalyst (Scheme 2.6): A 25 mL pear-shaped single necked flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it), cooled to rt under N2 and charged with VAPOL or VANOL (S or R, 0.05 mmol, 0.05 equiv), 30 mol% triphenyl borate (44 mg, 0.15 mmol, 0.15 equiv) and dry toluene o (2 mL). The Teflon valve was closed and the flask was heated at 80 C for 1 hour. After the flask was cooled to rt, the toluene was carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon value. After the solvent was removed, the Teflon valve was completely opened and the flask o was heated at 80 C under high vacuum for 30 min. The flask was then allowed to cool to rt. The catalyst was dissolved in 4 mL dry CCl4 and transferred via syringe to the flask containing aldimine 31a (271 mg, 1.00 mmol, 1.00 equiv) and the corresponding chiral imine (S)-60a (251 mg, 1.00 mmol, 1.00 equiv) or (R)45a (209 mg, 1.00 mmol, 1.00 equiv). The resulting light yellow solution was allowed to stir at rt for 5 min, then EDA 5 (21 µL, 0.20 mmol, 0.20 equiv) was added via syringe in one portion. The solution was stirred at rt for 24 h. The 200 reaction was quenched with n-hexane (5 mL) and concentrated to give the crude reaction mixture. The ratio of the two aziridines (61a vs. ent-32a) or (43a vs. 32a) 1 was determined by the H NMR integration of the crude product by comparing the C-2 and C-3 methine protons from the aziridines. The ratios can be found in Scheme 2.6. 201 7.2 Experimental Section for Chapter Three 7.2.1 Preparation of N-Boc imines General procedure for the preparation of N-Boc imines 79 – illustrated for the synthesis of imine 18 (Ar = Ph) O NH2Boc PhSO2Na HCOOH Ar 215 MeOH/H O 2 Ar = Ph HN Boc K CO , Na SO 2 3 2 4 N Boc Ar SO2Ph THF, reflux Ar 18 253 Ar = Ph Ar = Ph Preparation of α-sulfonyl amine 253: A mixture of benzaldehyde 215 (2.10 mL, 20.0 mmol, 2.00 equiv), tert-butyl carbamate (1.17 g, 10.0 mmol, 1.00 equiv), benzenesulfinic acid sodium salt (4.11 g, 25.0 mmol, 2.50 equiv) and formic acid (0.760 mL, 20.0 mmol, 2.00 equiv) in methanol (10 mL) and water (20 mL) was stirred at room temperature for 24 h. The resulting precipitate was filtered and washed well with diethyl ether. After drying under vacuum, the product 253 was obtained as a white solid (2.61 g, 7.50 mmol, 75%); mp 169-170 °C (Lit 79a 170 1 °C); H NMR (CDCl3, 300 MHz) δ 1.22 (s, 9H, 3CH3), 5.75 (d, 1H, J = 10.0 Hz), 5.90 (d, 1H, J = 10.0 Hz), 7.34-7.47 (m, 5H, Ar-H), 7.47-7.56 (m, 2H, Ar-H), 7.587.68 (m, 1H, Ar-H), 7.90 (d, 2H, J = 7.2 Hz, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 27.96, 73.90, 81.16, 128.72, 128.90, 129.00, 129.44, 129.80, 129.91, 133.89, 136.93, 153.46. Preparation of N-Boc imine 18: A 100 mL round bottom flask containing potassium carbonate (4.14 g, 30.0 mmol, 6.00 equiv) and sodium sulfate (4.97 g, 35.0 mmol, 7.00 equiv) was flame dried. After the flask was cooled to room 202 temperature under N2, sulfonyl amine 253 (1.74 g, 5.00 mmol, 1.00 equiv) was added along with dry THF (20 mL). The mixture was refluxed under N2 for 18 h. It was then allowed to cool to room temperature, filtered through Celite, and the filtrate was concentrated to give the imine 18 as a colorless oil (1.03 g, 5.00 mmol, 100%) which was used without further purification for the aziridination 1 reaction; H NMR (CDCl3, 300 MHz) δ 1.58 (s, 9H, 3CH3), 7.38-7.60 (m, 3H, ArH), 7.84-7.94 (m, 2H, Ar-H), 8.85 (s, 1H, CHN); 13 C NMR (CDCl3, 125 MHz) δ 27.93, 82.28, 128.85, 130.19, 133.49, 134.10, 162.64, 169.64. The purity of imine 18 by weight was calculated to be ca. 90% based on the 1 H NMR spectrum which revealed the presence of imine 18, aldehyde 215 and tert-butyl carbamate in a ratio of 1:0.09:0.09. O NH2Boc PhSO2Na HN SO2Ph HCOOH O2N Boc K2CO3 (aq) N Boc 254 MeOH/H O O2N 255 94 O2N 2 Preparation of α-sulfonyl amine 255: The general procedure was followed with 1.51 g p-nitrobenzaldehyde 254 (10.0 mmol) and a reaction time of 4 days to provide the product 255 as a white solid (1.045 g, 2.670 mmol) in 53% yield; mp 1 172-174 °C; H NMR (CDCl3, 600 MHz) δ 1.20 (s, 9H, 3CH3), 5.84 (d, 1H, J = 10.2 Hz), 6.04 (d, 1H, J = 10.8 Hz), 7.56 (t, 2H, J = 8.4 Hz), 7.60-7.70 (m, 3H, ArH), 7.92 (d, 2H, J = 7.2 Hz, Ar-H), 8.24 (d, 2H, J = 7.2 Hz, Ar-H); 203 13 C NMR (CDCl3, 150 MHz) δ 27.94, 73.03, 81.83, 123.71, 129.32, 129.43, 129.99, 134.48, 136.28, 136.89, 148.67, 153.33. Preparation N-Boc imine 94: To a solution of sulfonyl amine 255 (392 mg, 1.00 mmol, 1.00 equiv) in CH2Cl2 (16 mL) was added aq. 1.4 M K2CO3 solution (16 mL). The resulting mixture was stirred at rt vigorously for 5 hours. The aqueous layer was separated and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give imine 94 1 as a white solid (252 mg, 1.00 mmol, 100%). H NMR (CDCl3, 600 MHz) δ 1.58 (s, 9H, 3CH3), 8.06 (d, 2H, J = 9.5 Hz, Ar-H), 8.30 (d, 2H, J = 9.5 Hz, Ar-H), 8.85 (s, 1H, CHN); 13 C NMR (CDCl3, 150 MHz) δ 27.88, 83.24, 124.01, 130.64, 139.34, 150.50, 161.74, 166.23. O NH2Boc HN PhSO2Na Boc K2CO3, Na2SO4 N Boc SO2Ph HCOOH THF, reflux 95 F3C 257 F3C 256 MeOH/H2O Preparation of α-sulfonyl amine 257: The general procedure was followed with F3C 1.74 g p-trifluoromethylbenzaldehyde 256 (1.50 mL, 10.0 mmol) and a reaction time of 48 hours to provide the product 257 as a white solid (1.17 g, 2.82 mmol) 1 in 56% yield; mp 178-179 °C; H NMR (CDCl3, 300 MHz) δ 1.20 (s, 9H, 3CH3), 5.84 (d, 1H, J = 8.7 Hz), 5.98 (d, 1H, J = 10.5 Hz), 7.50-7.70 (m, 7H, Ar-H), 7.92 (d, 2H, J = 7.5 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 27.74, 73.03, 81.38, 204 123.50 (J = 271.2 Hz), 125.46 (J = 4.05 Hz), 129.00, 129.16, 129.24, 131.71 (J = 33.2 Hz), 133.66, 134.06, 136.32, 153.15. Preparation N-Boc imine 95: The general procedure was followed with sulfonyl amine 257 (830 mg, 2.00 mmol, 1.00 equiv) and a refluxing time of 20 hours. The 1 product 95 was obtained as a white solid (542 mg, 1.98 mmol, 99%). H NMR (CDCl3, 300 MHz) δ 1.58 (s, 9H, 3CH3), 7.77 (d, 2H, J = 9.5 Hz, Ar-H), 8.06 (d, 2H, J = 7.8 Hz, Ar-H), 8.90 (s, 1H, CHN); 13 C NMR (CDCl3, 150 MHz) δ 27.89, 82.89, 123.55 (J = 272.8 Hz), 125.84 (J = 4.3 Hz), 130.19, 134.59 (J = 29.8 Hz), 137.14, 162.09, 167.50. The purity of imine 95 by weight was calculated to be ca. 1 96% based on the H NMR spectrum that revealed the presence of imine 95, aldehyde 256 and tert-butyl carbamate in a ratio of 1:0.04:0.04. O NH2Boc PhSO2Na HCOOH Br HN Boc K2CO3, Na2SO4 SO2Ph N Boc THF, reflux Br 259 96 258 MeOH/H O Br 2 Preparation of α-sulfonyl amine 259: A mixture of p-bromobenzaldehyde 258 (1.11 g, 6.00 mmol, 1.20 equiv), tert-butyl carbamate (0.585 g, 5.00 mmol, 1.00 equiv), benzenesulfinic acid sodium salt (2.05 g, 12.5 mmol, 2.50 equiv) and formic acid (0.38 mL, 10.0 mmol, 2.00 equiv) in methanol (5 mL) and water (10 mL) was stirred at room temperature for 3 days. The resulting precipitate was filtered and washed well with diethyl ether. After drying under vacuum, the product 259 was obtained as a white solid (715 mg, 1.70 mmol, 34%); mp 1721 173 °C; H NMR (CDCl3, 500 MHz) δ 1.20 (s, 9H, 3CH3), 5.87 (dd, 2H, J = 10.0 205 Hz), 7.30 (d, 2H, J = 8.0 Hz, Ar-H), 7.52 (m, 4H, Ar-H), 7.64 (t, 1H, J = 7.0 Hz, Ar-H), 7.89 (d, 2H, J = 7.5 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 27.95, 73.28, 81.40, 124.32, 128.93, 129.11, 129.43, 130.46, 131.91, 134.10, 136.62, 153.42. Preparation of N-Boc imine 96: Following the general procedure, sulfonyl amine 259 (852 mg, 2.00 mmol, 1.00 equiv) was refluxed with K2CO3 and Na2SO4 for 24 hours. The product 96 was obtained as a white solid (590 mg, 2.08 mmol, 1 104%). H NMR (CDCl3, 500 MHz) δ 1.58 (s, 9H, 3CH3), 7.56-7.62 (m, 2H, ArH), 7.74-7.78 (m, 2H, Ar-H), 8.80 (s, 1H, CHN). The purity of imine 96 by weight 1 was calculated to be ca. 83% based on the H NMR spectrum that revealed the presence of imine 96 and sulfonyl amine 259 in a ratio of 1:0.14. O NH2Boc HN PhSO2Na Cl 260 HCOOH MeOH/H2O Cl Boc K2CO3, Na2SO4 SO2Ph THF, reflux 261 Cl N Boc 97 Preparation of α-sulfonyl amine 261: The general procedure was followed with 1.05 g p-chlorobenzaldehyde 260 (10.0 mmol) and a reaction time of 48 hours to provide the product 71 as a white solid (1.15 g, 3.02 mmol) in 61% yield; mp 1721 173 °C. H NMR (CDCl3, 500 MHz) δ 1.10 (s, 9H, 3CH3), 5.70 (d, 1H, J = 11.5 Hz), 5.88 (d, 1H, J = 11.0 Hz), 7.37 (s, 4H, Ar-H), 7.53 (t, 2H, J = 7.5 Hz, Ar-H), 7.64 (t, 1H, J = 7.5 Hz, Ar-H), 7.89 (d, 2H, J = 8.0 Hz, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 28.23, 73.43, 81.70, 128.69, 129.26, 129.40, 129.70, 130.44, 134.37, 136.40, 136.92, 153.62. 206 Preparation N-Boc imine 97: The general procedure was followed with sulfonyl amine 261 (762 mg, 2.00 mmol, 1.00 equiv) and a refluxing time of 24 hours. The 1 product 97 was obtained as a white solid (490 mg, 2.05 mmol, 103%). H NMR (CDCl3, 600 MHz) δ 1.58 (s, 9H, 3CH3), 7.40-7.44 (m, 2H, Ar-H), 7.80-7.85 (m, 2H, Ar-H), 8.80 (s, 1H, CHN); 13 C NMR (CDCl3, 150 MHz) δ 27.89, 82.50, 129.27, 131.28, 132.54, 139.79, 162.33, 168.22. The purity of imine 97 by weight 1 was calculated to be ca. 91% based on the H NMR spectrum that revealed the presence of imine 97 and sulfonyl amine 261 in a ratio of 1:0.06. O NH2Boc HN Boc K2CO3, Na2SO4 SO2Ph THF, reflux 263 F PhSO2Na N Boc HCOOH 262 MeOH/H O F 98 2 Preparation of α-sulfonyl amine 263: The general procedure was followed with F 1.24 g p-fluorobenzldehyde 262 (10.0 mmol) and a reaction time of 48 hours to provide the product 263 as a white solid (1.10 g, 3.01 mmol) in 60% yield; mp 1 168-170 °C; H NMR (CDCl3, 500 MHz) δ 1.20 (s, 9H, 3CH3), 5.72 (d, 1H, J = 10.0 Hz), 5.89 (d, 1H, J = 10.0 Hz), 7.04-7.12 (m, 2H, Ar-H), 7.42 (dd, 2H, J = 8.0, 5.0 Hz, Ar-H), 7.53 (t, 2H, J = 8.0 Hz, Ar-H), 7.63 (t, 1H, J = 7.0 Hz, Ar-H), 7.89 (d, 2H, J = 8.0 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 27.97, 73.11, 81.36, 115.87 (J = 21.7 Hz), 125.84 (J = 2.8 Hz), 129.10, 129.43, 130.81 (J = 8.0 Hz), 134.05, 136.71, 153.41, 163.61 (J = 248.4 Hz), 207 Preparation N-Boc imine 98: The general procedure was followed with sulfonyl amine 263 (730 mg, 2.00 mmol, 1.00 equiv) and a refluxing time of 18 hours. The 1 product 98 was obtained as a white solid (450 mg, 2.02 mmol, 101%); H NMR (CDCl3, 500 MHz) δ 1.60 (s, 9H, 3CH3), 7.14 (t, 2H, J = 8.5 Hz, Ar-H), 7.88-7.96 (m, 2H, Ar-H), 8.83 (s, 1H, CHN); 13 C NMR (CDCl3, 150 MHz) δ 27.90, 82.36, 116.21 (J = 22.1 Hz), 130.43 (J = 2.6 Hz), 132.49 (J = 9.2 Hz), 162.41, 166.03 (J = 254.3 Hz), 168.28. The purity of imine 98 by weight was calculated to be ca. 1 95% based on the H NMR spectrum that revealed the presence of imine 98 and sulfonyl amine 263 in a ratio of 1:0.03. O Br NH2Boc PhSO2Na 264 HCOOH MeOH/H2O HN Br Boc K2CO3, Na2SO4 SO2Ph THF, reflux Br 265 N Boc 99 Preparation of α-sulfonyl amine 265: The general procedure was followed with 1.85 g m-bromobenzladehyde 264 (10.0 mmol) and a reaction time of 36 hours to provide the product 265 as a white solid (1.91 g, 4.48 mmol) in 93% yield; mp 1 172-174 °C; H NMR (CDCl3, 500 MHz) δ 1.20 (s, 9H, 3CH3), 5.75 (d, 1H, J = 10.0 Hz), 5.88 (d, 1H, J = 10.0 Hz), 7.26 (t, 1H, J = 7.5 Hz, Ar-H), 7.38 (d, 1H, J = 7.5 Hz, Ar-H), 7.48-7.58 (m, 4H, Ar-H), 7.64 (t, 1H, J = 7.5 Hz, Ar-H), 7.89 (d, 2H, J = 8.0 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 28.23, 73.42, 81.74, 123.01, 127.96, 129.41, 129.71, 130.44, 132.04, 132.43, 133.20, 134.42, 136.87, 153.61. 208 Preparation of N-Boc imine 99: The general procedure was followed with sulfonyl amine 265 (852 mg, 2.00 mmol, 1.00 equiv) and a refluxing time of 16 hours. The 1 product 99 was obtained as a colorless oil (540 mg, 1.90 mmol) in 95% yield. H NMR (CDCl3, 500 MHz) δ 1.56 (s, 9H, 3CH3), 7.33 (t, 1H, J = 8.0 Hz, Ar-H), 7.64-7.68 (m, 1H, Ar-H), 7.76-7.80 (m, 1H, Ar-H), 8.08-8.12 (m, 1H, Ar-H), 8.76 (s, 1H, CHN); 13 C NMR (CDCl3, 125 MHz) δ 27.90, 82.67, 123.14, 129.02, 130.36, 132.30, 136.01, 136.23, 162.13, 167.81. The purity of imine 99 by weight 1 was calculated to be ca. 92% based on the H NMR spectrum that revealed the presence of imine 99, aldehyde 264 and tert-butyl carbamate in a ratio of 1:0.08:0.08. O NH2Boc PhSO2Na HCOOH 266 MeOH/H2O HN Boc K2CO3, Na2SO4 SO2Ph THF, reflux 267 N Boc 100 Preparation of α-sulfonyl amine 267: The general procedure was followed with 1.44 g p-toluadehyde 266 (12.0 mmol) and a reaction time of 36 hours to provide the product 267 as a white solid (1.63 g, 4.50 mmol) in 75% yield; mp 167-168 1 °C; H NMR (CDCl3, 300 MHz) δ 1.20 (s, 9H, 3CH3), 2.36 (s, 3H, CH3), 5.73 (d, 1H, J = 10.0 Hz), 5.87 (d, 1H, J = 10.0 Hz), 7.20 (d, 2H, J = 8.0 Hz, Ar-H), 7.31 (d, 2H, J = 8.0 Hz, Ar-H), 7.46-7.54 (m, 2H, Ar-H), 7.64 (t, 1H, J = 7.5 Hz, Ar-H), 7.89 (d, 2H, J = 8.0 Hz, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 21.52, 21.53, 209 28.26, 74.00, 81.38, 127.06, 129.02, 129.26, 129.73, 134.10, 137.34, 140.25, 2 153.69 (1 sp C not located). Preparation of N-Boc imine 100: The general procedure was followed with sulfonyl amine 267 (722 mg, 2.0 mmol, 1.0 equiv) and a refluxing time of 18 hours. The product 100 was obtained as colorless oil (442 mg, 2.02 mmol, 1 101%); H NMR (CDCl3, 500 MHz) δ 1.60 (s, 9H, 3CH3), 2.40 (s, 3H, CH3), 7.26 (d, 2H, J = 8.0 Hz, Ar-H), 7.80 (d, 2H, J = 8.0 Hz, Ar-H), 8.86 (s, 1H, CHN); 13 C NMR (CDCl3, 125 MHz) δ 21.79, 27.91, 82.04, 129.62, 130.33, 131.51, 144.53, 162.78, 169.90. Purity of imine 100 by weight was calculated to be ca. 94% based on the 1 H NMR spectrum that revealed the presence of imine 100, aldehyde 266 and tert-butyl carbamate in a ratio of 1:0.06:0.06. O 268 NH2Boc PhSO2Na HCOOH MeOH/H2O HN Boc K2CO3, Na2SO4 SO2Ph N Boc THF, reflux 269 101 Preparation of α-sulfonyl amine 269: The general procedure was followed with 1.20 g m-toluadehyde 268 (10.0 mmol) and a reaction time of 24 hours to provide the product 269 as a white solid (1.51 g, 4.17 mmol) in 83% yield; mp 169-170 1 °C; H NMR (CDCl3, 500 MHz) δ 1.22 (s, 9H, 3CH3), 2.38 (s, 3H, CH3), 5.73 (d, 1H, J = 10.0 Hz), 5.88 (d, 1H, J = 10.0 Hz), 7.20-7.34 (m, 4H, Ar-H), 7.53 (t, 2H, J = 8.0 Hz, Ar-H), 7.64 (t, 1H, J = 7.0 Hz, Ar-H), 7.92 (d, 2H, J = 8.0 Hz, Ar-H); 210 13 C NMR (CDCl3, 125 MHz) δ 21.37, 28.00, 73.89, 81.14, 126.00, 128.64, 129.00, 129.45, 129.54, 129.75, 130.65, 133.86, 137.05, 138.57, 153.41. Preparation of N-Boc imine 101: The general procedure was followed with sulfonyl amine 269 (722 mg, 2.00 mmol, 1.00 equiv) and a refluxing time of 24 hours. The product 101 was obtained as a colorless oil (424 mg, 1.96 mmol) in 1 98% yield; H NMR (CDCl3, 300 MHz) δ 1.57 (s, 9H, 3CH3), 2.37 (s, 3H, CH3), 7.30-7.38 (m, 2H, Ar-H), 7.60-7.70 (m, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 8.84 (s, 1H, CHN); 13 C NMR (CDCl3, 150 MHz) δ 21.13, 27.92, 82.18, 127.99, 128.71, 130.17, 134.01, 134.40, 138.71, 162.65, 170.05. The purity of imine 101 by weight was calculated to be ca. 93% based on the 1 H NMR spectrum that revealed the presence of imine 101, aldehyde 268 and tert-butyl carbamate in a ratio of 1:0.06:0.06. O NH2Boc p-MePhSO2Na HCOOH 270 MeOH/H2O HN Boc K2CO3, Na2SO4 SO2Ts 271 N Boc THF, reflux 102 Preparation of α-sulfonyl amine 271: The general procedure was followed with 1.20 g o-toluadehyde 270 (10.0 mmol) and toluene sulfinic acid sodium salt (2.20 g, 12.5 mmol, 2.5 equiv) and a reaction time of 24 hours to provide the product 1 271 as a white solid (980 mg, 2.71 mmol) in 54% yield; mp 152-154 °C; H NMR (CDCl3, 300 MHz) δ 1.30 (s, 9H, 3CH3), 2.46 (s, 3H, CH3), 2.47 (s, 3H, CH3), 5.74 (d, 1H, J = 10.8 Hz), 6.24 (d, 1H, J = 10.5 Hz), 7.22-7.50 (m, 6H, Ar-H), 7.82 211 (d, 2H, J = 8.4 Hz, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 19.70, 21.60, 27.99, 69.72, 81.06, 126.45, 127.52, 129.35, 129.62, 129.70, 130.81, 134.35, 138.14, 2 144.95, 153.57 (1 sp C not located). Preparation of N-Boc imine 102: The general procedure was followed with sulfonyl amine 271 (750 mg, 2.00 mmol, 1.00 equiv) and a refluxing time of 24 hours. The product 102 was obtained as a colorless oil (440 mg, 2.00 mmol, 1 100%). H NMR (CDCl3, 500 MHz) δ 1.57 (s, 9H, 3CH3), 2.57 (s, 3H, CH3), 7.16-7.30 (m, 2H, Ar-H), 7.36-7.44 (m, 1H, Ar-H), 8.06 (dd, 1H, J = 7.5, 1.0 Hz, Ar-H), 9.20 (s, 1H, CHN); 13 C NMR (CDCl3, 150 MHz) δ 19.23, 27.96, 82.17, 126.37, 128.74, 131.16, 132.04, 133.17, 140.84, 163.01, 167.99. The purity of imine 102 by weight was calculated to be ca. 90% based on the 1 H NMR spectrum that revealed the presence of imine 102, sulfonyl amine 271, aldehyde 270 and tert-butyl carbamate in a ratio of 1:0.05:0.03:0.03. Boc Boc O NH2Boc N HN K2CO3, Na2SO4 PhSO2Na SO2Ph THF, reflux HCOOH MeO MeO 272 MeOH/H O MeO 273 103 2 Preparation of α-sulfonyl amine 273: The general procedure was followed with 1.36 g p-methoxybenzaldehyde 272 (10.0 mmol, 2.00 equiv) and a reaction time of 36 hours to provide the product 273 as a white solid (1.056 g, 2.801 mmol) in 1 56% yield; mp 155-156 °C. H NMR (CDCl3, 500 MHz) δ 1.20 (s, 9H, 3CH3), 3.80 (s, 3H, CH3), 5.67 (d, 1H, J = 10.5 Hz), 5.85 (d, 1H, J = 11.0 Hz), 6.84-6.96 212 (m, 2H), 7.34 (d, 2H, J = 8.5 Hz), 7.62 (t, 2H, J = 8.0 Hz), 7.62 (t, 1H, J = 7.5 Hz), 7.89 (d, 2H, J = 7.5 Hz, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 27.99, 55.36, 73.43, 81.15, 114.24, 121.63, 129.01, 129.42, 130.18, 133.84, 136.99, 160.80 (1 2 sp C not located). Preparation N-Boc imine 103: The general procedure was followed with sulfonyl amine 273 (754 mg, 2.00 mmol, 1.00 equiv) and a refluxing time of 18 hours. The 1 product 103 was obtained as a white solid (469 mg, 1.00 mmol, 100%). H NMR (CDCl3, 300 MHz) δ 1.56 (s, 9H, 3CH3), 3.86 (s, 3H, CH3), 6.94 (d, 2H, J = 8.7 Hz, Ar-H), 7.86 (d, 2H, J = 9.0 Hz, Ar-H), 8.86 (s, 1H, CHN); No 13 C NMR was taken. The purity of imine 103 by weight was calculated to be ca. 87% based on 1 the H NMR spectrum that revealed the presence of imine 103, aldehyde 272 and tert-butyl carbamate in a ratio of 1:0.13:0.13. O O NH2Boc HN PhSO2Na Boc K2CO3, Na2SO4 N Boc SO2Ph THF, reflux PivO 275 HCOOH O 104 274 MeOH/H2O PivO Preparation of α-sulfonyl amine 275: The general procedure was followed with 2.47 g p-pivaloylbenzaldehyde 274 80a (12.0 mmol) and a reaction time of 22 hours to provide the product 275 as a white solid (1.36 g, 3.03 mmol) in 51% 1 yield; mp 175-176 °C. H NMR (CDCl3, 600 MHz) δ 1.25 (s, 9H, 3CH3), 1.34 (s, 9H, 3CH3), 5.64 (d, 1H, J = 10.2 Hz), 5.89 (d, 1H, J = 10.2 Hz), 7.10 (d, 2H, J = 8.4 Hz, Ar-H), 7.42 (d, 2H, J = 8.4 Hz, Ar-H), 7.52 (t, 2H, J = 7.8 Hz, Ar-H), 7.63 213 (t, 1H, J = 6.6 Hz, Ar-H), 7.88 (d, 2H, J = 7.2 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 27.07, 27.98, 39.12, 73.34, 81.23, 121.92, 127.26, 129.06, 129.45, 130.01, 133.98, 136.75, 152.30, 153.41, 176.61. Preparation N-Boc imine 104: The general procedure was followed with sulfonyl amine 275 (762 mg, 2.00 mmol, 1.00 equiv) and a refluxing time of 24 hours. The 1 product 104 was obtained as a white solid (490 mg, 2.05 mmol, 103%). H NMR (CDCl3, 300 MHz) δ 1.28 (s, 9H, 3CH3), 1.48 (s, 9H, 3CH3), 7.16 (d, 2H, J = 8.4 Hz, Ar-H), 7.98 (d, 2H, J = 8.4 Hz, Ar-H), 8.91 (s, 1H, CHN); 13 C NMR (CDCl3, 150 MHz) δ 26.84, 27.70, 39.03, 82.13, 121.93, 131.25, 131.32, 155.04, 162.26, 168.52, 176.24. The purity of imine 104 by weight was calculated to be ca. 92% based on the 1 H NMR spectrum that revealed the presence of imine 104, aldehyde 274 and tert-butyl carbamate in a ratio of 1:0.10:0.03. AcO AcO O NH2Boc PhSO2Na AcO HCOOH 276 MeOH/H2O HN Boc SO2Ph AcO 277 K2CO3 (aq) AcO AcO N Boc 105 Preparation of α-sulfonyl amine 277: The general procedure was followed with 1.16 g 3,4-diacetoxybenzaldehyde 276 80b (4.80 mmol, 1.20 equiv) and a reaction time of 24 hours to provide the product 277 as a white solid (1.04 g, 2.24 1 mmol) in 56% yield; mp 169-170 °C. H NMR (CDCl3, 300 MHz) δ 1.24 (s, 9H, 3CH3), 2.73, 2.74 (2s, 6H, 2CH3), 5.64 (d, 1H, J = 10.8 Hz), 5.89 (d, 1H, J = 10.8 Hz), 7.18-7.24 (m, 1H), 7.26-7.34 (m, 2H), 7.46-7.68 (m, 3H), 7.86 (d, 2H, J = 6.6 214 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 20.54, 20.61, 27.95, 73.02, 81.38, 123.76, 124.00, 127.19, 128.73, 129.10, 129.46, 134.06, 136.50, 142.20, 143.30, 153.33, 167.76, 167.87. Preparation N-Boc imine 105: To a solution of sulfonyl amine 277 (463 mg, 1.00 mmol, 1.00 equiv) in CH2Cl2 (16 mL) was added aq 1.4 M K2CO3 solution (16 mL). The resulting mixture was stirred at rt vigorously for 4 hours. The aqueous layer was separated and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the 1 product 105 as a white solid (330 mg, 1.03 mmol, 103%). H NMR (CDCl3, 300 MHz) δ 1.55 (s, 9H, 3CH3), 2.27, 2.28 (2s, 6H, 2CH3), 7.29 (d, 1H, J = 8.4 Hz, Ar-H), 7.45 (dd, 2H, J = 8.4, 2.1 Hz, Ar-H), 8.78 (s, 1H, CHN); 13 C NMR (CDCl3, 150 MHz) δ 20.46, 20.61, 27.84, 82.45, 123.93, 124.53, 128.72, 132.65, 142.56, 146.17, 162.08, 167.49, 167.56, 167.80. O NH2Boc HN Boc N Boc K2CO3 (aq)PivO PhSO2Na PivO SO2Ph HCOOH PivO PivO 106 279 278 MeOH/H OPivO 2 Preparation of α-sulfonyl amine 279: The general procedure was followed with PivO 2.34 g 3,4-bis[(pivaloyl)oxy]benzaldehyde 278 80c (7.66 mmol, 1.50 equiv) and a reaction time of 24 hours to provide the product 279 as a white solid (1.40 g, 2.56 1 mmol) in 52% yield; mp 104-105 °C. H NMR (CDCl3, 600 MHz) δ 1.25 (s, 9H, 215 3CH3), 1.32, 1.33 (2s, 18H, 6CH3), 5.67 (d, 1H, J = 12.0 Hz), 5.88 (d, 1H, J = 13.2 Hz), 7.15 (d, 1H, J = 8.4 Hz), 7.20-7.26 (m, 2H), 7.52 (t, 2H, J = 7.8 Hz), 7.62 (t, 1H, J = 7.2 Hz), 7.86 (d, 2H, J = 7.8 Hz); 13 C NMR (CDCl3, 150 MHz) δ 27.42, 27.47, 28.24, 39.40, 39.45, 73.40, 81.67, 123.92, 124.15, 127.12, 128.55, 129.33, 129.73, 134.26, 136.79, 142.92, 144.18, 153.62, 175.65, 175.71. Preparation N-Boc imine 106: To a solution of sulfonyl amine 279 (547 mg, 1.00 mmol, 1.00 equiv) in CH2Cl2 (16 mL) was added aq 1.4 M K2CO3 solution (16 mL). The resulting mixture was stirred at rt vigorously for 4 hours. The aqueous layer was separated and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the 1 product 106 as a semi-solid (410 mg, 1.01 mmol, 101%). H NMR (CDCl3, 300 MHz) δ 1.33 (s, 18H, 6CH3), 1.56 (s, 9H, 3CH3), 7.26 (d, 1H, J = 8.4 Hz), 7.70 (dd, 1H, J = 8.4, 2.1 Hz), 7.75 (d, 1H, J = 2.1 Hz), 8.81 (s, 1H, CHN); 13 C NMR (CDCl3, 150 MHz) δ 27.39, 27.46, 28.13, 39.40, 39.54, 82.76, 124.17, 124.55, 129.21, 132.56, 143.38, 147.23, 162.40, 168.30, 175.62, 175.78. O 280 NH2Boc PhSO2Na HCOOH MeOH/H2O HN Boc Cs2CO3, CH2Cl2 SO2Ph 281 N Boc rt 107 81 Preparation of α-sulfonyl amine 281 : tert-butyl carbamate (585 mg, 5.00 mmol, 1.00 equiv) was dissolved in THF (5 mL) and H2O (5 mL). Then benzenesulfinic 216 acid sodium salt (821 mg, 5.00 mmol, 1.00 equiv) and cyclohexanecarbaldehyde 280 (606 mg, 0.660 mL, 5.40 mmol, 1.08 equiv) were added, followed by the addition of formic acid (1.5 mL). The resulting mixture was stirred at rt overnight. The precipitate was filtered and washed well with Et2O. The product 281 was 1 obtained as a white solid (706 mg, 0.400 mmol) in 40% yield; mp 151-152 °C. H NMR (CDCl3, 300 MHz) δ 1.00-1.44 (m, 14H), 1.62-1.80 (m, 4H), 2.12 (d, 1H, CH), 2.40-2.48 (m, 1H, CH), 4.70 (dd, 1H, J = 10.4, 3.6 Hz), 5.12 (d, 1H, J = 10.6 Hz), 7.46-7.66 (m, 3H, Ar-H), 7.84-7.92 (m, 2H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 25.8, 26.0, 26.2, 27.5, 28.2, 30.8, 36.5, 74.5, 80.9, 129.1, 129.2, 133.8, 138.3, 154.2. Preparation of N-Boc imine 107 79e : A 100 mL round bottom flask containing Cs2CO3 (2.45 g, 7.50 mmol, 5.00 equiv) was flame-dried and cooled to rt under N2. Then sulfonyl amine 281 (530 mg, 1.50 mmol, 1.00 equiv) and dry CH2Cl2 (15 mL) was added. The resulting mixture was stirred at rt for 11 hours. After it was cooled to 0 °C, hexane (precooled to 0 °C, 15 mL) was added. Then the mixture was washed with water (2 × 5 mL), brine (5 mL) and dried (Na2SO4). The solvent was evaporated (water bath temperature was kept under 20 °C) to give imine 107 as a colorless oil (318 mg, 1.50 mmol, 100%). 1 H NMR (CDCl3, 500 MHz) δ 1.10-1.36 (m, 5H), 1.50 (s, 9H, CH3), 1.60-1.76 (m, 5H), 2.22-2.34 (m, 217 1H, CH), 8.14 (brs, 1H, CHN). The reported in the literature. 1 H NMR data was identical with those 79e 7.2.2 Preparation of the diazo compounds Preparation of ethyl-2-diazopropionate 88a SO2N3 O O O O N H (p-ABSA) DBU OEt OEt N2 88a 282 Diazo compound 88a was prepared following a modification of a procedure for 82 closely related compounds . To a solution of ethyl 2-methylacetoacetate 282 (0.29 g, 0.29 mL, 2.0 mmol, 1.0 equiv) and p-acetamidobenzenesulfonyl azide (p-ABSA) (0.72 g, 3.0 mmol, 1.5 equiv) in dry CH3CN (10 mL) was added DBU (0.46 g, 0.45 mL, 3.0 mmol, 1.5 equiv) dropwise at 0 °C. Then the mixture was stirred at 0 °C for 1 hour and at rt for another hour. To the mixture was added water (5 mL) and EtOAc (10 mL). And the aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The yellow crude product was purified by column chromatography (silica gel, 25 × 200 mm, hexane:EtOAc 15:1) to give the product 88a as a yellow liquid (volatile) (0.12 g, 0.94 mmol, 47%); Rf = 0.33 1 (hexane:EtOAc 9:1); H NMR (CDCl3, 500 MHz) δ 1.24 (t, 3H, J = 7.0 Hz, CH3), 1.92 (s, 3H, CH3), 4.18 (q, 2H, J = 7.0 Hz, CH2); 218 13 C NMR (CDCl3, 150 MHz) δ 2 1 8.38, 14.50, 60.76 (2 sp C not located). The H NMR spectra data of 88a are identical with those reported previously. 83 Preparation of ethyl-2-diazobutanoate 88b SO2N3 O O N OEt OEt H (p-ABSA) N2 88b DBU 283 Diazo compound 88b was prepared following the above procedure for 88a O O starting from ethyl 2-ethylacetoacetate 283 (0.35 g, 0.36 mL, 2.0 mmol). The product 88b was obtained as a yellow liquid (234 mg, 1.65 mmol) in 82% yield; 1 Rf = 0.50 (hexane:EtOAc 4:1); H NMR (CDCl3, 500 MHz) δ 1.12 (t, 3H, J = 7.5 Hz, CH3), 1.25 (t, 3H, J = 7.0 Hz, CH3), 2.32 (q, 2H, J = 7.5 Hz, CH2), 4.20 (q, 2H, J = 7.0 Hz, CH2); 13 C NMR (CDCl3, 150 MHz) δ 12.17, 14.77, 16.79, 60.92, 165.82 (1 sp2 C not located); IR 2984(m), 2085(s), 1732(s), 1695(s), 1142(s) cm 1 + – + ; HRMS (ESI ) calcd for C6H10N2O2Na, m/z 165.0640 ([M+Na] ), meas 165.0642. Preparation of ethyl-2-diazopentanoate 88c O O O O NaH OEt OEt SO2N3 N H (p-ABSA) O OEt N2 DBU 88c 285 Synthesis of β-ketoester 285: To a suspension of NaH (60% in mineral oil, 0.20 284 I O g, 5.0 mmol, 1.0 equiv) in dry THF (5 mL) was added ethyl acetoacetate 284 (0.65 g, 0.64 mL, 5.0 mmol, 1.0 equiv) dropwise. Then the resulting mixture was 219 stirred at rt for 30 min during which time the colorless suspension became a clear yellow solution. n-PrI (0.85 g, 0.50 mL, 5.0 mmol, 1.0 equiv) was added, and the resulting mixture was refluxed for 6 hours. After cooling to rt, aq sat NH4Cl (5 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 18 × 200 mm, hexane:EtOAc 5:1), giving the product 285 as a colorless liquid (730 mg, 4.22 mmol, 84%) which was used in the next step without further purification. Diazo transfer to give 88c: The diazo transfer step was performed on the crude 285 (346 mg, 2.00 mmol) following the procedure described for 88a. The product 88c was obtained as a yellow liquid (249 mg, 1.74 mmol) in 87% yield over 2 1 steps; Rf = 0.63 (hexane:EtOAc 4:1). H NMR (CDCl3, 300 MHz) δ 1.11 (t, 3H, J = 7.5 Hz, CH3), 1.25 (t, 3H, J = 7.0 Hz, CH3), 1.42-1.60 (m, 2H, CH2), 2.32 (q, 2H, J = 7.5 Hz, CH2), 4.19 (q, 2H, J = 7.0 Hz, CH2); 13 C NMR (CDCl3, 150 MHz) δ 13.46, 14.75. 21.18, 25.22, 60.91 (2 Csp2 not located); IR 2984(m), 2085(s), –1 + + 1732(s) cm ; HRMS (ESI ) calcd for C7H12N2O2Na, m/z 179.0796 ([M+Na] ), meas 179.0796. Preparation of ethyl-2-diazo-3-methylbutanoate 88d 220 SO2N3 O O O O NaH OEt 284 OEt I O O N H (p-ABSA) DBU 286 OEt N2 88d Synthesis of β-ketoester 286: To a suspension of NaH (60% in mineral oil, 0.20 g, 5.0 mmol, 1.0 equiv) in dry THF (5 mL) was added ethyl acetoacetate 284 (0.65 g, 0.64 mL, 5.0 mmol, 1.0 equiv) dropwise. The mixture was stirred at rt for 15 min during which time the colorless suspension became a clear yellow solution. i-PrI (1.75 g, 1.00 mL, 10.0 mmol, 2.00 equiv) was added and the resulting mixture was refluxed for 24 hours. After cooling to rt, aq sat NH4Cl (5 mL) was added. The aqueous layer was separated and extracted with ether (3 × 10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the crude product 286. This material was subjected to the next step without purification. The diazo transfer to give 88d: This reaction was performed on all of the crude 286 following the procedure described above for 88a on a 5.0 mmol scale. The product was obtained as a yellow liquid (390 mg, 2.50 mmol) in 50% yield over 2 1 steps; Rf = 0.63 (hexane:EtOAc 4:1). H NMR (CDCl3, 500 MHz) δ 1.12 (d, 6H, J = 7.5 Hz, 2CH3), 1.24 (t, 3H, J = 7.0 Hz, CH3), 2.72 (sept, 1H, J = 7.0 Hz, CH), 4.19 (q, 2H, J = 7.0 Hz, CH2); 13 C NMR (CDCl3, 150 MHz) δ 14.50, 20.51, 23.09, 60.55, 165.56 (1 sp2 C not located). The identical with those reported 83 1 H NMR spectra data of 88d are for this compound. 221 Preparation of α-diazo-N-propanyloxazolidine 26a SO2Cl 287 NaN3 NO2 SO2N3 288 NO2 The sulfonyl azide 288 was prepared following a literature procedure 84a . A solution of o-nitrobenzenesulfonyl chloride 287 (443 mg, 2.00 mmol, 1.00 equiv) in a mixture of H2O and acetone (v:v 1:1, 12 mL) was cooled to 0 °C. Sodium azide (195 mg, 3.00 mmol, 1.50 equiv) was added portionwise at 0 °C. After the addition, the ice bath was removed and the mixture was stirred at rt for 4 h. Acetone was then evaporated, and the aqueous layer was extracted with CH2Cl2 (20 mL + 2 × 10 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 3:1), affording 288 as a pale solid (400 mg, 1.76 mmol, 88%); mp 68-70 °C; Rf = 0.3 1 (hexane:EtOAc 4:1); H NMR (CDCl3, 600 MHz) δ 7.98-8.06 (m, 3H, Ar-H); 8.24 (dd, 1H, J = 7.8, 0.6 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 125.35, 131.69, 132.63, 133.05, 135.70, 147.74. The spectral data for 98 match those previously reported. 84 O HN 1 n-BuLi O 2 289 O O N O Cl O 290 222 1 LDA 2 o-NBSA 288 O O N N2 26a O 85 N-acylation of 289: Compound 290 was prepared by a published procedure . To a flame dried flask was added 2-oxazolidinone 289 (436 mg, 5.00 mmol, 1.00 equiv) and dry THF (10 mL). The mixture was cooled down to – 78 °C under N2. To the solution of 289 was added n-BuLi (2.2 M in Hexane, 2.5 mL, 5.5 mmol, 1.1 equiv) dropwise. The mixture was stirred at – 78 °C for 15 min. Then freshly distilled propiony chloride (0.51 g, 0.48 mL, 5.5 mmol, 1.1 equiv) was added dropwise. The reaction mixture was stirred at – 78 °C for 2 hours and allowed to warm up to room temperature over 30 min, and then aq sat NH4Cl (5 mL) was added. The aqueous layer was separated and extracted with CH2Cl2 (20 mL + 2 × 10 mL). The combined organic extracts were washed with aq sat NaHCO3 (10 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 25 × 250 mm, hexane:CH2Cl2:EtOAc 4:4:1), 8 which gave 100 as a white solid (644 mg, 4.50 mmol, 90%); mp 77-79 °C; (lit , 1 77-79 °C); Rf = 0.45 (hexane:CH2Cl2:EtOAc 2:2:1); H NMR (CDCl3, 500 MHz) δ 1.14 (t, 3H, J = 7.5 Hz, CH3), 2.90 (q, 2H, J = 7.5 Hz, CH2), 3.98 (t, 2H, J = 8.0 Hz, CH2), 4.40 (t, 2H, J = 8.0 Hz, CH2); 13 C NMR (CDCl3, 150 MHz) δ 8.24, 28.70, 42.48, 62.02, 153.56, 174.19. Diazo transfer to give 26a: Diazo 26a was prepared according to a procedure 86 reported for the synthesis of (S)-(–)-N-(α-diazo)acetyl-4-benzyl-2-oxazolidinone. 223 To a flame dried flask was added dry i-Pr2NH (66 mg, 0.10 mL, 0.65 mmol, 1.3 equiv) and dry THF (1 mL) under N2. The solution was cooled to –78 °C, and then n-BuLi (2.2 M in Hexane, 0.28 mL, 0.60 mmol, 1.2 equiv) was added dropwise via syringe. The resulting solution was stirred at the same temperature for 10 min. A solution of acyl-oxazolidinone 290 (72 mg, 0.50 mmol, 1.0 equiv) in dry THF (1 mL) was added dropwise via syringe. The flask containing 290 was rinsed with dry THF (1 mL) and this was added dropwise to the reaction mixture. After 30 min, a solution of o-nitrobenzenesulfonyl azide 288 (o-NBSA) (137 mg, 0.600 mmol, 1.00 equiv) in dry THF (1 mL) was added dropwise via syringe. The flask containing 288 was rinsed with dry THF (1 mL) and this was added to the reaction mixture. The resulting reaction mixture was kept at –78 °C for 4.5 h. Then aq sat NH4Cl (2.0 mL) was added via syringe dropwise at –78 °C. The mixture was warmed up to rt and the aqueous layer was separated and extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The product was purified by column chromatography (silica gel, 18 × 180 mm, CH2Cl2:MeOH 50:1) to afford 26a as a yellow oil which solidified in the refrigerator as a yellow solid (43 mg, 0.25 mmol, 50%); Rf = 0.40 1 (CH2Cl2:MeOH 20:1); H NMR (CDCl3, 500 MHz) δ 2.02 (s, 3H, CH3), 3.98 (t, 2H, J = 8.0 Hz, CH2), 4.40 (t, 2H, J = 8.0 Hz, CH2); 13 C NMR (CDCl3, 150 MHz) δ 9.91, 43.69, 57.70, 62.70, 152.90, 165.31; IR 2923(w), 2092(s), 1771(s), 224 –1 + + 1638(s) cm ; HRMS (ESI ) calcd for C6H7N3O3Na, m/z 192.0385 ([M+Na] ), meas 192.0386. Preparation of α-diazo-N-propanyloxazolidine 26b O O 1 n-BuLi O O 1 LDA O N O N O 2 o-NBSA 288 O O 2 N2 26b 291 289 Cl N-acylation of 289: The preparation of 291 was accomplished using the HN procedure described above for 290 starting from oxazolidinone 289 (436 mg, 5.00 mmol, 1.00 equiv) and butyryl chloride (639 mg, 0.620 mL, 6.00 mmol, 1.20 equiv). The product 291 was obtained as a white crystalline solid (667 mg, 4.25 mmol) in 85% yield; mp 32-34 °C; Rf = 0.15 (hexane:EtOAc 4:1). 1 H NMR (CDCl3, 300 MHz) δ 0.94 (t, 3H, J = 7.2 Hz, CH3), 1.54-1.72 (m, 2H, CH2), 2.84 (t, 2H, J = 7.2 Hz, CH2), 4.96 (t, 2H, J = 8.1 Hz, CH2), 4.36 (t, 2H, J = 8.1 Hz, CH2); 13 C NMR (CDCl3, 125 MHz) δ 13.55, 17.58, 36.82, 42.39, 61.93, 153.48, –1 + 173.26; IR 2952(m), 1768(s), 1698(s), 1388(s), 761(m) cm ; HRMS (ESI ) calcd + for C7H11NO3, m/z 157.0739 ([M] ), meas 157.0732. Diazo transfer to give 26b: The procedure for the preparation of 26a was used in the preparation of 26b starting with 157 mg (1.00 mmol) of 291 and gave the product 26b as a yellow solid (97 mg, 0.52 mmol) in 52% yield; Rf = 0.50 1 (CH2Cl2:MeOH 20:1). H NMR (CDCl3, 500 MHz) δ 1.10 (t, 3H, J = 7.5 Hz, CH3), 2.42 (q, 2H, J = 7.5 Hz, CH2), 3.98 (t, 2H, J = 8.0 Hz, CH2), 4.38 (t, 2H, J = 225 8.0 Hz, CH2); 13 C NMR (CDCl3, 125 MHz) δ 11.32, 17.70, 43.61, 62.64, 152.83, –1 164.65 (1 sp2 C not located); IR 2973(w), 2091(s), 1773(s), 1637(s) cm ; HRMS + + (ESI ) calcd for C7H9N3O3Na, m/z 206.0542 ([M+Na] ), meas 206.0546. Preparation of 2-diazopropamide 124 O N C N (DIC) OH Ph O P Ph 292 N OH O O O Ph P Ph N O 293 O 87 Compound 293 was prepared according to a literature procedure . To a suspension of 292 (532 mg, 2.00 mmol, 1.00 equiv) and N-hydroxysuccimide (460 mg, 4.00 mmol, 2.00 equiv) in dry CH2Cl2 (5 mL) was added diisopropylcarbodiimide (DIC) (0.37 mL, 2.4 mmol, 1.2 equiv) dropwise at 0 °C. Then the ice bath was removed and the reaction mixture was stirred at rt overnight under N2. The resulting mixture was filtered through Celite and the filtrate was concentrated. The crude product was purified by column chromatography (silica gel, 18 × 200 mm, hexane:EtOAc 2:1) giving the pure product 293 as a white solid (655 mg, 0.922 mmol, 92%); mp 101-103 °C; Rf = 1 0.20 (hexane:EtOAc 2:1); H NMR (CDCl3, 500 MHz) δ 2.38-2.46 (m, 2H, CH2), 2.62-2.68 (m, 2H, CH2), 2.70 (s, 4H, 2CH2), 7.30-7.46 (m, 10H, Ar-H); (CDCl3, 125 MHz, 31 1 13 C NMR P coupled, H decoupled) δ 22.57, 22.68, 25.55, 27.64, 226 27.81, 128.66, 128.71, 129.06, 132.61, 132.75, 136.90, 137.00, 168.33, 168.46, 168.97. O 1 NaN3 O NHBn 2 SOCl2 N3 295 3 BnNH2 To a suspension of sodium azide (812 mg, 12.5 mmol, 2.50 equiv) in DMSO (15 OH Br 294 mL) was added 2-bromopropinoic acid 294 (0.45 mL, 5.0 mmol, 1.0 equiv) dropwise. The resulting solution was stirred at rt overnight. Then the mixture was diluted with H2O (20 mL) and the pH was adjusted to ca. 1 with conc. HCl. The reaction mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (3 × 20 mL). After the organic layer was dried (Na2SO4), filtered and concentrated, the azido acid was obtained as a slightly brown colored oil (570 mg, 4.95 mmol, 99%). To a solution of the azido acid (230 mg, 2.00 mmol, 1.00 equiv) in dry benzene (10 mL) was added thionyl chloride (0.30 mL, 4.0 mmol, 2.0 equiv). The resulting solution was refluxed for 2 hours. After cooling to rt, benzylamine (1.10 mL, 10.0 mmol, 5.00 equiv) was added dropwise. After the mixture was stirred at rt for another 1 hour, water (5 mL) was added. The aqueous layer was separated and extracted with Et2O (3 × 10 mL). The combined organic extracts were washed with aq. HCl (3 M, 3 × 2 mL), dried (Na2SO4) and filtered. After concentration, the crude product was purified by column chromatography (silica gel, 25 × 250 mm, hexane:EtOAc 3:1), affording the product 295 as a pale yellow oil (exists as a solid only in the refrigerator) (331 1 mg, 1.62 mmol) in 81% yield; Rf = 0.25 (hexane:EtOAc 3:1). H NMR (CDCl3, 227 500 MHz) δ 1.54 (d, 3H, J = 7.0 Hz, CH3), 4.08 (q, 1H, J = 7.0 Hz, CH), 4.40 (d, 2H, J = 5.5 Hz, CH2), 6.64 (brs, 1H, NH), 7.20-7.34 (m, 5H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 17.17, 43.47, 59.22, 127.66, 127.72, 128.77, 137.60, –1 + 169.64; IR 3302(m), 2109(s), 1654(s), 1539(s) cm ; HRMS (ESI ) calcd for + C10H13N4O, m/z 205.1089 ([M+H] ), meas 205.1085. O O Ph P NHBn Ph N3 295 O O N O O 293 DBU NHBn N2 124 Diazo transfer to give 124: The preparation of 124 followed a procedure 87 reported for related compounds. To a solution of the azido amide 295 (204 mg, 1.00 mmol, 1.00 equiv) in THF/H2O (2 mL/300 µL) was added phosphine 293 (390 mg, 1.10 mmol, 1.10 equiv). The mixture was stirred at rt under N2 for 6 hours. The solution was diluted with aq sat NaCl (10 mL), and the resulting mixture was extracted with CH2Cl2 (3 × 15 mL). The organic extracts were combined, dried (Na2SO4), filtered through Celite and concentrated to give a pale yellow foamy solid. All of the solids were then dissolved in dry CH2Cl2 (2 mL) and cooled to 0 °C. Then DBU (274 mg, 0.270 mL, 1.80 mmol, 1.80 equiv) was added dropwise at 0 °C. The resulting yellow solution was stirred at 0 °C for 20 min during which time a precipitate appeared. Then the entire reaction mixture 228 including the precipitate was quickly loaded without concentration onto a silica gel column (18 × 180 mm) and eluted quickly with hexane:EtOAc:Et3N 25:25:1 to give the diazo amide 124 as a yellow solid (85 mg, 0.45 mmol, 45%); Rf = 0.43 1 (hexane:EtOAc 1:2); H NMR (CDCl3, 600 MHz) δ 1.98 (s, 3H, CH3), 4.50 (d, 2H, J = 4.5 Hz, CH2), 5.40 (brs, 1H, NH), 7.22-7.34 (m, 5H, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 8.99, 44.35, 127.75, 128.03, 128.91, 138.71, 166.94 (1 sp2 –1 + C not located); IR 3320(m), 2079(s), 1614(s), 1529(s) cm ; HRMS (ESI ) calcd + for C10H12N3O, m/z 190.0980 ([M+H] ), meas 190.0972. 7.2.3 Procedures for Asymmetric Catalytic Aziridination Reactions 7.2.3.1 Preparation of racemic aziridines To the mixture of the proper N-Boc imine (0.20 mmol, 2.0 equiv) and diazo compound 26 (0.10 mmol, 1.0 equiv) in CH2Cl2 (0.3 mL) at –78 °C under N2 was added 20 µL of a BF3•Et2O solution (prepared from 100 µL of neat BF3•Et2O in 1 mL of CH2Cl2). The reaction mixture was stirred at –78 °C for 10 min to 1 h, and then NEt3 (0.5 mL) was added at –78 °C. The solvent was evaporated, and the aziridine was purified by column chromatography on silica gel to give the corresponding aziridine in 38-86% yield. 7.2.3.2 Preparation of a catalyst stock solution (0.05 M in CH2Cl2) 229 A 25 mL pear-shaped single necked flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it) and cooled to rt under N2 and charged with VANOL ((S) or (R), 44 mg, 0.10 mmol, 1.0 equiv), sublimed PhOH (20 mg, 0.20 mmol, 2.0 equiv), dry toluene (1 mL), H2O (5.4 mg, 5.4 µL, 0.30 mmol, 3.0 equiv) and BH3•Me2S solution (2.0 M in toluene, 150 µL, 0.300 mmol, 3.00 equiv). The Teflon valve was closed and the flask was heated at 100 °C for 1 hour. After the flask was cooled to rt, the toluene was carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon value. After the solvent was removed, the Teflon valve was completely opened and the flask was heated to 100 °C under high vacuum for 30 min. The residue that remained was a white foamy solid, which was cooled to rt before the addition of dry CH2Cl2 (2 mL) to make a 0.05 M solution. 7.2.3.3. General procedure for the asymmetric catalytic aziridination reaction 10 mol% catalyst loading: A 25 mL round bottom flask was flame dried under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a rubber septum. The septum was removed briefly to allow introduction of the proper imine (0.20 mmol, 2.0 equiv), which was weighed in the flask with the septum. Subsequently, the septum was removed again to allow for the addition of dry stir bar and a pre-weighed amount of the solid diazo compound 26a or 26b (0.10 mmol, 1.0 equiv). Dry CH2Cl2 (0.3 mL) was then introduced through the septum with a syringe and then a balloon filled with nitrogen was attached via a 230 needle in the septum. After the flask was cooled to –78 °C under the N2 balloon, the VANOL catalyst solution (10 mol%, 0.2 mL) that had been precooled to –78 °C was quickly added. The reaction mixture was stirred at –78 °C for 4-30 h, and then NEt3 (0.5 mL) was added at –78 °C. The solvent was evaporated and the product was purified by column chromatography on silica gel to give the corresponding aziridine. 20 mol% catalyst loading: A 25 mL round bottom flask was flame dried under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a rubber septum. The septum was removed briefly to allow introduction of the proper imine (0.20 mmol, 2.0 equiv), which was weighed in the flask with the septum. Subsequently, the septum was removed again to allow for the addition of dry stir bar and a pre-weighed amount of the solid diazo compound 26a or 26b (0.10 mmol, 1.0 equiv). Dry CH2Cl2 (0.6 mL) was then introduced through the septum with a syringe and then a balloon filled with nitrogen was attached via a needle in the septum. After the flask was cooled to –78 °C under the N2 balloon, the VANOL catalyst solution (10 mol%, 0.2 mL) that had been precooled to –78 °C was quickly added. The reaction mixture was stirred at –78 °C for 4-7 h, and then NEt3 (0.5 mL) was added at –78 °C. The solvent was evaporated and the product was purified by column chromatography on silica gel to give the corresponding aziridine. 231 (2R,3S)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-phenylaziridine-2-carbonyl]-1oxazolidin-2-one 27a: Boc Ph N N N O N O H + Ph CH2Cl2, –78 °C N2 O O 18 26a (2R,3S)-27a The aziridine 27a was prepared from imine 18 (90% purity by weight, 46 mg, Boc O O (S)-VANOL catalyst (10 mol%) 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (S)-VANOL catalyst solution (10 mol%, 0.2 mL) by the general procedure with a reaction time of 6 hours. The reaction went to 98% conversion. The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05) to give the product (2R,3S)-27a as a white foamy solid (26 mg, 0.075 mmol, 76%). The optical purity was determined to be 94% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 11.4 min for (2R,3S)-27a (major) and tR = 23.1 min for (2S,3R)-27a (minor); A second run gave 97% conversion, 68% yield and 93.5% ee; mp 47-48 °C; Rf = 0.2 (hexane:EtOAc:CH2Cl2:NEt3 1 3:1:1:0.05); H NMR (CDCl3, 600 MHz) δ 1.38 (s, 3H, CH3), 1.54 (s, 9H, 3CH3), 3.88 (s, 1H, CH), 3.90-3.96 (m, 1H, CHH), 4.10 (q, 1H, J = 8.0 Hz, CHH), 4.384.52 (m, 2H, CH2), 7.25-7.36 (m, 3H, Ar-H), 7.44 (d, 2H, J = 7.2 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 15.42, 27.88, 43.33, 47.70, 52.05, 62.69, 81.70, 20 127.82, 127.95, 128.39, 133.41, 152.52, 160.10, 170.56; [α] D +30.8° (c 1.0, 232 CH2Cl2) on 94% ee material from (S)-VANOL. The effects of changes in the reaction conditions and the ligands in the catalyst on the formation of 27a are summaried in Table 3.2. (2S,3R)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-(4-nitrophenyl)aziridine-2carbonyl]-1-oxazolidin-2-one 108: N Boc O O N + 94 Boc O N (R)-VANOL catalyst (10 mol%) O O N O CH2Cl2, –78 °C (2S,3R)-108 O2N 26a O2N The aziridine 108 was prepared from imine 94 (100% purity by weight, 50 mg, N2 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (R)-VANOL catalyst solution (10 mol%, 0.2 mL) by the general procedure with a reaction time of 6 hours. The crude product was purified by column chromatography (1 st column, silica nd hexane:EtOAc:CH2Cl2:NEt3 2:1:1:0.05; 2 gel, 18 × 180 mm, column, silica gel, 18 × 180 mm, CH2Cl2:MeOH:NEt3 50:1:1) to give the product (2S,3R)-108 as a white foamy solid (24 mg, 0.062 mmol, 62%). The optical purity was determined to be 90% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 34.5 min for (2R,3S)-108 (minor) and tR = 48.2 min for (2S,3R)-108 (major); mp 72-75 °C; Rf = 0.3 (hexane:EtOAc:CH2Cl2:NEt3 1 2:1:1:0.05); H NMR (CDCl3, 600 MHz) δ 1.38 (s, 3H, CH3), 1.56 (s, 9H, 3CH3), 3.91 (s, 1H, CH), 3.92-3.98 (m, 1H, CHH), 4.08-4.16 (m, 1H, CHH), 4.44-4.54 (m, 233 2H, CH2), 7.62 (d, 2H, J = 8.4 Hz, Ar-H), 8.18 (d, 2H, J = 9.0 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 15.43, 27.63, 42.97, 46.25, 52.46, 62.62, 82.18, 122.98, 129.27, 140.75, 147.46, 152.44, 159.49, 169.45; IR 2982(w), 1786(s), 1720(s), –1 20 1700(m) cm ; [α] D –43.5° (c 1.0, CH2Cl2) on 90% ee material from (R)+ + VANOL; HRMS (ESI ) calcd for C18H21N3O7Na, m/z 414.1277 ([M+Na] ), meas 414.1287. The reaction with 20 mol% catalyst loading ((R)-VANOL) and a reaction time of 6 hours afforded aziridine 108 in 62% yield and 90% ee. (2S,3R)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-(4-trifluoromethylphenyl)aziridine2-carbonyl]-1-oxazolidin-2-one 109: N Boc O O N + 95 Boc O N (R)-VANOL catalyst (10 mol%) O O N O CH2Cl2, –78 °C (2S,3R)-109 F3C The aziridine 109 was prepared from imine 95 (96% purity by weight, 58 mg, F3C N2 26a 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (R)-VANOL catalyst solution (10 mol%, 0.2 mL) by the general procedure with a reaction time of 1 hour. The crude product was purified by column chromatography (1 st column, silica nd hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05; 2 gel, 18 × 180 mm, column, silica gel, 18 × 180 mm, CH2Cl2:MeOH:NEt3 100:1:1) to give the product (2S,3R)-109 as a white foamy solid (24 mg, 0.058 mmol, 58%). The optical purity was determined to be 95% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 hexane/2-PrOH, flow rate: 1 234 mL/min); Retention time: tR = 8.1 min for (2R,3S)-109 (minor) and tR = 13.9 min for (2S,3R)-109 (major); mp 122-126 °C; Rf = 0.25 (hexane:EtOAc:CH2Cl2:NEt3 1 3:1:1:0.05); H NMR (CDCl3, 600 MHz) δ 1.36 (s, 3H, CH3), 1.52 (s, 9H, 3CH3), 3.89 (s, 1H, CH), 3.90-3.98 (m, 1H, CHH), 4.04-4.16 (m, 1H, CHH), 4.40-4.54 (m, 2H, CH2), 7.52-7.62 (m, 4H, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 15.55, 27.86, 43.24, 46.85, 52.38, 62.78, 82.11, 124.15 (J = 271.8 Hz), 124.96 (J = 4.5 Hz), 128.85, 130 03 (J = 29.2 Hz), 137.56, 152.61, 159.86, 170.04; IR 2984(w), –1 20 1784(s), 1707(s), 1325(m) cm ; [α] D –13.6° (c 1.0, CH2Cl2) on 96% ee + material from (R)-VANOL; HRMS (ESI ) calcd for C19H21N2O5F3Na, m/z + 437.1300 ([M+Na] ), meas 437.1284. The reaction with 20 mol% catalyst loading ((R)-VANOL) and a reaction time of 1 hours afforded aziridine 109 in 48% yield and 96% ee. (2S,3R)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-(4-bromophenyl)aziridine-2carbonyl]-1-oxazolidin-2-one 110a: N Boc O N + Br 96 O N2 26a O (R)-VANOL catalyst (10 mol%) CH2Cl2, –78 °C Br Boc O N O N O (2S,3R)-110a The aziridine 110a was prepared from imine 96 (83% purity by weight, 69 mg, 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (R)-VANOL catalyst solution (10 mol%, 0.2 mL) using the general procedure with a reaction time of 8 hours. The crude aziridine was purified by column 235 chromatography (silica gel, 18 × 180 mm, hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05) to give the product (2S,3R)-110a as a white foamy solid (33 mg, 0.078 mmol, 78%). The optical purity was determined to be 96% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 11.5 min for (2R,3S)-110a (minor) and tR = 24.1 min for (2S,3R)-110a (major); A second run gave 62% yield and 96% ee; mp 72-74 °C; 1 Rf = 0.20 (hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05); H NMR (CDCl3, 600 MHz) δ 1.34 (s, 3H, CH3), 1.51 (s, 9H, 3CH3), 3.80 (s, 1H, CH), 3.90-3.95 (m, 1H, CHH), 4.06-4.13 (m, 1H, CHH), 4.36-4.50 (m, 2H, CH2), 7.28-7.32 (m, 2H, Ar-H), 7.427.46 (m, 2H, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 15.49, 27.87, 43.26, 46.92, 52.16, 62.74, 81.96, 122.00, 130.17, 131.13, 132.52, 152.57, 159.95, 170.23; IR –1 20 2980(w), 1789(s), 1720(s), 1160(m) cm ; [α] D –20.8° (c 1.0, CH2Cl2) on 96% ee material obtained from (R)-VANOL; HRMS + (ESI ) calcd for + 79 C18H21N2O5 BrNa, m/z 447.0532 ([M+Na] ), meas 447.0553. The reaction with 20 mol% catalyst loading ((S)-VANOL) and a reaction time of 4 hours afforded aziridine 110a in 71% yield and 96% ee. (2R,3S)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-(4-chlorophenyl)aziridine-2carbonyl]-1-oxazolidin-2-one 111: 236 N Boc + (S)-VANOL catalyst (10 mol%) O O N O CH2Cl2, –78 °C Cl Boc N H N O N2 O O 97 Cl 26a (2R,3S)-111 The aziridine 111 was prepared from imine 97 (91% purity by weight, 53 mg, 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and (S)-VANOL by the general procedure with a reaction time of 6 hours. The reaction went to 95% conversion. The crude mixture was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05) to give the product (2R,3S)-111 as a white foamy solid (30 mg, 0.080 mmol, 80%). The optical purity was determined to be 93% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 Hexane/2-PrOH, flow rate: 1 mL/min); Retention time: tR = 10.7 min for (2R,3S)-111 (major) and tR = 20.1 min for (2S,3R)-111 (minor). A second run gave 111 in 88% conversion, 68% yield and 1 93% ee. mp 72-74 °C; Rf = 0.25 (hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05); H NMR (CDCl3, 600 MHz) δ 1.34 (s, 3H, CH3), 1.52 (s, 9H, 3CH3), 3.82 (s, 1H, CH), 3.90-3.96 (m, 1H, CHH), 4.06-4.13 (m, 1H, CHH), 4.36-4.50 (m, 2H, CH2), 7.26-7.30 (m, 2H, Ar-H), 7.34-7.38 (m, 2H, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 15.69, 28.08, 43.48, 47.08, 52.41, 62.95, 82.15, 128.39, 130.04, 132.20, 133.99, –1 152.78, 160.18, 170.46; IR 2980(w), 1788(s), 1718(s), 1698(s), 1162(m) cm ; 20 [α] D +19.8° (c 1.0, CH2Cl2) on 93% ee material obtained from (S)-VANOL; 237 + + 35 HRMS (ESI ) calcd for C18H21N2O5 ClNa, m/z 403.1037 ([M+Na] ), meas 403.1053. With 20 mol% catalyst laoding ((S)-VANOL), the reaction went to 95% completion in 4 hours and gave the aziridine 111 in 71% yield and 93% ee. (2R,3S)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-(4-fluorophenyl)aziridine-2carbonyl]-1-oxazolidin-2-one 112: N Boc + F O O N N2 O (S)-VANOL catalyst (10 mol%) CH2Cl2, –78 °C Boc N H N O O O (2R,3S)-112 The aziridine 112 was prepared from imine 98 (95% purity by weight, 46 mg, F 98 26a 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (S)-VANOL catalyst solution by the general procedure with a reaction time of 8 hours. The reaction went to 81% conversion. The crude aziridine was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05) to give 112 as a white foamy solid (20 mg, 0.055 mmol, 55%). The optical purity was determined to be 96% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 11.0 min for (2R,3S)-112 (major) and tR = 18.7 min for (2S,3R)-112 (minor); A second run gave aziridine 112 in 80% conversion, 54% yield and 95% ee. mp 48-50 °C; Rf = 1 0.25 (hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05). H NMR (CDCl3, 500 MHz) δ 1.35 (s, 3H, CH3), 1.52 (s, 9H, 3CH3), 3.82 (s, 1H, CH), 3.88-3.96 (m, 1H, CHH), 4.06-4.14 (m, 1H, CHH), 4.38-4.51 (m, 2H, CH2), 6.98-7.04 (m, 2H, Ar-H), 7.34238 7.42 (m, 2H, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 15.43, 27.86, 43.28, 46.89, 52.15, 62.74, 81.85, 114.91 (J = 21.6 Hz), 129.14 (J = 3.1 Hz), 130.11 (J = 8.25 Hz), 152.59, 160.04, 162.53 (J = 244.6 Hz), 170.37; IR 2981(w), 1791(s), –1 20 o 1719(s), 1700(s), 1155(m) cm ; [α] D +32.7 (c 1.0, CH2Cl2) on 96% ee + material obtained from (S)-VANOL); HRMS (ESI ) calcd for C18H21N2O5FNa, + m/z 387.1332 ([M+Na] ), meas m/z 383.1522. The reaction with 20 mol% catalyst loading ((S)-VANOL) went to full conversion in 6 hours and gave 112 in 64% yield and 96% ee. (2S,3R)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-(3-bormophenyl)aziridine-2carbonyl]-1-oxazolidin-2-one 113: N Br Boc O + O N (R)-VANOL catalyst (10 mol%) O Boc O N Br O N O CH2Cl2, –78 °C (2S,3R)-113 26a The aziridine 113 was prepared from imine 99 (92% purity by weight, 63 mg, 99 N2 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (R)-VANOL catalyst by the general procedure with a reaction time of 4 hours. The aziridine was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05) to give 113 as a white foamy solid (25 mg, 0.059 mmol, 59%). The optical purity was determined to be 85% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 12.6 min for (2R,3S)-113 (minor) and tR = 26.4 min 239 for (2S,3R)-113 (major); A second run gave 113 in 53% yield and 85% ee. mp o 1 50-52 C; Rf = 0.24 (hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05); H NMR (CDCl3, 500 MHz) δ 1.37 (s, 3H, CH3), 1.52 (s, 9H, 3CH3), 3.82 (s, 1H, CH), 3.90-3.96 (m, 1H, CHH), 4.06-4.14 (m, 1H, CHH), 4.36-4.52 (m, 2H, CH2), 7.18 (t, 1H, J = 7.5 Hz, Ar-H), 7.36-7.44 (m, 2H, Ar-H), 7.54-7.58 (s, 1H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 15.52, 27.85, 43.24, 46.70, 52.36, 62.74, 82.03, 122.16, 127.46, 129.57, 130.10, 131.12, 135.83, 152.52, 159.90, 170.11; IR 2976(w), –1 20 1783(s), 1709(s), 1688(s), 1162(m) cm ; [α] D –25.3° (c 1.0, CH2Cl2) on 85% ee material obtained from (R)-VANOL; HRMS + (ESI ) calcd for + 79 C18H21N2O5 BrNa m/z 447.0532 ([M+Na] ), meas 447.0526. The reaction with 20 mol% catalyst loading ((R)-VANOL) and a reaction time of 4 hours afforded 113 in 48% yield and 85% ee. (2R,3S)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-(4-methylphenyl)aziridine-2carbonyl]-1-oxazolidin-2-one 114: Boc N O + O N N2 O (S)-VANOL catalyst (10 mol%) CH2Cl2, –78 °C Boc N H N O O 26a (2R,3S)-114 O The aziridine 114 was prepared from imine 100 (94% purity by weight, 48 mg, 100 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (S)-VANOL catalyst solution (10 mol%, 0.2 mL) by the general procedure with a reaction time of 27 hours. The aziridine was purified by column 240 chromatography (1 st column, silica nd hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05; 2 gel, 18 × 180 mm, column, silica gel, 18 × 180 mm, CH2Cl2:MeOH:NEt3 100:1:1) to give the product 114 as a white foamy solid (30 mg, 0.083 mmol, 83%). The optical purity was determined to be 96% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 10.0 min for (2R,3S)-114 (major) and tR = 23.0 min for (2S,3R)-114 (minor); A second run gave azirdine 114 in 82% yield and 97% 1 ee. mp 44-46 °C; Rf = 0.23 (hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05). H NMR (CDCl3, 500 MHz) δ 1.36 (s, 3H, CH3), 1.50 (s, 9H, 3CH3), 2.34 (s, 3H, CH3), 3.84 (s, 1H, CH), 3.89-3.96 (m, 1H, CHH), 4.06-4.14 (m, 1H, CHH), 4.38-4.50 (m, 2H, CH2), 7.14 (d, 2H, J = 8.0 Hz, Ar-H), 7.30 (d, 2H, J = 8.0 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 15.38, 21.16, 27.90, 43.34, 47.72, 51.95, 62.67, 81.63, 128.27, 128.69, 130.36, 137.54, 152.50, 160.14, 170.70; IR 2979(w), 1789(s), –1 20 1720(s), 1700(s), 1160(m) cm ; [α] D –15.8° (c 1.0, CH2Cl2) on 95% ee + material obtained from (R)-VANOL; HRMS (ESI ) calcd for C19H24N2O5Na, m/z + 383.1583 ([M+Na] ), meas 383.1568. With 10 mol% catalyst loading ((R)VANOL) and a reaction time of 9 hours, the reaction went to 60% conversion and gave aziridine 114 in 42% yield and 95% ee. The diazo compound 26a was recovered in 47% yield. The yield of 114 based on the recovered starting material was 70%. 241 (2R,3S)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-(3-methylphenyl)aziridine-2carbonyl]-1-oxazolidin-2-one 115: N Boc + O O N Boc N (S)-VANOL catalyst (10 mol%) O H N O CH2Cl2, –78 °C O (2R,3S)-115 O 26a The aziridine 115 was prepared from imine 101 (92% purity by weight, 48 mg, 101 N2 0.20 mmol, 2.0 equiv.), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (S)-VANOL catalyst solution (10 mol%, 0.2 mL) by the general procedure with a reaction time of 8 hours. The reaction went to 84% conversion. The aziridine was purified by column chromatography (silica gel, 18 × 180 mm, Hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05) to give the product as a white foamy solid (26 mg, 0.071 mmol, 71%). The optical purity was determined to be 92% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 9.6 min for (2R,3S)-115 (major) and tR = 20.1 min o for (2S,3R)-115 (minor); mp 166-167 C; Rf = 0.2 (hexane:EtOAc:CH2Cl2:NEt3 1 3:1:1:0.05). H NMR (CDCl3, 500 MHz) δ 1.42 (s, 3H, CH3), 1.54 (s, 9H, 3CH3), 2.36 (s, 3H, CH3), 3.88 (s, 1H, CH), 3.92-4.00 (m, 1H, CHH), 4.08-4.16 (m, 1H, CHH), 4.42-4.54 (m, 2H, CH2), 7.08-7.14 (m, 1H, Ar-H), 7.20-7.29 (m, 3H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 15.43, 21.38, 27.90, 43.36, 47.82, 52.04, 62.67, 81.69, 125.59, 127.87, 128.61, 128.87, 133.32, 137.59, 152.48, 160.17, 170.61; –1 20 IR 2979(w), 1790(s), 1718(s), 1691(s), 1161(m) cm ; [α] D –33.8° (c 2.0, 242 + CH2Cl2) on 92% ee material obtained from (R)-VANOL; HRMS (ESI ) calcd for + C19H24N2O5Na, m/z 383.1583 ([M+Na] ), meas 383.1568. The reaction with 20 mol% catalyst loading ((R)-VANOL) and a reaction time of 6 hours went to full conversion and gave 115 in 83% yield and 92% ee. (2S,3R)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-(4-pivaloylphenyl)aziridine-2carbonyl]-1-oxazolidin-2-one 118: N Boc + O O N Boc O N (R)-VANOL catalyst (10 mol%) O O N O CH2Cl2, –78 °C N2 (2S,3R)-118 PivO PivO 26a 104 The aziridine 118 was prepared from imine 104 (92% purity by weight, 67 mg, 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (R)-VANOL catalyst solution (10 mol%, 0.2 mL) by the general procedure with a reaction time of 11 hours. The reaction went to 87% conversion. The crude product was purified by column chromatography (1 nd mm, hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05; 2 st column, silica gel, 18 × 180 column, silica gel, 18 × 180 mm, CH2Cl2:MeOH:NEt3 100:1:1) to give the product (2S,3R)-118 as a white foamy solid (31 mg, 0.069 mmol, 69%). The optical purity was determined to be 98% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 11.7 min for (2R,3S)-118 (minor) and tR = 20.9 min for (2S,3R)-118 (major); 1 mp 58-60 °C; Rf = 0.2 (hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05); H NMR (CDCl3, 600 MHz) δ 1.33 (s, 243 9H, 3CH3), 1.36 (s, 3H, CH3), 1.52 (s, 9H, 3CH3), 3.86 (s, 1H, CH), 3.90-3.96 (m, 1H, CHH), 4.06-4.14 (m, 1H, CHH), 4.40-4.50 (m, 2H, CH2), 7.02 (d, 2H, J = 8.4 Hz, Ar-H), 7.43 (d, 2H, J = 8.4 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 15.49, 27.11, 27.88, 39.05, 43.32, 47.20, 52.12, 62.70, 81.83, 121.05, 129.43, 130.72, 150.80, 152.51, 160.01, 170.46, 176.92; IR 2978(w), 1790(s), 1730(s), –1 20 1718(s) cm ; [α] D –17.0° (c 1.0, CH2Cl2) on 98% ee material from (R)+ + VANOL; HRMS (ESI ) calcd for C23H30N2O7Na, m/z 469.1951 ([M+Na] ), meas 469.1941. The reaction with 20 mol% catalyst loading ((R)-VANOL) and a reaction time of 1 hours afforded aziridine 118 in 67% yield and 98% ee. (2S,3R)-3-[N-1-(t-butoxycarbonyl)-2-methyl-3-(3,4-diacetoxyphenyl)aziridine-2carbonyl]-1-oxazolidin-2-one 119: N AcO Boc + O O N N2 O (R)-VANOL catalyst (10 mol%) AcO Boc O N O N O CH2Cl2, –78 °C AcO (2S,3R)-119 26a 105 The aziridine 119 was prepared from imine 105 (100% purity by weight, 65 mg, AcO 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (R)-VANOL catalyst solution (10 mol%, 0.2 mL) by the general procedure with a reaction time of 11 hours. The reaction went to 88% conversion. The crude product was purified by column chromatography (1 nd mm, hexane:EtOAc:CH2Cl2:NEt3 1:1:1:0.05; 2 st column, silica gel, 18 × 180 column, silica gel, 18 × 180 mm, hexane:EtOAc:CH2Cl2:NEt3 1:1:1:0.05) to give the product (2S,3R)-119 as 244 a white foamy solid (30 mg, 0.065 mmol, 65%). The optical purity was determined to be 88% ee by HPLC (Chiralpak AS column, 222 nm, 80:20 hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 20.54 min for (2R,3S)119 (minor) and tR = 40.69 min for (2S,3R)-119 (major); mp 61-62 °C; Rf = 0.3 1 (hexane:EtOAc:CH2Cl2:NEt3 1:1:1:0.05). H NMR (CDCl3, 500 MHz) δ 1.38 (s, 3H, CH3), 1.50 (s, 9H, 3CH3), 2.25 (2s, 6H, 2CH3), 3.85 (s, 1H, CH), 3.88-3.96 (m, 1H, CHH), 4.04-4.12 (m, 1H, CHH), 4.40-4.50 (m, 2H, CH2), 7.02 (d, 1H, J = 8.5 Hz, Ar-H), 7.43 (d, 1H, J = 2.0 Hz, Ar-H), 7.34 (dd, 1H, J = 8.5, 2.0 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 15.88, 20.85, 20.91, 28.06, 43.48, 46.87, 52.67, 62.98, 82.23, 123.27, 123.62, 127.15, 132.68, 141.92, 141.99, 152.80, 160.07, –1 20 168.40, 168.43, 170.40; IR 2982(w), 1776(s), 1718(s), 1710(s) cm ; [α] D – o + 19.0 (c 2.0, CH2Cl2) on 88% ee material from (R)-VANOL; HRMS (ESI ) calcd + for C22H26N2O9Na, m/z 485.1536 ([M+Na] ), meas 485.1509. The reaction with 20 mol% catalyst loading ((R)-VANOL) and a reaction time of 11 hours afforded aziridine 119 in 69% yield and 88% ee. (2S,3R)-3-{N-1-(t-butoxycarbonyl)-2-methyl-3-[(3,4bispivaloyl)oxyl]phenyl)aziridine-2-carbonyl}-1-oxazolidin-2-one 120: Boc O N PivO PivO + 106 O N N2 26a O (R)-VANOL catalyst (10 mol%) PivO CH2Cl2, –78 °C 245 PivO Boc O N O N O (2S,3R)-120 The aziridine 120 was prepared from imine 106 (100% purity by weight, 82 mg, 0.20 mmol, 2.0 equiv), diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) and the (R)-VANOL catalyst solution (10 mol%, 0.2 mL) by the general procedure with a reaction time of 10 hours. The reaction went to 85% conversion. The crude product was purified by column chromatography (1 st column, silica gel, 18 × 180 mm, hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05) to give the product (2S,3R)-120 as a white foamy solid (25 mg, 0.046 mmol, 46%). The optical purity was determined to be 88% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 9.28 min for (2R,3S)120 (minor) and tR = 23.06 min for (2S,3R)-120 (major); mp 52-54 °C; Rf = 0.2 (hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05). 1 H NMR (CDCl3, 600 MHz) δ 1.30, 1.31 (2s, 18H, 6CH3), 1.38 (s, 3H, CH3), 1.50 (s, 9H, 3CH3), 3.88 (s, 1H, CH), 3.90-3.96 (m, 1H, CHH), 4.04-4.12 (m, 1H, CHH), 4.38-4.50 (m, 2H, CH2), 7.08 (d, 1H, J = 7.8 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.32 (d, 1H, J = 8.4 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 15.55, 27.21, 27.27, 27.86, 39.08, 39.12, 43.29, 46.90, 52.34, 62.67, 82.04, 122.98, 123.12, 126.67, 131.97, 142.16, 142.29, 152.42, –1 159.92, 170.22, 175.66, 175.77; IR 2978(w), 1786(s), 1761(s), 1722(s) cm ; 20 [α] D –20.1° (c 1.0, CH2Cl2) on 88% ee material from (R)-VANOL; HRMS + + (ESI ) calcd for C28H38N2O9Na, m/z 569.2475 ([M+Na] ), meas 569.2455. The 246 reaction with 20 mol% catalyst loading ((R)-VANOL) and a reaction time of 10 hours afforded aziridine 120 in 63% yield and 88% ee. (2R,3S)-3-[N-1-(t-butoxycarbonyl)-2-ethyl-3-phenylaziridine-2-carbonyl]-1oxazolidin-2-one 27b: N O Boc N + Ph O N2 O Boc O N (S)-VANOL catalyst (10 mol%) CH2Cl2, –78 °C Ph O N O (2R,3S)-27b 26b 18 The aziridine 27b was prepared from imine 18 (90% purity by weight, 46 mg, 0.20 mmol, 2.0 equiv), diazo compound 26b (19 mg, 0.10 mmol, 1.0 equiv) and the (S)-VANOL catalyst solution (10 mol%, 0.2 mL) by the general procedure with a reaction time of 30 hours. The reaction gave 70% conversion. The crude mixture was purified by the column (silica gel, 18 × 180 mm, hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05) to give the product 27b as a white foamy solid (21 mg, 0.060 mmol, 60%). The optical purity was determined to be 85% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 10.4 min for (2R,3S)-27b (major) and tR = 17.1 min for (2S,3R)-27b (minor); A second run gave aziridine 27b in 66% conversion, 50% yield and 85% ee; mp 146-148 °C; Rf = 0.30 (hexane:EtOAc:CH2Cl2:NEt3 1 3:1:1:0.05). H NMR (CDCl3, 500 MHz) δ 1.02 (t, 3H, J = 7.5 Hz, CH3), 1.38-1.26 (m, 1H, CHH), 1.54 (s, 9H, 3CH3), 1.92-1.80 (m, 1H, CHH), 3.84-3.96 (m, 2H, CHH and CH (s, overlap with CHH)), 4.14 (q, 1H, J = 9.5 Hz, CHH), 4.36-4.54 (m, 2H, CH2), 7.22-7.34 (m, 3H, Ar-H), 7.44 (d, 2H, J = 7.5 Hz, Ar-H); 247 13 C NMR (CDCl3, 150 MHz) δ 10.63, 22.42, 27.85, 43.21, 47.80, 57.54, 62.68, 81.35, 127.74, 127.86, 128.42, 133.61, 152.62, 160.15, 170.21; IR 3033(w), 1789(s), –1 20 1717(s), 1688(s) cm ; [α] D –49.5 o (c 1.0, CH2Cl2) on 83% ee material + obtained from (R)-VANOL; HRMS (ESI ) calcd for C19H24N2O5Na, m/z + 383.1583 ([M+Na] ), meas 383.1590. The reaction with 20 mol% catalyst loading ((S)-VANOL) and a reaction time of 7 hours gave 27b in 49% conversion, 47% yield and 86% ee. The diazo compound 26b was recovered in 63% yield. The yield of 27b based on the recovered starting material was 96%. The reaction with 10 mol% catalyst loading ((R)-VANOL) and a reaction time of 9 hours gave 27b in 35% conversion, 30% yield and 83% ee. The diazo compound 26b was recovered in 60% yield. The yield of 27b based on the recovered starting material was 86%. (2S,3R)-3-[N-1-(t-butoxycarbonyl)-2-ethyl-3-(4-bromophenyl)aziridine-2carbonyl]-1-oxazolidin-2-one 110b: N Boc O + Br O N N2 96 O 26b Boc O N (R)-VANOL catalyst (10 mol%) CH2Cl2, –78 °C O N O Br (2S,3R)-110b The aziridine 110b was prepared from imine 96 (83% purity by weight, 69 mg, 0.20 mmol, 2.0 equiv), diazo compound 26b (19 mg, 0.10 mmol, 1.0 equiv) and the (R)-VANOL catalysts solution (10 mol%, 0.2 mL) by the general procedure with a reaction time of 8 hours. The aziridine was purified by column chromatography (1 st column, silica 248 gel, 18 × 180 mm, nd hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05; 2 column, silica gel, 18 × 180 mm, CH2Cl2:MeOH:NEt3 100:1:1) to give the product as a white foamy solid (30 mg, 0.068 mmol, 68%). The optical purity was determined to be 94% ee by HPLC (Chiralpak AS column, 222 nm, 90:10 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: tR = 9.6 min for (2R,3S)-110b (minor) and tR = 18.1 min for (2S,3R)-110b (major); A second run gave 110b in 56% yield and 94% ee. mp 1 142-144 °C; Rf = 0.20 (hexane:EtOAc:CH2Cl2:NEt3 3:1:1:0.05); H NMR (CDCl3, 500 MHz) δ 1.04 (t, 3H, J = 7.5 Hz, CH3), 1.20-1.30 (m, 1H, CHH), 1.52 (s, 9H, 3CH3), 1.80-1.90 (m, 1H, CHH), 3.80 (s, 1H, CH), 3.86-3.94 (m, 1H, CHH), 4.084.16 (m, 1H, CHH), 4.38-4.52 (m, 2H, CH2), 7.30-7.33 (m, 2H, Ar-H), 7.40-7.44 (m, 2H, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 10.62, 22.52, 27.82, 43.14, 47.08, 57.54, 62.71, 81.59, 121.90, 130.18, 131.03, 132.73, 152.67, 159.98, 169.85; IR –1 20 2978(w), 1792(s), 1718(s), 1704(s) cm ; [α] D +53.9° (c 2.0, CH2Cl2) on 94% ee material obtained from (S)-VANOL; HRMS + (ESI ) calcd for + 79 C19H23N2O5 BrNa, m/z 461.0688 ([M+Na] ), meas 461.0706. The reaction with 20 mol% catalyst loading ((S)-VANOL) and a reaction time of 6 hours gave 110b in 85% yield and 98% ee. 7.2.3.4 Determination of absolute configuration of 27a 249 Boc O N O NaOMe CH3OH Boc N CO Me 2 0 °C, 10 min N Ph Ph O ee: 86% ee: 86% 81% yield trans-(2S,3R)-27a trans-(2S,3R)-126 To a solution of (2S,3R)-27a (86% ee from (R)-VANOL, 30 mg, 0.087 mmol, 1.0 o equiv) in anhydrous methanol (0.3 mL) and dry CH2Cl2 (0.2 mL) at 0 C was added sodium methoxide in methanol solution (0.5 M, 0.20 mL, 1.2 equiv) o dropwise under N2. The mixture was then stirred at 0 C for 10 min. H2O (1 mL) was added and the reaction mixture was neutralized to pH 7 using HCl solution (2 M). Then the reaction mixture was extracted with CH2Cl2 (10 mL+ 2 × 5 mL). The combined organic extracts were dried (Na2SO4), filtered through Celite and concentrated. The crude product was purified by column chromatography (silica gel, 18 × 150 mm, Hexane:EtOAc 9:1) to give (2S,3R)-126 (20 mg, 0.070 mmol, 81%) as a colorless oil. The optical purity was determined to be 86% by HPLC analysis (Chiralcel OD-H column, hexane/2-propanol 98:2, 222nm, flow 0.5 mL/min). Retention time: tR = 6.6 min (minor enantiomer) and tR = 7.3 min (major 1 enantiomer); Rf = 0.2 (Hexane:EtOAc 9:1); H NMR (CDCl3, 500 MHz) δ 1.20 (s, 3H, CH3), 1.40 (s, 9H, 3CH3), 3.80 (s, 3H, CH3), 4.10 (s, 1H, CH), 7.25-7.42 (m, 5H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 13.70, 27.99, 47.21, 49.30, 52.70, 20 81.61, 127.68, 127.94, 128.24, 134.07, 159.03, 170.03; [α] D +15.1° (c 1.1, CHCl3). Reported 22a 23 o for (2R,3S)-126 [α] D –15.5 (c 1.1, CHCl3). This result 250 reveals that the (2S,3R) enantiomer of 27a is generated from the (R)-VANOL catalyst. On this basis the absolute configurations of all aziridines produced from diazo compounds 26a and 26b and the (R)-VANOL catalyst were assigned the 2S,3R configuration. 7.2.3.5 Chemical correlation of trans-(2R,3S)-27a and trans-(2R,3S)-90a Boc Boc NaOEt Ph N Ph N N O COOEt 90% yield O O trans-(2R,3S)-90a trans-(2R,3S)-27a 93% ee 93% ee To a solution of trans-(2R,3S)-27a (93% ee from (S)-VANOL, 48 mg, 0.14 mmol, o 1.0 equiv) in absolute ethanol (0.3 mL) and dry CH2Cl2 (0.2 mL) at 0 C was added sodium ethoxide (21 wt% denatured, 61 µL, 0.17 mmol, 1.2 equiv) o dropwise under N2. The mixture was stirred at 0 C for 10 min, and then aq sat NaHCO3 (2 mL) and CH2Cl2 (10 mL) were added. And the aqueous layer was separated and extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The product was purified by column chromatography (silica gel, 18 × 200 mm, Hexane:EtOAc 9:1) to give trans-(2R,3S)-90a as a pale yellow oil (38 mg, 0.13 mmol, 90%). The optical purity was determined to be 93% ee by HPLC (Chiralcel OD-H column, 222 nm, 98:2 hexane/2-PrOH, flow rate: 0.5 mL/min). Retention time: tR = 5.8 min for (2R,3S)-90a (major) and tR = 6.5 min for (2S,3R)-90a (minor); Rf = 1 (hexane:EtOAc 9:1); H NMR (CDCl3, 500 MHz) δ 1.18 (s, 3H, CH3), 1.32 (t, 3H, 251 J = 7.0 Hz, CH3), 1.44 (s, 9H, 3CH3), 4.08 (s, 1H, CH), 4.12-4.24 (m, 1H, CHH), 4.24-4.36 (m, 1H, CHH), 7.25-7.36 (m, 5H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 13.66, 14.17, 28.01, 47.22, 49.28, 61.97, 81.54, 127.69, 127.88, 128.21, 134.20, –1 20 159.03, 169.57; IR 2980(m), 1738(s), 1158(s), 480(m) cm ; [α] D –21.0° (c + + 2.0, CH2Cl2); HRMS (ESI ) calcd for C17H23NO4Na, m/z 328.1525 ([M+Na] ), meas 328.1577. 7.2.3.6 Determination of diastereoselectivity for the reaction of imine 18 with 26a N Ph + O O Boc 18 O N (S)-VANOL catalyst (10 mol%) CH2Cl2 –78 oC N2 26a Boc Ph N N O O O trans-(2R,3S)-27a + Boc N N O Ph O O cis-27a EtONa Boc N Ph COOEt trans-(2R,3S)-90a + Boc N Ph COOEt cis-90a A solution of imine 18 (90% purity by weight, 46 mg, 0.20 mmol, 2.0 equiv) and diazo compound 26a (17 mg, 0.10 mmol, 1.0 equiv) in dry CH2Cl2 (0.3 mL) was cooled to –78 °C under N2, and then the (S)-VANOL-catalyst solution that had been precooled to –78 °C (10 mol%, 0.2 mL) was quickly added. After it was stirred at –78 °C for 6 hours, NEt3 (0.5 mL) was added at –78 °C. The mixture was warmed up to rt, H2O (2 mL) and CH2Cl2 (10 mL) were added. And the 252 aqueous layer was separated and extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were dried (Na2SO4), filtered through Celite and concentrated. The crude product was dissolved in dry CH2Cl2 (0.2 mL) and EtOH (0.3 mL), to which EtONa solution (21 wt% denatured, 53 mg, 61 µL, 0.15 mmol, 1.5 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. A solution of aq sat NaHCO3 (2 mL) and CH2Cl2 (10 mL) were added. The aqueous layer was separated and extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were dried (Na2SO4), filtered through Celite and 1 concentrated. The crude product mixture was subjected to H NMR analysis, and cis-90a could not be detected. Detection limit for cis-90a: Pure trans-90a (14 mg, 0.046 mmol) was dissolved in CDCl3 (ca. 0.6 mL). An authentic sample of cis-90a (7 mg, 0.02 mmol) prepared as described in Section 7.2.5 was dissolved in CDCl3 (2 mL). Solutions of trans90a and cis-90a were prepared with trans/cis ratios of 200:1, 100:1 and 50:1 by the addition of cis-90a solution (20 µL, 40 µL and 80 µL respectively) to the solution of trans-90a. For the 100:1 sample, cis-90a could still be observed from 1 the H NMR. Therefore, the dr was determined to be ≥100:1. Also notice that the absolute configurations for cis-27a and cis-90a were not determined. The structures shown in the scheme are assumed to result in a change in the configuration at the 3-position relative to the trans isomer. 253 7.2.4 Procedures for Asymmetric Catalytic Aziridination of α-Diazo Esters 7.2.4.1 Reaction of imine 31b and diazo compound 88a MEDAM MEDAM (S)-VANOL borate MeO OMe N catalyst (20 mol%) N CO Et 2 31b + O 8-Toluene Ph Me d OEt 89 MEDAM not observed N2 88a A 5 mL vial-shaped single necked flask which had its 14/20 joint replaced by a Ph threaded high vacuum Teflon valve was flame dried (with a stir bar in it) and cooled to rt under N2 and charged with imine 31b (39 mg, 0.1 mmol, 1.0 equiv) in 8 d -toluene (0.2 mL). To this was added the (S)-VANOL catalyst solution 8 (prepared as described in Section 7.2.3, d -toluene was used as solvent instead of CH2Cl2, 20 mol%, 0.4 mL) at rt, followed by the addition of a solution of diazo 8 compound 88a (64 mg, 0.5 mmol, 5.0 equiv) in d -toluene (0.4 mL). The Teflon o value was closed and the flask was heated at 80 C for 64 hours. Analysis of the 1 H NMR spectrum of the crude mixture with the aid of Ph3CH as internal standard showed that none of desired product 89 could be observed and that imine 31b (0.098 mmol, 98%) remained essentially unreacted. Only 16% of the initial amount of diazo compound 88a survived these conditions. 7.2.4.2 Reactionof N-Boc imine 18 with diazo compound 88a Boc O (S)-VANOL borate Boc Ph N N + EtOOC OEt catalyst (20 mol%) + H COOEt N2 Ph 18 CH2Cl2, –78 °Ctrans-(2R,3S)-90a 88a 254 NHBoc Ph 91 A 25 mL round bottom flask was flame dried under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a rubber septum. The septum was removed briefly to allow introduction of imine 18 (90% purity by weight, 69 mg, 0.30 mmol, 3.0 equiv) which was weighed in the flask with the septum. Subsequently, the septum was removed again to allow for the addition of dry stir bar. A solution of diazo compound 88a (12 mg, 0.10 mmol, 1.0 equiv) in dry CH2Cl2 (0.6 mL) was then added via syringe and a N2 balloon was attached via a needle in the septum. The flask was cooled to –78 °C under N2 balloon and the (S)-VANOL catalyst solution (see Section 7.2.3, 20 mol%, 0.4 mL) that had been precooled to –78 °C was quickly added. After the reaction mixture was stirred at –78 °C for 15 min, NEt3 (0.5 mL) was added at –78 °C. The solvent was st evaporated and the product was purified by column chromatography (1 column, silica gel, 18 × 180 mm, hexane:EtOAc 15:1; 2 nd column, silica gel, 18 × 180 mm, hexane:EtOAc 15:1) to give the product trans-(2R,3S)-90a (14 mg, 0.046 mmol, 46%) as a pale yellow oil. The optical purity was determined to be 93% ee 1 by HPLC with tR = 5.8 min for (2R,3S)-90a as the major enantiomer. From the H NMR spectrum of the crude mixture, the yield of 16a was calculated to be 12% based on the added internal standard triphenylmethane (12 mg, 0.050 mmol, 0.05 equiv). The presence of 91 was confirmed by the comparison with an authetic sample of 16a obtained as described below. The spectral data of a trans-90a matched that described above. The aziridine product from this reaction 255 was shown not to be cis-90a by comparison of its spectral data with those of an authentic sample of cis-90a prepared as described in Section 7.2.5. The absolute configuration of trans-90a was assigned by chemical correlation with trans-27a (Section 7.2.3.5). This establishes that the (2R,3S)-enantiomer of 90a is generated from the (S)-VANOL catalyst. On this basis, the absolute configurations of aziridines 90b and 90c from the (S)-VANOL catalyst were assigned as (2R,3S). The effects of changes in reaction conditions and the ligands in the catalyst on the formation of 90a can be found in Table 3.1. Isolation of enamine 91: To a mixture of the imine 18 (69 mg, 0.30 mmol, 1.5 equiv) and ethyl diazo ester 88a (24 mg, 0.20 mmol, 1.0 equiv) in dry CH2Cl2 (1 mL) at –78 °C under N2 was added triflic acid (2 µL, 20 mol%). The mixture was stirred at –78 °C for 15 min. Then NEt3 (0.5 mL) was added at –78 °C and the solvent was evaporated. The enamine product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 15:1 to 9:1), affording enamine 91 (12 mg, 0.040 mmol, 20%) as a white solid; mp 90-92 °C; Rf = 0.2 1 (hexane:EtOAc 4:1); H NMR (CDCl3, 500 MHz) δ 0.84 (t, 3H, J = 7.0 Hz, CH3), 1.34 (s, 9H, 3CH3), 2.06 (s, 3H, CH3), 3.86 (q, 2H, J = 7.0 Hz, CH2), 6.04 (brs, 1H, NH), 7.30 (m, 5H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 13.42, 16.15, 27.93, 60.34, 81.01, 127.83, 128.31, 128.47, 138.02, 141.44, 152.15, 165.57, 169.94; –1 + IR 3328(w), 2979(m), 1715(s), 1698(s), 1162(s) cm ; HRMS (ESI ) calcd for + 1 C17H23NO4Na, m/z 328.1525 ([M+Na] ), meas 328.1529. The H NMR spectra 256 of the crude reaction mixture showed a trans/cis-90a ratio of 5:1 and 37% yield of trans-90a based on the isolated yield of enamine 91. In a separate run, Ph3CH as internal standard was added to the crude reaction mixture and integration allowed the determination that trans-90a was formed in 42% yield with a trans/cis ratio of 3:1 and that enamine 91 was formed in 25% yield. 7.2.4.3 Reactionof N-Boc imine 18 with diazo compound 88b O Boc (S)-VANOL borate Boc N N Ph OEt catalyst (20 mol%) + N2 H COOEt Ph 18 CH2Cl2, –78 °C 88b trans-(2R,3S)-90b The aziridine trans-90b was prepared from imine 18 (90% purity by weight, 46 mg, 0.20 mmol, 2.0 equiv), diazo compound 88b (15 mg, 0.10 mmol, 1.0 equiv) with the (S)-VANOL catalyst solution by the general procedure described for trans-(2R,3S)-90a with a reaction time of 1 hour. The product was purified by column chromatography (1 st column, 18 × 200 mm, hexane:EtOAc 15:1; 2 nd column, 18 × 200 mm, hexane:EtOAc 15:1) to give the aziridine trans-(2R,3S)90b (10 mg, 0.032 mmol, 32%) as a colorless oil. The optical purity was determined to be 82% ee by HPLC (Chiralcel OD-H column, 222 nm, 98:2 Hexane/2-PrOH, flow rate: 0.5 mL/min). Retention time: tR = 5.5 min for (2R,3S)90b (major) and tR = 6.1 min for (2S,3R)-90b (minor); Rf = (hexane:EtOAc 9:1); 1 H NMR (CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.5 Hz, CH3), 1.28-1.20 (m, 1H, CHH), 1.30 (t, 3H, J = 7.0 Hz, CH3), 1.46 (s, 9H, 3CH3), 1.68-1.56 (m, 1H, CHH), 4.08 (s, 1H, CH), 4.22-4.14 (m, 1H, CHH), 4.36-4.28 (m, 1H, CHH), 7.40-7.20 (m, 257 5H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 10.24, 14.41, 20.86, 28.22, 50.22, 52.14, 62.03, 81.56, 128.00, 128.07, 128.37, 134.53, 159.32, 169.49; IR –1 20 2977(m), 1736(s), 1158(s) cm ; [α] D –3.6° (c 0.6, CH2Cl2) on 82% ee + material obtained from (S)-VANOL; HRMS (ESI ) calcd for C17H23NO4Na, m/z + 342.1681 ([M+Na] ), meas 342.1708. The aziridine product was shown not to be cis-17b by comparison of its spectra with those of an authentic sample of cis-90b prepared as described in Section 7.2.5. 7.2.4.4 Reactionof N-Boc imine 18 with diazo compound 88c O Boc (S)-VANOL borate Boc N OEt catalyst (20 mol%) Ph N + N2 H COOEt Ph CH2Cl2, –78 °C 18 88c trans-(2R,3S)-90c The aziridine 90c was prepared from imine 18 (90% purity by weight, 46 mg, 0.20 mmol, 2.0 equiv) and diazo compound 88c (15 mg, 0.10 mmol, 1.0 equiv) with the (S)-VANOL catalyst (20 mol%, 0.4 mL) by the general procedure described for trans-(2R,3S)-90a with a reaction time of 1 hour. The product was purified by column chromatography (1 hexane:EtOAc 15:1; 2 nd st column, silica gel, 18 × 180 mm, column, silica gel, 18 × 180 mm, hexane:EtOAc 15:1) to give the product 90c (8 mg, 0.025 mmol, 25%) as a colorless oil. The optical purity was determined to be 70% ee by HPLC (Chiralcel OD-H column, 222 nm, 98:2 hexane/2-PrOH, flow rate: 0.5 mL/min). Retention time: tR = 5.4 min for (2R,3S)-90c (major) and tR = 6.0 min for (2S,3R)-90c (minor); Rf = 0.50 1 (hexane:EtOAc 9:1); H NMR (CDCl3, 500 MHz) δ 0.80 (t, 3H, J = 7.5 Hz, CH3), 258 1.04-1.12 (m, 1H, CHH), 1.30 (t, 3H, J = 7.0 Hz, CH3), 1.40-1.50 (s+m, 11H, 3CH3 and CH2), 1.58-1.66 (m, 1H, CHH), 4.03 (s, 1H, CH), 4.22-4.14 (m, 1H, CHH), 4.28-4.36 (m, 1H, CHH), 7.20-7.40 (m, 5H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 14.07, 14.19, 19.26, 28.01, 29.12, 49.92, 51.12, 61.81, 81.34, 127.74, –1 127.86, 128.15, 134.30, 159.10, 169.48; IR 2964(m), 1734(s), 1157(s) cm ; 20 [α] D –18.0° (c 0.5, CH2Cl2) on 70% ee material obtained from (S)-VANOL; + + HRMS (ESI ) calcd for C19H27NO4Na, m/z 356.1838 ([M+Na] ), meas 356.1825. The aziridine product was shown not to be cis-90c by comparison of its spectra with those of an authetic sample of cis-90c prepared as described in Section 7.2.5. 7.2.5 Preparation of the tri-substituted cis-aziridines The optical purity of the starting disubstituted aziridines 32c 26c and 32d 26b were determined to be > 98% ee by chiral HPLC and to have an absolute configuration of 2R, 3R. The optical purities of the products are assumed to be unchanged as has been previously carboxylates. demonstrated for the alkylation of 44 Preparation of cis-90a BUDAM N Ph COOEt cis-(2R,3R)-32c 1 LDA, CH3I 2 TfOH, anisole Boc N Ph COOEt 3 Boc2O, NaHCO3 cis-(2R,3R)-90a 259 aziridine-2- To a solution of dry i-Pr2NH (107 mg, 0.150 mL, 1.05 mmol, 2.10 equiv) in dry THF (5 mL) was added n-BuLi (2.3M in hexane, 0.44 mL, 1.0 mmol, 2.0 equiv) at –78 °C. After the mixture was stirred at –78 °C for 5 min, it was stirred at 0 °C for 15 min. After recooling to –78 °C, a solution of cis-(2R,3R)-32c (321 mg, 0.500 mmol, 1.00 equiv) in dry THF (5 mL) was added dropwise at –78 °C. The resulting yellow solution was stirred at –78 °C for 30 min. Then methyl iodide (0.21 g, 0.10 mL, 1.5 mmol, 3.0 equiv) was added via syringe. The mixture was stirred at this temperature for 1 hour. Then the dry ice-acetone bath was removed and the reaction mixture was allowed to warm up to rt slowly over a period of 1 hour. Then aq sat NaHCO3 (5 mL) was added, and aqueous layer was separated and extracted with ether (3 × 10 mL). The combined organic extracts were dried (Na2SO4), filtered through Celite and concentrated. The product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 15:1), affording the alkylated aziridine as a white foamy solid which was subjected to the next step without further purification. To a solution of all of the above white foamy solids in freshly distilled anisole (5 mL) at 0 °C was added triflic acid (0.38 g, 0.20 mL, 2.5 mmol, 5.0 equiv) dropwise. Then the ice bath was removed and the reaction mixture was stirred at rt for 45 min. The reaction was quenched by the addition of aq sat Na2CO3 (2 mL). The aqueous layer was separated and extracted with ether (10 mL + 2 × 5 mL). The combined organic extracts were dried (Na2SO4), filtered through Celite 260 and concentrated. The crude N-H aziridine along with anisole (ca. 5 mL) was subjected to the next step without purification. To all of the crude aziridine was added methanol (2 mL) and NaHCO3 (252 mg, 3.00 mmol, 6.00 equiv). The mixture was place in an ultrasound bath for 5 min. After Boc2O (438 mg, 2.00 mmol, 4.00 equiv) was added, the mixture was sonicated for 3 hours. After this time, additional portions of NaHCO3 (252 mg, 3.00 mmol, 6.00 equiv) and Boc2O (438 mg, 2.00 mmol, 4.00 equiv) were added. The resulting mixture was sonicated for 2 hours. Then H2O (2 mL) was added and the mixture was extracted with ether (3 × 10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The product was purified by column chromatography (silica gel, 25 × 250 mm, pure hexane only first to elute anisole and then hexane:EtOAc 9:1), giving the product cis-(2R,3R)90a (142 mg, 0.410 mmol, 81% over three steps) as a colorless oil; Rf = 0.48 1 (hexane:EtOAc 4:1); H NMR (CDCl3, 500 MHz) δ 0.82 (t, 3H, J = 7.0 Hz, CH3), 1.50 (s, 9H, 3CH3), 1.70 (s, 3H, CH3), 3.58 (s, 1H, CH), 3.82-3.96 (m, 2H, CH2), 7.20-7.31 (m, 3H, Ar-H), 7.32-7.38 (m, 2H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 13.62, 17.49, 28.00, 49.48, 49.83, 61.13, 82.10, 127.32, 127.79, 127.93, 133.88, –1 20 159.23, 167.86; IR 2979(m), 1750(s), 1720(s), 1140(s) cm ; [α] D +12.0° (c 261 + + 1.0, CH2Cl2); HRMS (ESI ) calcd for C17H23NO4Na, m/z 328.1525 ([M+Na] ), meas 328.1512. Preparation of cis-90b DAM N 1 LDA, CH3CH2I Boc N Ph COOEt Ph COOEt 2 TfOH, anisole cis-(2R,3R)-32d 3 Boc2O, NaHCO3 cis-(2R,3R)-90b The cis-(2R,3R)-90b was prepared with the procedure described above for cis(2R,3R)-90a except that aziridine cis-(2R,3R)-32d (209 mg, 0.500 mmol, 1.00 equiv) was alkylated with iodoethane (0.23 g, 0.12 mL, 1.5 mmol, 3.0 equiv). The product cis-(2R,3R)-90b was obtained (101 mg, 0.320 mmol) in 64% yield over 1 three steps as a colorless oil; Rf = 0.35 (hexane:EtOAc 4:1); H NMR (CDCl3, 500 MHz) δ 0.84 (dt, 3H, J = 7.5, 2.0 Hz, CH3), 1.22 (td, 3H, J = 7.5, 1.5 Hz, CH3), 1.52 (s, 9H, 3CH3), 1.66-1.78 (m, 1H, CHH), 2.20-2.30 (m, 1H, CHH), 3.58 (s, 1H, CH), 3.84-3.96 (m, 2H, CH2), 7.34-7.20 (m, 5H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 10.73, 13.70, 25.92, 27.92, 47.54, 54.97, 60.96, 82.06, 127.11, –1 127.70, 127.96, 134.04, 159.46, 167.25; IR 2978(m), 1720(s), 1152(s) cm ; 20 + [α] D +18.0° (c 1.0, CH2Cl2); HRMS (ESI ) calcd for C18H25NO4Na, m/z + 342.1681 ([M+Na] ), meas 342.1672. Preparation of cis-90c DAM N 1 LDA, n-PrI Boc N Ph COOEt 2 TfOH, anisole Ph COOEt 3 Boc2O, NaHCO3 cis-(2R,3R)-90c cis-(2R,3R)-32d 262 The cis-(2R,3R)-90c was prepared with the procedure described above for cis(2R,3R)-90a except that cis-(2R,3R)-32d (209 mg, 0.500 mmol, 1.00 equiv) was alkylated with 1-iodopropane (0.26 g, 0.15 mL, 1.5 mmol, 3.0 equiv). The product cis-(2R,3R)-90c (96 mg, 0.29 mmol) was obtained in 58% yield over three steps 1 as a colorless oil; Rf = 0.50 (hexane:EtOAc 4:1); H NMR (CDCl3, 500 MHz) δ 0.80 (t, 3H, J = 7.0 Hz, CH3), 0.98 (t, 3H, J = 7.5 Hz, CH3), 1.42-1.54 (s+m, 10H, CH and 3CH3 overlap), 1.60-1.72 (m, 1H, CHH), 1.80-1.92 (m, 1H, CHH), 2.022.12 (m, 1H, CHH), 3.55 (s, 1H, CH), 3.84-3.90 (q, 2H, J = 7.0 Hz, CH2), 7.187.32 (m, 5H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 13.64, 14.06, 19.41, 27.89, 34.87, 47.71, 54.18, 60.88, 81.97, 127.05, 127.65, 127.92, 134.09, 159.38, –1 20 167.27; IR 2970(m), 1719(s), 1151(s) cm ; [α] D +22.8° (c 1.0, CH2Cl2); + + HRMS (ESI ) calcd for C19H27NO4Na, m/z 356.1838 ([M+Na] ), meas 356.1847. 7.2.6 Attempt towards direct asymmetric catalytic access to cis-trisubstituted aziridine Preparation of an authentic sample of aziridine 2-carboxamide trans-125 Boc O N Boc Boc HOBt, DIC, N COOH N CONHBn BnNH2 N O Ph Ph Ph trans-(2S,3R)-127 trans-(2S,3R)-27a trans-(2S,3R)-125 ee: 93.5% ee: 93% 85% yield 58% yield over 2 steps A sample of trans-(2S,3R)-27a was prepared with the (R)-VANOL catalyst. To a O LiOH, rt, 2h solution of trans-(2S,3R)-27a (28 mg, 0.080 mmol, 1.0 equiv) in THF (0.5 mL) 263 was added a solution of LiOH monohydrate (17 mg, 0.40 mmol, 5.0 equiv) in H2O (0.3 mL) at room temperature. The mixture was stirred at rt for 2 hours. Then aq HCl (6M) was added dropwise to pH ~1-2. The mixture was then extracted with Et2O (2 × 5 mL). The combined organic extracts were dried (Na2SO4), filtered through Celite and concentrated. The aziridine-2-carboxylic acid 127 was obtained as a pale yellow foamy solid, which was subjected to the next step without further purification. The yield of 127 was determined to be 85% 1 1 by H NMR analysis with the aid of added internal standard triphenylmethane. H NMR (CDCl3, 500 MHz) δ 1.25 (s, 3H, CH3), 1.52 (s, 9H, 3CH3), 4.15 (s, 1H, CH), 6.30 (brs, 1H, NH), 7.12-7.50 (m, 5H, Ar-H), 9.70 (brs, 1H, COOH). A mixture of all of the above acid 127 and 1-hydroxy-benzotriazole (HOBt) monohydrate (19 mg, 0.12 mmol, 1.5 equiv) was suspended in dry CH2Cl2 (0.5 mL), and then benzylamine (26 mg, 0.24 mmol, 3.0 equiv) was added. After the mixture was cooled to 0 °C, a solution of diisopropylcarbodiimide (DIC) (15 mg, 0.12 mmol, 1.5 equiv) in dry CH2Cl2 (0.3 mL) was added. The resulting mixture was stirred at rt overnight. Without concentration, the entire reaction mixture was loaded onto a silica gel column (18 × 200 mm) and eluted with a 4:1 mixture of Hexane and EtOAc to give the product trans-(2S,3R)-125 (14.2 mg, 0.0388 mmol) in 49% yield over 2 steps as a white foamy solid with an ee of 93% (Chiralcel OD-H column, 222 nm, 90:10 hexane/2-PrOH, flow rate: 1.0 mL/min). Retention time: tR = 4.3 min for (2S,3R)-125 (major) and tR = 11.3 min for 264 1 (2R,3S)-125 (minor); mp 144-145 °C; Rf = 0.3 (hexane:EtOAc 4:1); H NMR (CDCl3, 500 MHz) δ 1.20 (s, 3H, CH3), 1.42 (s, 9H, 3CH3), 4.20 (s, 1H, CH), 4.48 (dd, 1H, J = 14.5, 5.5 Hz, CHH), 4.58 (dd, 1H, J = 14.5, 5.5 Hz, CHH), 6.30 (brs, 1H, NH), 7.38-7.24 (m, 10H, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 13.93, 28.03, 44.37, 47.53, 48.44, 81.43, 127.74, 127.92, 128.12, 128.83, 134.63, 2 137.66, 159.51, 168.00 (2 sp C not located); IR 3372(m), 2998(m), 1726(s), –1 20 + 1720(s), 1161(s) cm ; [α] D +34.0° (c 1.0, CH2Cl2); HRMS (ESI ) calcd for + C22H26N2O3Na, m/z 389.1841 ([M+Na] ), meas 389.1857. Preparation of an authentic sample of aziridine 2-carboxamide cis-125 DAM N 1 LDA, then CH3I 2 KOH, EtOH DAM N Ph COOEt 3 HOBt, DIC, BnNH2 Ph CONHBn cis-(2R,3R)-32d cis-(2R,3R)-106 To a solution of dry i-Pr2NH (0.43 g, 0.60 mL, 3.4 mmol, 2.1 equiv) in dry THF (15 mL) was added n-BuLi (2.5M in hexane, 1.6 mL, 3.2 mmol, 2.0 equiv) at –78 °C. After the mixture was stirred at –78 °C for 5 min, it was stirred at 0 °C for 15 min. After recooling to –78 °C, a solution of cis-(2R,3R)-32d (836 mg, 2.00 mmol, 1.00 equiv, >98% ee) in dry THF (5 mL) was added dropwise at –78 °C. The resulting yellow solution was stirred at –78 °C for 30 min. Then methyl iodide (0.85 mg, 0.37 mL, 6.0 mmol, 3.0 equiv.) was added via syringe. The reaction mixture was stirred at this temperature for 1 hour. Then the dry ice-acetone bath was removed and the reaction mixture was allowed to warm up to rt slowly over a period of 1 hour. Then sat aq. NaHCO3 (5 mL) was added and the aqueous layer 265 was separated and extracted with ether (3 × 20 mL). The combined organic extracts were dried (Na2SO4), filtered through Celite and concentrated. The crude product was purified by column chromatography (silica gel, 25 × 250 mm, Hexane:EtOAc 5:1), affording the alkylated product as a white foamy solid. All of the white foamy solids were dissolved in EtOH (5 mL) and then a solution of aq KOH (549 mg, 9.8 mmol, 4.9 mmol) in H2O (5 mL) was added. The resulting mixture was refluxed for 1 hour during which time it became homogeneous. After the reaction mixture was cooled to rt, it was acidified with aq HCl (6 M) dropwise to pH ~1-2 and the mixture was extracted with Et2O (3 × 20 mL). The combined organic extracts were dried (Na2SO4), filtered through Celite and concentrated. The crude aziridinene carboxylic acid was purified by column (silica gel, 25 × 100 mm, hexane:acetone 3:1) to give the acid as a white solid (329 mg, 0.82 mmol, 41%). To a suspension of the above solid acid (101 mg, 0.250 mmol, 1.00 equiv) and 1hydroxy-benzotriazole (HOBt) monohydrate (58 mg, 0.38 mmol, 1.5 equiv) in CH2Cl2 (1.5 mL) was added a solution of benzylamine (81 mg, 0.75 mmol, 3.0 equiv) in CH2Cl2 (0.5 mL), followed by the addition of a solution of diisopropylcarbodiimide (DIC) (48 mg, 0.38 mmol, 1.5 equiv) in CH2Cl2 (0.5 mL). The resulting mixture was stirred at rt overnight. Without concentration, the entire reaction mixture was loaded onto a silica gel column (18 ×180 mm) eluting with hexane:EtOAc 2:1 to give the product cis-(2R,3R)-106 (118 mg, 0.24 mmol, 266 1 96%) as a white foamy solid; mp 52-56 °C; Rf = 0.25 (hexane:EtOAc 2:1); H NMR (CDCl3, 300 MHz) δ 1.68 (s, 3H, CH3), 3.12 (s, 1H, CH), 3.74 (s, 3H, CH3), 3.78 (s, 3H, CH3), 4.05 (dd, 1H, J = 15.5, 6.0 Hz, CHH), 4.23 (dd, 1H, J = 15.0, 6.0 Hz, CHH), 4.43 (s, 1H, CH), 6.76-6.84 (m, 6H), 7.02 (d, 2H, J = 7.5 Hz), 7.127.24 (m, 7H), 7.30-7.36 (m, 4H); 13 C NMR (CDCl3, 150 MHz) δ 12.62, 42.74, 49.70, 53.42, 55.13, 55.15, 69.82, 113.84, 113.86, 126.92, 127.17, 127.20, 127.41, 127.74, 128.10, 128.37, 129.06, 135.23, 135.38, 135.88, 138.01, 158.44, –1 23 158.83, 169.85; IR 3379(m), 1666(s), 1512(s), 1248(m) cm ; [α] D +66.2° (c + + 1.0, CH2Cl2); HRMS (ESI ) calcd for C32H33N2O3, m/z 493.2491 ([M+H] ), meas 493.2477. DAM N 1 Triflic acid Boc N Ph CONHBn Ph CONHBn 2 Boc2O cis-(2R,3R)-125 cis-(2R,3R)-106 To a solution of cis-(2R,3R)-106 (118 mg, 0.240 mmol, 1.00 equiv) in freshly distilled anisole (2 mL) at 0 °C was added triflic acid (0.11 mL, 1.2 mmol, 5.0 equiv) dropwise. Then the ice bath was removed and the reaction mixture was stirred at rt for 45 min, and then quenched by the addition of aq sat Na2CO3 (2 mL). The aqueous layer was separated and extracted with ether (3 x 10 mL). The combined organic extracts were dried (Na2SO4), filtered through Celite and concentrated. The crude product along with anisole (ca. 2 mL) was subjected to the next step without purification. 267 To all of the crude products obtained above was added methanol (2 mL) and NaHCO3 (61 mg, 0.72 mmol, 3.00 equiv). The mixture was put in an ultrasound bath for 5 min. Then Boc2O (105 mg, 0.480 mmol, 2.00 equiv) was added and sonicated for 3 hours. After this time, additional portions of NaHCO3 (61 mg, 0.72 mmol, 3.00 equiv) and Boc2O (105 mg, 0.480 mmol, 2.00 equiv) were added. The resulting mixture was sonicated for 3 hours and stirred at rt overnight. H2O (2 mL) was added and the mixture was extracted with ether (3 × 10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The product was purified by column chromatography (1 mm, hexane:EtOAc 3:2; 2 nd st column, silica gel, 18 × 180 column, silica gel, 18 × 180 mm, bezene:EtOAc 15:1), giving the product cis-125 as a white solid (4.5 mg, 0.012 mmol, 5%). The optical purity of cis-52 was determined to be >98% ee by HPLC (Chiralcel OD-H column, 222 nm, 90:10 hexane/2-PrOH, flow rate: 1.0 mL/min). Retention time: tR = 3.6 min for cis-(2R,3R)-125 (major) and tR = 11.3 min for cis-(2S,3S)-125 1 (minor). Rf = 0.20 (hexane:EtOAc 4:1). H NMR (CDCl3, 300 MHz) δ 1.49 (s, 9H, 3CH3), 1.71 (s, 3H, CH3), 3.65 (s, 1H, CH), 3.95 (dd, 1H, J = 15.0, 4.5 Hz, CHH), 4.29 (dd, 1H, J = 15.0, 7.5 Hz, CHH), 6.55 (brs, 1H, NH), 6.60-6.70 (m, 2H, ArH), 7.08-7.18 (m, 3H, Ar-H), 7.22-7.36 (m, 5H, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 16.84, 27.80, 42.86, 50.20, 50.34, 82.16, 126.90, 127.26, 127.29, 127.74, 268 128.17, 128.20, 133.75, 137.17, 159.11, 167.31; IR 3310(m), 2950(m), 1720(s), –1 20 + 1260(s) cm ; [α] D –20.0° (c 0.2, CH2Cl2); HRMS (ESI ) calcd for + C22H26N2O3Na, m/z 389.1841 ([M+Na] ), meas m/z 389.1857. Reaction between imine 18 and the secondary diazoamide 124 O Boc Boc Boc (S)-VANOL catalyst N N + N Ph + NHBn Ph 18 CH2Cl2, –78 °C CONHBn Ph N2 124 CONHBn trans-(2R,3S)-125 cis-(2R,3R)-125 NMR yield: 18% NMR yield: 12% ee: 37% ee: 20% A 25 mL round bottom flask was flame dried under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a rubber septum. The septum was removed briefly to allow introduction of imine 18 (90% purity by weight, 69 mg, 0.30 mmol, 3.0 equiv) which was weighed in the flask with the septum. Subsequently, the septum was removed again to allow for the addition of dry stir bar. Dry CH2Cl2 (0.2 mL) was then introduced through the septum with a syringe and then a balloon filled with nitrogen was attached via a needle in the septum. After the flask was cooled to –78 °C, the VANOL catalyst solution (20 mol%, 0.4 mL) was quickly added. Then diazo compound 124 (19 mg, 0.10 mmol, 1.0 equiv) in CH2Cl2 (0.4 mL) was added to the reaction mixture via syringe at –78 °C. The resulting mixture was stirred at –78 °C for 1 h, and then NEt3 (0.5 mL) was added at –78 °C. The solvent was evaporated and the product was purified by column chromatography (1 st column, 18 × 200 mm, hexane:EtOAc 3:1; 2 nd column, 18 × 200 mm, hexane:acetone 4:1) to give the aziridine trans-(2R,3S)-52 269 as a white solid (4.5 mg, 0.012 mmol) in 12% isolated yield. The optical purity of trans-125 was determined to be 37% ee by HPLC with trans-(2R,3S)-125 as the major enantiomer. Unfortunately, due to the low yield, it was not possible to obtain a pure sample of cis-125. However, a sample of cis-125 was obtained which was contamined with impurities but free of trans-125. The optical purity of cis-52 was determined on this sample to be 20% with cis-(2R,3R)-125 as the major enantiomer. In the 1 H NMR of the crude mixture, there was no diazo compound 124 left. The NMR yields for trans-125 and cis-125 were calculated to be 18% and 12%, respectively based on the internal standard triphenylmethane (12 mg, 0.050 mmol) that was added to the crude mixture. 7.2.7 Synthesis of L-methylDOPA derivative Boc O O MeOMgBr N N O PivO 86% yield trans-(2S,3R)-120 PivO PivO Boc N CO Me 2 130 PivO A 5 mL flame-dried round bottom flask filled with N2 was charged with anhydrous methanol (0.2 mL). The vacuum adapter was replaced with a septum to which a N2 balloon was attached. MeMgBr (25 mL, 0.069 mmol, 1.5 equiv) was added to form a suspension of MeOMgBr. Another 10 mL flame-dried round bottom flask filled with N2 was charged with trans-(2S,3R)-120 (25 mg, 0.046 mmol, 1.0 equiv), dry CH2Cl2 (0.2 mL) and anhydrous methanol (0.2 mL). The vacuum adapter was replaced with s septum to which a N2 balloon was attached. The flask was cooled to 0 °C. Then the suspension of MeOMgBr was transferred via 270 a syringe and added quickly to the solution. The residue in 5 mL flask was rinsed with methanol (0.1 mL) and added to the solution too. The resulting mixture was stirred at 0 °C for 3 min. sat aq NH4Cl (0.5 mL) and H2O (0.2 mL) were added to quench the reaction. CH2Cl2 (5 mL) was also added. The aqueous layer was separated and extracted with CH2Cl2 (2 × 5 mL). The organic layers were combined, dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc:NEt3 4:1:0.05) to give methyl ester 130 as a white foamy solid (19 mg, 0.039 mmol, 86%). 1 H NMR (CDCl3, 300 MHz) δ 1.21 (s, 3H, CH3), 1.31,1.32 (2s, 18H, 6CH3), 1.45 (s, 9H, 3CH3), 3.77 (s, 3H, CH3), 4.05 (s, 1H, CHH), 7.06-7.12 (m, 2H, Ar-H), 7.18 (dd, 1H, J = 8.4, 2.1 Hz, Ar-H); 13 C NMR (CDCl3, 125 MHz) δ 13.64, 27.19, 27.22, 27.97, 39.14, 47.47, 48.47, 48.50, 52.76, 81.89, 122.71, 123.30, 125.47, 132.52, 142.32, 142.44, 158.78, 169.76, 175.71, 175.82; IR –1 20 2978(w), 1761(s), 1741(s), 1115(s) cm ; [α] D +9.5° (c 1.0, CH2Cl2); HRMS + + (ESI ) calcd for C26H37NO8Na, m/z 514.2417 ([M+Na] ), meas 514.2377. PivO Boc N CO Me 2 H2 PivO CO2Me NHBoc Pd(OH)2/C, MeOH PivO 131 130 92% yield PivO To a solution was added methyl ester 130 (16 mg, 0.033 mmol, 1.0 equiv) in anhydrous methanol was added Pearlman’s catalyst (12 mg, 0.0065 mmol, 0.20 271 equiv). The flask was evacuated and filled with H2. This process was repeated for another 3 times. The resulting mixture was stirred at rt under a H2 balloon for 1 hour. After it was passed through a Celite pad in a short pippet and washed well with MeOH, the filtrate was concentrated to give 131 (15 mg, 0.030 mmol, 1 92%) as a colorless oil which solidified during storage; mp 50-52 °C; H NMR (CDCl3, 600 MHz) δ 1.30, 1.31 (2s, 18H, 6CH3), 1.44 (s, 9H, 3CH3), 1.51 (brs, 3H, CH3), 3.21 (d, 1H, J = 13.8 Hz), 3.34 (d, 1H, J = 13.8 Hz), 5.13 (brs, 1H, NH), 6.83 (s, 1H, Ar-H), 6.90 (d, 1H, J = 8.4 Hz, Ar-H), 7.01 (d, 1H, J = 7.8 Hz, Ar-H); 13 C NMR (CDCl3, 150 MHz) δ 23.95, 27.42, 27.43, 28.58, 39.27, 39.32, 40.66, 52.76, 60.41, 79.69, 123.08, 125.25, 128.00, 135.19, 141.65, 142.28, 154.45, –1 174.34, 175.86, 176.08; IR 3427(w), 2976(w), 1761(s), 1716(s), 1118(s) cm ; 20 + [α] D +6.8° (c 1.0, CH2Cl2); HRMS (ESI ) calcd for C26H39NO8Na, m/z + 516.2573 ([M+Na] ), meas 516.2545. 7.2.8 Reaction between imine 18 and EDA 5 or diazoacetamide 19 with VANOL borate catalyst N Boc Ph 18 O + N2 OEt 5 (S)-VANOL Boc + NH O catalyst Boc NHBoc unreacted (20 mol%) + N CO2Et + CONHPh 5 Ph OEt (H)Ph Ph CH2Cl2 N2 H(Ph) 134/135 133 A 25 mL round bottom flask was flame dried under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a rubber septum. The septum 272 was removed briefly to allow introduction of imine 18 (90% purity by weight, 69 mg, 0.30 mmol, 1.5 equiv) which was weighed in the flask with the septum. Subsequently, the septum was removed again to allow for the addition of dry stir bar. Dry CH2Cl2 (0.60 mL) was then introduced through the septum with a syringe and then a balloon filled with nitrogen was attached via a needle in the septum. After the flask was cooled to –78 °C or –46 °C, the (S)-VANOL catalyst solution (20 mol%, 0.40 mL) was quickly added. Then diazo compound 5 (32 µL, 0.20 mmol, 1.0 equiv) was added to the reaction mixture via syringe at –78 °C. The resulting mixture was stirred at –78 °C or –46 °C for 3 h, and then NEt3 (0.5 mL) was added at –78 °C. After evaporation, the crude reaction mixture was obtained. The results are shown in Scheme 3.16. The products were not isolated but identified from the crude reaction mixture in comparison with those 88 reported . N Boc NHBoc Boc + (S)-VANOL-catalyst Ph N CONHPh unreacted + (H)Ph Ph 18 19 (20 mol%) + CONHPh H(Ph) CH2Cl2 O 20 136/137 NHPh N2 19 A 25 mL round bottom flask was flame dried under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a rubber septum. The septum was removed briefly to allow introduction of imine 18 (90% purity by weight, 69 mg, 0.30 mmol, 1.5 equiv) and diazoacetamide 19 (33 mg, 0.20 mmol, 1.0 equiv) which were weighed in the flask with the septum. Subsequently, the septum was 273 removed again to allow for the addition of dry stir bar. Dry CH2Cl2 (0.60 mL) was then introduced through the septum with a syringe and then a balloon filled with nitrogen was attached via a needle in the septum. After the flask was cooled to – 78 °C or –46 °C, the (S)-VANOL catalyst solution (20 mol%, 0.40 mL) was quickly added. The resulting mixture was stirred at –78 °C or –46 °C for 3 h, and then NEt3 (0.5 mL) was added at –78 °C. After evaporation, the crude reaction mixture was obtained. The results are shown in Scheme 3.16. The products were not isolated but identified from the crude reaction mixture in comparison with 18 those reported . When the reaction was carried at room temperature, the above procedure was followed and the reaction mixture was stirred at rt for 24 h. 274 7.3 Experimental Section for Chapter Four 7.3.1 Preparation of acids Preparation of acid 138a BUDAM N COOEt 1) LDA, MeI 2) KOH, EtOH then H+ BUDAM N COOH 32c 138a 99% ee Alkylation: General procedure for alkylation, illustrated for the acid 138a. To a flame-dried 50 mL round bottom flask filled with N2 was charged with dry i-Pr2NH (0.050 mL, 0.33 mmol, 2.1 equiv) and dry THF (3 mL). The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. The flask was cooled in a dry ice-acetone bath (–78 °C). n-BuLi (2.3M, 0.14 mL, 0.32 mmol, 2.0 equiv) was added dropwise via syringe. After it was stirred at –78 °C for 5 min, the solution was stirred at 0 °C for 15 min. After the flask was cooled to –78 °C again, a solution of ester 32c (99% ee, 100 mg, 0.160 mmol, 1.00 equiv) in dry THF (2 mL) was added dropwise. The resulting yellow solution was stirred at –78 °C for 30 min. Then CH3I (0.030 mL, 0.48 mmol, 3.0 equiv) was added via syringe. The resulting mixture was stirred at –78 °C for 1 h, and then dry ice-acetone bath was removed. And the reaction mixture was allowed to warm up to rt slowly over a period of 1 h. Then aq sat NaHCO3 (2 mL) and ether (10 mL) were added. The aqueous layer was separated and extracted with ether (2 × 5 mL). The combined organic extracts were dried (Na2SO4) and filtered. The 275 filtrate was concentrated to afford the methylated ester used directly in the next step. Hydrolysis: To the mixture of the methylated ester in THF (1 mL) and ethanol (1 mL) was added an aqueous solution of KOH (45 mg, 0.80 mmol, 5.0 equiv) in H2O (1 mL). The resulting mixture was refluxed overnight (~17 h). After it was cooled to rt, the volatiles were evaporated and aq citric acid (2N, 2 mL) was added. The mixture was extracted with ether (10 mL + 2 × 5 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1). The product 138a was obtained as a white solid (85 mg, 0.14 mmol) in 87% yield over 2 steps; mp 72-74 °C; Rf = 0.30 (hexane:EtOAc 4:1). Spectral data for 1 138a: H NMR (500 MHz, CDCl3) δ 1.36, 1.38 (2s, 36H), 1.63 (s, 3H), 3.24 (s, 1H), 3.638, 3.642 (2s, 6H), 4.31 (s, 1H), 6.96-7.00 (m, 2H), 7.14-7.18 (m, 3H), 7.24 (s, 2H), 7.29 (s, 2H), 10.00 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 12.14, 32.01, 32.09, 35.80, 35.82, 49.48, 53.65, 64.19, 64.24, 71.06, 125.00, 126.08, 127.28, 128.03, 128.36, 134.54, 135.49, 135.85, 143.83, 143.90, 158.72, 159.15, –1 170.50; IR (thin film) 2963(s), 1768(m), 1414(m) cm ; HRMS calcd for + 20 o C41H58NO4 (M+H, ESI ) m/z 628.4366, meas 628.4321; [α] D 23.6 (c 1.0, Et2O). Preparation of acid 141a: 276 Bh N 1) LDA, MeI Bh N COOEt 2) KOH, EtOH COOH 32a 141a then H+ 98% ee Alkylation: The general procedure for the alkylation was followed with ester 32a (98% ee, 357 mg, 1.00 mmol, 1.00 equiv), i-Pr2NH (0.30 mL, 2.1 mmol, 2.1 equiv), n-BuLi (2.3M, 0.87 mL, 2.0 mmol, 2.0 equiv) and CH3I (0.20 mL, 3.0 mmmol, 3.0 equiv). After workup, the crude product was obtained which was used directly in the next step. Hydrolysis: To the mixture of the above methylated ester in ethanol (2 mL) was added an aqueous solution of KOH (280 mg, 5.00 mmol, 5.00 equiv) in H2O (5 mL). The resulting mixture was refluxed overnight (~12 h). After it was cooled to rt, aq citric acid (2N, 5 mL) was added. The resulting precipitate was collected by filtration. The product was obtained as a slightly brown solid (250 mg, 0.730 mmol) in 73% yield over 2 steps; mp 155-156 °C; Rf = 0.10 (hexane:EtOAc 4:1). 1 Spectral data for acid 141a: H NMR (500 MHz, DMSO-d6) δ 1.45 (s, 3H), 3.15 (s, 1H), 4.68 (s, 1H), 7.08-7.44 (m, 11H), 7.56 (d, 2H, J = 7.5 Hz), 7.71 (d, 2H, J = 7.5 Hz), 12.0 (brs, 1H); 13 C NMR (125 MHz, DMSO-d6) δ 13.22, 50.26, 51.56, 68.86, 126.58, 126.63, 126.77, 126.96, 127.17, 127.54, 127.68, 128.19, 128.27, –1 136.63, 143.92, 144.20, 170.84; IR (thin film) 1720(s), 1265(m) cm ; HRMS + 20 calcd for C23H22NO2 (M+H, ESI ) m/z 344.1651, meas 344.1626; [α] D 110.3° (c 0.67, CH2Cl2). 277 Preparation of acid 138b BUDAM N BUDAM N 1) LDA, MeI COOEt 2) KOH, EtOH COOH 300 138b then H+ 99% ee Alkylation: The general procedure for the alkylation was followed with ester 300 (99% ee, 656 mg, 1.00 mmol, 1.00 equiv), i-Pr2NH (0.30 mL, 2.1 mmol, 2.1 equiv), n-BuLi (2.5M, 0.84 mL, 2.1 mmol, 2.1 equiv) and CH3I (0.19 mL, 3.0 mmmol, 3.0 equiv). After workup, the crude product was obtained which was used directly in the next step. Hydrolysis: To the mixture of the crude product in THF (2.5 mL) and ethanol (2.5 mL) was added an aqueous solution of KOH (280 mg, 5.00 mmol, 5.00 equiv) in H2O (2.5 mL). The resulting mixture was refluxed for 42 h. After it was cooled to rt, the volatiles were evaporated and aq HCl (6N) was added to pH ~2. The mixture was extracted with ether (3 × 10 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 25 × 200 mm, hexane:acetone 9:1). The product was obtained as a white solid (602 mg, 0.937 mmol) in 94% yield over 2 steps; mp 82-85 °C; Rf = 0.50 (hexane:EtOAc 4:1). Spectral data for acid 138b: 1 H NMR (500 MHz, CDCl3) δ 1.40, 1.41 (2s, 36H), 1.65 (s, 3H), 2.26 (s, 3H), 3.24 (s, 1H), 3.67, 3.68 (2s, 6H), 4.32 (s, 1H), 6.89 (d, 2H, J = 8.0 Hz), 6.99 (d, 2H, J = 8.0 Hz), 7.28 (s, 2H), 7.34 (s, 2H), 9.50 (brs, 1H); 278 13 C NMR (125 MHz, CDCl3) δ 12.07, 21.07, 32.02, 32.08, 35.79, 35.80, 49.33, 53.48, 64.17, 64.24, 71.08, 124.99, 126.09, 127.17, 129.02, 131.59, 135.60, 135.92, 137.73, 143.78, –1 143.85, 158.68, 159.12, 170.66; IR (thin film) 2961(s), 1718(s), 1224(s) cm ; + 20 HRMS calcd for C42H60NO4 (M+H, ESI ) m/z 642.4522, meas 642.4482; [α] D 9.3° (c 2.0, CH2Cl2). Preparation of acid 138c BUDAM N 1) LDA, MeI BUDAM N COOEt 2) KOH, EtOH COOH + 301 then H Br Br 138c 99% ee Alkylation: The general procedure for the alkylation was followed with ester 301 (99% ee, 720 mg, 1.00 mmol, 1.00 equiv), i-Pr2NH (0.30 mL, 2.1 mmol, 2.1 equiv), n-BuLi (2.5M, 0.84 mL, 2.1 mmol, 2.1 equiv) and CH3I (0.19 mL, 3.0 mmmol, 3.0 equiv). After workup, the crude product was obtained which was used directly in the next step. Hydrolysis: To the mixture of the crude product in ethanol (2.5 mL) was added an aqueous solution of KOH (280 mg, 5.00 mmol, 5.00 equiv) in H2O (2.5 mL). The resulting mixture was refluxed for 3 h. After it was cooled to rt, CH2Cl2 (5 mL) was added and the mixture was refluxed for 66 hours until it became a homogeneous solution. After it was cooled to rt, the volatiles were removed by rotary evaporation and aq HCl (6N) was added to pH ~2. The mixture was extracted with ether (20 mL + 2 × 10 mL). The combined organic extracts were 279 dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 25 × 250 mm, hexane:acetone 9:1). The product 138c was obtained as a white solid (383 mg, 0.54 mmol) in 54% yield over 2 steps; mp 78-80 °C; Rf = 0.30 (hexane:acetone 9:1). Spectral data for acid 138c: 1 H NMR (300 MHz, CDCl3) δ 1.45, 1.47 (2s, 36H), 1.71 (s, 3H), 3.26 (s, 1H), 3.73 (s, 6H), 4.40 (s, 1H), 6.94 (d, 2H, J = 8.4 Hz), 7.30-7.40 (m, 6H), 9.60 (brs, 1H); 13 C NMR (150 MHz, CDCl3) δ 12.11, 32.01, 32.07, 35.78, 35.80, 49.63, 52.83, 64.17, 64.26, 70.91, 122.08, 124.96, 126.01, 129.04, 131.45, 133.75, 135.29, 135.75, 143.90, 143.92, 158.73, 159.17, 170.14; IR (thin film) 2961(s), 79 –1 + 1769(m), 1414(m) cm ; HRMS calcd for C41H57NO4 Br (M+H, ESI ) m/z 20 706.3471, meas 706.3450; [α] D 18.6° (c 1.0, CH2Cl2). Preparation of acid 138d: BUDAM N 1) LDA, MeI BUDAM N COOEt 2) KOH, EtOH COOH + 302 then H 138d 96% ee Alkylation: The general procedure for the alkylation was followed with ester 302 (96% ee, 656 mg, 1.00 mmol, 1.00 equiv), i-Pr2NH (0.30 mL, 2.1 mmol, 2.1 equiv), n-BuLi (2.5M, 0.84 mL, 2.1 mmol, 2.1 equiv) and CH3I (0.19 mL, 3.0 mmmol, 3.0 equiv). After workup, the crude product was obtained which was used directly in the next step. 280 Hydrolysis: To the mixture of the crude product in THF (2.5 mL) and ethanol (2.5 mL) was added an aqueous solution of KOH (280 mg, 5.00 mmol, 5.00 equiv) in H2O (5 mL). The resulting mixture was refluxed for 22 h. After it was cooled to rt, the volatiles were evaporated and aq HCl (6N, 5 mL) was added to pH ~2. The mixture was extracted with ether (20 mL + 2 × 10 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 25 × 180 mm, hexane:acetone 9:1). The product 138d was obtained as a white solid (507 mg, 0.780 mmol) in 78% yield over 2 steps; mp 76-78 °C; Rf = 0.50 (hexane:acetone 4:1). Spectral 1 data for acid 138d: H NMR (300 MHz, CDCl3) δ 1.43, 1.46 (2s, 36H), 1.71 (s, 3H), 2.30 (s, 3H), 3.23 (s, 1H), 3.68, 3.71 (2s, 6H), 4.40 (s, 1H), 7.00-7.20 (m, 4H), 7.34 (s, 2H), 7.39 (s, 2H), 9.80 (brs, 1H); 13 C NMR (150 MHz, CDCl3) δ 11.91, 18.86, 31.98, 32.08, 35.74, 35.78, 49.09, 53.75, 64.13, 64.15, 71.32, 124.92, 125.49, 126.00, 127.04, 127.93, 129.94, 132.96, 135.56, 135.83, 136.55, 143.72, 143.86, 158.66, 159.07, 170.32; IR (thin film) 2961(s), 1767(s), 1414(m) –1 + cm ; HRMS calcd for C42H60NO4 (M+H, ESI ) m/z 642.4522, meas 642.4491; 20 [α] D 31.3° (c 1.0, CH2Cl2). Preparation of acid 138e: BUDAM N 1) LDA, MeI COOEt 2) KOH, EtOH Br 303 then H+ 96% ee 281 BUDAM N COOH Br 138e Alkylation: The general procedure for the alkylation was followed with ester 303 (96% ee, 432 mg, 0.600 mmol, 1.00 equiv), i-Pr2NH (0.18 mL, 1.3 mmol, 2.1 equiv), n-BuLi (2.3M, 0.51 mL, 1.3 mmol, 2.0 equiv) and CH3I (0.12 mL, 1.8 mmmol, 3.0 equiv). After workup, the crude product was obtained which was used directly in the next step. Hydrolysis: To the mixture of the crude product in THF (2 mL) and ethanol (2 mL) was added an aqueous solution of KOH (168 mg, 3.00 mmol, 5.00 equiv) in H2O (2 mL). The resulting mixture was refluxed for 12 h. And another portion of KOH (168 mg, 3.00 mmol, 5.00 equiv) in H2O (2 mL) was added. The resulting mixture was refluxed for 48 h. After it was cooled to rt, the volatiles were removed by rotary evaporation and aq citric acid (2N, 5 mL) was added. The mixture was extracted with ether (3 × 10 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 25 × 200 mm, hexane:acetone 5:1). The product was obtained as a white solid (240 mg, 0.340 mmol) in 57% yield over 2 steps; mp 1 76-80 °C; Rf = 0.50 (hexane:acetone 5:1). Spectral data for acid 138e: H NMR (500 MHz, CDCl3) δ 1.37, 1.40 (2s, 36H), 1.71 (s, 3H), 3.27 (s, 1H), 3.63, 3.67 (2s, 6H), 4.38 (s, 1H), 7.00-7.16 (m, 3H), 7.27, 7.30 (2s, 4H), 7.44-7.50 (dd, 1H, J = 7.5, 1.5 Hz), 9.80 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 12.12, 32.00, 32.10, 35.79, 35.83, 49.88, 55.31, 64.19, 64.21, 71.03, 123.73, 124.98, 125.95, 126.95, 128.91, 129.55, 132.47, 134.44, 135.21, 135.71, 143.86, 143.95, 158.77, 159.12, 282 –1 169.57; IR (thin film) 2961(s), 1773(m), 1414(m) cm ; HRMS calcd for 79 + 20 C41H57NO4 Br (M+H, ESI ) m/z 706.3471, meas 706.3497; [α] D 12.0° (c 1.0, CH2Cl2). Preparation of acid 138f: BUDAM N 1) LDA, MeI BUDAM N COOEt 2) KOH, EtOH COOH 304 then H+ 98% ee 138f Alkylation: The general procedure for the alkylation was followed with ester 304 (98% ee, 691 mg, 1.00 mmol, 1.00 equiv), i-Pr2NH (0.30 mL, 2.1 mmol, 2.1 equiv), n-BuLi (2.5M, 0.84 mL, 2.1 mmol, 2.1 equiv) and CH3I (0.19 mL, 3.0 mmmol, 3.0 equiv). After workup, the crude product was obtained which was used directly in the next step. Hydrolysis: To the mixture of the crude product in ethanol (2.5 mL) was added an aqueous solution of KOH (280 mg, 5.00 mmol, 5.00 equiv) in H2O (2.5 mL). The resulting mixture was refluxed for 6 h. After it was cooled to rt, the volatiles were removed by rotary evaporation and aq HCl (6N) was added to pH ~2. The mixture was extracted with ether (3 × 10 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 25 × 200 mm, hexane:EtOAc 9:1). The product 138f was obtained as a white solid (380 mg, 0.560 mmol) in 56% yield over 2 steps; mp 88-91 °C; Rf = 0.45 (hexane:EtOAc 4:1). Spectral data for 138f: 283 1 H NMR (500 MHz, CDCl3) δ 1.37 (s, 18H), 1.41 (s, 18H), 1.83 (s, 3H), 3.27 (s, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 4.46 (s, 1H), 7.12 (d, 1H, J = 7.0 Hz), 7.20-7.26 (m, 1H), 7.32, 7.35 (2s, 4H), 7.44-7.54 (m, 2H), 7.70 (d, 1H, J = 8.5 Hz), 7.80 (d, 1H, J = 7.5 Hz), 7.85 (d, 1H, J = 7.5 Hz), 9.80 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 12.13, 32.02, 32.13, 32.23, 35.81, 35.85, 49.32, 53.18, 64.23, 71.47, 123.18, 124.86, 125.06, 125.15, 126.14, 126.17, 126.72, 128.62, 128.68, 130.76, 131.24, 133.38, 135.40, 135.81, 143.87, 143.98, 158.79, 159.20, 170.14; IR (thin –1 + film) 2963(s), 1770(m), 1414(m) cm ; HRMS calcd for C45H60NO4 (M+H, ESI ) 20 m/z 678.4522, meas 678.4510; [α] D 9.0° (c 1.0, CH2Cl2). Preparation of acid 143c: BUDAM N 1) LDA, MeI BUDAM N COOEt 2) KOH, EtOH COOH 301 143c Br Br then H+ 99% ee Alkylation: The general procedure for the alkylation was followed with ester 301 (99% ee, 720 mg, 1.00 mmol, 1.00 equiv), i-Pr2NH (0.30 mL, 2.1 mmol, 2.1 equiv), n-BuLi (2.5M, 0.84 mL, 2.1 mmol, 2.1 equiv) and ethyl iodide (0.24 mL, 3.0 mmmol, 3.0 equiv). After workup, the crude product was obtained which was used directly in the next step. Hydrolysis: To the mixture of the crude product in THF (2.5 mL) and ethanol (2.5 mL) was added an aqueous solution of KOH (280 mg, 5.00 mmol, 5.00 equiv) in H2O (2.5 mL). The resulting mixture was refluxed for 16 h. After it was cooled to rt, additional THF (2.5 mL) was added and the mixture was refluxed for 48 h. 284 After it was cooled to rt, the volatiles were removed by rotary evaporation and aq HCl (6N) was added to pH ~2. The mixture was extracted with ether (20 mL + 2 × 10 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 25 × 200 mm, hexane:acetone 9:1). The product 143c was obtained as a white solid (382 mg, 0.530 mmol) in 53% yield over 2 steps; mp 83-87 °C; Rf = 0.50 1 (hexane:EtOAc 4:1). Spectral data for 143c: H NMR (500 MHz, CDCl3) δ 0.80 (t, 3H, J = 7.0 Hz), 1.38, 1.40 (2s, 36H), 1.74 (dq, 1H, J = 7.5, 7.5 Hz), 2.31 (dq, 1H, J = 7.5, 7.5 Hz), 3.14 (s, 1H), 3.64 (s, 3H), 3.67 (s, 3H), 4.35 (s, 1H), 6.79 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 7.30 (s, 4H), 9.00 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 11.27, 20.09, 31.99, 32.07, 35.78, 35.79, 51.42, 54.64, 64.26, 64.30, 70.62, 122.03, 124.97, 126.01, 128.98, 131.44, 133.74, 135.17, 135.79, 143.95, 144.00, 158.83, 159.23, 169.38; IR (thin film) 2961(s), 1710(s), –1 + 79 1224(s) cm ; HRMS calcd for C42H59NO4 Br (M+H, ESI ) m/z 720.3627, 20 meas 720.3578; [α] D 6.4° (c 1.0, CH2Cl2). Preparation of acid 151a: Ph Ph KOH, EtOH N Ph Ph N COOEt then H+ COOH 32a 151a 98% ee To a 50 mL round bottom flask containing ester 32a (98% ee, 1.07 g, 3.00 mmol, 1.00 equiv) and ethanol (5 mL) was added an aqueous solution of KOH (840 mg, 285 15.0 mmol, 5.00 equiv) in H2O (5 mL). The resulting suspension was refluxed for 1 h during which time it became a homogeneous solution. After it was cooled to rt, ethanol was removed by rotary evaporation. To the remaining aqueous solution was added aq citric acid (2N, 10 mL). The resulting white precipitate was collected by filtration and washed with H2O and hexane to obtain the pure acid 151a (976 mg, 2.98 mmol, 99%) as a white solid; mp 143-145 °C; Rf = 0.10 1 (hexane:EtOAc 4:1). Spectral data for acid 151a: H NMR (600 MHz, CDCl3) δ 2.78 (d, 1H, J = 7.2 Hz), 3.40 (d, 1H, J = 6.6 Hz), 4.04 (s, 1H), 7.20-7.30 (m, 1 8H), 7.32 (q, 4H, J = 7.2 Hz), 7.47 (t, 4H, J = 8.4 Hz); H NMR (600 MHz, DMSOd6) δ 2.77 (d, 1H, J = 7.2 Hz), 3.32 (d, 1H, J = 6.6 Hz), 4.17 (s, 1H), 7.14-7.30 (m, 7H), 7.34 (t, 2H, J = 7.8 Hz), 7.41 (d, 2H, J = 7.8 Hz), 7.49 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 7.8 Hz), 12.22 (brs, 1H); 13 C NMR (150 MHz, DMSO-d6) δ 46.39, 47.14, 75.34, 126.94, 126.99, 127.05, 127.08, 127.25, 127.59, 127.63, 128.31, 128.34, 135.70, 143.07, 143.20, 168.58; IR (thin film) 1705(s), 1244(m) –1 + cm ; HRMS calcd for C22H20NO2 (M+H, ESI ) m/z 330.1494, meas 330.1506; 20 [α] D 19.6° (c 0.5, CH2Cl2). Preparation of acid 151b: Ph Ph N KOH, EtOH Ph Ph N COOEt 305 racemic then H+ 286 COOH 151b To a 50 mL round bottom flask containing ester 305 (racemic, 250 mg, 0.674 mmol, 1.00 equiv), ethanol (2 mL) and THF (1 mL) was added an aqueous solution of KOH (189 mg, 3.37 mmol, 5.00 equiv) in H2O (2 mL). The resulting suspension was refluxed for 2 h during which time it became a homogeneous solution. After it was cooled to rt, aq citric acid (2N, 5 mL) was added. The resulting white precipitate was collected by filtration and washed with H2O and hexane to obtain the pure acid 151b (230 mg, 0.670 mmol, 99%) as a white solid; mp 147-149 °C; Rf = 0.10 (hexane:EtOAc 4:1). Spectral data for acid 151b: 1 H NMR (500 MHz, DMSO-d6) δ 2.20 (s, 3H), 2.76 (d, 1H, J = 6.5 Hz), 3.32 (d, 1H, J = 6.5 Hz), 4.12 (s, 1H), 7.00-7.40 (m, 10H), 7.45 (d, 2H, J = 7.5 Hz), 7.57 (d, 2H, J = 7.5 Hz), 12.0 (brs, 1H); 13 C NMR (125 MHz, DMSO-d6) δ 20.67, 46.33, 47.03, 75.32, 126.92, 127.00, 127.20, 127.48, 128.24, 128.31, 132.64, 136.19, 143.09, 143.21, 168.58 (Two sp 2 carbon not located); IR (thin film) –1 + 1705(s), 1244(m) cm ; HRMS calcd for C23H22NO2 (M+H, ESI ) m/z 344.1651, meas 344.1679. Preparation of acid 151c: Ph Ph Ph KOH, EtOH N COOEt then H+ Ph N COOH 306 151c Br 90% ee To a suspension of ester 306 (90% ee, 872 mg, 2.00 mmol, 1.00 equiv) in Br ethanol (5 mL) was added a solution of KOH (560 mg, 10.00 mmol, 5.00 equiv) in 287 H2O (5 mL). The resulting mixture was refluxed for 1 h. After it was cooled to rt, aq citric acid (2N, 5 mL) was added. The white precipitate was collected by filtration and washed with H2O and hexanes. The solid was dissolved in Et2O (25 mL), dried (Na2SO4) and filtered. The filtrate was concentrated to afford the product 151c as a white solid (810 mg, 1.985 mmol) in 99% yield; mp 140-142 1 °C; Rf = 0.20 (hexane:EtOAc 4:1). Spectral data for acid 151c: H NMR (500 MHz, CDCl3) δ 2.79 (d, 1H, J = 7.0 Hz), 3.32 (d, 1H, J = 7.0 Hz), 4.03 (s, 1H), 7.17 (d, 2H, J = 8.5 Hz), 7.22-7.60 (m, 13H); 13 C NMR (125 MHz, CDCl3) δ 45.45, 48.15, 77.23, 122.04, 126.98, 127.40, 127.77, 127.88, 128.75, 128.84, 129.30, 131.45, 133.02, 141.14, 141.55, 169.82; IR (thin film) 1711(s), 1265(m) –1 + 79 cm ; HRMS calcd for C22H19NO2 Br (M+H, ESI ) m/z 408.0599, meas 20 408.0576; [α] D 3.5° (c 1.0, CH2Cl2). Preparation of acid 153a: Ph Ph N KOH, EtOH then H+ N Ph COOH Ph COOEt 153a 167a 62% ee To a suspension of ester 167a (62% ee, 170 mg, 0.600 mmol, 1.00 equiv) in ethanol (1 mL) was added a solution of KOH (170 mg, 3.00 mmol, 5.00 equiv) in H2O (2 mL). The resulting mixture was refluxed for 1 h. After it was cooled to rt, aq citric acid (2N, 2 mL) was added. The white precipitate was collected by filtration. The product was obtained as a white solid (150 mg, 0.593 mmol) in 288 1 99% yield; mp 123-125 °C; Rf = 0.10 (hexane:EtOAc). Spectral data for 153a: H NMR (500 MHz, DMSO-d6) δ 2.74 (d, 1H, J = 6.0 Hz), 3.18 (d, 1H, J = 6.5 Hz), 3.60 (d, 1H, J = 14.0 Hz), 3.81 (d, 1H, J = 14.0 Hz), 7.12-7.48 (m, 10H), 12.20 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 46.22, 46.74, 62.06, 126.90, 127.03, 2 127.63, 127.69, 128.23, 135.98, 138.73, 168.78 (One sp C not located); IR (thin –1 + film) 1718(s) 1224(s) cm ; HRMS calcd for C16H16NO2 (M+H, ESI ) m/z 20 254.1181, meas 254.1163; [α] D 18.2° (c 1.0, CH2Cl2). Preparation of acid 151g: Ph Ph N KOH, EtOH then H+ Ph Ph N COOEt COOH 307 99% ee 151g To a suspension of ester 307 (99% ee, 363 mg, 1.00 mmol, 1.00 equiv) in ethanol (3 mL) was added a solution of KOH (280 mg, 5.00 mmol, 5.00 equiv) in H2O (3 mL). The resulting mixture was refluxed for 1 h. After it was cooled to rt, the volatiles were removed by rotary evaporation. Then aq citric acid (2N, 5 mL) was added. The resulting precipitate was collected by filtration and washed with H2O, affording the product 151g as a white solid (306 mg, 0.913 mmol) in 93% yield; mp 151-152 °C; Rf = 0.25 (hexane:EtOAc 4:1). Spectral data for acid 151g: 1 H NMR (500 MHz, DMSO-d6) δ 0.46 (q, 1H, J = 10.5 Hz), 0.90-1.10 (m, 5H), 1.16-1.28 (m, 1H), 1.30-1.70 (m, 4H), 1.89 (t, 1H, J = 7.0 Hz), 2.22 (d, 1H, J = 7.0 Hz), 3.80 (s, 1H), 7.16-7.40 (m, 8H), 7.45 (d, 2H, J = 7.5 Hz), 12.40 (brs, 1H); 289 13 C NMR (125 MHz, CDCl3) δ 24.92, 25.09, 25.63, 29.44, 30.26, 35.60, 42.27, 51.07, 75.77, 126.67, 126.71, 127.96, 128.13, 128.19, 143.08, 143.28, 170.79 2 –1 (One sp C not located); IR (thin film) 2926(s), 1705(m), 1450(m) cm ; HRMS + 20 calcd for C22H26NO2 (M+H, ESI ) m/z 336.1964, meas 336.1950; [α] D 75.2° (c 0.5, CH2Cl2). Preparation of acid 153g: Ph Ph N KOH, EtOH N COOH COOEt then H+ 153g 308 99% ee To a mixture of ester 308 (99% ee, 287 mg, 1.00 mmol, 1.00 equiv) in ethanol (2 mL) was added a solution of KOH (280 mg, 5.00 mmol, 5.00 equiv) in H2O (2 mL). The resulting mixture was refluxed for 2 h. After cooling to rt, aq citric acid (2N, 5 mL) was added. The resulting white precipitate was collected by filtration. The product 153g was obtained as a white solid (217 mg, 0.838 mmol, 84%); mp 1 195-196 °C; Rf = 0.05 (hexane:EtOAc 4:1). Spectral data for acid 153g: H NMR (500 MHz, CDCl3) δ 0.84-1.24 (m, 6H), 1.50-1.70 (m, 5H), 1.84 (t, 1H, J = 8.0 Hz), 2.45 (d, 1H, J = 7.0 Hz), 3.48 (d, 1H, J = 13.0 Hz), 3.69 (d, 1H, J = 13.0 Hz), 1 7.10-7.40 (m, 5H), 7.70 (brs, 1H); H NMR (600 MHz, DMSO-d6) δ 0.80-1.28 (m, 6H), 1.50-1.70 (m, 5H), 1.70-1.80 (m, 1H), 2.24 (d, 1H, J = 7.2 Hz), 3.32 (d, 1H, J = 13.2 Hz), 3.54 (d, 1H, J = 13.2 Hz), 7.20-7.40 (m, 5H), 11.80 (s, 1H); 13 C NMR (125 MHz, DMSO-d6) δ 25.11, 25.19, 25.76, 29.50, 30.74, 35.68, 41.88, 50.76, 290 62.91, 126.97, 128.08, 128.28, 138.76, 170.91; IR (thin film) 2924(w), 1755(s) –1 + cm ; HRMS calcd for C16H22NO2 (M+H, ESI ) m/z 260.1651, meas 260.1667; 20 [α] D 52° (c 0.5, DMSO). Preparation of acid 161g: MEDAM N KOH, EtOH then H+ MEDAM N COOH COOEt 161g 309 23% ee To the mixture of ester 309 (23% ee, 200 mg, 0.420 mmol, 1.00 equiv) in ethanol (2 mL) was added a solution of KOH (117 mg, 2.09 mmol, 5.00 equiv) in H2O (2 mL). The resulting mixture was refluxed for 1 h. After cooling to rt, aq citric acid (2N, 2 mL) and ether (10 mL) were added. The aqueous layer was separated and extracted with ether (2 × 10 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 28 × 280 mm, hexane:acetone 4:1 to 3:1) to afford the product 161g (180 mg, 0.400 mmol) as a white solid in 96% yield; mp 85-90 1 °C; Rf = 0.30 (hexane:acetone 4:1). Spectral data for 161g: H NMR (300 MHz, CDCl3) δ 0.50-0.70 (m, 1H), 0.90-1.70 (m, 10H), 1.88 (dd, 1H, J = 9.3, 6.9 Hz), 2.22, 2.23 (2s, 12H), 2.37 (d, 1H, J = 6.9 Hz), 3.48 (s, 1H), 3.66, 3.67 (2s, 6H), 6.97 (s, 4H), 9.00 (brs, 1H); 13 C NMR (150 MHz, CDCl3) δ 16.11, 16.22, 25.28, 25.34, 25.95, 29.87, 30.97, 37.26, 43.16, 53.15, 59.58, 59.67, 76.72, 127.15, 127.98, 130.70, 131.06, 136.56, 137.12, 156.24, 156.41, 170.75; IR (thin film) 291 –1 + 2928(s), 1710(w) cm ; HRMS calcd for C28H38NO4 (M+H, ESI ) m/z 452.2801, 20 meas 452.2791; [α] D 10.6° (c 0.5, CH2Cl2). Preparation of 151h: ONH2Bh Ph N Ph Ph (R)-VANOL-B Ph KOH, EtOH Ph Ph N N EDA then H+ COOEt COOH Toluene 310 311 72% ee rt 151h Imine formation: The mixture of iso-butyraldehyde (173 mg, 0.220 mL, 2.40 MgSO4 mmol, 1.20 equiv), benzhydryl amine (378 mg, 2.00 mmol, 1.00 equiv), MgSO4 (960 mg, 8.00 mmol, 4.00 equiv) and dry CH2Cl2 (10 mL) was stirred under N2 for 2 h. After the reaction was filtered over a Celite pad on a sintered glass funnel, the filtrate was concentrated to give the product 310 (450 mg, 1.90 mmol, 1 95%) as a colorless oil; H NMR (300 MHz, CDCl3) δ 1.04 (d, 6H, J = 6.9 Hz), 2.40-2.54 (m, 1H), 5.24 (s, 1H), 7.08-7.30 (m, 10H), 7.64 (d, 1H, J = 5.1 Hz); 13 C NMR (150 MHz, CDCl3) δ 19.34, 34.18, 77.74, 126.79, 127.54, 128.32, 143.95, 169.83. Aziridination: A 25 mL pear-shaped single neck flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it), cooled to rt under N2 and charged with 5 mol% (R)-VANOL (22 mg, 0.050 mmol, 0.050 equiv), 20 mol% triphenyl borate (58 mg, 0.20 mmol, 0.20 equiv), H2O (9 µL) and dry toluene (1 mL). The Teflon valve was closed and the flask o was heated at 80 C for 1 hour. After the flask was cooled to rt, the toluene was 292 carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon value. After the solvent was removed, the Teflon valve was completely o opened and the flask was heated at 80 C under high vacuum for 30 min. The flask was then allowed to cool to rt. The solution of imine 310 (237 mg, 1.00 mmol, 1.00 equiv) in toluene (2 mL) was added. And then EDA (0.25 mL, 2.4 mmol, 2.4 equiv) was added via syringe in one portion. The solution was stirred at rt for 17 h. The reaction was quenched with hexane (5 mL) and concentrated. After column chromatography (silica gel, 28 × 280 mm, hexane:EtOAc 15:1), ester 311 was obtained as a white solid (230 mg, 0.712 mmol) in 71% yield. The optical purity was determined to be 72% ee by HPLC analysis (Chiralcel OD-H column, 99:1 hexane/2-propanol at 222 nm, flow-rate 1.0 mL/min); Retention times: tR = 3.24 min (major enantiomer) and tR = 5.98 min (minor enantiomer); mp 102-104 °C; Rf = 0.40 (hexane:EtOAc 4;1); 1 H NMR (500 MHz, CDCl3) δ 0.56 (d, 3H, J = 6.0 Hz), 0.85 (d, 3H, J = 7.0 Hz), 1.29 (t, 3H, J = 7.0 Hz), 1.601.70 (m, 1H), 1.81 (dd, 1H, J = 9.5, 7.0 Hz), 2.32 (d, 1H, J = 7.0 Hz), 3.68 (s, 1H), 4.14-4.32 (m, 2H), 7.20-7.26 (m, 2H), 7.28-7.36 (m, 4H), 7.38-7.44 (m, 2H), 7.55 (d, 2H, J = 8.0 Hz); 13 C NMR (125 MHz, CDCl3) δ 14.18, 19.53, 20.32, 27.25, 43.58, 53.52, 60.59, 78.01, 126.83, 126.97, 127.43, 128.21, 128.25, 128.29, –1 142.29, 142.75, 169.48; IR (thin film) 961(m), 1734(s) cm ; HRMS calcd for + 20 C21H26NO2 (M+H, ESI ) m/z 324.1964, meas 324.1964; [α] D –123.5° (c 0.5, CH2Cl2). 293 Hydrolysis: To the mixture of ester 311 (100 mg, 0.310 mmol, 1.00 equiv) in ethanol (0.5 mL) was added a solution of KOH (87 mg, 1.6 mmol, 5.0 equiv) in H2O (1 mL). The resulting mixture was refluxed for 30 min. After cooling to rt, aq citric acid (2N, 2 mL) and ether (10 mL) were added. The aqueous layer was separated and extracted with ether (2 × 5 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated to give the crude product as a white solid. CH2Cl2 (10 mL) was added to the solid and this mixture was filtered and washed well with CH2Cl2. The filtrate was concentrated to give the product 151h as a white foamy solid (80 mg, 0.27 mmol, 88%); mp 84-86 °C; 1 Rf = 0.005 (hexane:EtOAc 4:1). Spectral data for acid 151h: H NMR (600 MHz, DMSO-d6) δ 0.41 (d, 3H, J = 6.6 Hz), 0.75 (d, 3H, J = 7.2 Hz), 1.44-1.56 (m, 1H), 1.84 (dd, 1H, J = 9.0, 6.0 Hz), 2.22 (d, 1H, J = 6.6 Hz), 3.82 (s, 1H), 7.14-7.54 (m, 10H), 12.40 (brs, 1H); 13 C NMR (150 MHz, DMSO-d6) δ 19.30, 20.25, 26.67, 42.59, 52.70, 75.71, 126.70, 127.18, 127.97, 128.12, 128.18, 143.06, 143.32, 170.75 (One sp 2 carbon not located); 13 C NMR (150 MHz, CDCl3) δ 19.52, 20.50, 28.15, 43.47, 54.55, 77.48, 126.83, 127.55, 127.84, 127.93, 128.52, –1 128.74, 141.25, 141.82, 171.03; IR (thin film) 2963(m), 1720(s) cm ; HRMS + 20 calcd for C19H22NO2 (M+H, ESI ) m/z 296.1651, meas 296.1640; [α] D –51.1° (c 0.5, CH2Cl2). Preparation of acid 151i: 294 Ph Ph Ph KOH, EtOH N Ph N COOEt then H+ COOH 151i 80% ee To the mixture of ester 312 (80% ee, 70 mg, 0.22 mmol, 1.0 equiv) in ethanol (1 312 mL) was added a solution of KOH (60 mg, 1.54 mmol, 5.00 equiv) in H2O (1 mL). After the mixture was refluxed for 30 min, THF (1 mL) was added. And the resulting mixture was refluxed for another 30 min. After it was cooled to rt, the volatiles were removed by rotary evaporation and ether (5 mL) was added. The aqueous layer was separated and extracted with ether (2 × 5 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 18 × 180 mm, hexane:CH2Cl2:EtOAc 2:2:1 to 1:1:1) to obtain the product 151i (45 mg, 0.15 mmol) as a white foamy solid in 71% yield; mp 50-52 °C; Rf = 0.20 1 (hexane:CH2Cl2:EtOAc 2:2:1). Spectral data for acid 151i: H NMR (500 MHz, CDCl3) δ 0.77 (t, 3H, J = 7.0 Hz), 1.10-1.28 (m, 2H), 1.38-1.48 (m, 1H), 1.56-1.64 (m, 1H), 2.19 (q, 1H, J = 7.0 Hz), 2.48 (d, 1H, J = 7.0 Hz), 3.80 (s, 1H), 7.00-8.00 (m, 11H); 13 C NMR (150 MHz, CDCl3) δ 13.57, 20.18, 31.45, 43.22, 47.71, 77.02, 127.05, 127.37, 127.65, 127.70, 128.56, 128.81, 141.35, 141.74, 170.61; –1 + IR (thin film) 1720(s) cm ; HRMS calcd for C19H22NO2 (M+H, ESI ) m/z 20 296.1651, meas 296.1626; [α] D 8.9° (c 1.0, CH2Cl2). Preparation of acid 151j: 295 Ph O BhNH2 Ph N MgSO4 Ph (S)-vANOL-B Ph 313 EDA Toluene Ph rt Ph Ph KOH, EtOH N then H+ Ph COOEt 314 99% ee Ph Ph N COOH 151j Imine formation: The mixture of hydrocinnamaldehyde (90% by weight, 328 mg, 2.20 mmol, 1.10 equiv), BhNH2 (378 mg, 2.00 mmol, 1.00 equiv) and MgSO4 (960 mg, 8.00 mmol, 4.00 equiv) in CH2Cl2 (10 mL) was stirred at rt for 1.5 h. After it was filtered over a Celite pad on a sintered glass funnel, the filtrate was concentrated to give the imine 313 as a colorless oil which was put on the vacuum for 10 sec prior to use. Aziridination: A 25 mL pear-shaped single neck flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it), cooled to rt under N2 and charged with 5 mol% (S)-VANOL (22 mg, 0.050 mmol, 0.050 equiv), 20 mol% triphenyl borate (58 mg, 0.20 mmol, 0.20 equiv), H2O (9 µL) and dry toluene (1 mL). The Teflon valve was closed and the flask o was heated at 80 C for 1 hour. After the flask was cooled to rt, the toluene was carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon value. After the solvent was removed, the Teflon valve was completely o opened and the flask was heated at 80 C under high vacuum for 30 min. The flask was then allowed to cool to rt. The solution of imine 313 (306 mg, 1.00 mmol, 1.00 equiv) in toluene (2 mL) was added. And then EDA (311 µL, 3.00 mmol, 3.00 equiv) was added via syringe in one portion. The solution was stirred at rt for 22 h. The reaction was quenched with n-hexane (5 mL) and concentrated 296 st by removing all volatiles. After column chromatography (1 column, silica gel, 28 × 280 mm, hexane:EtOAc 9:1; 2 nd column, silica gel, 28 × 280 mm, benzene:EtOAc 50:1), ester 314 was obtained as a white solid (262 mg, 0.680 mmol) in 68% yield. The optical purity was determined to be 78% ee by HPLC analysis (Chiralcel OD-H column, 99:1 hexane/2-propanol at 222 nm, flow-rate 1.0 mL/min); Retention times: tR = 5.06 min (minor enantiomer) and tR = 10.16 min (major enantiomer). A single recrystallization of 78% ee material afforded the product (141 mg, 0.366 mmol) with 37% recovery and 99.1% ee; mp 114-115 °C; 1 Rf = 0.50 (hexane:EtOAc 4:1); H NMR (500 MHz, CDCl3) δ 1.27 (t, 3H, J = 7.5 Hz), 1.82-2.00 (m, 2H), 2.08 (q, 1H, J = 6.5 Hz), 2.28-2.40 (m, 2H), 2.44-2.54 (m, 1H), 3.71 (s, 1H), 4.14-4.26 (m, 2H), 6.98 (d, 2H, J = 7.5 Hz), 7.14-7.40 (m, 9H), 7.49 (d, 2H, J = 8.0 Hz), 7.53 (d, 2H, J = 7.5 Hz); 13 C NMR (125 MHz, CDCl3) δ 14.22, 29.58, 33.22, 43.19, 46.07, 60.72, 77.79, 125.70, 126.98, 127.02, 127.44, 127.83, 128.16, 128.31, 128.33, 128.39, 141.28, 142.40, 142.88, 169.33; –1 IR (thin film) 2918(m), 1734(s) cm ; Anal calcd for C26H27NO2: C, 81.01; H, 20 7.06; N, 3.63. Found: C, 80.86; H, 7.06; N, 3.63; [α] D 86.2° (c 0.5, CH2Cl2) based on the 99.1% ee material. Hydrolysis: To a suspension of ester 314 (100 mg, 0.260 mmol, 1.00 equiv) in ethanol (1 mL) was added a solution of KOH (73 mg, 1.3 mmol, 5.0 equiv) in H2O (2 mL). The resulting mixture was refluxed for 45 min. After cooling to rt, aq citric acid (2N, 2 mL) was added. The resulting precipitate was collected by 297 filtration. The product was obtained as a white solid (91 mg, 0.26 mmol, 98%); 1 mp 70-72 °C; Rf = 0.13 (hexane:EtOAc 4:1); H NMR (500 MHz, DMSO-d6) δ 1.72-1.90 (m, 2H), 2.15-2.24 (m, 1H), 2.28-2.38 (m, 1H), 2.38-2.50 (m, 2H), 3.97 (s, 1H), 6.98-7.04 (m, 2H), 7.20-7.60 (m, 13H), 12.50 (brs, 1H); 13 C NMR (125 MHz, DMSO-d6) δ 29.52, 32.71, 42.23, 45.23, 75.42, 125.69, 126.78, 127.14, 127.52, 128.01, 128.02, 128.19, 128.21, 128.30, 128.45, 141.20, 143.49, –1 + 170.61; IR (thin film) 1734(s) cm ; HRMS calcd for C24H24NO2 (M+H, ESI ) 20 m/z 358.1807, meas 358.1834; [α] D 30.5° (c 0.5, CH2Cl2). Preparation of acid 151k: Ph O BhNH2 MgSO4 N 315 Ph EDA Toluene rt Ph Ph KOH, EtOH N then H+ COOEt 316 86% ee (S)-VANOL-B Ph Ph N COOH 151k Imine formation: The mixture of iso-pentaldehyde (189 mg, 2.20 mmol, 1.10 equiv), BhNH2 (378 mg, 2.00 mmol, 1.00 equiv) and MgSO4 (960 mg, 8.00 mmol, 4.00 equiv) in CH2Cl2 (10 mL) was stirred at rt for 2 h. After it was filtered over a Celite pad on a sintered glass funnel, the filtrate was concentrated to give the imine 315 as a colorless oil which was put on the vacuum for 10 sec prior to use. Aziridination: A 25 mL pear-shaped single neck flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it), cooled to rt under N2 and charged with 5 mol% (S)-VANOL (22 mg, 0.050 mmol, 0.050 equiv), 20 mol% triphenyl borate (58 mg, 0.20 mmol, 0.20 equiv), 298 H2O (9 µL) and dry toluene (1 mL). The Teflon valve was closed and the flask o was heated at 80 C for 1 hour. After the flask was cooled to rt, the toluene was carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon value. After the solvent was removed, the Teflon valve was completely o opened and the flask was heated at 80 C under high vacuum for 30 min. The flask was then allowed to cool to rt. The solution of imine 315 (251 mg, 1.00 mmol, 1.00 equiv) in toluene (2 mL) was added. And then EDA (375 µL, 3.60 mmol, 3.60 equiv) was added via syringe in one portion. The solution was stirred at rt for 19 h. The reaction was quenched with n-hexane (5 mL) and concentrated by removing all volatiles. After column chromatography (silica gel, 28 × 280 mm, hexane:acetone 9:1), ester 316 was obtained as a white solid (205 mg, 0.608 mmol) in 61% yield. The optical purity was determined to be 86% ee by HPLC analysis (Chiralcel OD-H column, 99:1 hexane/2-propanol at 222 nm, flow-rate 1.0 mL/min); Retention times: tR = 3.26 min (minor enantiomer) and tR = 6.01 1 min (major enantiomer); mp 105-106 °C; Rf = 0.48 (hexane:acetone 4:1); H NMR (500 MHz, CDCl3) δ 0.65 (d, 3H, J = 6.5 Hz), 0.76 (d, 3H, J = 7.0 Hz), 1.23 (t, 3H, J = 7.0 Hz), 1.26-1.44 (m, 2H), 1.48-1.56 (m, 1H), 2.06 (q, 1H, J = 6.5 Hz), 2.27 (d, 1H, J = 7.0 Hz), 3.36 (s, 1H), 4.10-4.22 (m, 2H), 7.16-7.30 (m, 6H), 7.367.42 (m, 2H), 7.44-7.48 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 14.26, 21.63, 22.93, 26.66, 36.49, 43.43, 45.71, 60.70, 78.06, 126.99, 127.12, 127.36, 127.82, 128.36, 142.51, 142.79, 169.56 (One sp 299 2 carbon not located); IR (thin film) –1 + 1784(s) cm ; HRMS calcd for C22H28NO2 (M+H, ESI ) m/z 332.2120, meas 20 320.2141; [α] D 94.7° (c 1.0, CH2Cl2). Hydrolysis: To a mixture of ester 316 (60 mg, 0.18 mmol, 1.0 equiv) in ethanol (1 mL) was added a solution of KOH (50 mg, 0.90 mmol, 5.0 equiv) in H2O (1 mL). The resulting mixture was refluxed for 30 min. After the reaction mixture was cooled to rt, aq citric acid (2N, 2 mL) was added. And the mixture was extracted with ether (3 × 10 mL). The organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated to give a white viscous foamy solid (50 mg, 0.16 mmol, 91%); mp 124-125 °C; Rf = 0.50 (hexane:acetone 2:1). Spectral data for 1 acid 151k: H NMR (300 MHz, CDCl3) δ 0.71 (d, 3H, J = 6.6 Hz), 0.80 (d, 3H, J = 6.6 Hz), 1.16-1.70 (m, 3H), 2.23 (q, 1H, J = 6.7 Hz), 2.49 (d, 1H, J = 7.2 Hz), 3.83 (s, 1H), 7.00-8.00 (m, 11H); 13 C NMR (150 MHz, CDCl3) δ 21.79, 22.76, 26.67, 37.25, 43.32, 46.88, 127.05, 127.24, 127.71, 127.83, 128.62, 128.89, 141.25, –1 141.59, 169.86; IR (thin film) 1734(s) cm ; HRMS calcd for C20H24NO2 (M+H, + 20 ESI ) m/z 310.1807, meas 310.1811; [α] D 26.7° (c 1.0, Et2O). Preparation of acid 151l: Ph Ph N Ph KOH, EtOH then H+ Ph N COOEt COOH 151l 317 98% ee To the mixture of ester 317 (98% ee, 270 mg, 0.800 mmol, 1.00 equiv) in ethanol (4 mL) was added a solution of KOH (224 mg, 4.00 mmol, 5.00 equiv) in H2O (4 300 mL). After the mixture was refluxed for 1.5 h, THF (1 mL) was added. The resulting mixture was refluxed for another 1.5 h. After it was cooled to rt, aq citric acid (2N, 5 mL) was added. The resulting white precipitate was collected by filtration. The solid was then dissolved in ether (30 mL) and washed with H2O (3 × 5 mL). The organic layer was dried (Na2SO4) and concentrated to obtain the product 151l (234 mg, 0.757 mmol, 95%) as a white solid; mp 164-166 °C; Rf = 0.25 (hexane:EtOAc 4:1). Spectral data for acid 151l: 1 H NMR (500 MHz, CDCl3) δ 0.80 (s, 9H), 2.00 (d, 1H, J = 7.5 Hz), 2.36 (d, 1H, J = 8.0 Hz), 3.69 (s, 1 1H), 7.22-7.28 (m, 3H), 7.30-7.34 (m, 4H), 7.40-7.46 (m, 4H); H NMR (600 MHz, DMSO-d6) δ 0.66 (s, 9H), 1.81 (d, 1H, J = 7.2 Hz), 2.20 (d, 1H, J = 7.8 Hz), 3.78 (s, 1H), 7.18-7.22 (m, 2H), 7.26-7.30 (m, 4H), 7.38 (dd, 2H, J = 8.4, 1.2 Hz), 7.60 (dd, 2H, J = 8.4, 1.2 Hz), 12.40 (s, 1H); 13 C NMR (125 MHz, CDCl3) δ 27.57, 31.61, 42.98, 59.16, 78.86, 127.03, 127.60, 127.80, 127.86, 128.55, 128.97, 141.33, 141.81 (The carbonyl peak not located); 13 C NMR (150 MHz, DMSO-d6) δ 27.34, 31.29, 42.58, 54.89, 76.94, 126.92, 127.04, 127.98, 128.08, 128.24, 143.14, 143.87, 170.86 (One sp 2 carbon not located); IR (thin film) 2961(s), –1 + 1705(s) cm ; HRMS calcd for C20H24NO2 (M+H, ESI ) m/z 310.1807, meas 20 310.1781; [α] D 30.6° (c 0.5, CH2Cl2). Preparation of acid 163: 301 BUDAM N BUDAM N KOH, EtOH then H+ COOH COOEt 163 318 90% ee To the mixture of ester 318 (90% ee, 800 mg, 1.30 mmol, 1.00 equiv) in THF (2.5 mL) and ethanol (2.5 mL) was added a solution of KOH (364 mg, 6.50 mmol, 5.00 equiv). The resulting mixture was refluxed for 24 h. After cooling to rt, aq HCl (6N) was added to pH ~2. The mixture was extracted with ether (3 × 10 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 25 × 200 mm, hexane:acetone 5:1) to give the product 163 (565 mg, 0.976 mmol, 75%) as a white foamy solid; mp 73-76 °C; Rf = 0.25 (hexane:EtOAc). Spectral data for 163: 1 H NMR (500 MHz, CDCl3) δ 0.65 (t, 3H, J = 7.5 Hz), 1.30-1.52 (m, 38H), 1.54 (s, 3H), 1.96 (t, 1H, J = 7.0 Hz), 3.67 (s, 6H), 4.14 (s, 1H), 7.20 (s, 2H), 7.22 (s, 2H), 9.60 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 10.68, 11.91, 21.97, 31.80, 35.52, 35.54, 48.00, 53.60, 63.89, 63.97, 70.24, 124.78, 125.61, 135.57, 135.67, 3 143.32, 143.51, 158.37, 158.73, 171.17 (One sp carbon not located); IR (thin –1 + film) 2964(s), 1774(m) cm ; HRMS calcd for C37H58NO4 (M+H, ES ) m/z 20 580.4366, meas 580.4296; [α] D 33.1° (c 1.0, CH2Cl2). Preparation of acid 149g: H2NBn O COOEt 319 racemic Ph N COOEt 320 302 Ph KOH, EtOH then H+ N COOH trans-153g trans-ester formation: A mixture of trans-epoxide 319 (racemic, 500 mg, 2.50 mmol, 1.00 equiv), NH4Cl (400 mg, 7.50 mmol, 3.00 equiv) and benzylamine (1.35 mL, 12.5 mmol, 5.00 equiv) in absolute ethanol (5 mL) was refluxed for 8 h. After cooling, the solvent was evaporated and H2O (10 mL) was added. And the mixture was extracted with ether (3 × 10 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 28 × 280 mm, hexane: EtOAc 4:1) to give the ring-opening product (404 mg, 1.32 mmol, 53%). To a solution of the ringopening product and triphenylphosphine (694 mg, 2.65 mmol, 2.00 equiv) in THF (5 mL) at 0 °C was added diethylazodicarboxylate (DEAD, 0.420 mL, 2.65 mmol, 2.00 equiv) dropwise under N2. After it was stirred at 0 °C for 1 h, the resulting mixture was stirred at rt for 20 h. The reaction mixture was concentrated and purified by column chromatography (1 hexane:EtOAc 9:1; 2 nd st column, silica gel, 28 × 280 mm, column, silica gel, 18 × 180 mm, hexane:EtOAc 15:1) afforded the trans-aziridine 320 (100 mg, 0.348 mmol) as a colorless oil in 14% 1 over 2 steps; Rf = 0.60 (hexane:EtOAc 4:1); H NMR (500 MHz, CDCl3) δ 0.861.30 (m, 9H), 1.50-1.80 (m, 5H), 2.07 (dd, 1H, J = 7.0 , 2.5 Hz), 2.50 (d, 1H, J = 3.0 Hz), 3.87 (d, 1H, J = 13.5 Hz), 3.92 (d, 1H, J = 13.5 Hz), 4.10 (q, 2H, J = 7.5 Hz), 7.20-7.4 (m, 1H), 7.26-7.38 (m, 4H); 13 C NMR (125 MHz, CDCl3) δ 14.12, 25.62, 25.74, 26.22, 29.93, 30.71, 39.70, 40.71, 52.70, 55.64, 60.89, 126.94, 303 –1 128.24, 128.54, 139.32, 169.77; IR (thin film) 2926(s), 1728(s) cm ; HRMS + calcd for C18H26NO2 (M+H, ESI ) m/z 288.1964, meas 288.1972. Hydrolysis: To solution of ester 320 (100 mg, 0.348 mmol, 1.00 equiv) in ethanol (1 mL) was added a solution of KOH (97 mg, 1.7 mmol, 5.0 equiv) in H2O (2 mL). The resulting mixture was refluxed for 30 min. After cooling, aq citric acid (2N, 2 mL) was added. The resulting white precipitate was collected by filtration. Then the white solid was dissolved in ether (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated to give the product trans-153g (85 mg, 0.33 mmol, 94%) as a white solid; mp 135-136 °C (decomposition); Rf = 0.05 (hexane:EtOAc 4:1); 1 H NMR (500 MHz, DMSO-d6) δ 0.80-1.30 (m, 11H), 1.98 (d, 1H, J = 2.5 Hz), 2.37 (d, 1H, J = 2.5 Hz), 3.81 (d, 1H, J = 13.5 Hz), 3.86 (d, 1H, J = 13.0 Hz), 7.20-7.40 (m, 5H), 12.52 (brs, 1H); 13 C NMR (125 MHz, DCMSO-d6) δ 25.14, 25.24, 25.78, 29.36, 30.03, 38.82, 39.77, 51.63, 54.69, 126.79, 128.12, 128.33, –1 139.60, 170.74; IR (thin film) 2924(s), 1722(s) cm ; HRMS calcd for + C16H22NO2 (M+H, ES ) m/z 260.1651, meas 260.1660. Preparation of acid 170a: Ph N KOH, EtOH Ph N then H+ COOH COOEt 170a 43a To a suspension of ester 43a (150 mg, 0.500 mmol, 1.00 equiv) in EtOH (1 mL) was added an aqueous solution KOH (140 mg, 2.50 mmol, 5.00 equiv) in H2O (1 304 mL). The resulting mixture was refluxed for 30 min. After it was cooled to rt, aq citric acid (2N, 2 mL) and ether (10 mL) were added. The aqueous layer was separated and extracted with ether (2 × 5 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated to give the product 170a a white foamy solid 130 mg (0.487 mmol, 94%). mp 48-50 °C; Rf = 0.10 (hexane:EtOAc 4:1). Spectral data for acid 170a: 1 H NMR (500 MHz, CDCl3) δ 1.61 (d, 3H, J = 7.0 Hz), 2.80 (d, 1H, J = 7.0 Hz), 3.07 (q, 1H, J = 6.5 Hz), 3.28 (d, 1H, J = 7.0 Hz), 7.20-7.80 (m, 11H); 13 C NMR (125 MHz, CDCl3) δ 22.60, 44.88, 47.71, 68.44, 126.95, 127.41, 127.78, 127.92, 128.33, 128.69, –1 133.96, 142.16, 175.51; IR (thin film) 3400(m), 1775(s) cm ; HRMS calcd for + 20 C17H18NO2 (M+H, ESI ) m/z 268.1338, meas 268.1331; [α] D 16.6° (c 1.0, CH2Cl2). Preparation of acid 170c: Ph KOH, EtOH N COOEt then H+ Ph N COOH 170c 43c Br Br To a suspension of ester 43c (187 mg, 0.500 mmol, 1.00 equiv) in EtOH (1 mL) was added an aqueous solution KOH (140 mg, 2.50 mmol, 5.00 equiv) in H2O (2 mL). The resulting mixture was refluxed for 30 min. After it was cooled to rt, aq citric acid (2N, 2 mL) was added, followed by the addition of ether (10 mL). The aqueous layer was separated and extracted with ether (2 × 10 mL). The 305 combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated to give a white foamy solid 175 mg (0.505 mmol, 101%); mp 80-82 1 °C; Rf = 0.10 (hexane:EtOAc 4:1). Spectral data for acid 170c: H NMR (500 MHz, CDCl3) δ 1.55 (d, 3H, J = 6.5 Hz), 2.74 (d, 1H, J = 7.0 Hz), 2.98 (q, 1H, J = 6.5 Hz), 3.12 (d, 1H, J = 7.0 Hz), 7.00-7.40 (m, 10H); 13 C NMR (125 MHz, DMSO-d6) δ 22.91, 45.71, 46.16, 67.62, 120.13, 126.58, 127.02, 128.30, 129.75, –1 130.49, 135.51, 143.97, 168.78; IR (thin film) 3408(m), 1770(s) cm ; HRMS + 79 20 calcd for C17H17NO2 Br (M+H, ESI ) m/z 346.0443, meas 346.0435; [α] D – 19.4° (c 1.0, CH2Cl2). 7.3.2 N-carboxy anhydride (NCA) formation The formation of NCA 142a: Bh N (COCl)2, DCM Cl Bh N O O O 141a 142a General procedure for N-carboxyanhydride (NCA) formation: Illustrated for the COOH formation of NCA 142a. A flame-dried 25 mL round bottom flask filled with N2 was charged with the acid 141a (69 mg, 0.20 mmol, 1.0 equiv). The vacuum adapter was replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (2.0 mL) was added via syringe. The flask was cooled to 0 °C. And (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) was added at 0 °C dropwise. 306 After it was stirred at 0 °C for 5 min and at rt for 1 h, the volatiles were removed. The crude mixture was purified by column (silica gel, 18 × 180 mm, hexane:EtOAc 5:1) to give the product 142a as a white fomay solid (44 mg, 0.11 mmol) in 54% yield; mp 49-50 °C; Rf = 0.30 (hexane:EtOAc 4:1). Spectral data 1 for NCA 142a: H NMR (500 MHz, CDCl3) δ 1.62 (s, 3H), 5.13 (s, 1H), 5.30 (s, 1H), 7.10-7.16 (m, 2H), 7.22-7.48 (m, 13H); 13 C NMR (125 MHz, CDCl3) δ 22.02, 62.73, 65.45, 71.33, 127.63, 127.94, 128.33, 128.44, 128.49, 128.64, 128.76, 129.33, 129.73, 133.11, 137.89, 139.16, 150.23, 170.09; IR (thin film) 1848(s), –1 + 35 1780(s) cm ; HRMS calcd for C24H21NO3 Cl (M+H, ESI ) m/z 406.1210, 20 meas 406.1235; [α] D 21.3° (c 1.0, CH2Cl2). The formation of NCA 140a: BUDAM (COCl)2, DCM N Cl BUDAM N O COOH O O 140a 138a General procedure for NCA formation was followed with acid 138a (70 mg, 0.11 mmol, 1.0 equiv), (COCl)2 (0.020 mL, 0.23 mmol, 2.0 equiv) and CH2Cl2 (2 mL). After column chromatography (1 hexane:EtOAc 15:1; 2 nd st column, silica gel, 18 × 180 mm, column, silica gel, 18 × 180 mm, benzene:EtOAc 100:1), the product 140a was obtained as a white solid (54 mg, 0.078 mmol) in 69% 1 yield; mp 41-42 °C; Rf = 0.50 (hexane:EtOAc 4:1). Spectral data for 140a: H NMR (600 MHz, CDCl3) δ 1.31 (s, 18H), 1.42 (s, 18H), 1.68 (s, 3H), 3.64 (s, 3H), 307 3.75 (s, 3H), 5.06 (s, 1H), 5.27 (s, 1H), 6.89 (s, 2H), 7.18-7.26 (m, 6H), 7.35 (t, 1H, J = 7.2 Hz); 13 C NMR (150 MHz, CDCl3) δ 22.00, 31.93, 32.10, 35.70, 35.89, 62.61, 64.20, 64.33, 65.21, 71.33, 126.79, 127.34, 128.38, 128.82, 129.48, 132.17, 132.96, 133.44, 143.24, 143.43, 149.70, 158.78, 159.07, 170.39; IR (thin –1 35 film) 2960(m), 1847(m), 1785(s) cm ; HRMS calcd for C42H57NO5 Cl (M, + 20 ESI ) m/z 690.3925, meas 690.3954; [α] D 5.8° (c 0.5, CH2Cl2). The formation of NCA 140b: BUDAM N Cl BUDAM N O COOH O O 138b 140b General procedure for NCA formation was followed with acid 138b (129 mg, (COCl)2, DCM 0.200 mmol, 1.00 equiv), (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) and CH2Cl2 (2 mL). After column chromatography (silica gel, 18 × 180 mm, benzene:EtOAc 100:1), the product 140b was obtained as a white foamy solid (106 mg, 0.0150 mmol) in 75% yield; mp 71-78 °C; Rf = 0.60 (benzene:EtOAc 100:1). Spectral 1 data for NCA 140b: H NMR (500 MHz, CDCl3) δ 1.28 (s, 18H), 1.39 (s, 18H), 1.63 (s, 3H), 2.31 (s, 3H), 3.61 (s, 3H), 3.72 (s, 3H), 5.08 (s, 1H), 5.21 (s, 1H), 6.86 (s, 2H), 7.01 (d, 2H, J = 8.0 Hz), 7.04 (d, 2H, J = 8.5 Hz), 7.21 (s, 2H); 13 C NMR (150 MHz, CDCl3) δ 20.79, 21.82, 31.66, 31.84, 35.43, 35.62, 62.20, 63.95, 64.07, 64.85, 71.08, 126.58, 127.05, 128.43, 128.78, 130.18, 131.96, 132.69, 139.23, 142.94, 143.14, 149.44, 158.50, 158.79, 170.19; IR (thin film) 2961(m), 308 –1 + 35 1846(m), 1784(s) cm ; HRMS calcd for C43H59NO5 Cl (M+H, ESI ) m/z 20 704.4082, meas 704.4030; [α] D 3.2° (c 1.0, CH2Cl2). The formation of NCA 140c: BUDAM N Cl BUDAM N O COOH Br O O 140c Br 138c General procedure for NCA formation was followed with acid 138c (141 mg, (COCl)2, DCM 0.200 mmol, 1.00 equiv), (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) and CH2Cl2 (2 mL). After column chromatography (silica gel, 18 × 180 mm, benzene:EtOAc 100:1), the product 140c was obtained as a white foamy solid (120 mg, 0.0156 mmol) in 78% yield; mp 78-80 °C; Rf = 0.60 (benzene:EtOAc 100:1). Spectral 1 data for 140c: H NMR (300 MHz, CDCl3) δ 1.29 (s, 18H), 1.40 (s, 18H), 1.73 (s, 3H), 3.62 (s, 3H), 3.73 (s, 3H), 4.99 (s, 1H), 5.15 (s, 1H), 6.88 (s, 2H), 6.94 (d, 2H, J = 8.4 Hz), 7.22 (s, 2H), 7.29 (d, 2H, J = 8.7 Hz); 13 C NMR (150 MHz, CDCl3) δ 21.74, 31.91, 32.09, 35.71, 35.91, 62.67, 64.18, 64.39, 64.41, 71.24, 123.72, 126.85, 127.35, 130.38, 131.51, 132.20, 132.40, 132.48, 143.37, 143.57, –1 149.55, 158.97, 159.09, 169.95; IR (thin film) 2963(m), 1848(m), 1784(s) cm ; 79 35 + HRMS calcd for C42H56NO5 Br Cl (M+H, ESI ) m/z 768.3030, meas 20 768.2977; [α] D –11.3° (c 2.0, CH2Cl2). The formation of NCA 140d: 309 Cl BUDAM N O COOH O O 140d 138d General procedure for NCA formation was followed with acid 138d (129 mg, BUDAM N (COCl)2, DCM 0.200 mmol, 1.00 equiv), (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) and CH2Cl2 (2 mL). After column chromatography (silica gel, 18 × 180 mm, benzene:EtOAc 100:1), the product 140d was obtained as a white foamy solid (100 mg, 0.0142 mmol) in 71% yield; mp 72-78 °C; Rf = 0.60 (benzene:EtOAc 100:1). Spectral 1 data for 140d: H NMR (600 MHz, CDCl3) δ 1.29 (s, 18H), 1.38 (s, 18H), 1.62 (s, 3H), 2.35 (s, 3H), 3.62 (s, 3H), 3.70 (s, 3H), 5.33 (s, 1H), 5.59 (s, 1H), 6.94-7.00 (m, 3H), 7.15 (d, 1H, J = 7.2 Hz), 7.20-7.24 (m, 3H), 7.42 (d, 1H, J = 7.8 Hz); 13 C NMR (150 MHz, CDCl3) δ 20.15, 20.79, 32.16, 32.30, 35.93, 36.70, 62.39, 63.25, 64.40, 64.50, 71.63, 126.55, 126.70, 128.13, 129.40, 129.62, 131.02, 132.37, 132.98, 133.55, 136.33, 143.21, 143.45, 150.13, 158.74, 159.25, 170.81; IR (thin 35 –1 film) 2961(m), 1846(m), 1784(s) cm ; HRMS calcd for C43H59NO5 Cl (M+H, + 20 ES ) m/z 704.4082, meas 704.4040; [α] D –9.0° (c 1.0, CH2Cl2); The formation of NCA 140e: BUDAM (COCl)2, DCM N COOH Br Cl BUDAM N O O O 140e Br 138e General procedure for NCA formation was followed with acid 138e (71 mg, 0.10 mmol, 1.0 equiv), (COCl)2 (0.020 mL, 0.23 mmol, 2.0 equiv) and CH2Cl2 (1 mL). 310 After column chromatography (silica gel, 18 × 180 mm, benzene:EtOAc 100:1), the product 140e was obtained as a white foamy solid (56 mg, 0.073 mmol) in 73% yield; mp 75-80 °C; Rf = 0.75 (benzene:EtOAc 100:1). Spectral data for 1 140e: H NMR (500 MHz, CDCl3) δ 1.35 (s, 18H), 1.43 (s, 18H), 1.80 (s, 3H), 3.67 (s, 3H), 3.74 (s, 3H), 5.39 (s, 1H), 5.96 (s, 1H), 7.03 (s, 2H), 7.12-7.18 (m, 1H), 7.22-7.32 (m, 3H), 7.49 (d, 1H, J = 8.0 Hz), 7.61 (d, 1H, J = 8.0 Hz); 13 C NMR (125 MHz, CDCl3) δ 20.23, 31.96, 32.11, 35.74, 35.88, 62.89, 64.20, 64.32, 64.57, 71.17, 124.56, 126.39, 127.80, 127.86, 130.97, 131.07, 132.14, 133.02, 133.06, 134.15, 143.15, 143.22, 149.78, 158.64, 159.04, 169.72; IR (thin film) 79 –1 35 2961(m), 1848(m), 1784(s) cm ; HRMS calcd for C42H56NO5 Br Cl (M+H, + 20 ESI ) m/z 768.3030, meas 768.3070; [α] D –6.4° (c 0.5, CH2Cl2). The formation of NCA 140f: BUDAM (COCl)2, DCM N Cl BUDAM N COOH O O O 138f 140f General procedure for NCA formation was followed with acid 138f (136 mg, 0.200 mmol, 1.00 equiv), (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) and CH2Cl2 (2 mL). After column chromatography (silica gel, 18 × 180 mm, benzene:EtOAc 100:1), the product 140f was obtained as a white foamy solid (118 mg, 0.016 mmol) in 80% yield; mp 89-91 °C; Rf = 0.65 (benzene:EtOAc 50:1). Spectral data 1 for 140f: H NMR (500 MHz, CDCl3) δ 1.21 (s, 18H), 1.41 (s, 18H), 1.52 (s, 3H), 311 3.56 (s, 3H), 3.71 (s, 3H), 5.12 (s, 1H), 6.31 (s, 1H), 6.82 (s, 2H), 7.12 (t, 1H, J = 8.0 Hz), 7.26 (s, 2H), 7.52 (t, 1H, J = 7.0 Hz), 7.60 (t, 2H, J = 8.5 Hz), 7.83 (d, 1H, J =8.0 Hz), 7.89 (d, 1H, J = 8.5 Hz), 8.03 (d, 1H, J = 8.5 Hz); 13 C NMR (125 MHz, CDCl3) δ 21.94, 31.88, 32.14, 35.65, 35.91, 61.12, 63.08, 64.13, 64.37, 72.10, 122.34, 124.98, 126.13, 126.44, 127.31, 127.99, 128.73, 129.39, 129.69, 130.27, 131.23, 132.34, 133.16, 133.38, 143.04, 143.06, 150.09, 158.54, 158.94, –1 171.10; IR (thin film) 2963(m), 1848(m), 1784(s) cm ; HRMS calcd for + 35 20 C46H59NO5 Cl (M+H, ES ) m/z 740.4082, meas 740.4075; [α] D –10.3° (c 1.0, CH2Cl2). The formation of NCA 144c: BUDAM N Cl BUDAM N O COOH Br O O 143c 144c Br General procedure for NCA formation was followed with acid 143c (144 mg, (COCl)2, DCM 0.200 mmol, 1.00 equiv), (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) and CH2Cl2 (2 mL). After column chromatography (1 benzene:EtOAc 100:1; 2 nd st silica gel, 18 × 180 mm, silica gel, 18 × 180 mm, benzene:EtOAc 100:1), the product 144c was obtained as a white foamy solid (30 mg, 0.038 mmol) in 20% yield; mp 60-61 °C; Rf = 0.725 (benzene:EtOAc 100:1). Spectral data for 144c: 1 H NMR (500 MHz, CDCl3) δ 0.42 (t, 3H, J = 7.5 Hz), 1.28 (s, 18H), 1.36 (s, 18H), 1.74 (dq, 1H, J = 7.5, 7.5 Hz), 2.02 (dq, 1H, J = 7.5, 7.5 Hz), 3.58 (s, 3H), 312 3.70 (s, 3H), 4.94 (s, 1H), 5.35 (s, 1H), 6.93 (s, 2H), 7.18 (s, 2H), 7.23 (d, 2H, J = 8.5 Hz), 7.40 (d, 2H, J = 8.5 Hz); 13 C NMR (150 MHz, CDCl3) δ 7.73, 27.97, 31.90, 32.11, 35.67, 35.91, 62.87, 64.25, 64.32, 64.72, 76.19, 123.86, 126.19, 128.29, 130.41, 131.55, 131.71, 132.75, 133.12, 143.07, 143.64, 150.01, 158.54, –1 159.42, 169.60; IR (thin film) 2963(m), 1846(m), 1782(s) cm ; HRMS calcd for 35 79 + 20 C43H58NO5 Cl Br (M+H, ES ) m/z 782.3187, meas 782.3253; [α] D 9.8° (c 1.0, CH2Cl2). 7.3.3 Morpholine-2,3,5-trione formation The formation of morpholine-2,3,5-trione 152a: Ph Ph N (COCl)2, DCM Cl Ph Bh H N O O O 152a 151a General procedure for the formation of morpholine-2,3,5-trione: Illustrated for the Ph O COOH formation of 152a: To a flame-dried 25 mL round bottom flask filled with N2 was added acid 151a (132 mg, 0.400 mmol, 1.00 equiv) and CH2Cl2 (4 mL). The vacuum adapter was replaced with a septum to which a N2 balloon was attached via a needle. The flask was cooled in an ice bath. And (COCl)2 (102 mg, 0.0700 mL, 0.800 mmol, 2.00 equiv) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 5 min and the ice bath was removed. After the mixture was stirred at rt for 1 h, the volatiles were removed by rotary evaporation. And a foamy solid was obtained. Hexane was then added and the solid was collected 313 by filtration and washed with a mixture of CH2Cl2 and hexane (v/v 10:1, 2 mL). The product 152a was obtained as a pale yellow solid (124 mg, 0.296 mmol, 74%). Recrystallization from CH2Cl2 and hexane gave X-ray quality crystals; mp 1 129-131 °C. Spectral data for 152a: H NMR (300 MHz, CDCl3) δ 3.77 (d, 1H, J = 3.9 Hz), 5.02 (d, 1H, J = 3.9 Hz), 6.98-7.10 (m, 4H), 7.15 (s, 1H), 7.28-7.46 (m, 6H), 7.40-7.62 (m, 5H); 13 C NMR (150 MHz, CDCl3) δ 58.35, 62.30, 64.51, 126.39, 128.40, 128.82, 129.26, 129.70, 130.08, 130.38, 130.47, 131.01, 131.05, 135.73, 136.27, 148.33, 151.23, 157.65; IR (thin film) 1832(m), 1782(s), 1705(s) –1 35 + cm ; HRMS calcd for C24H19NO4 Cl (M+H, ESI ) m/z 420.1003, meas 20 420.0970; [α] D –164.5° (c 0.5, CH2Cl2). The formation of morpholine-2,3,5-trione 152b: Ph Ph (COCl)2, DCM N COOH 151b Cl H Bh N O O O O 152b The general procedure for the formation of morpholine-2,3,5-trione was followed with acid 151b (35 mg, 0.10 mmol, 0.10 equiv), (COCl)2 (0.030 mL, 0.30 mmol, 3.0 equiv) and CH2Cl2 (1 mL). The product 152b was obtained as a yellow solid. The NMR yield was 82% with the aid of triphenylmethane. Spectral data for 1 152b: H NMR (600 MHz, CDCl3) δ 2.34 (s, 3H), 3.73 (d, 1H, J = 4.0 Hz), 5.00 (d, 1H, J = 3.5 Hz), 6.90 (d, 2H, J = 7.8 Hz), 7.03 (d, 2H, J =7.5 Hz), 7.10-7.60 314 -1 (m, 11H); IR (thin film) 1832(s), 1782(s), 1703(s) cm . Unfortunately, it was contaminated with some impurities. A clean 13 C NMR was not obtained. The formation of morpholine-2,3,5-trione 152c: Ph Ph (COCl)2, DCM N COOH Cl Br H Bh N O O O O 151c 152c Br The general procedure for the formation of morpholine-2,3,5-trione was followed with acid 151c (82 mg, 0.20 mmol, 1.0 equiv), (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) and CH2Cl2 (2 mL). The product 152c was obtained as a yellow solid 1 (42 mg, 0.084 mmol, 42%); mp 120-122 °C. Spectral data for 152c: H NMR (600 MHz, CDCl3) δ 3.74 (d, 1H, J = 4.2 Hz), 5.00 (d, 1H, J = 3.6 Hz), 6.90 (d, 2H, J = 7.8 Hz), 7.03 (d, 2H, J =7.8 Hz), 7.13 (s, 1H), 7.32-7.42 (m, 4H), 7.467.60 (m, 6H); 13 C NMR (150 MHz, CDCl3) δ 58.01, 62.64, 64.57, 125.91, 126.62, 128.71, 129.53, 130.36, 130.48, 130.60, 130.70, 133.15, 135.72, 136.47, 148.81, 2 151.36, 157.60 (One sp carbon not located); IR (thin film) 1832(m), 1784(s), –1 79 35 + 1708(s) cm ; HRMS calcd for C24H18NO4 Br Cl (M+H, ESI ) m/z 498.0108, 20 meas 498.0150; [α] D –90.3° (c 0.5, CH2Cl2). The formation of morpholine-2,3,5-trione 154a: Ph Bn Ph H N O (COCl)2, DCM Cl N Ph 153a O COOH 315 O O 154a The procedure for the formation of morpholine-2,3,5-trione was followed with acid 153a (28 mg, 0.10 mmol, 0.10 equiv), (COCl)2 (0.020 mL, 0.20 mmol, 2.0 equiv) and CH2Cl2 (1 mL). The product 154a was obtained as a yellow solid. The NMR 1 yield was 91% with the aid of triphenylmethane. Spectral data for 154a: H NMR (500 MHz, CDCl3) δ 3.21 (d, 1H, J = 15.0 Hz), 4.77 (d, 1H, J = 3.0 Hz), 5.18 (d, 1H, J = 15.0 Hz), 5.39 (d, 1H, J = 2.5 Hz), 6.80-7.60 (m, 10H); IR (thin film) -1 1830(s), 1780(s), 1701(s) cm . Unfortunately, the product was contaminated with some impurities. Thus, a clean 13 C NMR could not be obtained. 7.3.4 β-lactam formation with (COCl)2 The formation of β-lactam 159g: Ph Ph Ph (COCl)2, DCM N Ph N O Cl 159g COOH 151g The general procedure for β-lactam formation with (COCl)2: Illustrated for 159g: A flame-dried 25 mL round bottom flask filled with N2 was charged with acid 151g (67 mg, 0.20 mmol, 1.0 equiv). The vacuum adapter was replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (2 mL) was added via syringe. The flask was cooled to 0 °C. And (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 5 min and 1 h at rt. After the volatiles were removed, the crude mixture 316 was placed under high vacuum (0.1 mmHg) to give the product 159g (70 mg, 0.198 mmol, 99%) as a white foamy solid; The optical purity was determined to be >99% ee by HPLC analysis (Chiralpak AS column, 90:10 hexane/2-propanol at 222 nm, flow-rate 1.0 mL/min); Retention times: tR = 9.57 min and tR = 32.35 min (its enantiomer); mp 113-114 °C; Rf = 0.50 (hexane:EtOAc 4:1). Spectral 1 data for 159g: H NMR (500 MHz, CDCl3) δ 0.84-0.98 (m, 1H), 1.02-1.36 (m, 4H), 1.62-1.94 (m, 6H), 3.57 (dd, 1H, J = 8.5, 5.0 Hz), 4.80 (d, 1H, J = 5.0 Hz), 5.62 (s, 1H), 7.26-7.46 (m, 10H); 13 C NMR (125 MHz, CDCl3) δ 25.55, 25.80, 26.23, 29.94, 30.01, 38.96, 58.69, 62.94, 64.88, 127.92, 128.21, 128.39, 128.55, –1 128.70, 128.88, 138.28, 139.25, 165.08; IR (thin film) 2927(m), 1764(s) cm ; 35 + HRMS calcd for C22H25NO Cl (M+H, ESI ) m/z 354.1625, meas 336.1638; 20 [α] D –96.6° (c 1.0, CH2Cl2). The formation of β-lactam cis- and trans-166g: Ph Ph Ph (COBr)2, DCM Ph N N Ph O + Br COOH cis-166g 151g Ph N O Br trans-166g A flame-dried 25 mL round bottom flask filled with N2 was charged with acid 151g (67 mg, 0.20 mmol, 1.0 equiv). The vacuum adapter was replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (2 mL) was added via syringe. The flask was cooled to 0 °C. And (COBr)2 (0.040 mL, 0.40 317 mmol, 2.0 equiv) was added dropwise at 0 °C. After it was stirred at 0 °C for 15 min, the reaction mixture was concentrated. 1 H NMR of the crude mixture showed a 2:1 trans:cis ratio. The crude product was purified by column chromatography (1 st nd column, silica gel, 18 × 180 mm, hexane:EtOAc 5:1; 2 column, silica gel, 18 × 180 mm, hexane:EtOAc 15:1). The pure trans-166g (22 mg, 0.055 mmol) was obtained as a colorless oil in 28% yield. And the overall yield for cis and trans-isomers after column chromatography was 94%. A flame-dried 25 mL round bottom flask filled with N2 was charged with acid 151g (34 mg, 0.10 mmol, 1.0 equiv). The vacuum adapter was replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (1 mL) was added via syringe. The flask was cooled to 0 °C. And (COBr)2 was added dropwise at 0 °C. After the reaction mixture was stirred at 0 °C for 15 min, aq sat NaHCO3 (1 mL) was added at 0 °C via syringe along with CH2Cl2 (10 mL). Aqueous layer was separated and extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was 1 concentrated and H NMR of this crude mixture showed a 7:1 cis:trans ratio. The crude product was purified by column chromatography (silica gel, 18 × 180 mm, 1 hexane:EtOAc 9:1). The pure cis-166g (100:1 cis:trans ratio by H NMR, 33 mg, 0.083 mmol) was obtained as a colorless oil in 83% yield. Overall yield after column chromatography for cis and trans isomers was 95%. 318 Spectral data for cis-166g: solidified in the refrigerator, mp 83-85 °C; Rf = 0.35 1 (hexane:EtOAc 4:1); H NMR (600 MHz, CDCl3) δ 0.86 (qd, 1H, J = 11.4, 3.0 Hz), 1.02-1.32 (m, 4H), 1.62-1.74 (m, 3H), 1.78-1.90 (m, 3H), 3.48 (dd, 1H, J = 9.0, 5.4 Hz), 4.86 (d, 1H, J = 5.4 Hz), 5.61 (s, 1H), 7.20-7.40 (m, 10H); 13 C NMR (150 MHz, CDCl3) δ 25.21, 25.52, 25.98, 29.84, 30.01, 40.02, 47.94, 61.30, 64.78, 127.70, 127.99, 128.187, 128.36, 128.48, 128.66, 138.04, 139.04, 165.00; –1 79 + IR (thin film) 1765(s) cm ; HRMS calcd for C22H25NO Br (M+H, ESI ) m/z 20 398.1120, meas 398.1125; [α] D –33.9° (c 0.5, CH2Cl2). 1 Spectral data for trans-166g: Rf = 0.35 (hexane:EtOAc 4:1); H NMR (500 MHz, CDCl3) δ 0.60-1.80 (m, 11H), 3.72 (dd, 1H, J = 5.0, 2.0 Hz), 4.51 (d, 1H, J = 2.0 Hz), 5.78 (s, 1H), 7.20-7.60 (m, 10H); 13 C NMR (125 MHz, CDCl3) δ 25.36, 25.76, 26.03, 26.47, 29.31, 38.86, 43.53, 62.25, 69.23, 127.81, 128.02, 128.05, 128.36, 128.59, 128.69, 138.09, 138.17, 163.76; IR (thin film) 1765(s), 1265(m) –1 79 + cm ; HRMS calcd for C22H25NO Br (M+H, ESI ) m/z 398.1120, meas 20 398.1117; [α] D –8.3° (c 1.0, CH2Cl2); The formation of β-lactam 160g: Ph Ph N (COCl)2, DCM N O Cl 160g COOH 153g 319 The general procedure for β-lactam formation with (COCl)2 was followed with acid 153g (52 mg, 0.20 mmol, 1.0 equiv), (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) and CH2Cl2 (2 mL). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1). The product 160g was obtained as a white crystalline solid (46 mg, 0.17 mmol) in 83% yield; mp 118-119 °C from hexane and benzene; Rf = 0.40 (hexane:EtOAc 4:1). Spectral 1 data for 160g: H NMR (500 MHz, CDCl3) δ 0.80 (qd, 1H, J = 11.0, 3.5 Hz), 0.98 (qd, 1H, J = 12.0, 3.5 Hz), 1.10 (qt, 1H, J = 13.0, 3.5 Hz), 1.18-1.32 (m, 2H), 1.62-1.80 (m, 6H), 3.33 (dd, 1H, J = 9.0, 5.0 Hz), 4.08 (d, 1H, J =15.0 Hz), 4.81 (d, 1H, J = 5.0 Hz), 4.86 (d, 1H, J = 15.0 Hz), 7.18-7.22 (m, 2H), 7.26-7.36 (m, 3H); 13 C NMR (125 MHz, CDCl3) δ 25.29, 25.54, 25.95, 29.78, 29.80, 38.63, 47.06, 58.93, 61.18, 127.95, 128.20, 128.90, 135.06, 165.44; IR (thin film) –1 35 + 2924(m), 1755(s) cm ; HRMS calcd for C16H21NO Cl (M+H, ESI ) m/z 20 278.1312, meas 278.1313; [α] D –20.3° (c 0.5, CH2Cl2). The formation of β-lactam 162g: MEDAM N MADEM (COCl)2, DCM N O Cl COOH 162g 161g A flame-dried 25 mL round bottom flask filled with N2 was charged with acid 161g (45 mg, 0.10 mmol, 1.0 equiv). The vacuum adapter was replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (1 mL) was 320 added via syringe. The flask was cooled to 0 °C. And (COCl)2 (0.020 mL, 0.20 mmol, 2.0 equiv) was added dropwise at 0 °C. After it was stirred at 0 °C for 10 min, the reaction mixture was concentrated. The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1) to afford the product as a white solid (42 mg, 0.090 mmol) in 89% yield; mp 58-60 °C; Rf = 1 0.30 (hexane:EtOAc 4:1). Spectral data for 162g: H NMR (500 MHz, CDCl3) δ 0.89 (qd, 1H, J = 12.0, 2.0 Hz), 1.00-1.30 (m, 4H), 1.60-1.90 (m, 6H), 2.23, 2.24 (2s, 12H), 3.52 (dd, 1H, J = 8.5, 5.5 Hz), 3.69, 3.70 (2s, 6H), 4.78 (d, 1H, J = 5.5 Hz), 5.37 (s, 1H), 6.87, 6.88 (2s, 4H); 13 C NMR (150 MHz, CDCl3) δ 16.24, 16.29, 25.41, 25.70, 26.06, 29.68, 29.71, 38.79, 58.34, 59.62, 62.40, 63.85, 128.45, 128.64, 130.73, 130.99, 133.42, 134.48, 156.30, 156.53, 164.85 (One 3 –1 sp carbon not located); IR (thin film) 2928(s), 1765(w) cm ; HRMS calcd for 35 + 20 C28H37NO3 Cl (M+H, ESI ) m/z 470.2462, meas 470.2459; [α] D 10.6° (c 0.5, CH2Cl2). The formation of β-lactam 159h: Ph Ph N Ph (COCl)2, DCM Ph N O Cl COOH 151h 159h The general procedure for β-lactam formation with (COCl)2 was followed with acid 151h (30 mg, 0.10 mmol, 1.0 equiv), (COCl)2 (0.020 mL, 0.20 mmol, 2.0 321 equiv) and CH2Cl2 (1 mL). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1). The product 159h was obtained as a white solid (30 mg, 0.096 mmol) in 96% yield; mp 110-112 °C; Rf = 0.35 (hexane:EtOAc 4:1). Spectral data for 159h: 1 H NMR (600 MHz, CDCl3) δ 0.95 (d, 3H, J = 6.6 Hz), 0.99 (d, 3H, J = 7.2 Hz), 2.08-2.18 (m, 1H), 3.56 (dd, 1H, J = 9.0, 5.4 Hz), 4.82 (d, 1H, J = 5.4 Hz), 5.62 (s, 1H), 7.24-7.40 (m, 10H); 13 C NMR (150 MHz, CDCl3) δ 19.55, 19.71, 29.36, 58.49, 64.25, 64.31, 127.78, 128.00, 128.23, 128.29, 128.55, 128.66, 138.09, 138.89, 164.69; –1 35 + IR (thin film) 1759(s) cm ; HRMS calcd for C19H21NO Cl (M+H, ESI ) m/z 20 314.1312, meas 314.1299; [α] D 66.9° (c 0.5, CH2Cl2). The formation of β-lactam 159i: Ph Ph N 151i Ph (COCl)2, DCM Ph N O Cl COOH 159i The general procedure for β-lactam formation with (COCl)2 was followed with acid 151i (30 mg, 0.10 mmol, 1.0 equiv), (COCl)2 (0.020 mL, 0.20 mmol, 2.0 equiv) and CH2Cl2 (1 mL). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1). The product 159i was obtained as a colorless oil (25 mg, 0.080 mmol) in 81% yield; Rf = 0.30 1 (hexane:EtOAc 4:1). Spectral data for 159i: H NMR (500 MHz, CDCl3) δ 0.83 322 (t, 3H, J = 7.0 Hz), 1.04-1.18 (m, 1H), 1.26-1.40 (m, 1H), 1.44-1.54 (m, 1H), 1.701.82 (m, 1H), 3.64-3.74 (m, 1H), 4.88 (d, 1H, J = 5.0 Hz), 5.96 (s, 1H), 7.18-7.42 (m, 10H); 13 C NMR (150 MHz, CDCl3) δ 13.69, 18.98, 31.57, 57.71, 59.15, 61.04, 127.83, 127.85, 128.13, 128.58, 128.69, 128.77, 137.60, 138.57, 164.07; –1 35 + IR (thin film) 1765(s) cm ; HRMS calcd for C19H21NO Cl (M+H, ESI ) m/z 20 314.1312, meas 314.1313; [α] D –28.5° (c 1.0, CH2Cl2). The formation of β-lactam 159j: Ph Ph N Ph 151j Ph (COCl)2, DCM Ph COOH Ph N 159j O Cl The general procedure for β-lactam formation with (COCl)2 was followed with acid 151j (36 mg, 0.10 mmol, 1.0 equiv), (COCl)2 (0.020 mL, 0.20 mmol, 2.0 equiv) and CH2Cl2 (1 mL). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1). The product 159j was obtained as a white solid (27 mg, 0.072 mmol) in 72% yield; mp 93-94 °C; Rf 1 = 0.13 (hexane:EtOAc 4:1). Spectral data for 159j: H NMR (300 MHz, CDCl3) δ 1.72-1.88 (m, 1H), 2.00-2.16 (m, 1H), 2.28-2.44 (m, 1H), 2.58-2.72 (m, 1H), 3.64-3.76 (m, 1H), 4.90 (d, 1H, J = 5.1 Hz), 5.94 (s, 1H), 6.94-7.02 (m, 2H), 7.207.40 (m, 13H); 13 C NMR (125 MHz, CDCl3) δ 31.12, 31.72, 57.03, 58.96, 60.92, 126.20, 127.78, 127.87, 128.18, 128.23, 128.50, 128.64, 128.66, 128.81, 137.33, –1 138.39, 140.31, 163.94; IR (thin film) 1765(s) cm ; HRMS calcd for 323 35 + 20 C24H23NO Cl (M+H, ESI ) m/z 376.1468, meas 376.1441; [α] D –50.8° (c 1.0, CH2Cl2). The formation of β-lactam 159k: Ph Ph N Ph (COCl)2, DCM Ph N O Cl 159k COOH 151k The general procedure for β-lactam formation with (COCl)2 was followed with acid 151k (31 mg, 0.10 mmol, 1.0 equiv), (COCl)2 (0.02 mL, 0.20 mmol, 2.0 equiv) and CH2Cl2 (1 mL) with a reaction time to be 30 min at rt. The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1). The product 159k was obtained as a pale yellow solid (24 mg, 0.074 mmol) in 75% yield; solidified in the refrigerator, mp 72-73 °C; Rf = 1 0.25 (hexane:EtOAc 4:1). Spectral data for 159k: H NMR (300 MHz, CDCl3) δ 0.68 (d, 3H, J = 6.3 Hz), 0.81 (d, 3H, J = 6.6 Hz), 1.22-1.34 (m, 1H), 1.40-1.56 (m, 1H), 1.72-1.82 (m, 1H), 3.66-3.76 (m, 1H), 4.86 (d, 1H, J = 4.8 Hz), 5.96 (s, 1H), 7.14-7.20 (m, 10H); 13 C NMR (125 MHz, CDCl3) δ 21.64, 23.04, 25.06, 37.97, 56.27, 59.40, 60.90, 127.77, 127.81, 128.21, 128.60, 128.77, 128.85, –1 137.50, 138.55, 164.19; IR (thin film) 1767(s) cm ; HRMS calcd for 35 + 20 C20H23NO Cl (M+H, ESI ) m/z 328.1468, meas 328.1475; [α] D –10.4° (c 1.0, CH2Cl2). 324 The formation of β-lactam 159l: Ph Ph N Ph (COCl)2, DCM Ph N Ph O Ph + N Cl COOH 151l O Cl cis-159l trans-159l A flame-dried 25 mL round bottom flask filled with N2 was charged with acid 151l (62 mg, 0.20 mmol, 1.0 equiv). The vacuum adapter was replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (2 mL) was added via syringe. The flask was cooled to 0 °C. And (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) was added dropwise at 0 °C. After it was stirred at 0 °C for 5 min and rt for 5 h, the reaction mixture was concentrated and kept at rt for 3 months. The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 9:1). The pure cis-159l (40 mg, 0.12 mmol) was obtained as a white solid in 62% yield. And the pure trans-159l (10 mg, 0.031 mmol) was obtained as a white solid in 15% yield. 1 Spectral data for cis-159l: mp 136-138 °C; Rf = 0.33 (hexane:EtOAc 4:1); H NMR (600 MHz, CDCl3) δ 1.12 (s, 9H), 3.74 (d, 1H, J = 6.0 Hz), 4.82 (d, 1H, J = 5.4 Hz), 5.48 (s, 1H), 7.18-7.44 (m, 10H); 13 C NMR (150 MHz, CDCl3) δ 26.84, 34.10, 57.58, 65.60, 67.63, 127.73, 128.03, 128.15, 128.41, 128.53, 128.72, –1 138.24, 138.87, 164.69; IR (thin film) 1763(s) cm ; HRMS calcd for 35 + 20 C20H23NO Cl (M+H, ESI ) m/z 328.1468, meas 328.1476; [α] D –89.5° (c 0.5, CH2Cl2); 325 1 Spectral data for trans-159l: mp 101-103 °C; Rf = 0.40 (hexane:EtOAc 4:1); H NMR (600 MHz, CDCl3) δ 0.98 (s, 9H), 3.51 (d, 1H, J = 2.4 Hz), 4.41 (d, 1H, J = 2.4 Hz), 5.44 (s, 1H), 7.24-7.38 (m, 10H); 13 C NMR (150 MHz, CDCl3) δ 26.08, 33.11, 56.30, 65.44, 73.80, 127.86, 127.91, 127.98, 128.54, 128.59, 128.79, –1 138.29, 138.41, 163.77; IR (thin film) 2963(m), 1768 (s) cm ; HRMS calcd for 35 + 20 C20H23NO Cl (M+H, ESI ) m/z 328.1468, meas 328.1453; [α] D –15.4° (c 1.0, CH2Cl2). Ph Ph N (COCl)2, DCM Ph Ph N Cl COOH 151l 165l O A flame-dried 25 mL round bottom flask filled with N2 was charged with acid 151l (93 mg, 0.30 mmol, 1.0 equiv). The vacuum adapter was replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (3 mL) was added via syringe. The flask was cooled to 0 °C. And (COCl)2 (0.15 mL, 1.5 mmol, 5.0 equiv) was added dropwise at 0 °C. After it was stirred at 0 °C for 5 min and rt for 1 h, the reaction mixture was concentrated. The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 9:1) to obtain the product 165l (20 mg, 0.033 mmol) as a white solid in 22% yield; mp 85-86 °C; 1 Rf = 0.70 (hexane:EtOAc 4:1). Spectral data for 165l: H NMR (600 MHz, CDCl3) δ 0.78 (s, 9H), 2.07 (d, 1H, J = 7.0 Hz), 2.67 (d, 1H, J = 7.0 Hz), 3.66 (s, 1H), 326 7.20-7.42 (m, 8H), 7.57 (d, 2H, J = 7.5 Hz); 13 C NMR (150 MHz, CDCl3) δ 27.77, 32.83, 52.33, 60.27, 79.18, 127.20, 127.55, 127.98, 128.25, 128.72, 128.81, –1 141.93, 142.66, 170.36; IR (thin film) 1790(s) cm ; Anal calcd for C20H22NOCl: 20 C, 73.27; H, 6.76; N, 4.27. Found: C, 72.84; H, 6.71; N, 4.18. [α] D 139.2° (c 0.5, CH2Cl2). The formation of β-lactam 164: BUDAM BUDAM (COCl)2, DCM N N O COOH Cl 163 164 The general procedure for β-lactam formation with (COCl)2 was followed with acid 163 (58 mg, 0.20 mmol, 1.0 equiv), (COCl)2 (0.040 mL, 0.40 mmol, 2.0 equiv) and CH2Cl2 (2 mL). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 15:1). The product 164 was obtained as a white foamy solid (23 mg, 0.39 mmol) in 39% yield; mp 73-76 1 °C; Rf = 0.30 (hexane:EtOAc 4:1). Spectral data for 164: H NMR (300 MHz, CDCl3) δ 0.74 (t, 3H, J = 7.2 Hz), 1.26-1.50 (m, 37H), 1.64-1.80 (m, 4H), 3.10 (dd, 1H, J = 10.2, 3.3 Hz), 3.65, 3.66 (2s, 6H), 5.94 (s, 1H), 7.00 (s, 2H), 7.06 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 10.35, 24.13, 24.41, 32.05, 32.08, 35.79, 35.85, 59.59, 64.26, 64.28, 67.11, 71.60, 125.98, 127.23, 131.51, 132.41, –1 143.34, 143.74, 158.79, 158.94, 166.94; IR (thin film) 2964(s), 1770(s) cm ; 327 + 35 HRMS calcd for C37H57NO3 Cl (M+H, ESI ) m/z 598.4027, meas 598.4039; 20 [α] D –7.1° (c 0.5, CH2Cl2). The formation of β-lactam trans-160g: Ph Ph N N (COCl)2, DCM O Cl 160g COOH 153g The general procedure for β-lactam formation with (COCl)2 was followed with trans-acid 153g (50 mg, 0.193 mmol, 1.0 equiv), (COCl)2 (0.04 mL, 0.40 mmol, 2.0 equiv) and CH2Cl2 (2 mL). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1). The product trans160g was obtained as a colorless oil (45 mg, 0.162 mmol) in 85% yield; Rf = 0.33 1 (hexane:EtOAc 4:1). Spectral data for trans-160g: H NMR (500 MHz, CDCl3) δ 0.88-1.26 (m, 5H), 1.48-1.78 (m, 6H), 3.33 (d, 1H, J = 6.0, 2.0 Hz), 4.06 (d, 1H, J =15.5 Hz), 4.74 (d, 1H, J = 2.0 Hz), 4.80 (d, 1H, J = 15.0 Hz), 7.20-7.40 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 25.46, 25.55, 25.96, 27.52, 29.45, 39.17, 45.82, 57.22, 67.73, 127.95, 128.10, 128.89, 134.86, 164.15; IR (thin film) –1 35 + 2928(m), 1770(s) cm ; HRMS calcd for C16H21NO Cl (M+H, ESI ) m/z 278.1312, meas 278.1316. 7.3.5 β-lactam formation with Vilsmeier reagent The formation of β-lactam 159a: 328 Ph Ph Vilsmeier reagent N Ph COOH Ph Ph DCM N O Ph Cl 159a Vilsmeier reagent preparation: To a flame-dried 50 mL round bottom flask filled 151a with N2 was added dry DMF (0.10 mL, 1.2 mmol, 1.0 equiv). The vacuum adapter was replaced with a septum to which a N2 balloon was attached via a needle. Dry CH2Cl2 (5 mL) was added via syringe. Then (COCl)2 (0.10 mL, 1.2 mmol, 1.0 equiv) was added dropwise at rt. The resulting solution was stirred at rt for at least 5 min prior to use. The concentration of Vilsmeier reagent is 0.23M in CH2Cl2. General procedure for β-lactam formation with Vilsmeier reagent: illustrated for βlactam 159a: To a flame-dried 25 mL round bottom flask filled with N2 was added acid 151a (33 mg, 0.10 mmol, 1.0 equiv). The vacuum adapter was replaced with a septum to which a N2 balloon was attached via a needle. The flask was cooled to 0 °C. Vilsmeier reagent (0.23M, 1 mL, 0.23 mmol, 2.3 equiv) was added to the flask via syringe all at once at 0 °C. After it was stirred at 0 °C for 15 min, the reaction mixture was concentrated. The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1), affording the product 159a (20 mg, 0.057 mmol, 57%) as a white solid; mp 107-108 °C; Rf = 1 0.20 (hexane:EtOAc 4:1). Spectral data for 159a: H NMR (300 MHz, CDCl3) δ 4.95 (d, 1H, J = 5.0 Hz), 5.13 (d, 1H, J = 5.0 Hz), 5.65 (s, 1H), 7.20-7.46 (m, 329 15H); 13 C NMR (125 MHz, CDCl3) δ 60.28, 61.86, 62.89, 127.92, 127.96, 128.17, 128.26, 128.41, 128.56, 128.61, 128.64, 128.91, 133.14, 137.52, 138.22, –1 35 + 164.31; IR (thin film) 1767(s) cm ; HRMS calcd for C22H19NO Cl (M+H, ES ) 20 m/z 348.1155, meas 348.1161; [α] D –59.2° (c 1.0, CH2Cl2). The formation of β-lactam 159b: Ph Ph Ph Vilsmeier reagent Ph N N O Cl COOH 147b 155b General procedure for β-lactam formation with Vilsmeier reagent was followed with acid 151b (35 mg, 0.10 mmol, 1.0 equiv), Vilsmeier reagent (0.23M, 1 mL, 0.23 mmmol, 2.3 equiv) with a reaction time of 1 h at 0 °C. After the column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1), the product was obtained as a pale yellow oil (13 mg, 0.036 mmol, 36%); Solidified in frigerator, 1 mp 65-67 °C; Rf = 0.30 (hexane:EtOAc 4:1). Spectral data for 159b: H NMR (600 MHz, CDCl3) δ 2.30 (s, 3H), 4.89 (d, 1H, J = 5.4 Hz), 5.08 (d, 1H, J = 5.0 Hz), 5.58 (s, 1H), 7.05 (d, 2H, J = 8.4 Hz), 7.10 (d, 2H, J =7.8 Hz), 7.20-7.46 (m, 10H); 13 C NMR (150 MHz, CDCl3) δ 21.22, 60.40, 61.76, 62.96, 127.36, 127.87, 127.95, 128.19, 128.54, 128.62, 128.65, 128.94, 130.05, 137.55, 138.45, 138.88, –1 35 + 164.34; IR (thin film) 1767(s) cm ; HRMS calcd for C23H21NO Cl (M+H, ESI ) m/z 362.1312, meas 362.1303. The formation of β-lactam 159c: 330 Ph Ph Ph Vilsmeier reagent Ph N N O Cl COOH 147c Br 155c Br The general procedure for β-lactam formation with Vilsmeier reagent was followed with acid 151c (41 mg, 0.10 mmol, 1.0 equiv) and Vilsmeier reagent (0.23M, 1.0 mL, 0.23 mmmol, 1.0 equiv). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1), affording the product 159c (14 mg, 0.033 mmol, 33%) as a white foamy solid; mp 48-50 1 °C; Rf = 0.30 (hexane:EtOAc 4:1). Spectral data for 159c: H NMR (600 MHz, CDCl3) δ 4.89 (d, 1H, J = 5.4 Hz), 5.12 (d, 1H, J = 4.8 Hz), 5.68 (s, 1H), 6.967.01 (m, 2H), 7.14-7.18 (m, 2H), 7.20-7.26 (m, 5H), 7.28-7.34 (m, 3H), 7.36-7.40 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 60.06, 61.41, 62.78, 123.04, 128.04, 128.10, 128.31, 128.34, 128.67, 130.25, 131.35, 132.37, 137.33, 137.95, 164.12 (One sp 2 –1 carbon not located); IR (thin film) 1767(s) cm ; HRMS calcd for 35 79 + 20 C22H18NO Cl Br (M+H, ESI ) m/z 426.0260, meas 426.0274; [α] D –85.0° (c 1.0, CH2Cl2). The formation of β-lactam 169a: Ph N Ph Ph Ph Vilsmeier reagent COOH DCM Ph N O Ph Cl 169a The general procedure for β-lactam formation with Vilsmeier reagent was 141a followed with acid 141a (34 mg, 0.10 mmol, 1.0 equiv), Vilsmeier reagent (0.23M, 331 2.0 mL, 0.46 mmmol, 4.6 equiv). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1), affording the product 169a (8 mg, 0.022 mmol, 22%) as a white solid; mp 130-132 °C; Rf = 1 0.50 (hexane:EtOAc 4:1). Spectral data for 169a: H NMR (500 MHz, CDCl3) δ 1.84 (s, 3H), 4.57 (s, 1H), 5.53 (s, 1H), 7.15-7.40 (m, 15H); 13 C NMR (125 MHz, CDCl3) δ 24.38, 62.80, 69.72, 72.91, 127.93, 127.94, 128.17, 128.25, 128.30, 128.50, 128.55, 128.72, 128.88, 134.19, 137.64, 138.63, 167.28; IR (thin –1 35 + film) 1767(s) cm ; HRMS calcd for C23H21NO Cl (M+H, ESI ) m/z 362.1312, 20 meas 362.1299; [α] D –9.6° (c 1.0, CH2Cl2). The formation of β-lactam 160a: Ph Vilsmeier reagent Ph N O N DCM Ph Cl Ph COOH 153a 160a The general procedure for β-lactam formation with Vilsmeier reagent was followed with acid 153a (26 mg, 0.10 mmol, 1.0 equiv), Vilsmeier reagent (0.23 M, 1.0 mL, 0.23 mmmol, 1.0 equiv). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1), affording the product 160a (20 mg, 0.074 mmol, 74%) as a viscous oil; Rf = 0.35 1 (hexane:EtOAc 4:1). Spectral data for 160a: H NMR (300 MHz, CDCl3) δ 3.90 (d, 1H, J = 14.5 Hz), 4.78 (d, 1H, J = 5.0 Hz), 4.90 (d, 1H, J = 14.5 Hz), 5.07 (d, 1H, J = 5.0 Hz), 7.10-7.24 (m, 4H), 7.31 (d, 3H, J = 5.0 Hz), 7.42 (d, 3H, J = 5.5 Hz); 13 C NMR (125 MHz, CDCl3) δ 44.96, 60.26, 61.15, 128.13, 128.25, 128.55, 332 128.62, 128.93, 129.14, 132.69, 134.34, 163.99; IR (thin film) 2922(m), 1770(s) –1 20 cm ; [α] D –56.0° (c 1.0, CH2Cl2). Spectral data matches previously reported data. 89 The formation of β-lactam 171a: Ph N Vilsmeier reagent Ph O N Cl 171a The general procedure for β-lactam formation with Vilsmeier reagent was COOH 170a followed with acid 170a (27 mg, 0.10 mmol, 1.0 equiv) and Vilsmeier reagent (0.23M, 1.0 mL, 0.23 mmmol, 2.3 equiv). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1), affording the product 171a (22 mg, 0.077 mmol, 77%) as a white foamy solid; mp 95-96 1 °C; Rf = 0.30 (hexane:EtOAc 4:1). Spectral data for 171a: H NMR (500 MHz, CDCl3) δ 1.43 (d, 3H, J = 7.0 Hz), 4.69 (d, 1H, J = 5.0 Hz), 4.98 (d, 1H, J = 5.0 Hz), 5.07 (q, 1H, J = 7.0 Hz), 7.20-7.40 (m, 10H); 13 C NMR (125 MHz, CDCl3) δ 19.08, 53.04, 60.29, 60.42, 127.28, 128.15, 128.72, 128.81, 129.08, 134.21, 2 –1 138.99, 164.22 (One sp carbon not located); IR (thin film) 1761(s) cm ; HRMS 35 + 20 calcd for C17H17NO Cl (M+H, ESI ) m/z 286.0999, meas 286.0975; [α] D – 84.5° (c 1.0, CH2Cl2). The formation of β-lactam 171c: 333 Ph Vilsmeier reagent Ph N N Cl 171c COOH 170c Br O Br The general procedure for β-lactam formation with Vilsmeier reagent was followed with acid 170c (35 mg, 0.10 mmol, 1.0 equiv) and Vilsmeier reagent (0.23M, 1.0 mL, 0.23 mmmol, 2.3 equiv). The crude product was purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1), affording the product 171c (25 mg, 0.069 mmol, 69%) as a white foamy solid; mp 102-103 1 °C; Rf = 0.20 (hexane:EtOAc 4:1). Spectral data for 171c: H NMR (500 MHz, CDCl3) δ 1.41 (d, 3H, J = 7.5 Hz), 4.60 (d, 1H, J = 5.0 Hz), 4.94 (d, 1H, J = 5.0 Hz), 5.01 (q, 1H, J = 7.0 Hz), 7.08-7.14 (m, 2H), 7.16-7.20 (m, 2H), 7.28-7.34 (m, 3H), 7.46-7.50 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 19.08, 53.18, 59.86, 60.10, 123.22, 127.25, 128.27, 128.88, 130.31, 131.40, 133.36, 138.77, 164.00; –1 35 79 + IR (thin film) 1767(s) cm ; HRMS calcd for C17H16NO Cl Br (M+H, ESI ) m/z 20 364.0104, meas 364.0078; [α] D –116.3° (c 1.0, CH2Cl2). 7.3.6 Transformation of 159g Transformation of 159g with NaN3: Ph Ph Ph N O Cl NaN3, DMSO Ph N N3 86% 159g 172 334 O To a flame-dried test tube sized Schlenck flask filled with N2 were added the lactam 159g (36 mg, 0.10 mmol, 1.0 equiv), NaN3 (66 mg, 1.0 mmol, 10 equiv) and DMSO-d6 (0.20 mL). The resulting mixture was stirred at 80 °C for 48 h and 100 °C for 12 h. H2O (2 mL) was added. Then the mixture was extracted with ether (3 × 5 mL). The combined organic extracts were washed with H2O (2 × 1 mL), dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 18 × 150 mm, hexane:EtOAc 5:1) to afford the product 172 (31 mg, 0.086 mmol) as a white solid in 86% yield; mp 105-107 1 °C; Rf = 0.50 (hexane:EtOAc 4:1). Spectral data for 172: H NMR (300 MHz, CDCl3) δ 0.78-1.40 (m, 6H), 1.46-1.76 (m, 5H), 3.42 (dd, 1H, J = 5.4, 2.4 Hz), 4.31 (d, 1H, J = 2.1 Hz), 5.73 (s, 1H), 7.20-7.40 (m, 10H); 13 C NMR (125 MHz, CDCl3) δ 25.48, 25.77, 26.06, 26.89, 29.53, 37.91, 62.36, 64.80, 65.39, 127.84, 128.04, 128.16, 128.33, 128.59, 128.72, 138.08, 138.24, 164.36; IR (thin film) –1 + 2928(m), 2106(s) 1765(s) cm ; HRMS calcd for C22H25N4O (M+H, ESI ) m/z 20 361.2028, meas 361.2041; [α] D 74.4° (c 0.5, CH2Cl2). Transformation of 159g with NaI: Ph O Ph N Cl 159g Ph NaI, DMSO Ph N O I 76% 173 335 To a flame-dried test tube sized Schlenck flask filled with N2 were added the lactam 159g (36 mg, 0.10 mmol, 1.0 equiv), NaI (150 mg, 1.00 mmol, 10.0 equiv) and DMSO-d6 (0.40 mL). The resulting mixture was stirred at 100 °C for 66 h. After cooling to rt, H2O (2 mL) and ether (10 mL) were added. The aqueous layer was separated and extracted with ether (2 × 5 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1) to afford the product 172 (34 mg, 0.076 mmol) as a viscous oil in 76% yield; Rf = 1 0.50 (hexane:EtOAc 4:1). Spectral data for 172: H NMR (300 MHz, CDCl3) δ 0.78-1.30 (m, 6H), 1.42-1.70 (m, 5H), 3.78 (dd, 1H, J = 5.1, 2.1 Hz), 4.60 (d, 1H, J = 1.8 Hz), 5.75 (s, 1H), 7.20-7.40 (m, 10H); 13 C NMR (125 MHz, CDCl3) δ 15.65, 25.33, 25.80, 26.07, 26.32, 29.34, 39.82, 62.22, 70.05, 127.76, 128.02, 128.19, 128.36, 128.55, 128.64, 138.21, 138.36, 164.89; IR (thin film) 2926(m), –1 + 1759(s) 1265(s) cm ; HRMS calcd for C22H25NOI (M+H, ESI ) m/z 446.0981, 20 meas 446.0948; [α] D –12.8° (c 1.0, CH2Cl2). Transformation of 159g with LiAlH4: Ph O Ph LiALH4 N Ph HN Ph OH Cl 159g 174 336 To a flame-dried 25 mL round bottom flask filled with N2 was added LiAlH4 (20 mg, 0.50 mmol, 5.0 equiv). The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. Then dry THF (0.5 mL) was added. And it was cooled to 0 °C. A solution of 4-chlorolactam 159g (36 mg, 0.10 mmol, 1.0 equiv) in THF (0.5 mL) was added dropwise via syringe. After it was stirred at 0 °C for 5 min, the ice bath was removed. After the reaction mixture was stirred at rt for 2 h, H2O (0.1 mL) was added carefully at 0 °C. After it was stirred at 0 °C for 15 min, the mixture was filtered through a Celite pad and Na2SO4 on a sintered glass funnel. The filtrate was concentrated and purified by column chromagraphy (silica gel, 18 × 180 mm, hexane:EtOAc 3:1) to give the product 174 as a white solid (29 mg, 0.090 mmol, 90%). mp 92-94 °C; Rf = 0.30 1 (hexane:EtOAc 3:1). Spectral data for 174: H NMR (600 MHz, CDCl3) δ 0.440.54 (m, 1H), 0.90-1.20 (m, 5H), 1.28 (d, 1H, J =12.6 Hz),1.42-1.64 (m, 6H), 1.79 (q, 1H, J = 6.0 Hz), 3.52-3.60 (m+s, 2H), 3.67-3.74 (m, 1H), 7.16-7.30 (m, 6H), 7.37 (d, 2H, J = 7.2 Hz), 7.43 (d, 2H, J = 7.2 Hz); 13 C NMR (150 MHz, CDCl3) δ 25.62, 25.74, 26.19, 30.92, 31.42, 36.93, 44.68, 50.58, 60.66, 78.90, 127.07, 127.17, 127.25, 127.95, 128.23, 128.59, 143.15, 143.55; IR (thin film) 3400(m), –1 + 2926(s) cm ; HRMS calcd for C22H30NO (M+H, ESI ) m/z 324.2327, meas 20 324.2303; [α] D 4.0° (c 1.0, CH2Cl2). The transformation of 159g with Bu3SnH: 337 Ph Ph N O Cl AIBN Ph Ph N O Bu3SnH 175 159g To a flame-dried Schlenk flask filled with N2 was added 4-chlorolactam 159g (36 mg, 0.10 mmol, 1.0 equiv), AIBN (10 mg), and dry benzene (1 mL) And tributyltin hydride (119 mg, 0.100 mL, 0.400 mmol, 4.00 equiv) was quickly added under a N2 stream. Then the Schlenk flask was sealed and the reaction was stirred at 80 °C for 19 h. After it was cooled to rt, aq sat KF (3 mL) and CH2Cl2 (10 mL) were added. The aqueous layer was separated and extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 18 × 180 mm, hexane:EtOAc 5:1) to obtain the product 175 as a white solid (31 mg, 0.097 mmol, 97%). mp 74-76 °C; Rf = 0.50 (hexane:EtOAc 4:1). 1 Spectral data for 175: H NMR (500 MHz, CDCl3) δ 0.78-1.12 (m, 5H), 1.22-1.32 (m, 1H), 1.46-1.68 (m, 5H), 2.69 (dd, 1H, J = 2.5, 15.0 Hz), 2.85 (dd, 1H, J = 5.5, 15.0 Hz), 3.55 (td, 1H, J = 5.5, 2.5 Hz), 5.78 (s, 1H), 7.22-7.38 (m, 10H); 13 C NMR (150 MHz, CDCl3) δ 25.52, 25.90, 26.23, 26.37, 29.76, 38.21, 39.34, 57.07, 62.19, 127.47, 127.65, 128.17, 128.43, 128.49, 139.01, 139.30, 167.72 (One sp –1 2 C not located); IR (thin film) 2924(m), 1749(s) cm ; HRMS calcd for C22H26NO + 20 (M+H, ESI ) m/z 320.2014, meas 320.2007; [α] D –82.8° (c 1.0, CH2Cl2). 338 The transformation of 159g with allyltributyltin: Ph O Ph AIBN N Cl Bu3allylSn 159g Ph Ph N O 176 To a flame-dried test-tube size Schlenk flask filled with N2 was added 4chlorolactam 159g (36 mg, 0.10 mmol, 1.0 equiv), AIBN (10 mg) and dry benzene (0.5 mL). Allyl tri-butyltin (134 mg, 0.130 mL, 0.400 mmol, 4.00 equiv) was added under a N2 stream. Then the Teflon valve was closed the reaction mixture was heated at 80 °C for 17 h. After it was cooled to rt, the reaction mixture was concentrated and purified by column chromatography (silica gel, 18 × 18 mm, hexane:EtOAc 5:1) to give the product 176 (32 mg, 0.089 mmol, 89%) as a colorless oil and solidified during storage; mp 62-64 °C; Rf = 0.50 1 (hexane:EtOAc 4:1). Spectral data for 176: H NMR (500 MHz, CDCl3) δ 0.781.12 (m, 5H), 1.26-1.34 (m, 1H), 1.46-1.70 (m, 5H), 2.26-2.34 (m, 1H), 2.42-2.50 (m, 1H), 2.88-2.94 (m, 1H), 3.24 (dd, 1H, J = 2.5, 5.5 Hz), 5.01 (dd, 1H, J = 10.0, 2.0 Hz), 5.07 (dt, 1H, J = 17.0, 1.5 Hz), 5.68-5.78 (m+s, 2H), 7.20-7.50 (m, 10H); 13 C NMR (150 MHz, CDCl3) δ 25.67, 25.99, 26.23, 27.27, 30.24, 33.27, 39.37, 50.49, 62.11, 63.41, 117.23, 127.44, 127.60, 128.27, 128.36, 128.42, 128.43, –1 134.91, 139.06, 139.36, 170.01; IR (thin film) 2926(m), 1747(s) cm ; HRMS + 20 calcd for C25H30NO (M+H, ESI ) m/z 360.2327, meas 360.2334; [α] D –42.7° (c 1.0, CH2Cl2). 339 Transformation of 159g under Suzuki coupling condition: Ph Ph NiCl2•glyme, (S)-prolinol O O Ph Ph N phenyl boronic acid N KHMDS, i-PrOH Cl Cl 80 °C, 24h trans-159g 159g To a flame-dried test-tube size Schlenk flask filled with N2 was added (S)-prolinol (5 mg, 0.048 mmol, 0.48 equiv), NiCl2•glyme (5 mg, 0.024 mmol, 0.24 equiv), phenylboronic acid (24 mg, 0.20 mmol, 2.0 equiv), KHMDS (40 mg, 0.20 mmol, 2.0 equiv) and i-PrOH (0.5 mL). Then the mixture was stirred at rt for 5 min. The starting material 159g (36 mg, 0.10 mmol, 1.0 equiv) was added. Then the Teflon 1 valve was closed and the flask was heated at 80 °C for 24 h. H NMR spectrum of the crude reaction mixture indicated a 95% conversion. The trans-159g was 1 identified according to the H NMR spectrum of the crude reaction mixture: 3.60 (dd, 1H, J = 5.0, 2.0 Hz), 4.49 (d, 1H, J =1.5 Hz), 5.77 (s, 1H). 340 7.4 Experimental Section for Chapter Five 7.4.1 Preparation of imine 197 N + MEDAM O MgSO4, CH2Cl2 N N NH2 OMe MEDAM MeO 197 MEDAM The mixture of 4-dimethylaminobenzaldehyde (261 mg, 1.75 mmol, 1.03 equiv), MEDAM amine (510 mg, 1.70 mmol, 1.00 equiv) and MgSO4 (1.5 g, 8.5 mmol, 5.0 equiv) in dry CH2Cl2 (5 mL) was stirred under a N2 balloon for 1 week. After it was filtered, the filtrate was concentrated to give the crude product which was recrystallized from EtOAc and hexane to give the product 197 as pale yellow 1 crystals (550 mg, 1.28 mmol, 75%); mp 167-169 °C; H NMR (500 MHz, CDCl3) δ 2.25 (s, 12H), 3.00 (s, 6H), 3.70 (s, 6H), 5.32 (s, 1H), 6.70 (d, 2H, J = 9.0 Hz), 7.00 (s, 4H), 7.70 (d, 2H, J = 9.0 Hz), 8.24 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 16.21, 40.26, 59.59, 77.30, 111.83, 125.37, 128.16, 129.93, 130.44, 134.00, 152.36, 155.96, 160.09. 7.4.2 Preparation of the BINOL derivative 93b-d Preparation of (R)-3,3’-diphenyl-2,2’-dihydroxy-1,1’-binaphthyl 93b 341 I OH NaH, MOMCl OH BINOL OMOM OMOM n-BuLi, I2 183 53% yield Ph OH OH Ph 93b 84% yield HCl, THF OMOM OMOM 184 I 45% yield Pd(PPh3)4 PhB(OH)2 Ph OMOM OMOM Ph 185 93% yield To a flame dried flask filled with N2 was added NaH (60% suspension in mineral oil, 500 mg, 12.5 mmol, 2.50 equiv) and dry THF (5 mL). The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. And a solution of (R)-BINOL (1.44 g, 5.00 mmol, 1.00 equiv) in THF (5 mL) was added at 0 °C. It was stirred at 0 °C for 1 hour. Then the ice bath was removed and the mixture was stirred at room temperature for 15 min. After it was cooled to 0 °C, MOMCl (1.006 g, 1.000 mL, 12.50 mmol, 2.500 equiv) was added dropwise. The resulting mixture was stirred at room temperature for another 3 hours. Then aq sat NH4Cl (5 mL) was added and THF was removed via rotavap. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 30 × 300 mm, hexane:EtOAc 9:1) to give a solid which was recrystallized in 342 CH2Cl2:hexane (1:10) to provide the product 183 as a colorless crystalline solid 992 mg, 53%. To a flame-dried flask filled with N2 was added 183 (374 mg, 1.00 mmol, 1.00 equiv) and dry THF (2 mL). The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. After it was cooled to 0 °C, n-BuLi (2.47 M in Hexane, 1.30 mL, 3.00 mmol, 3.00 equiv) was added dropwise. After it was stirred at 0 °C for 10 min, the ice bath was removed and the mixture was stirred at room temperature for 1 hour. Then it was cooled to 0 °C again and a solution of I2 (762 mg, 3.00 mmol, 3.00 equiv) in dry THF (5 mL) was added dropwise via syringe. It was stirred at room temperature overnight (~13 hours). Water (5 mL) and EtOAc (20 mL) were added. The aqueous layer was separated and extracted with EtOAc (2 ×20 mL). The combined organic extracts were washed successively with aq 5% Na2S2O3 (2 × 10 mL), water (5 mL) and brine (5 mL) and concentrated. The crude product was purified by column chromatography (1 nd 15:1; 2 st column, silica gel, 25 × 300 mm, hexane:EtOAc column, silica gel, 25 × 200 mm, hexane:EtOAc 15:1), affording the product 184 as white foamy solid 280 mg, 45%. The mixture of the starting material 184 (275 mg, 0.440 mmol, 1.00 equiv) and Pd(PPh3)4 (101 mg, 0.0880 mmol, 0.200 equiv) in DME (2 mL) was stirred at room temperature for 10 min under N2. Then PhB(OH)2 (188 mg, 1.54 mmol, 343 3.50 equiv) was added in one portion, followed by the addition of aq Na2CO3 (2 M, 1.1 mL, 2.2 mmol, 5.0 equiv). The resulting mixture was kept refluxing for 15 hours under a N2 balloon. After it was cooled to room temperature, the aqueous layer was separated and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated to give the dark crude product which was purified by column chromatography (silica gel, hexane:EtOAc 15:1, 25 × 200 mm), affordinging the product 185 as a white foamy solid, 216 mg, 93%. The mixture of the starting material 185 (215 mg, 0.41 mmol, 1.0 equiv) in THF (1 mL) and MeOH (1 mL) and con HCl (0.5 mL) was stirred at room temperature overnight. Then it was extracted with EtOAc (3 ×20 mL). The combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, hexane:EtOAc 15:1, 20 × 200 mm), giving the product 93b as white crystals 150 mg, 84%. mp 199-200 °C (Lit 65a : 200-202 °C). 1 Spectral data for 93b: H NMR (500 MHz, CDCl3) δ 5.30 (s, 2H), 7.16-7.54 (m, 12H), 7.82 (d, 4H, J = 7.5 Hz), 7.90 (d, 2H, J = 8.0 Hz), 8.00 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 112.304, 124.23, 124.30, 127.32, 127.74, 128.42, 128.46, 129.40, 129.57, 130.61, 131.38, 132.86, 137.40, 150.08; MS (EI) 439 (M+1, 39), 438 (M, 100), 191 (83); [α]D 20 106.2° (c 1.0, THF). 344 Preparation of (R)-3,3’-dibromo-2,2’-dihydroxy-1,1’-binaphthyl 93c Br OMOM OMOM n-BuLi, Br2 183 OMOM OMOM 186 HCl, THF Br 91% yield Br OH OH Br 93c 76% yield To a flame-dried flask filled with N2 was added starting material (R)-183 (356 mg, 0.950 mmol, 1.00 equiv) and dry THF (5 mL). The vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. After it was cooled to 0 °C, n-BuLi (2.47M in Hexane, 1.3 mL, 3.0 mmol, 3.0 equiv) was o added dropwise via syringe. After it was stirred at 0 C for 10 min, the ice bath was removed and the mixture was stirred at room temperature for 1 hour. Then it was cooled to –78 °C and a solution of Br2 (456 mg, 0.150 mL, 2.85 mmol, 3.00 equiv) in dry THF (1 mL) was added. And it was stirred at –78 °C for 15 min. Then it was allowed to warm up to room temperature and stirred at room temperature overnight (~12 hours). Water (5 mL) and EtOAc (20 mL) were added. The aqueous layer was separated and extracted with EtOAc (2 ×10 mL). The combined organic extracts were washed successively with aq 5% Na2S2O3 (2 × 10 mL), water (5 mL) and brine (5 mL) and dried (MgSO4). After it was filtered, the filtrate was concentrated and purified by column chromatography (silica gel, 25 × 250 mm, hexane:EtOAc 9:1), affording the product 186 as a white foamy solid (455 mg, 0.865 mmol, 91%). 345 The mixture of the starting material 186 (455 mg, 0.865 mmol, 1.00 equiv) in THF (1 mL) and MeOH (1 mL) and con HCl (0.9 mL) was stirred at room temperature overnight. Then EtOAc (20 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 15:1), giving the product as a white solid 93c (287 mg, 0.657 mmol, 76%); mp > 250 °C (Lit 65a : 256-257 °C). 1 Spectral data for 93c: H NMR (500 MHz, CDCl3) δ 5.54 (s, 2H), 7.12 (d, 2H, J = 8.5 Hz), 7.24-7.42 (m, 4H), 7.82 (d, 2H, J = 8 Hz), 8.25 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 112.22, 114.57, 124.60, 124.86, 127.39, 127.58, 129.70, 132.73, 132.75, 147.98; MS (EI) 444 (M, 39), 442 (M-2, 20), 446 (M+2, 20); [α]D 20 98.6° (c 1.0, THF). Preparation of (R)-3,3’-ditriphenylsilyl-2,2’-dihydroxy-1,1’-binaphthyl 93d SiPh3 SiPh3 n-BuLi HCl, THF OMOM SiPh3Cl OMOM OH OMOM OMOM OH 183 SiPh3 187 47% yield 93d SiPh3 68% yield To a stirred solution of (R)-183 (1.87 g, 5.00 mmol, 1.00 equiv) in dry Et2O (50 mL) was added n-BuLi (2.47M in hexane, 6.10 mL, 15.0 mmol, 3.00 equiv) dropwise at room temperature over 10 min. Then it was stirred at room temperature for 1.5 hours. After it was cooled to 0 °C, dry THF (10 mL) was 346 added and the mixture was stirred for another 15 min. Then a solution of Ph3SiCl (4.41 g, 15.0 mmol, 3.00 equiv) in dry THF (10 mL) was added. The ice bath was removed after 10 min and the mixture was stirred at room temperature for 38 hours. Then it was quenched by aq sat NH4Cl (20 mL). The aqueous layer was separated and extracted with CH2Cl2 (50 mL + 2 × 25 mL). The combined organic extracts were washed with brine, dried (MgSO4) and filtered. The filtrate was concentrated and purified by column (1 CH2Cl2:Et2O:pentane 1:1:20; nd 2 st column, column, silica gel, 30 × 300 mm, silica gel, 20 × 200 mm, CH2Cl2:Et2O:pentane 1:1:20), giving the product 187 as a white solid (2.089 g, 2.350 mmol, 47%). The mixture of the starting material 187 (2.089 g, 2.350 mmol, 1.000 equiv) in dioxane (20 mL) and con HCl (0.4 mL) was kept at 70 °C for 12 hours. Another portion of con HCl (0.5 mL) was added and it was stirred at 70 °C for another 11 hours. Then the reaction was cooled to 0 °C and aq sat NaHCO3 (20 mL) was added. The reaction mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with water (2 × 20 mL), brine (20 mL), dried (MgSO4) and filtered. The filtrate was concentrated to give the crude product as a brownish white solid. Triturating with CH2Cl2:Et2O (v/v 1:10) provided the product 93d as a white solid 1.287 g, 68%, in which it contains 1 some dioxane. H NMR showed a 96% purity by weight; mp 161-163 °C. 347 1 Spectral data for 93d: H NMR (CDCl3, 500 MHz) δ 5.26 (s, 2H), 7.22-7.44 (m, 24H), 7.63 (d, 12 H, J = 8.0 Hz), 7.70 (d, 2H, J = 8.0 Hz), 7.90 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 110.67, 123.65, 123.85, 123.91, 127.81, 128.17, 129.04, 129.22, 129.50, 134.28, 134.76, 136.30, 142.08, 156.51; [α]D 65c CHCl3) (Lit : [α]D 20 20 110.9 °C (c 1.2, 102.7 °C (c 1.2, CHCl3) ). 7.4.3 Catalytic asymmetric aziridination reaction 7.4.3.1 General procedure Catalyst preparation procedure A: To a flame-dried Schlenk flask filled with N2 was added the ligand (BINOL or BINOL derivative) (0.050 mmol, 0.10 equiv) B(OPh)3 (44 mg, 0.15 mmol, 0.30 equiv) and dry toluene (1 mL) were added. The Teflon valve was closed and the mixture was heated at 80 °C for 1 hour. Then the solvent was removed under high vacuum by slightly cracking the Teflon valve. Then the Teflon valve was completely open and the residue was kept at 80 °C for another 30 min. After it was cooled to room temperature, the corresponding imine (0.50 mmol, 1.0 equiv) and toluene (dry, 1 mL) were added, followed by the addition of EDA (63 µL, 0.60 mmol, 1.2 equiv). The resulting mixture was stirred at the specified temperature for 24 hours. Then hexane was added and the volatiles were removed. The residue was purified by column chromatography to give the corresponding product. Catalyst preparation procedure B: The catalyst preparation procedure A was followed except that ligand (0.050 mmol, 0.10 equiv), BH3•SMe2 (2M, 75 µL, 348 0.15 mmol, 0.30 equiv), PhOH (10 mg, 0.10 mmol, 0.20 equiv), H2O (2.7 µL, 0.15 mmol, 0.30 equiv) in dry toluene (1 mL) were added. Catalyst preparation procedure C: The catalyst preparation procedure A was followed except that ligand (0.050 mmol, 0.10 equiv), B(OPh)3 (58 mg, 0.20 mmol, 0.40 equiv), H2O (0.9 µL, 0.05 mmol, 0.10 equiv) in dry toluene (1 mL) were added. Catalyst preparation procedure D: The catalyst was prepared from BINOL (57 mg, 0.20 mmol, 0.20 equiv) and B(OPh)3 (29 mg, 0.10 mmol, 0.10 equiv) at room temperature in CH2Cl2 (1 mL). Then imine 31 (271 mg, 1.00 mmol, 1.00 equiv) was added, followed by the addition of EDA (120 µL, 1.20 mmol, 1.20 equiv). Then the reaction was stirred at room temperature for 24 h. Hexane (5 mL) was added. After concentration, the crude product was purified by column chromatography. The spectroscopic data for the products 32a and 32b were reported in the literature. 26a,d 7.4.3.2 Aziridination reaction of 31a and EDA with the catalyst prepared from (R)-93b (entry 5, Table 5.1) The reaction of imine 31a (136 mg, 0.500 mmol, 0.500 equiv) with EDA was performed according to the general procedure: catalyst preparation procedure A with BINOL derivative (R)-93b (22 mg, 0.050 mmol, 0.10 equiv). The crude product was purified by the column (silica gel, 35 × 320 mm, hexane:EtOAc 19:1) 349 to give the product 32a as a white solid (158 mg, 0.440 mmol, 88%). The optical purity was determined to be 76% ee by HPLC analysis (Chiralcel OD-H column, hexane/2-propanol 90:10, 222 nm, 0.7 mL/min). Retention times: tR = 4.67 min (major enantiomer) and tR = 9.36 (minor enantiomer). As has been reported, the major enantiomer is (2S, 3S)-32a. 1 Spectral data for (2S,3S)-32a: H NMR (300 MHz, CDCl3) δ 1.00 (t, 3H, J = 7.2 Hz), 2.70 (d, 1H, J = 6.6 Hz), 3.20 (d, 1H, J = 6.9 Hz), 3.88-4.02 (m, 3H), 7.687.14 (m, 15H); 13 C NMR (75 MHz, CDCl3) δ 167.72, 142.50, 142.36, 135.00, 128.48, 127.77, 127.75, 127.51, 127.39, 127.31, 127.18, 77.68, 60.56, 48.01, 46.36, 13.93, 46.36, 48.01, 60.56, 77.68, 127.18, 127.31, 127.39, 127.51, 127.75, 127.77, 128.48, 135.00, 142.36, 142.50, 167.72; [α]D 23 o –30.1 (c 1.0, CH2Cl2) based on 76% ee material. 7.4.4 11 B NMR shown in Figure 5.3 was prepared according to the following procedure: To a flame-dried Schlenk flask filled with N2 were added BINOL derivative (0.050 mmol, 1.0 equiv), B(OPh)3 (58 mg, 0.20 mmol, 4.0 equiv), H2O (0.90 µL, 0.050 mmol, 1.0 equiv) and THF (dry, 2 mL) under a N2 stream. The Teflon valve was then closed and the reaction mixture was kept at 80 °C for 1 hour. Then the solvent was removed under high vacuum by slightly cracking the Teflon valve. o The valve was completely open and the residue was kept at 80 C for another 30 350 min. After it was cooled to room temperature under N2, CDCl3 (0.5-1.0 mL) was added and the solution was transferred to the NMR tube (flame dried and cooled 1 to room temperature prior to use). H NMR and 11 B NMR were taken for the borate species. Then imine 197 (22 mg, 0.050 mmol, 1.0 equiv) was quickly 1 added to the NMR tube and shaken to dissolve. H NMR and also taken again. 351 11 B NMR were 7.5 Experimental Section for Chapter Six 7.5.1 Preparation of different dibenzylamines bis-(2-naphthylmethyl)amine 222b: N H 222b To a flame-dried 25 mL round bottom flask filled with N2 was added NH4Cl (535 mg, 10.0 mmol, 2.00 equiv), absolute ethanol (10 mL), dry NEt3 (1.40 mL, 10.0 mL, 2.00 equiv) and 2-naphthyl aldehyde (781 mg, 5.00 mmol, 1.00 equiv). Then the vacuum adapter was quickly replaced with a septum to which a N2 balloon was attached via a needle. Then Ti(O-i-Pr)4 (3.00 mL, 10.0 mmol, 2.00 equiv) was added dropwise via syringe. The resulting mixture was stirred at rt for 6 hours. NaBH4 (285 mg, 7.50 mmol, 1.50 equiv) was added in one portion. The reaction mixture was stirred at rt for another 3 hours. After it was poured into aq ammonia (2M, 5 mL), the mixture was filtered and washed well with EtOAc (20 mL). The aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried (MgSO4) and filtered. After the column chromatography (silica gel, 25 × 200 mm, hexane:EtOAc 4:1 to 2:1), the product 222b was obtained as a white solid (147 mg, 0.495 mmol, 20%); mp 76-77 °C 90a (Lit: 1 82-83 °C); Rf = 0.20 (hexane:EtOAc 1:1). Spectral data for 222b: H NMR (500 MHz, CDCl3) δ 1.75 (brs, 1H), 4.24 (s, 4H), 7.50-7.60 (m, 6H), 7.828.04 (m, 8H); 13 C NMR (125 MHz, CDCl3) δ 53.11, 125.45, 125.90, 126.42, 126.52, 127.58, 127.62, 127.99, 132.61, 133.37, 137.69. 352 bis-(4-methoxybenzyl)amine 222c: MeO N H 222c OMe The procedure for the preparation of 222b was followed with NH4Cl (214 mg, 4.00 mmol, 2.00 equiv), absolute ethanol (4 mL), dry NEt3 (0.56 mL, 4.0 mmol, 2.0 equiv), 4-methoxybenzaldehyde (272 mg, 0.250 mL, 2.00 mmol, 1.00 equiv), Ti(O-i-Pr)4 (1.14 g, 1.20 mL, 4.00 mmol, 2.00 equiv) and NaBH4 (114 mg, 3.00 mmol, 1.50 equiv). The filtrate was concentrated and purified by column chromatography (silica gel, 25 × 200 mm, hexane:EtOAc 4:1 to 1:1). The product 222c was obtained as a pale yellow oil (177 mg, 0.689 mmol, 69%); Rf = 0.05 1 (hexane:EtOAc 1:1). Spectral data for 222c: H NMR (500 MHz, CDCl3) δ 1.70 (brs, 1H), 3.72 (s, 4H), 3.78 (s, 6H), 6.87 (d, 4H, J = 8.5 Hz), 7.25 (d, 4H, J = 8.5 Hz); 13 C NMR (125 MHz, CDCl3) δ 52.05, 54.80, 113.35, 128.90, 132.14, 158.21; MS (EI) 257.1 (10.88), 121.0 (100). reported data. 1 H NMR data match previously 90b bis-(4-bromobenzyl)amine 222d: Br N H 222d Br To a flame dried 50 mL round bottom flask filled with N2 was added 4bromobenzaldehyde (925 mg, 5.00 mmol, 1.0 equiv), LiClO4 (532 mg, 5.00 mmol, 1.00 equiv) and hexamethyldisilazane (HMDS, 2.20 mL, 10.0 mmol, 2.00 equiv). The mixture was stirred at 60 °C for 2 hours. After it was cooled to 0 °C, 353 MeOH (10 mL) was added. Then NaBH4 (568 mg, 15.0 mmol, 3.00 equiv) was added in three portions. After it was stirred at 0 °C for 10 min, the reaction mixture was stirred at rt overnight. Then the volatiles were removed, and aq sat NaHCO3 (10 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and filtered. The filtrate was concentrated. The crude product was dissolved in CH2Cl2 (10 mL) and aq HCl (6M, ~5 mL) was added dropwise until pH ~1. The resulting white precipitate was collected by filtration and suspended in EtOAc (20 mL). aq sat Na2CO3 (~10 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated and purified by column chromatography (silica gel, 25 × 200 mm, Hexane:EtOAc 3:1). The product 222d was obtained as a colorless oil (536 mg, 1.51 mmol, 60%); Rf = 0.30 1 (hexane:EtOAc). Spectral data for 222d: H NMR (500 MHz, CDCl3) δ 1.60 (brs, 1H), 3.70 (s, 4H), 7.20 (d, 4H, J = 8.0 Hz), 7.43 (d, 4H, J = 8.0 Hz); 1 13 C NMR (125 MHz, CDCl3) δ 52.27, 120.69, 129.73, 131.40, 139.07. H NMR data match previously reported data. 90c bis-(4-chlorobenzyl)amine 222e: Cl N H 222e 354 Cl The procedure for the preparation of 222d was followed with 4- chlorobenzaldehyde (703 mg, 5.00 mmol, 1.00 equiv). The product 222e was obtained as a colorless oil (410 mg, 1.54 mmol, 61.7%); Rf = 0.30 1 (Hexane:EtOAc 1:1). Spectral data for 222e: H NMR (500 MHz, CDCl3) δ 1.60 (brs, 1H), 3.70 (s, 4H), 7.20-7.40 (m, 8H); 128.58, 129.50, 132.72, 138.67. data. 1 13 C NMR (125 MHz, CDCl3) δ 52.36, H NMR data match previously reported 90c bis-(4-fluorobenzyl)amine 222f: The procedure for N H F 222f the preparation of F 222d was followed with 4- fluorobenzaldehyde (620 mg, 5.00 mmol, 1.00 equiv). The filtrate was concentrated and purified by column chromatography (silica gel, 25 × 200 mm, Hexane:EtOAc 3:1), affording the product 222f as a colorless oil (400 mg, 1.72 1 mmol, 69%); Rf = 0.30 (hexane:EtOAc 1:1). Spectral data for 222f: H NMR (500 MHz, CDCl3) δ 1.60 (brs, 1H), 3.72 (s, 4H), 6.96-7.14 (m, 4H), 7.26-7.50 (m, 4H); 13 C NMR (125 MHz, CDCl3) δ 52.34, 115.14 (J = 21.1 Hz), 129.60 (J = 7.8 Hz), 1 135.91 (J = 3.1 Hz), 161.92 (J = 243.0 Hz). H NMR data match previously reported data. 90b 7.5.2 Catalytic asymmetric Ugi-type reaction General procedure for the catalytic asymmetric Ugi-type reaction 355 A 25 mL pear-shaped single neck flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it), cooled to rt under N2 and charged with 20 mol% ligand (0.050 mmol, 0.20 equiv), 40 mol% PhOH (9 mg, 0.10 mmol, 0.40 equiv), 60 mol% H2O (27 mg, 2.7 µL, 0.15 mmol, 0.60 equiv), dry toluene (2 mL) and 60 mol% BH3•Me2S (2M, 75 µL, 0.15 mmol, 0.60 equiv). The Teflon valve was closed and the flask was heated at 100 o C for 1 hour. After the flask was cooled to rt, the toluene was carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon valve. After the solvent was removed, the Teflon valve was completely opened and the flask was heated at 100 °C under high vacuum for 30 min. The flask was then allowed to cool to rt. Then a solution of dibenzylamine or its derivative (0.50 mmol, 2.00 equiv) in specified solvent (0.5 mL) was added under a N2 stream, followed by the addition of a solution of benzaldehyde (27 mg, 0.25 mmol, 1.0 equiv) in specified solvent (0.5 mL). t-butyl isocyanide (45 µL, 0.37 mmol, 1.5 equiv) was added under N2. The Teflon valve was then closed, and the resulting mixture was stirred at rt for a specified time (24-46 h). After the reaction, the entire solution was loaded onto the silica gel column to obtain the corresponding product. The absolute stereochemistry for the products was not determined. N-(tert-butyl)-2-(dibenzylamino)-2-phenylacetamide 223a (Table 6.4, entry 1): Bn Bn N H N Ph O 223a 356 The general procedure for the catalytic asymmetric Ugi-type reaction was followed with (S)-VAPOL (27 mg, 0.050 mmol, 0.20 equiv), 2,4,6-tri-t-butylphenol (27 mg, 0.10 mmol, 0.40 equiv) and mesitylene (1 mL) as the solvent with a reaction time of 36 h at rt. After the column (silica gel, 18 × 250 mm, hexane:EtOAc 19:1), the product was obtained as a pale yellow solid (85 mg, 0.021 mmol, 85%). The optical purity was determined to be 66% ee by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 98:2, 222 nm, flow 1 mL). Retention times: tR = 12.73 min (major enantiomer) and tR = 23.70 min (minor enantiomer); mp 112-114 °C; Rf = 0.40 (hexane: EtOAc 4:1). Spectral data for 1 223a: H NMR (500 MHz, CDCl3) δ 1.38 (s, 9H), 3.33 (d, 2H, J = 14.0 Hz), 3.81 (d, 2H, J = 14.0 Hz), 4.28 (s, 1H), 7.10 (brs, 1H), 7.20-7.42 (m, 15H); 13 C NMR (125 MHz, CDCl3) δ 28.81, 50.97, 54.55, 68.14, 127.27, 127.67, 128.09, 128.53, 128.61, 130.31, 134.55, 138.79, 170.65; MS (EI) 386 (M, 0.23), 314 (M-72, 1.30), 286 (M-100, 89.80), 91 (M-295, 100); IR (thin film) 3343(w), 2966(w), 1684(s) –1 + cm ; HRMS (ESI) calcd for C26H31N2O m/z 387.2436 ([M+H] ), meas 387.2461. 2-(bis(naphthalen-2-ylmethyl)amino)-N-(tert-butyl)-2-phenylacetamide (Table 6.5, entry 2): 357 223b N Ph H N 223b O The general procedure for the catalytic asymmetric Ugi-type reaction was followed with (R)-VAPOL (27 mg, 0.050 mmol, 0.20 equiv), phenol (10 mg, 0.10 mmol, 0.40 equiv), bis-(naphthalene-2-ylmethyl)amine 222b (188 mg, 0.500 mmol, 2.00 equiv) and toluene (1 mL) as the solvent with a reaction time of 36 h at rt. After the column (1 2 nd st column, silica gel, 20 × 200 mm, hexane:EtOAc 9:1; column, silica gel, 18 × 200 mm, hexane:EtOAc 15:1), the product was obtained as a yellow semi-solid (92 mg, 0.19 mmol, 76%). The optical purity was determined to be 8% ee by HPLC analysis (Chiralcel OD-H column, hexanes/2propanol 98:2, 222 nm, flow 1 mL). Retention times: tR = 12.73 min (minor enantiomer) and tR = 23.70 min (major enantiomer); Rf = 0.25 (hexane:EtOAc). 1 Spectral data for 223b: H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 3.60 (d, 2H, J = 14.0 Hz), 4.05 (d, 2H, J = 14.0 Hz), 4.39 (s, 1H), 7.10 (brs, 1H), 7.32-7.60 (m, 11H), 7.74-7.92 (m, 8H); 13 C NMR (125 MHz, CDCl3) δ 28.84, 51.05, 54.77, 68.10, 125.78, 126.18, 126.56, 127.58, 127.63, 127.65, 127.75, 128.16, 128.32, 130.30, 132.80, 133.33, 134.74, 136.35, 170.64; IR (thin film) 3343(w), 2966(w), 358 –1 1680(s), 1508(s) cm ; HRMS (ESI) calcd for C34H35N2O m/z 487.2749 + ([M+H] ), meas 487.2788. 2-(bis(4-methoxybenzyl)amino)-N-(tert-butyl)-2-phenylacetamide 223c (Table 6.5, entry 3): OMe N MeO H N Ph 223c O The general procedure for the catalytic asymmetric Ugi-type reaction was followed with (R)-VAPOL (27 mg, 0.050 mmol, 0.20 equiv), phenol (10 mg, 0.10 mmol, 0.40 equiv), bis-(4-methoxybenzyl)amine 222c (129 mg, 0.500 mmol, 2.00 equiv) and toluene (1 mL) as the solvent with a reaction time of 48 h at rt. After the column (silica gel, 20 × 200 mm, hexane:EtOAc 9:1), the product was obtained as a yellow semi-solid (90 mg, 0.021 mmol, 82%). The optical purity was determined to be 15% ee by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: tR = 6.90 min (minor enantiomer) and tR = 19.59 min (major enantiomer). Rf = 0.30 1 (hexane:EtOAc 4:1). Spectral data for 223c: H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 3.26 (d, 2H, J = 13.5 Hz), 3.76 (s, 6H), 3.81 (d, 2H, J = 13.5 Hz), 4.30 (s, 1H), 6.90 (d, 4H, J = 9.0 Hz), 7.18 (brs, 1H), 7.25 (d, 4H, J = 8.5 Hz), 7.28-7.42 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 28.78, 50.84, 53.58, 55.20, 67.95, 359 113.87, 127.55, 128.00, 129.69, 130.29, 130.68, 134.60, 158.78, 170.77; MS (EI) 346 (M-100, 32.94), 121 (100); IR (thin film) 3348(w), 2963(w), 1680(s), 1512(s) –1 + cm ; HRMS (ESI) calcd for C28H35N2O3 m/z 447.2648 ([M+H] ), meas 447.2631. 2-(bis(4-fluorobenzyl)amino)-N-(tert-butyl)-2-phenylacetamide 223d (Table 6.5, entry 4): Br Br N H N Ph 223d O The general procedure for the catalytic asymmetric Ugi-type reaction was followed with (R)-VAPOL (27 mg, 0.050 mmol, 0.20 equiv), phenol (10 mg, 0.10 mmol, 0.40 equiv), bis-(4-bromobenzyl)amine 222d (178 mg, 0.500 mmol, 2.00 equiv) and toluene (1 mL) as the solvent with a reaction time of 36 h at rt. After the column (1 st nd column, silica gel, 20 × 200 mm, hexane:EtOAc 15:1; 2 column, silica gel, 18 × 150 mm, hexane:EtOAc 15:1), the product was obtained as a white foamy-solid (93 mg, 0.0 mmol, 72%). The optical purity was determined to be 27% ee by HPLC analysis (Chiralpak AD column, hexanes/2propanol 98:2, 222 nm, flow 1 mL); Retention times: tR = 9.77 min (minor enantiomer) and tR = 45.91 min (major enantiomer). mp 108-109 °C; Rf = 0.50 1 (hexane:EtOAc 4:1); Spectral data for 223d: H NMR (500 MHz, CDCl3) δ 1.40 360 (s, 9H), 3.41 (d, 2H, J = 14.5 Hz), 3.74 (d, 2H, 14.0 Hz), 4.20 (s, 1H), 6.50 (brs, 1H), 7.14-7.24 (m, 4H), 7.26-7.40 (m, 5H), 7.42-7.52 (m, 4H); 13 C NMR (125 MHz, CDCl3) δ 28.50, 50.94, 53.61, 67.98, 120.79, 127.66, 128.04, 129.48, 129.94, 131.33, 134.77, 137.51, 179.10; IR (thin film) 3337(w), 2966(w), 1669(s), –1 79 + 1487(s) cm ; HRMS (ESI) calcd for C26H29N2O Br2 m/z 543.0647 ([M+H] ), meas 543.0645. 2-(bis(4-chlorobenzyl)amino)-N-(tert-butyl)-2-phenylacetamide 223e (Table 6.5, entry 5): Cl Cl N H N Ph 223e O The general procedure for the catalytic asymmetric Ugi-type reaction was followed with (R)-VAPOL (27 mg, 0.050 mmol, 0.20 equiv), phenol (10 mg, 0.10 mmol, 0.40 equiv), bis-(4-chlorobenzyl)amine 222e (133 mg, 0.500 mmol, 2.00 equiv) and toluene (1 mL) as the solvent with a reaction time of 24 h at rt. After the column (1 st nd column, silica gel, 20 × 200 mm, hexane:EtOAc 15:1; 2 column, silica gel, 18 × 150 mm, 15:1), the product was obtained as a white foamy-solid (83 mg, 0.018 mmol, 73%). The optical purity was determined to be 23% ee by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 98:2, 222 nm, flow 1 mL). Retention times: tR = 9.76 min (minor enantiomer) and tR = 361 45.91 min (major enantiomer); mp 105-106 °C, Rf = 0.50 (hexane:EtOAc 4:1). 1 Spectral data for 223e: H NMR (300 MHz, CDCl3) δ 1.40 (s, 9H), 3.44 (d, 2H, J = 14.1 Hz), 3.78 (d, 2H, J = 14.1 Hz), 4.23 (s, 1H), 6.60 (brs, 1H), 7.22-7.46 (m, 13H); 13 C NMR (125 MHz, CDCl3) δ 28.75, 51.17, 53.77, 68.16, 127.90, 128.28, 128.64, 129.78, 129.82, 132.96, 134.91, 137.20, 170.41; IR (thin film) 3337(w), –1 35 2966(w), 1668(s), 1491(s) cm ; HRMS (ESI) calcd for C26H29N2O Cl2 m/z + 455.1657 ([M+H] ), meas 455.1680. 2-(bis(4-fluorobenzyl)amino)-N-(tert-butyl)-2-phenylacetamide 223f (Table 6.5, entry 5): F F N H N Ph 223f O The general procedure for the catalytic asymmetric Ugi-type reaction was followed with (R)-VAPOL (27 mg, 0.050 mmol, 0.20 equiv), phenol (10 mg, 0.10 mmol, 0.40 equiv), bis-(4-chlorobenzyl)amine 222f (117 mg, 0.500 mmol, 2.00 equiv) and toluene (1 mL) as the solvent with a reaction time of 36 h at rt. After the column (silica gel, 18 × 250 mm, hexane:EtOAc 15:1), the product 223f was obtained as a yellow foamy-solid (78 mg, 0.018 mmol, 72%). The optical purity was determined to be 27% ee by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 98:2, 222 nm, flow 1 mL). Retention times: tR = 9.71 min 362 (minor enantiomer) and tR = 25.12 min (major enantiomer); mp 105-107 °C; Rf = 1 0.40 (hexane:EtOAc). Spectral data for 223f: H NMR (500 MHz, CDCl3) δ 1.38 (s, 9H), 3.38 (d, 2H, J = 14.0 Hz), 3.74 (d, 2H, J = 14.0 Hz), 4.20 (s, 1H), 6.66 (brs, 1H), 6.96-7.20 (m, 4H), 7.20-7.38 (m, 9H); 13 C NMR (125 MHz, CDCl3) δ 28.79, 51.12, 53.70, 68.28, 115.34 (J = 21.13 Hz), 127.85, 128.26, 129.90, 130.06 (J = 7.75 Hz), 134.46 (J = 3.3 Hz), 135.03, 162.03 (J = 244.6 Hz), 170.50; –1 IR (thin film) 3339(w), 2968(w), 1684(s), 1508(s) cm ; HRMS (ESI) calcd for + C26H29N2OF2 m/z 423.2248 ([M+H] ), meas 423.2268. 363 REFERENCES 364 REFERENCES 1. Dahanukar, V. H.; Zavialov, L. A. Curr. Opin. Drug. 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