BOROX-ANION INDUCED CATALYTIC ASYMMETRIC REACTIONS AND THEIR SYNTHETIC APPLICATIONS By Wenjun Zhao A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry—Doctor of Philosophy 2014   ABSTRACT BOROX-ANION INDUCED CATALYTIC ASYMMETRIC REACTIONS AND THEIR SYNTHETIC APPLICATIONS By Wenjun Zhao The development of a catalytic asymmetric three-component Ugi reaction is described. The first chiral catalyst for the three-component Ugi reaction was identified as a result of a screen of a large set of different polyborate catalysts (BOROX catalysts). The BOROX catalysts were assembled in situ from a chiral biaryl ligand, an amine, water, BH3·SMe2, and an alcohol or phenol. The optimal catalyst system (LAP 78-5-47) provided α-amino amides from an aryl aldehyde, a secondary amine, and an isonitrile with high asymmetric induction. It is considered likely that the BOROX bind to the iminium ion or nitrilium ion as a chiral counter anion catalyst, as suggested by 1H and 11B NMR studies. The second project involves the application of BOROX-catalyzed aziridination to the synthesis of β-amino esters. A general study is undertaken to examine the scope of the reductive ring-opening of aziridine-2-carboxylates with samarium diiodide. The competition between C-C and C-N bond cleavage is examined as a function of the nature of the N-substituent of the aziridine, the nature of the substituent in the 3-position of the aziridine and on whether the substituent in the 3-position is in a cis- or trans-relationship with the carboxylate in the 2-position. Exclusive formation of the C-N cleavage product is observed for all aziridines with the strongly N-activating p-toluene sulfonate group. Nearly as high a selectivity is observed for the 2-trimethylsilylethyl sulfonate group (SES) which is easier to remove. The utility of these methods is illustrated in the synthesis of (R)-β3-DOPA and L-DOPA from the same aziridine, the former by SmI2 mediated reductive opening at C-2 and the latter by palladium mediated reductive opening at C-3. Lastly, the BOROX-catalyzed asymmetric aziridination is applied in the studies of total synthesis of one of the “two-headed” sphingoid bases, rhizochalinin C. The synthesis of left head 168 and right head 169 was developed. Late stage coupling of the two head-pieces provided the product with the complete carbon skeleton in high yield. The hydrogenation catalyzed by Pd(OH)2 in the presence of (Boc)2O successfully removed the two MEDAM groups, reduced the triple bond, removed the Bn group and reductively opened the aziridine ring. The final steps planned for the synthesis involving selective reduction of the carboxylic acid or the ester in the presence of a ketone failed to give any desired product. The synthesis will be further investigated. To my dearest parents, my husband and my brother   iv   ACKNOWLEDGEMENTS This dissertation would not have been completed without the support offered to me along the way. I owe my sincere gratitude to all those people who have made this dissertation possible and because of whom my graduate experience has been one that I will cherish forever. First and foremost, I would like to thank my advisor, Dr. William D. Wulff, for his consistent support, invaluable guidance and encouragement throughout this research work. His direction and patience greatly aided me, especially in my early research endeavors. He has taught me, both consciously and un-consciously, the right attitude toward research. The joy and enthusiasm he has for organic chemistry was contagious and motivational for me. He is always available whenever I need his help. Thank you, Dr. Wulff, for all your help and support, for providing me the opportunity to work on these exciting projects. It is a great experience to do research under your guidance. I would also like to thank Dr. Robert E. Maleczka Jr., Dr. Babak Borhan and Dr. Aaron L. Odom for serving on my Ph.D. committee. I am grateful for their time, insightful suggestions and constructive feedbacks on my research. Thank them for supporting me in my postdoc application. Special thanks to Dr. Robert E. Maleczka Jr. for passing me information about some potential job opportunities. I am also grateful to the current and the former lab mates: Dr. Aman Desai, Dr. Li Huang, Dr. Yong Guan, Dr. Hong Ren, Dr. Dima Berbasov, Dr. Anil Gupta, Dr. Munmun Mukherjee, Dr. Nilanjana Majumder, Dr. Wynter Gilson, Dr. Mathew Vetticatt, Xin Zhang, Yubai Zhou, Xiaopeng Yin and Yijing Dai for their friendship and collaboration. In   v   particular, I would like to thank Dr. Hong Ren and Dr. Li Huang for their great help in both my research and my daily life. I am grateful to Dr. Anil Gupta for his training me during my first several months and Dr. Mathew Vetticatt for his encouragement and valuable advice on my research. I would like to thank my friends, Yimeng Wang, Li Cui, Jinlan Dong, Li Xie, for all the wonderful moments we have shared together since the very first month of my Ph.D. life. I am also grateful to Ms. Dottie Schmidt for being a caring landlord and friend in the last several months of my Ph.D. life. Special thanks to my naughty pet bunny, doudou, who filled my life with fun and responsibility. I would like to thank Dr. Daniel Holmes and other NMR staff for their tremendous help in NMR training and problem solving. I am also grateful to Dr. Rui Huang for his help in elemental analysis. Great thanks to Ms. Lijun Chen and Prof. Daniel Jones from the Department of Biochemistry, Michigan State University for their kind help in HRMS training and the service. I would like to thank the Department of Chemistry for offering me teaching assistantships, travel grants and fellowships. Finally, I would like to thank my father, Guoqi Zhao and my mother, Meiling Yang for their love, support and encouragement over the years. They are always there for me throughout my life. Special thanks to my dear husband, Dr. Chao Wang, whose patience, understanding and unconditional love accompanied and supported me throughout my Ph.D. journey.   vi   TABLE OF CONTENTS LIST OF TABLES ............................................................................................................. x LIST OF FIGURES .......................................................................................................... xi LIST OF SCHEMES ....................................................................................................... xii CHAPTER 1 ..................................................................................................................... 1 INTRODUCTION AND REVIEWS .................................................................................... 1 1.1 Chiral Counteranions Directed Asymmetric Catalysis ............................................. 1 1.2 BOROX Anion Directed Asymmetric Catalysis ....................................................... 7 1.2.1 The Identification of BOROX Catalyst in Asymmetric Aziridination .................. 8 1.2.2 BOROX-Anion-Directed Asymmetric Aziridination ......................................... 10 1.2.3 BOROX-Anion-Directed Hetero-Diels-Alder Reaction .................................... 12 1.2.4 BOROX-Anion-Directed Aza-Cope Rearrangement ....................................... 13 1.2.5 BOROX-Anion-Directed Three-Component Ugi Reaction .............................. 14 1.3 Conclusion ............................................................................................................ 14 CHAPTER 2 ................................................................................................................... 16 CATALYTIC ASYMMETRIC THREE-COMPONENT UGI REACTION .......................... 16 2.1 Introduction ........................................................................................................... 16 2.2 Catalyst Diversity of BOROX Catalytic System ..................................................... 21 2.3 The Discovery and Initial Optimization of a Catalytic Asymmetric ThreeComponent Ugi Reaction ...................................................................................... 22 2.4 The Early Impediments to the Further Optimization .............................................. 25 2.5 Revisit of the Ugi Reactions with Amines A-1 and A-6 ......................................... 28 2.6 Variation of the Catalysts with Different Chiral Ligands ........................................ 29 2.7 Study of Solvent Effect on the BOROX Catalyst ................................................... 31 2.8 Effects of Concentration and Amine Stoichiometry on the Three-Component Ugi Reaction ................................................................................................................ 32 2.9 Effects of Different Additives in the Catalytic System ........................................... 33 2.10 Variation of the Catalysts by Incorporating Different Alcohols and Phenols ....... 35 2.11 Study of the Reactivities of Different Dibenzylamine Derivatives ........................ 36 2.12 Substrate Scope of Different Aryl Aldehydes at Both RT and 0 °C ..................... 38 2.13 Substrate Scope of Different Isocyanides at RT ................................................. 41 2.14 Studies of Catalyst Loading ................................................................................ 42 2.15 Determination of the Absolute Configuration of the Ugi Product 65a .................. 43 2.16 Reaction Progress Monitored by 1H NMR Spectroscopy .................................... 44 2.16.1 Ugi-3CR with Different Aldehydes ................................................................ 44   vii   2.16.2 Reaction Progress of Ugi-3CR of 63a with Different Amounts of 4Å MS or H2O as An Additive ....................................................................................... 45 2.17 Proposed Mechanism for the Asymmetric Catalytic Three Component Ugi-3CR ........................................................................................................................... 47 2.18 NMR Evidence for the Formation of BOROX Anion Catalyst .............................. 49 2.19 Attempted Asymmetric Four-Component Ugi Reaction ...................................... 54 2.20 Conclusion .......................................................................................................... 55 CHAPTER 3 ................................................................................................................... 57 β-AMINO ESTERS FROM THE REDUCTIVE RING OPENING OF AZIRIDINES-2CARBOXYLATES .......................................................................................................... 57 3.1 Introduction ........................................................................................................... 57 3.2 Initial Studies of Ring-Opening Reactions with cis-Fmoc-Protected Aziridines .... 60 3.3 SmI2 Mediated Ring-Opening Reactions with Various N-Protected Aziridines ..... 62 3.4 SmI2 Mediated Ring-Opening Reactions with un-Activated Aziridines ................. 65 3.5 SmI2 Mediated Ring-Opening Reactions with a Tri-Substituted Aziridine ............. 67 3.6 Mechanistic Rationale for the Selectivity Observed in the SmI2-Mediated Ring Opening Reactions of Aziridines ........................................................................... 68 3.7 Syntheses of L-DOPA and (R)-β3-DOPA .............................................................. 73 3.8 Conclusion ............................................................................................................ 77 CHAPTER 4 ................................................................................................................... 79 STUDIES ON THE SYNTHESES OF TWO-HEADED SPHINGOID BASES ................. 79 4.1 Introduction ........................................................................................................... 79 4.2 Synthetic Strategy towards the Four Two-Headed Sphingoids ............................. 83 4.3 Retrosynthetic Analysis of Rhizochalinin C ........................................................... 84 4.4 Synthesis of Right Head 169 and Left Head 168 .................................................. 85 4.4.1 Synthesis of Right Head 169 .......................................................................... 85 4.4.2 Synthesis of Left Head 168............................................................................. 86 4.5 Late-stage Coupling of Left Head 168 and Right Head 169 Followed by Removal of the TBS group ................................................................................................... 90 4.6 Global Deprotection, Alkyne Reduction and Ring Opening of Aziridine 184 by Hydrogenation Followed by Hydrolysis ................................................................. 92 4.7 Attempted Selective Reduction of the Carboxylic Acid in the Presence of a Ketone .............................................................................................................................. 93 4.8 Attempted Selective Reduction of the Ethyl Ester in the Presence of a Ketone ... 93 4.9 Conclusion ............................................................................................................ 95 CHAPTER 5 ................................................................................................................... 97 EXPERIMENTAL SECTION ........................................................................................... 97 5.1 Experimental Part for Chapter 1 ............................................................................ 98 5.1.1 Preparation of Chiral Ligand (R)-76 and (R)-78.............................................. 98 5.1.2 Preparation of Phenols ................................................................................. 110   viii   5.1.3 Preparation of Amines A-11 and A-12.......................................................... 121 5.1.4 General Procedure A for Optimization of the Ugi-3CR ................................. 123 5.1.5 Attempted Ugi Reaction with Amines A-1 and A-6 (Scheme 2.8) ................ 124 5.1.6 Ugi Reaction with Amines A-7—A-12 with General Procedure A (Part 5.1.4) and B (Part 5.1.7) ......................................................................................... 126 5.1.7 Formation of α-Amino Amides 65a—65q with General Procedure B ........... 133 5.1.8 Intramolecular Interception of the Nitrilium Cation ........................................ 152 5.1.9 Formation of α-Amino Amides with Different Isocyanides ............................ 153 5.1.10 Determination of the Absolute Configuration of the Ugi Product 65a (Scheme 2.10) ............................................................................................................ 159 5.1.11 Preparation of the Aminal 85a .................................................................... 162 5.1.12 1H NMR Study of the Reaction Progress (Figures 2.2-2.4) ........................ 163 5.1.13 Effect of PhCOOH on the Ugi-3CR............................................................. 165 5.1.14 Four-Component Ugi Reaction ................................................................... 166 5.2 Experimental Part for Chapter 3 .......................................................................... 168 5.2.1 Preparation of Protected Aziridines ............................................................. 168 5.2.2 Reductive Ring Opening of Aziridines-2-Carboxylates with SmI2 ................. 176 5.2.3 Determination of the Relative Stereochemistry of anti-124 .......................... 187 5.2.4 Formation of Aziridines 145-147 ................................................................... 188 5.2.5 Synthesis of Protected Forms of L-DOPA .................................................... 191 5.2.6 Formation of Aziridines 149-151 ................................................................... 193 5.2.7 Reductive Ring Opening of Aziridines 149-151 ............................................ 198 5.3 Experimental Part for Chapter 4 .......................................................................... 204 5.3.1 Preparation of Left Head 169........................................................................ 204 5.3.2 Procedures for Catalytic Azymmetric Aziridination of Aldehyde 176 (Table 4.1) ............................................................................................................................... 205 5.3.3 Procedure for Ring Opening Reaction of Aziridine 174 (Table 4.1, illustrated for entry 5) ............................................................................................................. 207 5.3.4 Procedure for Converting Compound 172 to Left Head 168 ........................ 209 5.3.5 Procedure for Coupling Reaction of Left Head 168 and Right Head 169 ..... 212 5.3.6 Procedure for Removal of TBS Group in 183 ............................................... 214 5.3.7 Preparation of 185 and 188 by Hydrogenation ............................................. 215 5.3.8 Preparation of 186 by Hydrolysis of 185 ....................................................... 217 REFERENCES ............................................................................................................. 219   ix   LIST OF TABLES Table 2.1 Screen of VANOL and BINOL ligands ............................................................ 23 Table 2.2 Reactions with selected phenols and impurities from P-24 ............................ 27 Table 2.3 Synergism in the arrangement of the substituents in the boroxinate core[a] ... 30 Table 2.4 Solvent effect on the three-component Ugi reaction ...................................... 32 Table 2.5 Ugi-3CR with different concentrations and equivalents of amine .................. 33 Table 2.6 The effects of different additives on the three-component Ugi reaction ......... 34 Table 2.7 Screen of substituted dibenzyl amines with ligand 78[a] ................................. 37 Table 2.8 Substrate scope of the catalytic asymmetric 3-component Ugi reaction[a] ..... 39 Table 2.9 Ugi-3CR with different isocyanides ................................................................ 42 Table 2.10 Effect of molecular sieves on catalyst loading .............................................. 43 Table 3.1 Reductive opening of cis- and trans-Fmoc aziridines[a] .................................. 62 Table 3.2 Reductive opening of cis- and trans-N-activated aziridines[a] ......................... 63 Table 3.3 Reductive opening of cis-unactivated aziridines[a] .......................................... 66 Table 4.1 Catalytic asymmetric aziridination with aldehyde 176 .................................... 87 Table 4.2 Ring opening reaction of aziridine 174 ........................................................... 89 Table 4.3 Removal of TBS group in 183 ........................................................................ 91   x   LIST OF FIGURES Figure 1.1 Key activation modes in chiral anion directed asymmetric catalysis ............... 2 Figure 1.2 X-ray structure of BOROX-iminium ion pair .................................................. 10 Figure 2.1 Screen of different phenols and alcohols ...................................................... 25 Figure 2.2 1H NMR study of the Ugi-3CR with aldehydes 63a, 63d and 63n................. 45 Figure 2.3 1H NMR study of the Ugi-3CR of 63a with different amounts of 4Å MS ........ 46 Figure 2.4 1H NMR study on the formation of 65a from the Ugi-3CR with 4Å MS and H2O ............................................................................................................... 47 Figure 2.5 1H NMR spectra in d8-toluene of the pre-catalyst and catalyst (bay proton region) with 1.0 equivalent amine A-5 .......................................................... 50 Figure 2.6 11B NMR spectra in d8-toluene of the pre-catalyst and catalyst with 1.0 equivalent amine A-5 .................................................................................... 51 Figure 2.7 1H NMR spectra in d8-toluene of the pre-catalyst and catalyst (bay proton region) ........................................................................................................... 53 Figure 2.8 11B NMR spectra in d8-toluene of the pre-catalyst and catalyst .................... 54 Figure 4.1 The general structure of sphingolipids and examples of sphingoid bases .... 79 Figure 4.2 The first member of the “two-headed” sphingolipids series .......................... 81   xi   LIST OF SCHEMES Scheme 1.1 Tetracoordinated borate anion directed asymmetric catalysis ..................... 3 Scheme 1.2 Selected examples of chiral phosphate anion directed asymmetric catalysis and activation mode of anion-binding catalysis ............................................ 5 Scheme 1.3 Asymmetric aziridination and the formation of BOROX catalysts ................ 8 Scheme 1.4 The Wulff asymmetric cis-aziridination reaction ......................................... 11 Scheme 1.5 The Wulff asymmetric trans-aziridination reaction ..................................... 11 Scheme 1.6 Multicomponent asymmetric cis-aziridination reaction ............................... 12 Scheme 1.7 Asymmetric hetero-Diels-Alder reaction ..................................................... 13 Scheme 1.8 Catalytic asymmetric aza-Cope rearrangement ......................................... 13 Scheme 1.9 Catalytic asymmetric three-component Ugi reaction .................................. 14 Scheme 2.1 Typical Ugi four component reaction and the proposed mechanism ......... 16 Scheme 2.2 Four-component Ugi reaction with a 2° amine ........................................... 17 Scheme 2.3 Examples of three-component Ugi reaction with 2° amine ........................ 19 Scheme 2.4 Catalytic three-component Ugi reaction reported by List’s group .............. 19 Scheme 2.5 Catalytic asymmetric Ugi-type reactions .................................................... 20 Scheme 2.6 Catalyst diversity via in situ substrate induced assembly .......................... 21 Scheme 2.7 Initial screen of amines with benzaldehyde and t-butyl isonitrile ................ 22 Scheme 2.8 Attempted Ugi reactions with amines A-1 and A-6 .................................... 28 Scheme 2.9 Screen of additional phenol substituents in the boroxinate core with ligand 78 ............................................................................................................... 36 Scheme 2.10 Intramolecular interception of the nitrilium cation .................................... 41 Scheme 2.11 Determination of absolute stereochemistry of 65a ................................... 44   xii   Scheme 2.12 Proposed mechanism for the catalytic asymmetric Ugi reaction .............. 48 Scheme 2.13 Catalyst formation with 1.0 equivalent of dibenzylamine A-5 ................... 49 Scheme 2.14 Catalyst formation with 10.0 equivalent of dibenzylamine A-5 ................. 52 Scheme 2.15 Ugi-4CR with benzoic acid ....................................................................... 55 Scheme 3.1 Proposed catalytic asymmetric route to β-amino esters ............................ 58 Scheme 3.2 Ring-opening of aziridine-2-carboxylates with an aryl group at the 3position under different conditions ............................................................. 59 Scheme 3.3 Selective ring-opening of aziridine-2-carboxylate at the 2-position with Mg(0) and SmI2 .......................................................................................... 59 Scheme 3.4 Ring-opening of cis-96a by Mg(0) and SmI2 .............................................. 61 Scheme 3.5 Ring-opening of aziridine 123 by SmI2 and determination of relative stereochemistry of anti-124 ........................................................................ 68 Scheme 3.6 Mechanistic rationales for SmI2-mediated ring opening process ............... 69 Scheme 3.7 Mechanistic rationale for different selectivities observed for trans- and cisaziridines .................................................................................................... 72 Scheme 3.8 Reported example of a C-C cleavage product from reductive ring opening process....................................................................................................... 72 Scheme 3.9 Reported example of C-C cleavage product from reductive ring ............... 73 Scheme 3.10 Syntheses of protected forms of L-DOPA and (R)-β3-DOPA ................... 75 Scheme 4.1 Total synthesis of rhizochalinin C from a chiral pool .................................. 82 Scheme 4.2 Proposed synthetic approach to the four sphingoid bases ........................ 84 Scheme 4.3 Retrosynthetic analysis for rhizochalinin C ................................................ 85 Scheme 4.4 Synthesis of right head 169 ........................................................................ 86 Scheme 4.5 Synthesis of 168 from 172 ......................................................................... 90 Scheme 4.6 Coupling of 168 with 169 ............................................................................ 90 Scheme 4.7 Entry point to rhizochalin C ........................................................................ 92   xiii   Scheme 4.8 Hydrogenation and hydrolysis .................................................................... 92 Scheme 4.9 Proposed final steps toward the synthesis of rhizochalinin C .................... 93 Scheme 4.10 Modified strategy toward the synthesis of rhizochalinin C ....................... 94 Scheme 4.11 Modified strategy toward the synthesis of rhizochalinin C ....................... 95   xiv   CHAPTER 1 INTRODUCTION AND REVIEWS This work has focused on BOROX-anion directed catalysis, including the development of a BOROX-catalyzed asymmetric three-component Ugi reaction and the application of BOROX-catalyzed asymmetric aziridination to the synthesis of β-amino acids and total synthesis of “two headed sphingolipids”. The catalytic asymmetric three component Ugi reaction is proposed to proceed via a strict ion pair between a fully substituted iminium and the BOROX anion, while the BOROX catalyzed asymmetric aziridination involves a hydrogen-bonding assisted ion pair, and thus is a Brønsted acid catalyzed process. 1.1 Chiral Counteranions Directed Asymmetric Catalysis The field of asymmetric catalysis has witnessed explosive growth over the last 40 years due to the increasing demands of both industry and academia for enantiomerically enriched molecules. The interactions between chiral catalysts and the substrates, which are key to achieving high levels of asymmetric induction in the products, include covalent bonding as in enamine1 or iminium2 catalysis and noncovalent bonding, such as coordinative interactions, hydrogen bonding3 and ion pairing interactions4. Since many organic reactions proceed via ionic intermediates or reagents, an ion paring between a chiral ion and the charged intermediate can be a powerful strategy to achieve highly efficient asymmetric synthesis. The use of a chiral cation through ion-pairing has been effectively applied in reactions involving anionic intermediates via asymmetric phase transfer catalysis since 1984.5 However, the charge-inverted process, 1 asymmetric catalysis using chiral anions, has only emerged recently as an important approach for stereochemical control in reactions proceeding via a cationic intermediate. Figure 1.1 Key activation modes in chiral anion directed asymmetric catalysis organocatalysis transition metal catalysis R3 substrate M Y* strict ion pair Type I N R1 H Y* R2 H-bonding assisted ion pair Type II R3 R1 N R4 Y* R2 strict ion pair Type III The synthesis, identification and resolution of a number of different chiral anions led to the fast progression of chiral anion-directed catalysis. Typically, there are three types of activation modes in asymmetric counteranion-directed catalysis (ACDC) (Figure 1.1).6 Type I is the application of ACDC in transition metal catalysis, which involves an ion pairing between a chiral anion and a cationic substrate-metal complex. Type II is the application of ACDC in Brønsted acid catalysis. In this case the key interaction for achieving asymmetric induction is an ion pair between a protonated substrate and the counteranion of the acid catalyst. The ion pair is generated as a result of an initial proton transfer from the strong Brønsted acid catalyst to the basic substrate. Then a non-covalent interaction involving H-bonding is developed between the resulting ion pair of the protonated substrate and the chiral counteranion of the acid catalyst.6c If the hydrogen bonding is excluded, as in reactions proceeding via a fully substituted iminium cation where there is no site to accept a hydrogen bonding, it can be 2 considered as the third category (Figure 1.1, type III). This third type actually can be a very powerful strategy to develop efficient asymmetric organocatalysis. Different classes of chiral anions have been explored in ACDC. Tetracoordinated borate and hexacoordinated phosphate were selected as suitable candidates in the early attempts of chiral anion directed catalysis due to their non-coordinating nature. In 2000, Arndtsen and co-workers reported the first example of a chiral anion directed transition metal catalysis (type I activation mode) (Scheme 1.1, a)).7 Scheme 1.1 Tetracoordinated borate anion directed asymmetric catalysis a) Ph + 1 5 equiv PhINTs 2 1 equiv Ts N 3 mol % [Cu +] [3] 3.1 mol % 2,2'-bipyridine benzene, 0 °C 4 Ph 43% yield 10% ee Cl Cl O O O B O O 3 B O Ph [(CH 3CN)nCu NTs ] 5 b) Ph Cl Ph N 7 3 Cl O O N 6 Ph [Et 3NH +][3] or [Bu 3NH +][9] (50 mol %) BnNH 2 (2.0 equiv) Et 3N (2.0 equiv) THF/toluene, 100 °C O Cl O Cl Ph O Cl N 6 Ph Ph Ph 8 Cl P Cl O O 9O Cl Cl Cl Cl NHBn [6][3] 15 % e.e. 25 % yield N [6][9] 12 % e.e. 22 % yield The existence of ion pair [5][3] was supported by the adverse effect of increasing solvent dielectric constant on the enantioselectivities and also by crystal structure analysis. This spiro-borate anion 3 was later applied to organocatalysis by Nelson and co-workers in an aziridinium ring opening reaction 3 (type III activation mode) (Scheme 1.1, b)).8 The NMR chemical shifts and proton splitting information observed in their 1H and 13 C NMR studies indicated that there was an ion-paring interaction between the chiral anion 3 and the mesoaziridinium cation 6, but not to a great extent, which was consistent with the low enantioselectivities obtained. Phosphate 9 was also investigated in this work, which gave the same level of enantioselectivity. Despite the low level of asymmetric inductions achieved, the early studies with chiral borate and phosphate anions validated the concept of using chiral counteranions to introduce asymmetric induction, which set the stage for future advances in ACDC. The more recent developments of ACDC are closely related to Brønsted acid catalysis. The conjugate base of strong chiral Brønsted acid is a widely used class of counteranion in ACDC. The research groups of Akiyama and Terada published their seminal work on chiral monophosphoric acid catalysis in 2004 (Scheme 1.2, a and b, respectively).9 An ion pairing interaction between the protonated imine 10-H+ and the chiral phosphate anion (R)-13 was proposed by Akiyama and co-workers for their Mannich-type reaction (type II activation mode). Two years later, List and Mayer reported a landmark work involving type III activation mode (Scheme 1.2, c) in ACDC.6a The catalyst was generated from an achiral secondary amine and a chiral phosphoric acid. Since hydrogen bonding was not possible in this case due to the full substitution on iminium nitrogen, the asymmetric hydrogenation was achieved via a strict ion pair [19][(R)-14a]. 4 Scheme 1.2 Selected examples of chiral phosphate anion directed asymmetric catalysis and activation mode of anion-binding catalysis a) HO OSiMe3 + N Ph OEt Me 10 10 mol % (R)-13-H PhCH 3, -78 °C HO H [(R)-13] N R HN O O P O O CO 2Et Ph 11 via ion pair: HO 12 87:13 syn/anti 100% yield, 96% ee (R)-13 R = R NO 2 Naph (R)-14a R = Ph iPr b) O NBoc 2 mol % (R)-14b + Ar O 20 c) N 16H 2 (20 mol %) CO2Me O N iPr 17 H (1.1 equiv) Dioxane, 50 °C, 24 h 15 iPr H H MeO 2C [(R)-14a] Ar (R)-14b R = iPr Ac 22 93-99% yield 90-98% ee 21 O CHO Ar CH 2Cl 2, r.t. NHBoc Ac CHO N via ion pair: [(R)-14a] 18 Ar 19 Ar 63-90% yield 96-99% ee * O (R)-14 P O O O O H LAu d) H OH 2.5 mol % dppm(AuCl)2 5 mol % Ag-(R)-14 23 e) 25a benzene, 23 °C, 1h O via: 24 90% yield 97% ee R R R O O P NTf O SO2 N SO2 O O O O P P N O O R R R 25b 5 R 25c R 23-Au f) anion-binding catalysis S N H N H R X ion-pair intermediates Chiral phosphate anions have also been effectively applied to asymmetric transition metal catalysis. In 2007, the Toste group reported an asymmetric hydroalkoxylation reaction mediated by a dinuclear gold (I) complex, which was the first example of highly enantioselective transition metal catalysis directed by a chiral anion (Scheme 1.2, d).10 The role of phosphate as a counteranion and not a ligand was revealed by the fact that both of the two available coordination sites on AuI center are occupied by the substrate and one phosphorus atom of the bisphosphine ligand. The ion pairing was also supported by the strong solvent effect observed. The reaction that was carried out in the less-polar benzene provided the product with very high asymmetric induction, while a significant drop in the enantioselectivity was observed in more-polar solvent, such as nitromethane or acetone. This work demonstrated that high asymmetric inductions can be achieved by ion pairing strategy using chiral counteranions in asymmetric transition metal catalysis, which represents a breakthrough in the application of ACDC in transition metal catalysis. Successful asymmetric catalysis directed by the conjugate bases of several other chiral strong Brønsted acids have also been reported, such as Ntriflyphosphoramidate anions, disulfonimide anions and imidodiphosphate anions (Scheme 1.2, e).4 Another class of useful chiral couteranions was identified in anion binding catalysis. Anion binding catalysis can be viewed as a special case of ACDC (type III), where the chiral anion is generated from complexation between a chiral neutral thiourea molecule and an achiral anionic leaving group provided by the 6 substrate (Scheme 1.2, f). The ion pairing interaction activates the substrate and also provides high enantioselectivity. This strategy has found a variety of applications in asymmetric organocatalysis.11 1.2 BOROX Anion Directed Asymmetric Catalysis In the previous section, the typical types of ACDC and the major classes of chiral anions have been discussed. Tetrahedral spiro-borate is a class of counteranion that was explored in the development of ACDC. Our group has previously developed an anionic chiral poly-borate catalyst for asymmetric reactions that involve iminium ions including aziridination12, hetero-Diels-Alder reactions13 and aza-Cope rearrangements14. The catalyst structure involves a spiro-borate anion in a boroxinate core and thus we named catalysts of this kind as “BOROX catalysts” (Scheme 1.3, B3). There was no report of utility of a boroxine as a catalyst in organic synthesis prior to our work.15 7 Scheme 1.3 Asymmetric aziridination and the formation of BOROX catalysts Ar O R N Ar + 3-10 mol % BOROX-catalyst Ar N OEt up to 99% ee H Ar R CO2Et N2 28 26 27 Ar = C6H 5, 4-MeOC6H 4, 3,5-Me2-4-MeO-C 6H 2, 3,5-tBu2-4-MeO-C 6H 2 Method A: B(OPh) 3 (3 equiv) B1 (Lewis base) + or B2 an amine or Method B: BH 3· SMe2 (3 equiv) precatalyst an imine H 2O (3 equiv) mixture ROH (2 equiv) OH Ph Ph OH B3 [H-Base] 29 for (S)-VANOL 30 for (S)-VAPOL H-imine Ph Ph O O B OR B1 31 for (S)-VANOL 32 for (S)-VAPOL Ph Ph O O OR B O B OR B2 33 for (S)-VANOL 34 for (S)-VAPOL Ph Ph OR O B O B O O O B OR B3 35 for (S)-VANOL 36 for (S)-VAPOL 1.2.1 The Identification of BOROX Catalyst in Asymmetric Aziridination The structure of the BOROX catalyst was identified during our investigation of the catalytic asymmetric aziridination reaction. There are two standard protocols for the preparation of BOROX catalyst (Scheme 1.3). One typical protocol involves reacting the chiral vaulted bisphenol ligand, either VAPOL or VANOL, with commercial B(OPh)3 (Method A). We have also demonstrated that an equally effective mixture can be generated from the ligand, 8 BH3·SMe2, phenols or alcohols and H2O (Method B). Detailed 1H and 11 B NMR studies and high resolution mass spectroscopy analysis revealed that there were two boron species, tentatively assigned as B1 and B2, in the mixture generated from either of the protocols, with ratios from 10:1 to 1:20 depending on the exact temperature and equivalents of reagents applied.12p The fact that the reaction catalyzed by a precatalyst mixture with higher ratio of B2/B1 gave higher asymmetric introduction led us to think of B2 as a Lewis acid catalyst that was responsible for the high enantioselectivities. Shortly after that, it was found that a mixture of B1 and B2 was converted to a BOROX-involved ion pair when there was a base present.12n Under the asymmetric aziridination reaction conditions, the imine was basic enough to induce the formation of the BOROX-substrate ion pair, which consists of a BOROX anion and an iminium cation resulting from protonation of the imine. This is strongly supported by both NMR and X-ray structure analysis (Figure 1.2)12k. At that point, we realized that the asymmetric aziridination that we have developed involves BOROX-anion directed Brønsted acid catalysis and not Lewis acid catalysis. The effectiveness of a number of different bases on the formation of the BOROX skeleton was investigated. Besides imines, the assembly of BOROX catalyst can be triggered by primary, secondary, tertiary amines. Ethyl diazoacetate and aldehydes are too weak to induce the formation of a BOROX catalyst. The very week base dimethyl acetamide (pKa ~ –0.5) only led to an 18% yield of the boroxinate.12e 9 Figure 1.2 X-ray structure of BOROX-iminium ion pair OCH3 Ph Ph OPh O B O B O O O B H N OPh d2 d1 d3 d4 d5 OCH3 B3 [H–26-B-a] 1.2.2 BOROX-Anion-Directed Asymmetric Aziridination Our group has put considerable effort into the development of a universal asymmetric aziridination reaction where either cis- or trans- aziridines can be prepared from the same imine and the same catalyst. The BOROX-catalyzed aziridination can provide cis-aziridines in high asymmetric inductions with diazo acetate and benzhydryl imines derived from a broad range of aldehydes including primary, secondary and tertiary aliphatic aldehydes and both electronrich and electron-poor aromatic aldehydes (Scheme 1.4).12r, s Our subsequent studies revealed that certain substituted benzhydryl imine derivertives were even more effective.12j, 12o, 12q In addition to diazoacetate, cis-aziridines can be made from diazomethyl ketones12i and tertiary diazo acetamides12h, 12j as well. We have also investigated BOROX-catalyzed asymmetric cis-aziridination with chiral imines, where both matched and mis-matched cases were observed.12d 10 Scheme 1.4 The Wulff asymmetric cis-aziridination reaction R N 26 H Ar Ar 2-10 mol % BOROX-catalyst 35 or 36 Ar + O N R CO2Et cis-28 OEt N2 Ar Ar C6H 5 4-MeOC6H 4 3,5-Me2-4-MeO-C 6H 2 3,5-tBu2-4-MeO-C 6H 2 27 R = aryl or alkyl cis-28P cis-28D cis-28M cis-28B %Yield 60-91 11-92 57-99 67-98 %ee 90-98 63-97 78-99 91-99.8 The diastereoselectivity of the aziridination with the same imine and same BOROX-catalyst is switched to trans- if sec-diazo acetamides are used (Scheme 1.5).12l A companion publication with combined experimental and computational studies revealed that the binding of the diazo acetamide to the BOROX catalyst involves two H-bonding interactions rather than one for a diazo ester, which leads to the switch in diastereoselectivity from cis- to trans-.12h Scheme 1.5 The Wulff asymmetric trans-aziridination reaction R N 26 H + O Ar Ar Ar Ar N 5-20 mol % (S)-35 0 or –20 °C R NHPh trans-28 66-90% yield 81-99% ee NHPh N 2 27 R = aryl and 1°, 2°, 3° alkyl Ar = 3,5-Me2-4-MeO-C 6H 2 or 3,5-tBu2-4-MeO-C 6H 2 More recently, we asymmetric aziridination12e, have 12g developed a multi-component catalytic which largely simplifies the traditional reaction procedure and also expands the substrate scope to some unbranched aliphatic aldehydes that fail to give the desired aziridines when the reaction is performed 11 with pre-formed imines (Scheme 1.6).16 The multi-component trans-aziridination is under investigation and fruitful results have been obtained.17 Scheme 1.6 Multicomponent asymmetric cis-aziridination reaction Ar O R H Ar + O Ar + NH 2 5-10 mol % (S)-36 OEt N2 R = alkyl or aryl Ar = 3,5-Me2-4-MeO-C 6H 2 4 Å MS –10 to 25 °C, 24 h Ar N R CO2Et 19 examples up to 99% ee The development of a universal asymmetric aziridination sets the stage for our investigation on its application in organic synthesis. A large part of this dissertation will focus on the application of BOROX-catalyzed asymmetric aziridination to the synthesis of several classes of important functionalized molecules. 1.2.3 BOROX-Anion-Directed Hetero-Diels-Alder Reaction In addition to aziridination, our group applied the BOROX catalyst to a hetero-Diels-Alder reaction involving benzhydryl imines that were previously identified as suitable substrates for asymmetric aziridination reaction (Scheme 1.7)13. The pre-catalyst mixture was prepared from chiral ligand VAPOL and B(OPh)3 (method A). Analogous to aziridination, when this mixture was exposed to imine 26P, there would be an in situ assembly of the BOROX catalyst. The imine was activated as an iminium cation which was ion-paired with the chiral BOROX anion B3. This is another example of BOROX-anion directed Brønsted acid catalysis. It was found that 10-20 equivalents of B(OPh)3 relative to the 12 chiral ligand VAPOL were required to achieve high yield and high asymmetric induction. Scheme 1.7 Asymmetric hetero-Diels-Alder reaction H R Ph N O OSiMe3 5-10 mol% (S)-36 + Ph 26P R = aryl or 2 ° alkyl 37 R Toluene/CH2Cl2 (1:1) OMe - 45 °C, 24-50 h Ph 11 examples up to 93% ee N 38 Ph 1.2.4 BOROX-Anion-Directed Aza-Cope Rearrangement In 2011, our group published a catalytic asymmetric aza-Cope rearrangement mediated by a modified BOROX catalyst (Scheme 1.8).14 The initial attempt of the rearrangement of imine 39 with BOROX (35) derived only from VANOL and B(OPh)3 gave very low asymmetric induction, while a significant increase in the enatioselectivity was observed by the addition of benzoic acid as an additive. It is proposed that the benzoate, the conjugate base of benzoic acid, adds to one of the two three coordinated boron in the boroxinate core, which results in a chiral BOROX dianion interacting with the protonated imine [39-H]+. After a bit optimization, the reaction can be done in a multicomponent fashion directly from aldehydes 63 and amine 41 on gram-scale, where high yields and inductions up to 97% ee can be achieved. Scheme 1.8 Catalytic asymmetric aza-Cope rearrangement. O R 63 + H Ar H 2N Ar 41 1) 5 mol% (R)-35 5 mol% benzoic acid m-xylene, 5 Å MS, 60 °C Ar NH 2·HCl N R 2) 2N HCl, THF/H2O, 25 °C R = aryl or alkyl, Ar = 3,5-Me2C6H 3 13 42 20 examples up to 97% ee Ar R H 39 1.2.5 BOROX-Anion Directed Three-Component Ugi Reaction A major part of the work in this thesis has focused on the development of the first catalytic asymmetric three-component Ugi reaction (Scheme 1.9), which provides access to chiral α–amino amides. An effective chiral catalyst has been identified in this work, which is proposed as a BOROX catalyst derived from a VAPOL derivative and a substituted phenol. The reaction proceeds via a strict ion pair between the fully substituted iminium 46 and BOROX anion B3, which is different from previous BOROX-anion directed Brønsted acid catalysis involving hydrogen bond assisted ion pair. Most of the substrates, including aryl aldehydes with both electron-withdrawing and electron-donating groups, reacted to give α– amino amides with high enantiomeric ratio. Scheme 1.9 Catalytic asymmetric three-component Ugi reaction Ph N Ph H A-5 O Ar + H 63 Ph 20 mol% VAPOL-BOROX catalyst CN 64 mesitylene, 4 Å MS, 25 °C, 24 h 66-87% yield Ar Ph N H N R 65 16 examples, up to 95:15 er (>99.5 :0.5 er after crystallization in many cases) O N Ar 46 OR Ar O B O B O * O O B B3 OR strict ion pair Type III activation mode 1.3 Conclusion Asymmetric counteranion-directed catalysis is a young but fast growing research field. The concept of using chiral anions to introduce asymmetry through ion pairing has led to fruitful results in asymmetric synthesis in the last few years. In this context, our group has identified a new class of chiral borate anions, the BOROX anions, which can be applied to a number of different asymmetric reactions involving cationic intermediates (usually iminiums). The 14 BOROX catalyst functions as a Brønsted acid in asymmetric aziridination reactions, hetero-Diels-Alder reactions, and aza-Cope rearrangements. We have recently developed a BOROX-catalyzed asymmetric three component Ugi reaction (chapter two), where the BOROX catalyst functions as a pure “chiral anion catalyst” without hydrogen bonding involved. In addition to the expansion of BOROX catalysts to new chemistry, this dissertation has also focused on the application of the well-developed BOROXcatalyzed asymmetric aziridination reactions to the synthesis of important functionalized molecules (chapter three and chapter four). 15 CHAPTER 2 CATALYTIC ASYMMETRIC THREE-COMPONENT UGI REACTION 2.1 Introduction Multicomponent reactions (MCRs) are convergent processes where more than two starting materials react to form a product in a time-saving one-pot procedure thus providing exceptional synthetic efficiency. The MCRs producing α-amino amides from isonitriles have been of interest ever since the first example of this process was discovered by Ugi in 1959 (Scheme 2.1).18 Since that time, the Ugi reaction has been extensively studied and widely used in organic synthesis19 presumably due to one of its most salient attractions—the diversity associated with the coupling of many components.20 The generally accepted mechanism involves an initial formation of an imimium carboxylate ion pair from an aldehyde, an amine and a carboxylic acid, followed by the subsequent nucleophilic addition of an isocyanide to the iminium, interception of the resulting nitrilium by the carboxylate and finally a Mumm rearrangement (Scheme 2.1).21 Scheme 2.1 Typical Ugi four component reaction and the proposed mechanism Four-Component Ugi Reaction O O R1 O H + R 2 NH 2 + R 3 N C + R4 R4 OH NR 2 R1 H N C R3 O Mumm rearrangement and proton transfer Possible mechanism: O R1 H H N + R1 O R 2 NH 2 + O R4 H 2O R4 O R2 R2 H CN R 3 R2 NH R O N R3 NH N R O O R4 O R4 OH 16 R3 The four-component Ugi reaction can tolerate variations in the acid component (carboxylic acids, hydrazoic acid, cyanates, thiocyanates, 2° amine salts, water, H2S, H2Se) and in the amine component (1° or 2° amines, hydrazines and hydroxyl amines).19 The Ugi reaction with a 2° amine differs from that with a 1° amine in the acyl migration step (Mumm rearrangement). In 2011, Tron’s group developed a four-component Ugi reaction with a 2° amine22 based on Ugi’s procedure with pre-formed enamine (Scheme 2.2).23 In the case of a 2° amine where the amine nitrogen in the transient O-acyl imidate 51 is not able to capture the acyl group from the caboxylate, the isocyanide nitrogen serves as an acyl group acceptor providing an imide as the product in a non-nucleophilic solvent. Scheme 2.2 Four-component Ugi reaction with a 2° amine 47 N H 48 + N3 HO 2C NC O O CH 2Cl 2 N rt, 4 Å MS OHC 49 N O N3 N3 N 80 % O N 50 51 52 Usually the four-component Ugi reaction can proceed smoothly in the absence of a catalyst with high yield especially in protic solvents due to the activation of the imine by the acid component. A few catalysts have been developed to improve the yields of certain reactions with less reactive substrates, such as aromatic aldehydes.24 The Ugi reaction can also be effected in the absence of the acid component in a three component fashion where the amine component can be either a 1° 25 or 2° 26 amine. Without the acid component, the 17 three-component Ugi reaction requires an external activator to ensure sufficient iminium formation for the following transformations. In 1963, McFarland reported a three-component Ugi reaction with the 2° amine 54 mediated by acetic acid (Scheme 2.3, a).26a The reaction with only one equivalent acetic acid and one equivalent of amine 54 gave the Ugi product 56 in a low yield along with a significant amount of Passerini product 57. The yield of 56 was largely improved when the amounts of acetic acid and amine 54 were doubled. In 2007, Suginome and coworkers reported that the aminoborane 58 could serve as an iminium ion generator to facilitate the same type of transformation (Scheme 2.3, b).26b A variety of 2° amines, aldehydes and isocyanides were investigated in this work and most of the substrates gave the products in good to excellent yields. They later demonstrated that the same reaction could be effectively promoted by B(OMe)3.26c All the examples described above involve an excess amount of the activators, and thus do not involve any turnover. Pan and List were recently the first to report turnover for a three-component Ugi reaction with a 1° amine and the achiral organocatalyst 59 (Scheme 2.4).25 18 Scheme 2.3 Examples of three-component Ugi reaction with 2° amine a) O + H 53 1.0 equiv + N H 54 1.0 equiv 2.0 equiv N NC MeOH, rt C AcOH 80b 1.0 equiv Method A: 1.5 equiv O R1 2 + R NH + H R3 1.0 equiv 1.5 equiv R4 N C 1.5 equiv OAc THF, rt O B O NiPr 2 58 Method B: 3 equiv B(OMe) 3 DCE, 80 °C H N C + 56 O 35% 94% 1.0 equiv 2.0 equiv b) H N 57 O 41% 6% R3 N R1 R2 C H N R4 O Method %yield A 53-96 B 71-91 Scheme 2.4 Catalytic three-component Ugi reaction reported by List’s group O P 10 mol % Ph OH H 59 O R1 H + R2 NH 2 + R3 N C toluene, 80 °C, 24 h H R1 N R2 H N C R3 O 36-91% yield Unlike the related Passerini reaction,27 an asymmetric catalyst has yet to be reported for either the three- or four-component Ugi reaction.19d, 20c, 26b, 28 Asymmetric catalysts have been reported for closely related Ugi-type reactions involving azomethine imines (Scheme 2.5, a)29 and the formation of oxazoles from α-isocyanoacetamides (Scheme 2.5, b),30 both of which involve the interception of the nitrilium ion by an amide functional group in an intramolecular fashion. 19 Scheme 2.5 Catalytic asymmetric Ugi-type reactions a) R1 N H H N Ph (R)-60 (5 mol%) + O R 2CHO + CN R2 N R1 H N Ph R5 CO2H CO2H O O P O OH R5 R4 R1 R 5 = 2,4,6-(CH3) 3C6H 2 H 2N NR 3R 4 R2 X (R)-61 X O + Yield: 55-99% ee: 42-93% R4 R 4 = 3,5-(NO2) 2C6H 3 (R)-60 CN R3 BzO BzO O OBz N R4 R3 b) Ph O R2 O N R3 N N NHAr (R)-61 (20 mol%) Toluene - 20 °C O R1 * NR 3R 4 N O R1 N R2 NR 3R 4 Yield: 51-99% ee: 56-90% R2 As discussed previously, the Ugi reaction is commonly thought to involve an iminium ion, which is a key intermediate in many of the reactions catalyzed by our asymmetric BOROX catalysts. Therefore, the unsolved problem of an asymmetric catalytic Ugi reaction was an attractive target for the application of the BOROX catalysts, which might provide a new approach to make chiral αamino amides that are very important synthetic targets.31 Since the fourcomponent Ugi reaction has a severe background reaction mediated by the acid component, we decided to first investigate the three-component variant. 20 2.2 Catalyst Diversity of BOROX Catalytic System The BOROX catalyst is typically assembled in situ from a ligand, B(OPh)3 and an imine (or amine) which would produce the catalyst in Scheme 2.6 with R1 = Ph. We have also shown that the same BOROX catalyst can be directly assembled by a molecule of an imine (or amine) from the ligand, 3 molecules of BH3·SMe2, 3 molecules of water and 2 molecules of phenol as discussed in Chapter 1. This protocol should allow for a facile diversity-oriented generation of an array of BOROX catalysts by incorporation of different ligands and different phenols or alcohols into the boroxinate core during in situ catalyst assembly (Scheme 2.6). This essentially instant access to diversity has enabled the identification of the first effective chiral catalyst for the three-component Ugi reaction. Scheme 2.6 Catalyst diversity via in situ substrate induced assembly BH 3•SMe 2 H 2O amine * OH OH ligand HO R1 [H-amine] O R1 O B * O B O O O B O R1 BOROX H 2O HO R1 BH 3•SMe 2 H 2O BH 3•SMe 2 21 2.3 The Discovery and Initial Optimization of a Catalytic Asymmetric ThreeComponent Ugi Reaction Our former group member Li Huang initiated this project and put a lot of effort into the first stage of the optimization.32 The first encouraging result obtained by Li was with the VAPOL-BOROX catalyst prepared from PhOH (P-11) for the reaction of benzaldehyde 63a with dibenzylamine A-5 and t-butyl isonitrile 64 (Scheme 2.7). The reaction gave the α-amino amide 65a in 76% yield with 41:59 er. There was no reaction at all in the same time frame without the catalyst. The 1° amine A-6 and 2° amines including diethylamine, pyrrolidine and aniline derivatives (A-1 to A-4) produced no detectable amount of product under the same conditions. The bis-p-methoxybenzylamine A-7 gave a similar result to that obtained with A-5. Scheme 2.7 Initial screen of amines with benzaldehyde and t-butyl isonitrile 1 equiv Ligand ((R)-VAPOL) 100 °C, 1 h 2 equiv ROH (P-11) 3 equiv BH 3!SMe2 toluene 3 equiv H 2O 100 °C vaccum, 0.5 h H R R + CN OH N H N H A-1 Ph toluene 25 °C 24-48 h 64 A 63a P-11 N H Ph A-2 N H N H Ph MeO 22 N R H N O 65a Ph A-3 Ph 76% yield A-5 59:41 er R 20 mol % (R)-BOROX pre-catalyst O + pre-catalyst N H Ph A-4 N H 82% yield A-7 57:43 er Ph Ph NH 2 A-6 OMe A few chiral ligands were also investigated by Li Huang (Table 2.1). The catalyst from the VANOL ligand 29 gave an even lower selectivity (entry 2). The most effective catalyst among those that are derived from the BINOL ligands 66 to 69 led to the formation of the Ugi product 65a with 55:45 er, but with a reduced yield compared to the VAPOL catalyst (entries 3-6). The catalyst for each reaction is represented as “LAP X-Y-Z", which means it is generated from the ligand X, the amine A-Y and the phenol P-Z. Table 2.1 Screen of VANOL and BINOL ligands Ph Ph O + H 63a Ph N H A-5 + N 20 mol % (S)-BOROX catalyst CN toluene 25 °C 64 Ph H N O 65a R OH OH Ph Ph 30 (S)-VAPOL OH OH OH OH Ph Ph 29 (S)-VANOL 66 67 68 69 R R R R R = H (R)-BINOL = Br = Ph = SiPh 3 Entry ligand L amine A phenol[b] P catalyst # time [h] yield [%][c] 65a er[d] 65a 1 30 A-5 P-11 LAP 30-5-11 24 76 59:41 2 29 A-5 P-11 LAP 29-5-11 36 60 53:47 3 66 A-5 P-11 LAP 66-5-11 40 9[h] 56:44 23 Table 2.1 (cont’d) 4 67 A-5 P-11 LAP 67-5-11 24 37 45:55[f] 5 68 A-5 P-11 LAP 68-5-11 43 30 45:55[f] 6 69 A-5 P-11 LAP 69-5-11 24 trace — [a] Unless otherwise specified, all reactions were carried out at 0.2 M in 63 (0.25 mmol) in toluene with 2.0 equiv amine and 1.5 equiv of 64 at RT for the indicated time with 20 mol % of the catalyst. The pre-catalyst was prepared by heating 20 mol % of the (R)-ligand, 40 mol % of the phenol or alcohol, 60 mol % H2O, 60 mol % of BH3·SMe2 in toluene at 100 °C for 1 h. After removal of all volatiles, the BOROX catalyst was generated in situ by the addition of the amine at rt and this was followed by the addition of aldehyde and then the isonitrile. [c] Isolated yield after chromatography on silica gel. nd = not detected. [d] Determined by HPLC. [f] Catalyst was generated from (R)-ligand. [h] 1H NMR yield with internal standard. Additionally, many other alcohol and phenol derivatives were screened by Li Huang for the preparation of different VAPOL-BOROX catalysts, among which the 2,4,6-tri-t-butylphenol P-24 gave the best result, i.e., 82% yield with 58% ee (Figure 2.1). The electronic nature of the phenol does not have a significant effect on the asymmetric induction (P-3 vs P-13). Essentially the same induction was observed with 3° and 2° alcohols as with phenol P-11, but the use of ethanol stopped the reaction (P-5, P-6, P-1). Also, the use of either (–)-menthol (P-6) or (+)-menthol (P-7) gave the product with the same sense of chirality, which indicates that auxiliary chiral centers may not be a useful method for selectivity modification. 24 Figure 2.1 Screen of different phenols and alcohols OH OH Br OH OH OH OMe MeO OMe P-1 % yield: trace % ee: — P-2 % yield: trace % ee: — P-3 % yield: 64 % ee: 13 OH P-4 % yield: 76 % ee: 14 OH OH HO P-5 % yield: 86 % ee: 15 OH OH OH Ph OMe P-8 P-9 P-10 P-11 P-12 P-13 % yield: 71 % ee: 17 % yield: 76 % ee: 17 % yield: 76 % ee: 18 % yield: 70 % ee: 18 % yield: 75 % ee: 18 OH OH Ph F P-6 % yield: 91 % ee: 16 OH P-7 % yield: 73 % ee: 17 OH Ph % yield: 56 % ee: 17 Ph HO OMe NO 2 OH OH OH P-14 % yield: 82 % ee: 19 OH P-15 % yield: 76 % ee: 19 OH F F F Ph Ph F F 3C P-16 P-17 P-18 P-19 % yield: 87 % ee: 19 % yield: 65 % ee: 19 % yield: 77 % ee: 19 % yield: 70 % ee: 19 OH OH OH Ph P-23 % yield: 69 % ee: 24 OH F 3C OH OH P-21 P-22 % yield: 89 % ee: 22 % yield: 76 % ee: 24 OH OH Br Ph P-24 P-25 P-26 P-27 % yield: 80 % ee: 25 % yield: 70 % ee: 26 % yield: 92 % ee: 26 OH CF 3 % yield: 42 % ee: 20 % yield: 82 % ee: 58 OH P-20 OH OH OMe Br OH Br P-28 % yield: 82 % ee: 26 OH P-29 % yield: 61 % ee: 46 OH P-30 % yield: 83 % ee: 27 OH CF 3 P-31 P-32 P-33 P-34 P-35 % yield: 77 % ee: 31 % yield: 59 % ee: 33 % yield: 76 % ee: 35 % yield: 68 % ee: 36 % yield: 60 % ee: 36 Ph P-36 % yield: 72 % ee: 40 P-37 % yield: 73 % ee: 40 P-38 % yield: 73 % ee: 40 2.4 The Early Impediments to the Further Optimization At this point, I took over this project to further optimize the asymmetric catalytic three-component Ugi reaction. Firstly, the reactions with several 25 selected phenols were repeated (Table 2.2). All the phenols were carefully purified before they were used in the experiments. Unexpectedly, the result with the optimal phenol P-24 could not be reproduced (entry 1, compared to Li’s result in Figure 2.1: 58% ee). The enantioselectivity varies with different trials. After all of the reaction parameters were systematically probed, evidence showed that the variability of the results could be traced to phenol P-24. The phenol sample that was stored for a long time was slightly greenish yellow, with which the product was obtained with 36-49% ee (entry 2); but if it was purified by sublimation or crystallization to give absolutely pure white material, the ee was only 24% (entry 1). Thus, an impurity was assumed to be responsible for the originally observed 58% ee. It was hypothesized that the impurity resulted in a more efficient assembly of the catalyst. With great efforts, two impurities 70 and 71 were isolated and identified from a large quantity of colored phenol sample. Reactions with both 70 and 71 gave better selectivities than pure P-24 (entry 3-4), but still not close to the original result, 58% ee. Reactions with impurity/P-24 mixtures were also investigated, which gave similar results to those of P-24 (entry 5-6). Since the reaction with P-24 did not produce a desirable result, we turned our attention to phenol P-29 that gave second highest enantioselectivity (Figure 2.1, 46% ee) in the Ugi reaction. Again, the enantioselectivity of reactions with phenol P-29 could not be reproduced and low asymmetric inductions were observed (Table 2.2, entry 7). Luckily, it was found that phenol P-36, which gave the most selective BOROX catalyst among the rest of the phenols, gave very reproducible results. Thus, P-36 was the choice for further optimization. 26 Table 2.2 Reactions with selected phenols and impurities from P-24 O H 63a OH + Bn N H 20 mol % (R)-VAPOL-BOROX Bn + CN OH N toluene 25 °C 41 h 64 A-5 Bn 65a OH P-24 P-29 H N O O OH Bn 70 P-36 O O 71 Entry Phenol or quinone[b] yield [%][c] 65a %ee[d] 65a 1 P-24 (white) 48 24[e] 2 P-24 (yellow) 81-88 36-49[f] 3 70 68 31 4 71 76 34 5 70/P-24 (1:1) 54 27 6 71/P-24 (1:15) 65 26 7 P-29 50 26[g] 8 P-36 87 40[g] [a] Unless otherwise specified, all reactions were carried out at 0.2 M in 63a (0.25 mmol) in toluene with 2.0 equiv amine and 1.5 equiv of 64 at RT for the indicated time with 20 mol % of the catalyst. The pre-catalyst was prepared by heating 20 mol % of the (R)-ligand, 40 mol % of the phenol or alcohol, 60 mol % H2O, 60 mol % of BH3·SMe2 in toluene at 100 °C for 1 h. After removal of all volatiles, the BOROX catalyst was generated in-situ by the addition of the amine at rt and this was followed by the addition of aldehyde and then the isonitrile. [c] Isolated yield after chromatography on silica gel. nd = not detected. 27 Table 2.2 (cont’d) [d] Determined by HPLC. [e] Average of six runs. [f] Results from six runs. [g] Average of four runs. 2.5 Revisit of the Ugi Reactions with Amines A-1 and A-6 As shown previously (Scheme 2.7), dibenzylamines were the only class of amines that gave the desired Ugi product. To get some insight about the failures of other amines, the reactions with 1° amine A-6 and 2° amine A-1 were reexamined more closely with the BOROX catalyst derived from phenol P-11 and the VAPOL ligand 30. It was found that the primary amine A-6 only led to the formation of imine 26Pa in quantitative yield (Scheme 2.8), and in the case of amine A-1, the only identifiable compound present other than starting materials was the aminal 72 (50%, Scheme 2.8). Heating the mixture containing 72 at 80 °C for 18 h resulted in a complex mixture with 65a still not detectable. Scheme 2.8 Attempted Ugi reactions with amines A-1 and A-6 20 mol % BOROX catalyst cat # LAP-30-1-11 O H + Ph Ph + CN NH 2 63a + N H A-1 Ph 26Pa 100% 64 20 mol % BOROX catalyst cat # LAP-30-1-11 O H N toluene, rt,18- 89 h A-6 63a Ph + CN toluene, rt, 19h 64 28 N N 72 50% 2.6 Variation of the Catalysts with Different Chiral Ligands A series of BOROX catalysts containing 2,4,6-trimethylphenol P-36 were then generated from a series of newly prepared VANOL and VAPOL ligands. Catalysts prepared from P-36 and the 7,7’-disubstituted VANOL derivatives 73 and 74 were hardly any more selective (entries 4 and 5) than those from the parent VANOL ligand which gave essentially racemic material (entry 3).33 The substituted VAPOL ligands 75 to 79, however, were generally significantly more selective than the parent VAPOL ligand. The optimal BOROX catalyst is obtained from the VAPOL derivative 78 which gave an er of 85:15 (entry 9). The asymmetric synergism between the ligand and phenol components was revealed by the fact that while the substituted VAPOL ligand 78 gave just a skosh of improvement in induction over VAPOL with phenol P-11 (entries 11 vs 1), a much greater increase in enantioselectivity was observed when 78 was used instead of VAPOL with P-36 (entries 11 vs 9). 29 Table 2.3 Synergism in the arrangement of the substituents in the boroxinate core [a] Ph Ph O H 63a + Ph N H A-5 + N 20 mol % (S)-BOROX catalyst CN toluene 25 °C 64 R Ph H N O 65a R3 30 R1 = H, R 2 = H, R 3 = H (S)-VAPOL R1 75 R1 = Me, R 2 = H, R 3 = H R2 OH 29 R = H (S)-VANOL R1 73 R = OMe R1 OH 74 R = t-Bu R2 R1 OH 76 R1 = Ph, R 2 = H, R 3 = H OH 77 R1 = Me, R 2 = OMe, R 3 = H 78 R1 = t-Bu, R 2 = OMe, R 3 = H 79 R1 = H, R 2 = n-Bu, R 3 = SiPh2(t-Bu) R R3 Entry ligand phenol/ alcohol catalyst # time [h] yield [%][b] 65a er[c] 65a 1 30 P-11 LAP 30-5-11 24 76 59:41 2 30 P-36 LAP 30-5-36 36 72 70:30 3 29 P-36 LAP 29-5-36 39 52 49:51[d] 4 73 P-36 LAP 73-5-36 42 62 54:46 5 74 P-36 LAP 74-5-36 45 62 52:48 6 75 P-36 LAP 75-5-36 39 89 74:26 7 76 P-36 LAP 76-5-36 39 64 35:65[d] 8 77 P-36 LAP 77-5-36 39 93 74:26 9 78 P-36 LAP 78-5-36 39 94 15:85[d] 10 79 P-36 LAP 79-5-36 42 90 71:29 11 78 P-11 LAP 78-5-11 39 74 62:38[e] 12 78 P-26 LAP 78-5-26 39 93 78:22[e] 30 Table 2.3 (cont’d) [a] Unless otherwise specified, all reactions were carried out at 0.2 M in 63a (0.25 mmol) in toluene with 2.0 equiv amine and 1.5 equiv of 64 at RT for the indicated time with 20 mol % of the catalyst. The catalyst was made from the (S)enantiomer of the ligand (≥99% ee) according to the procedure in Table 2.1. [b] Isolated yield after chromatography on silica gel. [c] Determined by HPLC. [d] Catalyst generated from (R)-ligand. [e] The ligand for this run was 97% ee. 2.7 Study of Solvent Effect on the BOROX Catalyst At this point a solvent screen was performed on the optimal catalyst prepared from the substituted VAPOL ligand 78 and the 2,4,6-trimethyphenol P36 (Table 2.4). The reactions carried out in non-polar solvents gave good aymmetric inductions (entry 1-5). The induction dropped dramatically with polar coordinating solvents such as THF and acetonitrile (entry 6-7) which is consistent with an ion-pair mechanism that will be discussed later. The electrostatic interactions between the anionic BOROX catalyst and cationic intermediate would be expected to decrease in polar solvents, resulting in a loose ion pair and a loss in stereoselectivity. The optimal solvent was found to be mesitylene (Table 2.4, entry 3) and all further optimizations were performed in this solvent. 31 Table 2.4. Solvent effect on the three-component Ugi reaction. O Ph H 63a + 20 mol % (R)-BOROX catalyst (LAP 78-5-36) Ph N H + A-5 CN Ph Ph N solvent, rt, 39-40 h H N O 65a 64 Entry[a] Solvent %Yield[c] 65a er 65a 1 toluene 94 85:15 2 m-xylene 92 86:14 3 mesitylene 91 88:12 4[b] 1,3,5-triisopropyl benzene 90 13:87 5 CCl4 90 86:14 6 THF 77 54:46 7 CH3CN 26 64:36 [a] Unless otherwise specified, all reactions were carried out at 0.2 M in 63a (0.25 mmol) in toluene with 2.0 equiv amine and 1.5 equiv of 64 at RT for the indicated time with 20 mol % of the catalyst. The catalyst was made from phenol P-36 and the ligand (R)-78 (≥99% ee) according to the procedure in Table 2.1. [b] Catalyst was generated from (S)-78 (97% ee). [c] Isolated yield after chromatography on silica gel. 2.8 Effects of Concentration and Amine Stoichiometry on the ThreeComponent Ugi Reaction The three-component Ugi reaction operates efficiently with almost no change in the enantioselectivity within the concentration range of 0.1 M to 0.4 M (Table 2.5, entries 2-4). However, a decrease in the concentration from 0.1 M to 32 0.05 M leads to a drop in both the enantioselectivity and the yield (Table 2.5, entries 1-2). The stoichiometry of the amine does not seem to have a big impact on the reaction with the yields and inductions falling only slightly in the range of 2.0 to 1.02 equivalents (entries 6-8). Table 2.5 Ugi-3CR with different concentrations and equivalents of amine O Ph H 63a + 20 mol % (R)-BOROX catalyst (LAP 78-5-36) Ph N H + A-5 CN Ph Ph N H N solvent, rt, 39 h O 65a 64 Entry[a] Amine equivalents Concentration (M) %Yield[b] 65a er 65a 1 2.00 0.05 53 77:23 2 2.00 0.1 89 86:14 3 2.00 0.2 92 87:13 4 2.00 0.4 93 87:13 5 1.20 0.2 86 86:14 6 1.02 0.2 75 84:16 [a] The general procedure described in Table 2.1 was followed with (S)-78 ligand (41.5 mg, 0.0504 mmol, 97% ee), phenol P-36 (14 mg, 0.10 mmol), amine A-5 (0.05-0.1 mL) and mesitylene (0.45-5.0 mL) as the reaction solvent with a reaction time of 39 h. [b] Isolated yield after chromatography on silica gel. 2.9 Effects of Different Additives in the Catalytic System We have explored the effects of several different additives, including H2O, molecular sieves and the salt Mg(ClO4)2. In one possible mechanism for the three-component Ugi reaction, the hemiaminal formed from the aldehyde and 33 dibenzylamine (Scheme 2.12, 87) loses a molecule of H2O which can trap the nitrilium cation (Scheme 2.12, 86) to form the product 65. Thus, we would like to test the effect of free H2O on the reaction. We also investigated the salt Mg(ClO4)2 as an additive to the reaction, since our former group member Li Huang found that it improved the asymmetric induction of the same reaction catalyzed by a different BOROX catalyst.34 The results are shown in Table 2.6 and the reaction progressions for entries 1-6 are plotted in Figures 2.3 and 2.4. Most of the additives tested have either adverse effects or no effects on the reaction. The presence of a small amount of H2O or MgClO4 was detrimental to both the enantioselectivity and the yield. The reaction with 1.0 equivalent of H2O gave the product in only 9% yield after 91 hours with hardly any selectivity. It was found that the reaction could be accelerated a bit by the proper amount of 4Å MS (Figure 2.3), with the enantioselectivity almost unchanged (Table 2.6, entries 57). Table 2.6 The effects of different additives on the three-component Ugi reaction O Ph H + N H A-5 63a 20 mol % (R)-BOROX catalyst (LAP 78-5-36) Ph + CN Ph Ph N Additive solvent, rt H N O 65a 64 Entry[a] Solvent Additive/Amount Time (h) %Yield[b] 65a er 65a 1 toluene none 39 94[c] 85:15 2 d8-toluene H2O/100 mol % 91 8.6 59:41 34 Table 2.6 (cont’d) 3 d8-toluene H2O/50 mol % 91 17.3 61:39 4[d] d8-toluene H2O/20 mol % 88 78 24:76 5 d8-toluene 4Å MS/13 mg 18.3 83 85:15 6 d8-toluene 4Å MS/6 mg 18.3 80 85:15 7 mesitylene none 39 89[c] 87:13 8 mesitylene 5Å MS/13 mg 39 80[c] 87:13 9 mesitylene Mg(ClO4)2/20 mol % 39 15[c] 65:35 [a] The general procedure described in Table 2.1 was followed with ligand (R)-78 (41.5 mg, 0.0504 mmol, 97% ee) and phenol P-36 (14 mg, 0.10 mmol); The additive was added after the addition of benzaldehyde 63a. [b] 1H NMR yield with Ph3CH as an internal standard. [c] Isolated yield after chromatography on silica gel. [d] Catalyst was generated from ligand (S)-78. 2.10 Variation of the Catalysts by Incorporating Different Alcohols and Phenols With the identification of the VAPOL derivative 78 as the optimal ligand, a final screen of this ligand and 13 different phenols was performed in mesitylene (Scheme 2.9). The optimal phenol was found to be the 2,6-dimethyl-4-methoxy phenol P-47 and the resultant catalyst (LAP 78-5-47) gave 65a with a 90:10 enantiomeric ratio in a total of 88% yield. In contrast to the VAPOL derived catalysts which are insensitive to the electronic nature of the phenol (Figure 2.1, P-3, P-11, P-13), the catalysts derived from the VAPOL derivative 78 are quite sensitive (Scheme 2.9, P-36, P-44, P-47). The induction slightly increased when 35 the p-methyl group in P-36 was replaced by a methoxyl group (P-47) and dramatically dropped when it was replaced with a nitro group (P-44). This is consistent with an ion-pair mechanism in which the strength of the electrostatic attraction is important for the asymmetric induction (see Scheme 2.12). Scheme 2.9 Screen of additional phenol substituents in the boroxinate core with ligand 78 O Ph H + + N H OH OH CN N P-26 P-11 TMS % yield: 94 % ee: 66 OH P-42 % yield: 28 % ee: 26 TMS H N O 65a 64 OH OH OH OH Br % yield: 72 % ee: 34 Ph mesitylene, rt, 38-41 h A-5 63a Ph 20 mol % BOROX catalyst (LAP 78-5-P) Ph P-28 % yield: 72 % ee: 36 P-36 % yield: 89 % ee: 74 P-39 % yield: 95 % ee: 64 OH Br MeO OMe P-40 % yield: 54 % ee: 10 P-41 % yield: 35 % ee: 34 OH OH OH OH OH P-43 NO 2 P-44 OtBu P-45 OEt P-46 OMe P-47 % yield: 81 % ee: 69 % yield: 76 % ee: 17 % yield: 90 % ee: 67 % yield: 87 % ee: 76 % yield: 88 % ee: 80 2.11 Study of the Reactivities of Different Dibenzylamine Derivatives. Based on our experiences with other BOROX-catalyzed systems, the substituent on the amine or imine nitrogen has a great effect on the reaction results. Since dibenzylamines are the only class of amines that work in the three component Ugi reaction, we screened several substituted dibenzylamines (Table 2.7). Most of these dibenzylamines gave high selectivities (87:13 to 90:10 entries 2-5). The p-nitro substituted dibenzylamine A-11 gave a dramatic drop in the 36 yield and induction (entry 6) and this could be attributed to destabilization of the iminium ion formed from the aldehyde and the amine. A large decrease in both yield and enantioselectivity was also observed when A-5 was replaced with the 3,5-disubstituted amine A-12, which was probably caused by steric effects in the transition state. Table 2.7 Screen of substituted dibenzyl amines with ligand 78[a] O Ar H + N H A 63a N H X 20 mol % (R)-BOROX catalyst (LAP 78-A-P) Ar + CN Ar Ar N H N mesitylene, rt O 65 64 X A-7 A-8 A-9 A-10 A-11 X = OMe X=F X = Cl X = Br X = NO 2 N H A-12 Entry Amine A Phenol P catalyst # time [h] yield [%][b] 65 er[c] 65 1 A-5 P-47 LAP 78-5-47 38 91 90:10[g,h] 2 A-7 P-47 LAP 78-7-47 24 91 88:12 3 A-8 P-47 LAP 78-8-47 24 85 90:10 4 A-9 P-47 LAP 78-9-47 24 80 88:12 5 A-10 P-47 LAP 78-10-47 24 79 87:13 6 A-11 P-47 LAP 78-11-47 24 22 73:27 7 A-12 P-36 LAP 78-12-36 39 65 39:61[d] 8 A-5 P-36 LAP 78-5-36 39 89 13:87[d] 37 Table 2.7 (cont’d) [a] Unless otherwise specified, all reactions were carried out at 0.2 M in 63a (0.25 mmol) in mesitylene with 2.0 equiv amine and 1.5 equiv of 64 at RT for the indicated time with 20 mol % of the catalyst. Entries 2-6 were carried out in the presence of 4Å molecular sieves. The catalyst was prepared according to the procedure in Table 2.1 with (R)-78 unless otherwise specified. Ligand (R)-78 was >99% ee. [b] Isolated yield after chromatography on silica gel. [c] Determined by HPLC. [d] Catalyst generated from (S)-78, 97% ee. [g] The er was 89:11 when (S)-78 was 97% ee. [h] The yield was 86% after 24 h. 2.12 Substrate Scope of Different Aryl Aldehydes at Both RT and 0 °C Having established the most effective combination of the all of the parts in the boroxinate catalyst, an evaluation of different aryl aldehydes in the Ugi reaction was undertaken with amine A-5 and the results are presented in Table 2.8. Most of the substrates reacted to give α-amino amides with enantiomeric ratios of 90:10 to 95:5 including aryl aldehydes with both electron-withdrawing and electron-donating groups. The reaction of cyclohexane carboxaldehyde gave racemic product (47%) and this result will require further examination (not shown in Table 2.8). The reactions in Table 2.8 were performed in the presence of 4 Å molecular sieves, whereas most of the previous reactions in this work were without the sieves. The sieves have essentially no effect on the induction but do seem to accelerate the reaction slightly (Figures 2.3 and 2.4). The rate is slower at 0°C than at 25 °C but the inductions are not substantially different. In many cases the α-amino amide 65 can be crystallized and a few examples are shown where the er can be often enhanced to >99.5:0.5. The ligand 78 can also be recovered from these reactions in high yield (~90%) with no loss in enantiomeric 38 purity (>99.5:0.5). The reaction can be extended to heterocyclic aldehydes as illustrated by the reaction with pyridine carboxaldehydes. 3-Pyrridyl carboxaldehyde is the most reactive, and the 4-pyrridyl isomer reacts slowly (entries 27 & 28) and the 2-pyrridyl isomer is unreactive (not shown). The reaction with salicylaldehyde 63r did not provide the desired product 65. Instead, compound 93 was obtained in 22% yield as a result of an intramolecular interception of the nitrilium cation by the 2-hydroxyl group in 93 (Scheme 2.10). Table 2.8 Substrate scope of the catalytic asymmetric 3-component Ugi reaction [a] Ph O R H 63 + 20 mol % (R)-BOROX catalyst (LAP 78-5-47) Ph N H + CN Ph N H N R mesitylene 4Å MS 64 A-5 Ph 65 O Entry series R time [h] temp [°C] yield [%][b] 65 er[c] 65 1 a C6 H5 7 40 87[e] 86:14 2[d] a C6 H5 24 25 86 (71) 90:10 (>99.5:0.5) 3 a C6 H5 66 0 75 92:8 4[f] b 4-NO2C6H4 24 25 83 93:7 5[f] b 4-NO2C6H4 66 0 51[e] 92:8 6 c 4-CF3C6H4 24 25 85 91:9 7 d 4-BrC6H4 24 25 85 93:7 8 d 4-BrC6H4 48 0 65[g] 95:5 9[f] d 4-BrC6H4 48 0 75[h,i] 95:5 39 Table 2.8 (cont’d) 10[f] e 3-BrC6H4 22 25 82 93:7 11 e 3-BrC6H4 66 0 66[h] 92:8 12 f 3,4-Cl2C6H3 24 25 85 94:6 13 f 3,4-Cl2C6H3 66 0 54[e] 95:5 14 g 4-FC6H4 24 25 87[e] 91:9 15 g 4-FC6H4 67 0 62 94:6 16 h 4-MeO2CC6H4 24 25 80 93:7 17[f] h 4-MeO2CC6H4 67 0 62 93:7 18 i 4-AcOC6H4 24 25 86 85:15 19 j 4-AcNHC6H4 24 25 77 (47) 85:15 (96:4) 20[f] k 4-MeC6H4 24 25 84 (47) 91:9 (>99.5:0.5) 21 k 4-MeC6H4 66 0 80[e] 92:8 22 l 2-MeC6H4 24 25 76 (56) 78:22 (>99:1) 23 m 4-t-BuC6H4 24 25 83 84:16 24 n 4-MeOC6H4 40 25 84[j] 88:12 25 n 4-MeOC6H4 24 25 70 89:11 26 n 4-MeOC6H4 24 0 51 92:8 27 o 3-pyridyl 25 25 80 (61) 90:10 (>99:1) 28 p 4-pyridyl 70 25 66 89:11 40 Table 2.8 (cont’d) [a] Unless otherwise specified, all reactions were carried out at 0.2 M in 63a (0.25 mmol) in mesitylene with 2.0 equiv amine and 1.5 equiv of 64 at RT in the presence of 4Å MS for the indicated time with 20 mol % of the catalyst. The catalyst was made from the (R)-enantiomer of the ligand (≥99% ee) according to the procedure in Table 1. [b] Isolated yield after chromatography on silica gel. Yield in paranthesis is % recovery of the first crop after crystallization. [c] Determined by HPLC. The er in parentheses is of the first crop. [d] Average of 4 runs. [e] 1H NMR yield with internal standard (Ph3CH). [f] Average of 2 runs. [g] Yield was 46% after 24 h. [h] Reaction at 0.4 M. [i] Yield was 76% after 66 h. The yield was 60% after 66 h in the absence of 4Å MS. [j] Run in the absence of 4Å MS. Scheme 2.10 Intramolecular interception of the nitrilium cation O Ph H + OH 63r 20 mol % (R)-BOROX catalyst (LAP 78-5-47) Ph N H A-5 + CN 4Å MS mesitylene, rt, 44 h 64 O NH tBu N Bn Bn 93 22% 2.13 Substrate Scope of Different Isocyanides at RT Although t-butylisonitrile (64) was the optimal isonitrile, a number of other isonitriles (80a-f) were effective with inductions ranging from 51:49 to 88:12 under the conditions in Table 2.9. Reactions with tertiary alkyl and aromatic isonitriles gave high asymmetric inductions, although the yields varied in different cases. It seemed that the isonitriles with larger substituents proceeded slower and gave lower yields (entries 1 vs 2, entries 6 vs 7). There was a big drop in the selectivity when a 2° alkyl isonitrile was used (entry 3). Reactions with primary isonitriles gave the product in moderate yields, but with almost no selectivities (entries 4 and 5). 41 Table 2.9 Ugi-3CR with different isocyanides Ph O Ph H + 63 20 mol % (R)-BOROX catalyst (LAP 78-5-47) Ph N H A-5 + CN R mesitylene 4Å MS 64,80 Ph Ph N Ph H N R O 65,81 Entry Isocyanide R Time (h) %Yield[a] er 1 64 t-Bu 24 86 90:10 2 80a 1,1,3,3tetramethylbutyl 68 55 87:13 3 80b Cy 24 75 67:33 4 80c n-Bu 39 48 52:48 5 80d Bn 29 46 51:49 6 80e 2,6-diMeC6H3 44 29 85:15 7 80f 4-MeOC6H4 24 65 88:12 [a] Isolated yield after chromatography on silica gel. 2.14 Studies of Catalyst Loading The catalyst loading can be reduced to 10 mol% with no significant drop in yield or induction if molecular sieves are employed (Table 2.10). The er drops from 90:10 to 87:13 when the loading is reduced from 20 to 10 mol%. Both the 90:10 and the 87:13 mixture can be enhanced to an er of >99.5:0.5 by crystallization with 70-71% recovery for the first crop. When there are no molecular sieves present, the changes in catalyst loading has a much larger effect on both reaction rate and enantioselectivity. The yield of 65a with 5 mol% catalyst was 62% after 73 h (er = 74:26) with sieves and 7% without sieves. 42 Table 2.10 Effect of molecular sieves on catalyst loading O Ph Bn H 63a + N H A-5 Bn N C 64 x mol% (R)-BOROX catalyst LAP 78-5-47 mesitylene, 4 Å MS 25 °C Bn N Ph Bn H N C O 65a Entry Cat Loading mol% Sieves Time (h) %Yield 65a er % yield 65a first crop er 65a first crop 1 20 yes 23 86 90:10 71 >99.5:0.5 2 10 yes 30 83 87:13 70 >99.5:0.5 3 5 yes 73 62 74:26 – 4 20 no 38 88 90:10 – 5 10 no 50 68 71:29 – 6 5 no 73 7 nd – 2.15 Determination of the Absolute Configuration of the Ugi Product 65a The absolute configuration of the Ugi product 65a was determined by removal of the benzyl groups to give the α-amino amide (R)-82 whose optical rotation and er were compared to those of an authentic sample prepared from (S)-phenyl glycine 83 (Scheme 2.11). The other α-amino amides in Table 2.8 were assumed to be homo-chiral with 65a. 43 Scheme 2.11 Determination of absolute stereochemistry of 65a Ph Ph N H N O 65a 90:10 er NH 2 1) (Boc) 2O Dioxane/H 2O 2:1 OH 1M NaOH, NaHCO 3 O 83 > 99:1 er NH 2 Pd(OH) 2/C H 2 (1 atm) EtOH, 25 °C 90% [!]20D BocHN 2) tBuNH2 DCC DCM 51% over two steps H N O 84 H N O (R)-82 91.5:8.5 er = – 23.1 (c 1.0, CH2Cl2) NH 2 TFA DCM 100% [!]20D H N O (S)-82 > 99:1 er = + 27.1 (c 1.0, CH2Cl2) 2.16 Reaction Progress Monitored by 1H NMR Spectroscopy Several sets of Ugi three-component reactions were monitored by 1H NMR spectroscopy to gain more insight into the factors that contribute to the reaction rate and outcome. Reactions with three different aromatic aldehydes and reactions with different amount of added H2O or 4 Å MS were investigated. 2.16.1 Ugi-3CR with Different Aldehydes. We first investigated the reaction with benzaldehyde 63a, and two psubstituted benzaldehydes, one electron poor (63d) and one electron rich (63n). The 1H NMR spectra were taken at certain intervals and the amount of the corresponding product 65 was calculated based on the 1H NMR integration against Ph3CH as an internal standard (Figure 2.2). Aminal 85 was identified as one of the components in the reaction mixture. It was found that once all the three components were mixed together, there was a 10-20% formation of the aminal 85, which was slowly converted to the Ugi product as the reaction 44 proceeded. The reaction with benzaldehyde was slightly faster than its psubstituted analogs. Figure 2.2 1H NMR study of the Ugi-3CR with aldehydes 63a, 63d and 63n Ph Ph 20 mol % (S)-BOROX catalyst (LAP 78-5-36) N O H A-5 + CN H 64 d8-toluene, rt R R 63a R = H 63d R = Br 63n R = MeO Ph Ph Ph N Ph N H N N O 65a R = H 65d R = Br 65n R = MeO R Ph Ph 85a R = H 85d R = Br 85n R = MeO Yield/% 100 90 65d 65a 80 65n 70 R=H 60 R=Br 50 R=MeO 40 R=H, aminal 30 20 R=Br, aminal 85d 85a 85n 10 R=MeO, aminal t/min 0 0 300 600 900 1200 1500 1800 2100 2400 2700 3000 3300 3600 3900 2.16.2 Reaction Progress of Ugi-3CR of 63a with Different Amounts of 4Å MS or H2O as An Additive Reactions of different amounts of 4Å MS or H2O were carried out under the same condition as that was shown in Figure 2.2 and monitored by 1H NMR spectroscopy. As shown in Figure 2.3, 4 Å MS does have some effect in bringing the reaction to the ultimate yield in a slightly shorter time (6 and 13 mg 4 Å MS). However, too much sieves will diminish the yield, which is revealed by the reaction with 60 mg 4 Å MS. The sieves have essentially no effect on the 45 asymmetric induction (see Table 2.6). The results shown in Figure 2.4 reveal that the addition of H2O will slow down the reaction and diminish the ultimate yield. It was also found that the reactions with H2O as an additive gave lower asymmetric inductions than those without H2O (Table 2.6). The formation of aminal 85a was observed but not plotted for reactions shown in Figure 2.4. Figure 2.3 1H NMR study of the Ugi-3CR of 63a with different amounts of 4Å MS Ph Ph N O H A-5 + CN H 64 63a Ph 20 mol % (S)-BOROX catalyst (LAP 78-5-36) Ph N d8-toluene, rt H N O 65a Yield/% 100 90 80 70 13 mg 4Å MS 65a 6 mg 4Å MS 65a 60 mg 4Å MS 65a 0 mg 4Å MS 65a 13 mg 4Å MS, aminal 6 mg 4Å MS, aminal 60 mg 4Å MS, aminal 0 mg 4Å MS, aminal 60 50 40 30 20 10 t/min 0 0 500 1000 1500 2000 46 2500 3000 3500 Figure 2.4 1H NMR study on the formation of 65a from the Ugi-3CR with 4Å MS and H2O Ph Ph N O H A-5 + CN H 64 63a 20 mol % (S)-BOROX catalyst (LAP 78-5-36) d8-toluene, rt Ph Ph N H N O 65a Yield/% 100 90 80 70 H2O 50 mol % H2O 60 H2O 100 mol % H2O 50 13 mg 4Å 40 20 mol % H2O H2O 30 20 10 t/min 0 0 1000 2000 3000 4000 5000 6000 2.17 Proposed Mechanism for the Asymmetric Catalytic Three Component Ugi-3CR It is considered likely that the catalyst is the boroxinate anion B3 that exists as an ion pair with the iminium ion 46 and thus this Ugi reaction is an example of “chiral anion catalysis” (Scheme 2.12).6b The mechanism can be envisioned to involve the addition of the isonitrile 64 to the iminium cation 46 to give the nitrilium cation 86 which is also ion-paired with the chiral anion catalyst B3. We propose that the next step is hydroxyl exchange between the nitrilium cation 86 and the hemi-aminal 87 which would result in the regeneration of the 47 iminium ion 46 and the formation of the product in the form of the tautomer 88. It is also possible that the hemi-aminal 87 is protonated and releases H2O which adds to nitrilium ion 86. Evidence against the presence of free H2O in this reaction comes from the fact that the presence of molecular sieves does not greatly affect the rate of the reaction and the addition of H2O slows down the reaction (see Table 2.6 and Figures 2.3 and 2.4). When the reaction is followed by 1H NMR spectroscopy it is observed that there is an initial build-up of the aminal 85 (~15% at 10% completion) and then it slowly disappears and is gone at the end of the reaction (Part 2.16.2, Figure 2.3). Scheme 2.12 Proposed mechanism for the catalytic asymmetric Ugi reaction Ar Ar + H+ N – A-5 Ar + A-5 R Ar N Ar 85 Ar N Ar N R N Ar 46 OR R O O B B O O O B B3 OR C N 64 Ar R O 88 H Ar Ar Ar N R C N R 87 Ar 86 N OR O B O B O O O B B3 OR Ar O N H O H N + R 65 O 48 H 63 Ar N H Ar A-5 2.18 NMR Evidence for the Formation of BOROX Anion Catalyst The involvement of a BOROX catalyst containing a boroxinate core is supported by 1H and 11 B NMR studies. A DMAP-BOROX complex has been previously synthesized and fully characterized by our group.12n Its structure was elucidated by X-ray diffraction analysis. The most distinctive absorption in the 1H NMR spectrum for this DMAP-BOROX complex is the bay-region (Scheme 2.13, Hb) peak at 10.4 ppm. The 11 B NMR spectrum of the complex shows a sharp peak at 5.7 ppm for the tetra-coordinated boron in the structure. Both of these two distinctive absorptions were observed for the catalyst for the Ugi-3CR. We first investigated the BOROX catalyst formation with 1.0 equivalent of amine A-5 (Scheme 2.13). After the addition of 1 equiv of the amine A-5 to the pre-catalyst solution, the 1H NMR spectrum showed a peak around 10.6 ppm (Figure 2.5, b-d) and the 11 B NMR spectrum revealed a sharp peak at 5.9 ppm (Figure 2.6, b-d). These results are indicative of the formation of the amine A-5BOROX complex. The absorption for the bay proton of the free ligand (R)-78 in the 1H NMR spectrum appears at 9.6 ppm in d8-toluene. Scheme 2.13 Catalyst formation with 1.0 equivalent of dibenzylamine A-5 1 equiv (R)-78 2 equiv phenol P-47 3 equiv BH 3!SMe2 3 equiv H 2O Ph 1.0 equiv pre-catalyst Ph N H2 Ph OMe O H N A-5 Ph Ar Ar H O b O B B O OH O B b O OMe Ar = 3,5-tBu2-4-Me 2-C6H 2 49 BOROX catalyst B3 and dibenzylamine A-5 complex Figure 2.5 1H NMR spectra in d8-toluene of the pre-catalyst and catalyst (bay proton region) with 1.0 equivalent amine A-5 a) b) c) d) (a) Pre-catalyst; Pre-catalyst formation: a flame-dried 25 mL Schlenk flask equipped with a stir bar was cooled to rt under N2 and charged with (R)-78 (91.6 mg, 0.111 mmol), P-47 (35.0 mg, 0.229 mmol), H2O (5.9 mg, 5.9 µL, 0.33 mmol), dry toluene (3.3 mL) and BH3·SMe2 (2M, 165 µL, 0.33 mmol). The Teflon valve on the Schlenk flask was then closed, and the mixture heated at 100 °C for 1 h. After the flask was cooled to rt, the valve was carefully opened to gradually apply high vacuum (0.1 mm Hg) and the solvent and volatiles were removed. Then the flask was heated at 100 °C under high vacuum for 30 min. The resulting mixture was dissolved in dry d8-toluene (1.04 mL) after it was cooled to room temperature. To an oven-dried quartz NMR tube filled with nitrogen was added Ph3CH (10.4 mg, 0.0426 mmol) as an internal standard, the pre-catalyst stock solution (0.49 mL, 0.05 mmol (R)-78) and 0.21 mL d8-toluene. The tube was 50 Figure 2.5 (cont’d) sealed with a rubber cap. The 1H NMR and 11 B NMR spectra of the pre-catalyst were taken at this point. (b) 1 h at rt after the addition of 1 equiv dibenzylamine; (c) 2 h at rt after the addition of dibenzylamine; (d) 6 h at rt after the addition of dibenzylamine (The integrations are based on the methine proton in Ph3CH, which was set to 1.00.) Figure 2.6 11B NMR spectra in d8-toluene of the pre-catalyst and catalyst with 1.0 equivalent amine A-5 a) b) c) d) (a) Pre-catalyst; (b) 30 min after the addition of 1 equiv dibenzylamine; (c) 2 h after the addition of dibenzylamine; (d) 3.5 h after the addition of dibenzylamine We then investigated the catalyst formation under the reaction condition where 10 equivalents of amine A-5 were added (Scheme 2.14). After the addition 51 of 10 equiv of the amine A-5 to the pre-catalyst solution, a peak around 10.8 ppm in the 1H NMR spectrum (Figure 2.7, b) and a sharp peak at 5.7 ppm in the 11 B NMR spectrum (Figure 2.8, b) were indicative of the formation of the A-5-BOROX complex. After the addition of 5 equiv benzaldehyde, three broad absorptions around 10.8 ppm were observed (Figure 2.7, c). This is not surprising since the protonated amine [A-5]H+, iminium 46, protonated hemiaminal 87-H+ and protonated aminal 85-H+ could all pair up with the BOROX anion (Scheme 2.14). These different ion pairs are in equilibrium in the reaction mixture, resulting in slightly different absorptions in the bay-region in 1H NMR spectrum. The addition of isocyanide 64 hardly resulted in any change in both 1H NMR and 11 B NMR spectra (Figure 2.6 and 2.7, d). Scheme 2.14 Catalyst formation with 10.0 equivalent of dibenzylamine A-5 1 equiv (R)-78 2 equiv phenol P-47 3 equiv BH 3!SMe 2 10 equiv 3 equiv H 2O H Ph Ph Ar N A-5 Ar pre-catalyst Ph N H2 Ph X O OR H O b O B OH B O b O B OR H 63a 5 equiv X= Ph N Ph N Ph or H2 or Ph 46 [A-5]H+ Ar Ar OH b B O O B OR B3 R = 2,6-diMe-4-MeOC6H 2 Ph OH H N Ph 87-H 52 H O b O B NC 64 7.5 equiv BOROX catalyst B3 and dibenzylamine A-5 complex Ph OR Ph Ph Ph or Ph N Ph H N 85-H Ph Ph Figure 2.7 1H NMR spectra in d8-toluene of the pre-catalyst and catalyst (bay proton region) a) b) c) d) (a) Pre-catalyst; Sample preparation: To an oven-dried quartz NMR tube filled with nitrogen was added Ph3CH (11.7 mg, 0.0479 mmol) as an internal standard, the pre-catalyst stock solution (0.49 mL, 0.05 mmol (R)-78) (prepared according to the procedure described in Figure 2.5) and 0.21 mL d8-toluene. The tube was sealed with a rubber cap. The 1H NMR and 11 B NMR spectra of the pre-catalyst were taken at this point. The integration of the methine proton in Ph3CH was set to 1.00. (b) After the addition of 10 equiv dibenzylamine A-5 at rt; (c) After the addition of 5 equiv benzaldehyde 63a at rt; (d) After the addition of 7.5 equiv isocyanide 64 at rt. 53 Figure 2.8 11B NMR spectra in d8-toluene of the pre-catalyst and catalyst a) b) c) d) (a) Pre-catalyst; (b) After the addition of 10 equiv dibenzylamine A-5 at rt; (c) After the addition of 5 equiv benzaldehyde 63a at rt; (d) After the addition of 7.5 equiv isocyanide 64 at rt. 2.19 Attempted Asymmetric Four-Component Ugi Reaction Finally, a four-component version of this reaction with the optimal BOROX catalyst (LAP 78-5-47) was performed with benzoic acid 89 (Scheme 2.15). The reaction rate was much faster than that of the three-component version (2 h vs >24 h). The carboxylic acid component is known to accelerate the 4-component Ugi reaction and this was observed in the present case as well where the reaction was complete in 2 h to give the amino imide 90 in 75% yield but the product was racemic. The control experiment without the chiral catalyst still 54 proceeds but at a slightly slower reaction rate (59% conversion after 2 h). One possible explanation involves the protonation of the hemi-aminal 87 by benzoic acid 89 to give the iminium ion 46 and then upon addition of the isonitrile, the non-chiral ion pair 91. Subsequent combining of the ions gives 92 and then an O to N acyl migration would produce 90. Scheme 2.15 Ugi-4CR with benzoic acid Ph O 63a 1.0 equiv OH + + N H H + 20 mol % (S)-BOROX catalyst (LAP 8-5-47) O Ph CN 89 1.6 equiv A-5 2 equiv Ph Ph N N mesitylene 25 °C, 2 h 4 Å MS 64 1.5 equiv O O 90 75% (0% ee) without catalyst: 59% conversion after 2 h, 80% yield after 24 h. O Ar N R Ar O H 87 OH 89 – H 2O Ar Ar N R Ar Ar 46 tBuNC N Ar N R R O N O O N Ar O O O 91 92 2.20 Conclusion A great diversity of BOROX catalysts can be quickly generated and the optimal combination of the ligand, amine and phenol/alcohol components of the catalyst were sought and found for the three-component asymmetric Ugi reaction. The optimal catalyst was found to give high enantioselectivity for αamino amides from the reaction of a variety of aryl and heteroaryl aldehydes with dibenzyl amine and t-butyl isocyanide. A number of p-substituted dibenzyl amines and some other isonitriles are also effective under the optimal reaction 55 conditions with benzaldehyde giving the product in high asymmetric induction. The active catalyst is proposed to involve an ion-pair between a chiral boroxinate anion and an achiral iminium ion. 56 CHAPTER 3 β -AMINO ESTERS FROM THE REDUCTIVE RING OPENING OF AZIRIDINES-2-CARBOXYLATES 3.1 Introduction The synthesis of β-amino acids has been a subject of great interest and importance for quite some time35 but especially since it was discovered that βpeptides derived from β-amino acids have many of the properties of α-peptides but are much more proteolytically stable.36 There has been a decided uptick in the efforts to develop catalytic asymmetric methods for the synthesis of β-amino acids in the last decade. Some important catalytic asymmetric approaches to βamino acids include transformations based on the Mannich reaction, hydrogenation of β-aminoacrylic acid derivatives and conjugate addition to α,βunsaturated carbonyl compounds.37 Our interest in this area follows from the experiences we have gained in the development of a method for the catalytic asymmetric synthesis of aziridines as discussed in Chapter 1.38 We have found that cis-aziridine-2-carboxylates can be prepared with a high degree of enantio- and diastereoselection by a threecomponent coupling of an aldehyde, and amine and ethyl diazoacetate under the aegis of a BOROX catalyst (Scheme 3.1).12 High yields of aziridine-2carboxylates can be realized starting with aryl, alkyl or alkynyl aldehydes with a typical selectivity for the cis-isomer of ≥50:1. The enantioselection can depend on the nature of the amine substitutent or on the nature of the ligand, and with the right combination a minimum of 96% ee can be obtained with aryl, alkynyl and 57 primary (1°), secondary (2°) and tertiary (3°) aliphatic aldehydes. The diastereoselection for the aziridine can be switched to trans with the use of a 2° diazoacetamide.9 The purpose of the present work is to explore the reductive opening of cis-aziridine-2-carboxylates with the goal of directing opening at the C-2 position to provide for an efficient and highly stereoselective catalytic asymmetric route to β-amino esters which can be easily hydrolyzed to give βamino acids. Scheme 3.1 Proposed catalytic asymmetric route to β-amino esters O R1 O PG + + NH 2 H H OR2 N2 PG BOROX catalyst N R1 CO2R 2 [H-base] [H] 3 2 1 Ph Ph O O B OPh O B 4 O O B OPh PG R1 NH O OR2 VANOL/VAPOL BOROX catalyst 35/36 A number of methods are known for the reductive opening of aziridines-2carboxylates to give β-amino esters, such as hydrogenolysis and processes involving electron transfer.39,40 The nature of the reducing agent can be quite critical when it comes to aziridines with an aryl group in the 3-position. As illustrated in Scheme 3.2, such aziridines 94 are prone to undergo reductive opening to give α-amino esters 95b by hydrogenolysis or with Lewis or Brønsted 58 acid mediated reduction.39,41 However, this proclivity for reduction can be reversed by using electron transfer reduction methods due to the fact that the electron preferentially adds to the carbonyl function thus directing ring opening to the 2-position resulting in β-amino esters 95a. This has been reported with samarium diiodide,42 and magnesium metal (Scheme 3.3).43 Scheme 3.2 Ring-opening of aziridine-2-carboxylates with an aryl group at the 3position under different conditions reduction via e – transfer PG O OR2 Ar PG N 95a CO2R 2 Ar NH 94 reduction via hydrogenolysis or Lewis/ Brønsted acids O OR2 Ar PG NH 95b Scheme 3.3 Selective ring-opening of aziridine-2-carboxylate at the 2-position with Mg(0) and SmI2 a) Ts N Ts Mg° (4 equiv) MeOH, –23 °C, 2 h Ph b) Ph SmI2 DMEA CO2Et O OMe 35% The major product is the desulfonylated aziridine. CO2Me PG N NH PG THF, 0 °C 59 Ph NH O Ph OEt PG = Ts, 87% PG = Boc, 82% While 3-arylaziridine-2-carboxylates can be reductively opened to β-amino esters with either samarium diiodide or magnesium(0), all examples in the literature are with trans-isomers of the aziridine (Scheme 3.3).42-43 Therefore, since the BOROX catalyst produces very high selectivities for cis-aziridines, it became imperative to determine if the same regioselectivities observed in the reductive opening of trans-aziridines would translate to cis-aziridines. 3.2 Initial Studies of Ring-Opening Reactions with cis-Fmoc-Protected Aziridines We began our studies with Fmoc aziridines since this would be the most desirable N-substituent for the purposes of solid state synthesis of β-peptides. The ring opening reaction with Fmoc aziridine cis-96 that has a phenyl group in the 3-position cis to the ethyl carboxylate was examined by our former group member Zhenjie Lu with magnesium in methanol and with samarium diiodide in the presence of N,N-dimethylethanol amine (DMEA). The purpose of the DMEA is to sequester the samarium(III) that is formed and prevent it from opening the aziridine as a Lewis acid giving the α-amino ester product 99.42c, d The reduction with magnesium(0) did not occur under the reported conditions (Scheme 3.3 a; Scheme 3.4, method A; Fmoc aziridines were not included in this reported study)43 and high conversion was only realized after prolonged heating at 55 °C, however, neither the α-cleavage product 97, the β-cleavage product 99 nor the C-C cleavage product 98 were observed in the crude reaction mixture. This reaction was later repeated during the work of this dissertation and the same results were obtained. The products that were formed were not separated and 60 identified. The reduction of cis-96 with samarium diiodide was performed with the reported conditions42c, d indicated in Scheme 3.4 and the result was that both the α-cleavage product 97 and the C-C cleavage product 98 were formed in substantial amounts. Scheme 3.4 Ring-opening of cis-96a by Mg(0) and SmI2 Fmoc N Ph Fmoc Ph CO2Et cis-96a 0% conversion 92% conversion 67% conversion NH Method A: Mg° (4 equiv) MeOH/THF (1:1) –23 °C, 2 h 55 °C, 46 h Method B: SmI2 (2.5 equiv) DMEA (5 equiv) THF, 0 °C, 0.7 h O + OEt 97a Ph Fmoc N CO2Et 98a — not detected — not detected 32 68 O + Ph OEt NH Fmoc 99a — not detected possible trace After a bit of optimization, the reductive ring-opening of cis-96a could be brought to completion with 4 equiv SmI2 and 8 equiv DMEA in THF in 1 hour at 0 °C (Table 3.1, entry 1).44 This reaction resulted in the isolation of the α-cleavage product 97a in 45% yield and the C-C cleavage product 98a in 46% yield. Upon examining the reductive ring-opening of the corresponding trans-aziridine trans96a under the optimized conditions, it became clear that there is a big dependence in the product distribution on the stereochemistry of the aziridine. Whereas the cis-aziridine 96a gives a 1 : 1 mixture of 97a : 98a, the transaziridine 96a gives a 16.7 : 1 mixture of 97a : 98a (Table 3.1, entries 1 vs 3). This was not the case with aziridines bearing an alkyl group in the 3-position. Both the cis- and trans-isomers of the 3-cyclohexyl aziridine 96b gave exclusive 61 opening at the α-position and a highly selective formation of the β-amino ester 97b (Table 3.1, entries 2 vs 4). Table 3.1 Reductive opening of cis- and trans-Fmoc aziridines [a] Fmoc N R 96 CO2Et SmI2 DMEA Fmoc THF, 0 °C, 1h NH O R + OEt R 97a,b Fmoc N CO2Et 98a,b entry aziridine R 97 : 98 [b] % yield 97 [c] % yield 98 [d] 1 [e] cis-96a phenyl 1:1 45 46 [c] 2 [e] cis-96b cyclohexyl >99 : 1 89 <1 3 [f] trans-96a phenyl 16.7 : 1 82 [d] 5 4 [g] trans-96b cyclohexyl >99 : 1 73 [d] <1 [a] Unless otherwise specified, all reactions were run with 0.2 mmol aziridine in THF (0.07 M) with 4 equiv SmI2 and 8 equiv DMEA at 0 °C for 1 h and went to completion. [b] Determined from the 1H NMR spectrum of the crude reaction mixture. [c] Isolated yield after silica gel chromatography. [d] Yield from the 1H NMR spectrum of crude reaction mixture with internal standard. [e] Data contributed by Zhenjie Lu. [f] Reaction with 5.5 equiv SmI2 and 11 equiv DMEA. [g] Reaction with 6 equiv SmI2 and 12 equiv DMEA. 3.3 SmI2 Mediated Ring-Opening Reactions with Various N-Protected Aziridines In the search for a more general method for the reductive ring opening of aziridines to β-amino esters, a number of different N-protecting groups were examined and the results are presented in Table 3.2. As a carbamate, it was not 62 surprisingly to find that the profile for the SmI2 mediated reductive ring opening of the Boc-protected aziridines closely matched that for the Fmoc aziridines with just slightly lower selectivities. Again the ring-opening of phenyl substituted cisaziridine was not selective (1.4:1, Table 3.2, entry 1). The phenyl substituted trans-aziridine 100a was more selective 6.7:1 (entry 3) and both isomers of the cyclohexyl substituted aziridines 100b were highly selective (entries 2 and 4). Clearly, the most felicitous N-protecting group with regard to selectivity of reductive ring-opening by samarium diiodide is the tosyl group. The profile here is flat with >99:1 selectivity for the β-amino ester with both cis- and transaziridines and with both phenyl and cyclohexyl substituted aziridines, all with very high yields (Table 2, entries 5-8). Table 3.2 Reductive opening of cis- and trans-N-activated aziridines. [a] PG N SmI2 DMEA CO2Et R 100-103 PG THF, 0 °C, 1h NH O R + OEt A R PG N CO2Et B entry PG aziridine R A : B [b] % yield A [c] % yield B[c] 1 Boc cis-100a phenyl 1.4 : 1 55 (104a) 32 (108a) 2[e] Boc cis-100b cyclohexyl >99 : 1 84 (104b) — (108b) 3 Boc trans-100a phenyl 6.7 : 1 85 (104a) 10 (108a) 4 Boc trans-100b cyclohexyl >99 : 1 84 (104b) [d] — (108b) 5[e] Ts cis-101a phenyl >99 : 1 93 (105a) — (109a) 63 Table 3.2 (cont’d) 6 Ts cis-101b cyclohexyl >99 : 1 97 (105b) [f] — (109b) 7 Ts trans-101a phenyl >99 : 1 88 (105a) — (109a) 8 Ts trans-101b cyclohexyl >99 : 1 95 (105b) — (109b) 9 SES cis-102a phenyl 23 : 1 84 (106a) [g] 4 (110a) 10[e] Ac cis-103a phenyl >99 : 1 52 (107a) [h] — (111a) [a] Unless otherwise specified, all reactions were run with 0.2 mmol aziridine in THF (0.07 M) with 6 equiv SmI2 and 12 equiv DMEA at 0 °C for 1 h and went to completion. [b] Determined from the 1H NMR spectrum of the crude reaction mixture. [c] Isolated yield after silica gel chromatography. [d] Yield from 1H NMR spectrum of crude reaction mixture with internal standard. [e] Data contributed by Zhenjie Lu. [f] Reaction with 5 equiv SmI2 and 10 equiv DMEA. [g] A small amount (~6%) of SES protected benzylamine was also observed. [h] Reaction with 4 equiv SmI2 and 8 equiv DMEA. The ring opening product from N-C3 cleavage to give an α-amino ester was obtained in 13 % isolated yield. The SES group45 (trimethylsilyl ethyl sulfonyl) is an attractive activating group for an amino function since it is easier to remove than tosyl and very good selectivity for the β-amino ester 106a is seen with the cis-aziridine 102a (23:1, Table 3.2, entry 9). The slightly lower selectivity for the SES group compared to tosyl (entries 5 vs 9) perhaps could be expected for an alkyl sulfonate compared to an aryl sulfonate (vide infra). Finally, it was found that the N-acetyl group is also capable of delivering very high selectivity for the β-amino ester 107a over the C-C cleavage product in the ring opening of the cis-phenyl aziridine cis-103a, 64 however, the isolated yield of the β-amino ester 107a was only moderate and the reaction occurs with the formation of 13% of the α-amino ester corresponding to 99 in Scheme 3.4 (Table 2, entry 10). The latter may result from initial electron transfer to the amide carbonyl and then ring opening to a benzyl radical (or anion, vide infra). 3.4 SmI2 Mediated Ring-Opening Reactions with un-Activated Aziridines The reductive ring opening of un-activated aziridines by samarium diiodide would be a very useful reaction since this is the class of aziridines for which the BOROX catalysts are most efficient at producing (Scheme 3.1). In previous studies, Kumamoto and coworkers examined the samarium diiodide mediated ring opening of trans-aziridine-2-carboxylates with an aryl group in the 3-position and a benzyl group on the aziridine nitrogen and found that β-amino esters could only be obtained in very low yields.42a The corresponding cis-aziridines were not investigated. Interestingly, this report finds that if the samarium diiodide is generated from samarium metal and iodine instead of methylene iodide, the major outcome is the isomerization of the trans-aziridine to a mixture of cis- and trans-aziridines. There are no other examples of the reductive ring opening of aziridines bearing an alkyl group on the nitrogen with samarium diiodide in which the aziridines have a carbonyl group in the 2-position and either an aryl or alkyl substituent in the 3-position. Thus we decided to probe the first examples of the reductive ring opening of un-activated cis-aziridine-2-carboxylates with samarium diiodide (Table 3.3). The samarium diiodide used in these studies was prepared from samarium metal and methylene iodide and no isomerization of the aziridine 65 was observed. If the substituent in the 3-position is a phenyl group, then the only product that is observed is the C-C cleavage product. Good yields (69-75%) were observed for this product with N-H aziridines as well as with benzhydryl substituents on the aziridine nitrogen (Table 3.3, entries 1-2). Table 3.3 Reductive opening of cis-unactivated aziridines [a] PG N SmI2 DMEA CO2Et R 117-118 THF 0 °C 40 min GP NH O R OEt + PG N R A CO2Et Ph + B Ph NH 2 122 entry PG aziridine R A : B [b] % yield A[c] % yield B[c] 1[f] H cis-117a phenyl <1 : 99 — 75 (120a) 2[f] CHPh2 cis-118a phenyl <1 : 99 — 69 (121a) 3 CHPh2 cis-118b cyclohexyl >99 : 1 22 (119b) [d] — 4 CHPh2 cis-118b cyclohexyl >99 : 1 22 (119b) [e] — [a] Unless otherwise specified, all reactions were run with 0.2 mmol aziridine in THF (0.07 M) with 5 equiv SmI2 and 10 equiv DMEA at 0 °C for 40 min and went to completion. [b] Determined from the 1H NMR spectrum of the crude reaction mixture. [c] Isolated yield after silica gel chromatography. [d] Isolated as a 1:1.4 mixture of 119b and cis-118b (22% + 31%). The 1H NMR indicated the formation of the amine 122 in 39% yield. [e] Reaction was run for 2 h at 25 °C. The amine 122 was isolated in 52% yield and the aziridine cis-118b was isolated in 20% yield. [f] Data contributed by Zhenjie Lu. A complete switch in the product distribution was seen with cis-azridines bearing a cyclohexyl group in the 3-position. 66 Here the β-amino ester was generated to the exclusion of the C-C cleavage product, however, the yields were quite low (Table 3.3, entries 3 and 4). These reactions produce a complex mixture of products from which only the β-amino ester 119b, the starting cisaziridine 118b and benzhydryl amine 122 could be isolated and characterized. The isolation of 122 suggests that β-cyclohexyl ethyl acrylate should also be formed but it could not be detected in the 1H NMR spectrum of the crude reaction mixture. 3.5 SmI2 Mediated Ring-Opening Reactions with a Tri-Substituted Aziridine The reductive process mediated by SmI2 with a tri-substituted aziridine was also investigated (Scheme 3.5). The reductive ring opening of the stereoisomerically pure tri-substituted aziridine 12346 occurred with loss of stereochemical information and the formation of two diastereomers in a ratio of 4.8 : 1. The major diastereomer was identified as the anti-isomer of 124 by chemical correlation to the known compound anti-126. This loss of stereochemistry is to be expected considering the likely mechanism for this reaction (Scheme 3.6, 132 to 133). The ring opening of 123 also occurred with the formation of the C-C cleavage product 125 in 30% yield. Note that this distribution between C-N and C-C cleavage products is essentially the same as for the cis-di-substituted N-Boc aziridine cis-100a (Table 3.2, entry 1). 67 Scheme 3.5 Ring-opening of aziridine 123 by SmI2 and determination of relative stereochemistry of anti-124 Boc N Me CO2Et NH 2 O 123 OEt Me anti-126 74% SmI2 (5 equiv) DMEA (10 equiv) THF, 0 °C, 1 h TFA CH2Cl2 Boc NH Boc O OEt Me anti-124 43% NH O OEt + + Boc O N OEt Me syn-124 9% 125 30% 3.6 Mechanistic Rationale for the Selectivity Observed in the SmI2-Mediated Ring Opening Reactions of Aziridines The generally accepted mechanism for the reductive ring opening of aziridines by samarium diiodide is illustrated in Scheme 3.6.42c After initial reduction to form the ketyl 128 and in the absence of a proton source, the ketyl undergoes a ring opening to give the nitrogen based radical 129 which upon further reduction gives the species 130 containing both a samarium enolate and a samarium amide. The intermediacy of this enolate 130 has been demonstrated and its utility displayed in its alkylation with alkyl halides42c and aldol reactions with aldehydes (R’ = H) to generate 131.42b Under conditions where a proton source is present, the ketyl 128 is thought to be protonated to give the neutral radical 132 which, depending on the nature of the aziridine, then undergoes a CN and/or C-C bond scission. Subsequent reduction of the resulting nitrogen or 68 carbon based radicals 133 and 136 and final protonation would provide the βamino ester 135 and/or the glycine derivative 138. Scheme 3.6 Mechanistic rationale for SmI2-mediated ring opening process PG N PG N SmI2 • OEt R 128 O SmI2 CO2Et R C-N 127 PG cleavage N• R OEt 129 SmI2 + ROH – ROSmI 2 PG N• O R H OEt PG N C-N cleavage 133 SmI2 C-N PG • OEt R C-C O 132H R SmI2 N R PG R N SmI2 H O 134 OEt PG N R • O OEt 130 E NH PG N 135 OEt R PG OEt SmI2 O H O + O OEt E 131 H OEt SmI2 137 NH R 136 + ROH – ROSmI 2 SmI2 O C-C cleavage PG SmI2 O + ROH – ROSmI 2 R PG N O OEt 138 This mechanistic interpretation can be used to account for the observations made in the present work. In all of the examples in Tables 3.1 and 3.2, the aziridines with a cyclohexyl group in the 3-position gives a much higher selectivity for the β-amino ester over the glycine derivative than do aziridines with a phenyl group in the 3-position. This reflects a higher preference for C-C over C-N cleavage for the phenyl aziridines than the cyclohexyl aziridines and this can 69 be attributed to the greater stability of a benzyl radical compared to an alkyl radical in intermediate 136. Conversely, the presence of a radical stabilizing group on the nitrogen facilitates the ring opening with C-N bond scission over CC bond scission. This can be seen in the ring opening reactions of activated aziridines (Tables 3.1 and 3.2) versus un-activated aziridines (Table 3.3). This is illustrated in the comparison of the N-tosyl aziridine cis-101a (Table 3.2, entry 5) versus the N-benzhydryl aziridine cis-118a (Table 3.3, entry 3) and in the comparison of the N-tosyl aziridine cis-101a (Table 3.2, entry 5) versus the NBoc aziridine cis-100a (Table 3.2, entry 1). The ratio of C-N versus C-C cleavage is not only a function of the radical stabilizing ability of the substituent on the nitrogen and the substituent on the C-3 position of the aziridine, but also of the stereochemistry of the aziridine. The cisaziridines give a much greater preference for C-C bond cleavage than the transaziridines. The N-Boc aziridine trans-100a gives a 6.7 : 1 mixture of C-N to C-C cleavage products, whereas, the corresponding cis-100a gives a much greater propensity for the C-C cleavage product (1.4 : 1, Table 3.2, entries 1 vs 3). The same is also true for the N-Fmoc aziridines cis-96a and trans-96a (Table 3.1, entries 1 vs 3). The existence of cis-132 in a conformation with the large protecting group (PG) on the nitrogen trans to both substituents on C-2 and C-3 (Scheme 3.7, a) is supported by the X-ray crystal structures obtained for several similar aziridines.47 The greater preference for C-C cleavage products with cisaziridines may be attributed to a relief in steric interactions between the two cissubstituents in the transition state where the C-C bond is beginning to lengthen 70 (Scheme 3.7, cis-132). This relief in steric interaction would not be realized as the C-C bond begins to lengthen in the trans-aziridine. The trans-aziridine probably exists in both conformations shown in Scheme 3.7, with PG cis to one of the substituents on C-2 and C-3 (Scheme 3.7, b, trans-132 and trans-132’). In the case of conformer trans-132, the steric interaction between the PG and the R group can be hardly released by either C-C or N-C cleavage. However, the relief in the steric interaction between the PG and ketyl group in the conformer trans132’ can be achieved via C-N cleavage, which explains the high selectivity for βamino ester in the reaction with trans-aziridines. It is interesting that C-C cleavage products have been rarely seen in the reductive ring opening of aziridines involving single electron transfer processes and this may be due to the fact that cis-aziridines have not been previously evaluated in this reaction. The only example that we are aware of involves an un-activated (N-H) aziridine-2carboxylate trans-139a with a phenyl group in the 3-position which gives a 28:16 split between C-N (140a) and C-C (141a) cleavage products (Scheme 3.8).42c This is to be compared with the aziridine cis-117a which gave exclusively the CC cleavage product 120a in 75% yield (Table 3.3, entry 1). 71 Scheme 3.7 Mechanistic rationale for different selectivities observed for transand cis-aziridines a) PG N R • O H OEt C-C cleavage 136 R • O H OEt C-C R • cleavage • NH R R PG C-N • OEt O OEt C-C R cleavage PG N cleavage 136 H OEt • NH H OEt 133 PG C-N • OEt O R O H trans-132 (PG cis to R) H O 133 PG N cleavage 136 PG N • OEt R PG C-N O H cis-132 b) PG N PG N cleavage • NH O R H OEt 133 O H trans-132' (PG cis to the ketyl) Scheme 3.8 Reported example of a C-C cleavage product from reductive ring opening process H N CO2Me Ph trans-139a SmI2 DMEA THF, 0 °C NH 2 O Ph 140a 28% 72 + OMe Ph H N 141a 16% CO2Me 3.7 Syntheses of L-DOPA and (R)-β 3-DOPA The utility of aziridine-2-carboxylates to approach both α- and β-amino acids is illustrated in Scheme 3.9 by the synthesis of L-DOPA and (R)-β3-DOPA, from the same aziridine. L-DOPA is the biological precursor to the catecholamine neurotransmitters, is used in the treatment of Parkinson’s disease48 and is a key compound in the formation of marine adhesive proteins.49 L-DOPA became the first commercial pharmaceutical agent to be manufactured by a nonproteinaceous asymmetric catalyst which was acknowledged in the 2001 Nobel Prize in chemistry to William S. Knowles.50 The isomeric (R)-β3-DOPA has been isolated as an iron(III) complex from a dark blue-violet colored mushroom of the species Cortinarius violaceus.51,52 Both natural products could potentially be obtained from the reductive opening of the same aziridine via controlled reductive ring-opening at the C-2 and C-3 positions. Scheme 3.9 Reported example of C-C cleavage product from reductive ring PG N CO2Et RO RO reductive opening at C-2 reductive opening at C-3 NH 2 O HO O HO OH HO HO OH NH 2 L-DOPA (R)-! 3-DOPA 73 From the synthetic point of view, the N-tosyl group is the protecting group of choice for samarium diiodide mediated reductive ring-opening of aziridines if removal of the tosyl group does not cause problems in a later stage. N-Tosyl aziridines are completely selective for the C-N cleavage product (>99:1) for both the cis- and trans-aziridines and with both aryl an alkyl substituents in the 3position (Table 3.2, entries 5-8). The SES-protecting group can be considered as an alternative to a tosyl sulfonamide which is notorious for its potential in being troublesome during deprotection. The SES-protected aziridine cis-102a gave excellent selectivity (23:1, Table 3.2) for the β-amino ester and the deprotection of SES is known to proceed under much milder reaction conditions. Thus, we decided to examine both Ts and SES protecting groups. Our first approach to the synthesis of L-DOPA and (R)-β3-DOPA began with the bis-acetoxy aziridine 145 which was prepared in one step in 98% yield and >98.5% ee from aldehyde 142, the amine 44 and ethyl diazoacetate 45 by a catalytic asymmetric multicomponent aziridination with 5 mol% VAPOL BOROX catalyst (Scheme 3.10).12e, 12g To set the stage for the regio-complimentary reductive ring-opening of the aziridine 145, the MEDAM group was cleaved with trifluoracetic acid in anisole and the resulting N-H aziridine was not purified but rather directly protected by TsCl or SESCl to give the N-protected aziridines 149 and 150 in 70% and 78% yield, respectively, for the two steps. The samarium diiodide ring-opening of both the tosyl aziridine 149 and SES-aziridine 150 gave complex mixtures due to the cleavage of zero, one or two of the acetoxy groups on the benzene ring. By treating the crude mixtures with acetic anhydride in the 74 presence of triethylamine, the β-amino esters 152A and 153A were isolated in good yields, although an increase in the yield of C-C cleavage product was observed in both cases compared to the corresponding phenyl substituted aziridines cis-101a and cis-102a (Table 3.2). This may be due to the electronic effect of the two acetate groups on the benzene ring. Despite the prolonged effort that was taken to investigate the removal of the tosyl group following many of the standard procedures, 152A could not be deprotected without decomposition. Scheme 3.10 Syntheses of protected forms of L-DOPA and (R)-β3-DOPA O O RO MeO OMe H + MEDAM NH 2 142: R = Ac 143: R = Piv 144: R = Me 1.05 equiv 44 5 mol% (R)-VAPOL BOROX toluene, 25 °C, 20 h i TFA/anisole CO2Et CO2Et ii TsCl or SESCl RO Et 3N, DCM RO RO R = Ac: I. SmI2, DMEA II. Ac2O, Et 3N PG + R Ts SES SES Ac Ac Piv NH O RO OEt CO2Et 152-154B RO 152-154A Yields of A and B 152B 153B 154B (Boc) 2O MeOH R = Piv PG = SES, R = Piv CsF, DMF 95 °C R = Piv: SmI2, DMEA PG N H 2, Pd(OH) 2 PivO 145: R = Ac, 98% yield, > 98.5% ee 146: R = Piv, 97% yield, 98% ee 147: R = Me, 90% yield 149: PG = Ts, R = Ac, 70% 150: PG = SES, R = Ac, 78% 151: PG = SES, R = Piv, 86% PG 45 1.2 equiv N N RO OEt N2 MEDAM PG RO H RO MEDAM RO + 8% 19% 16% 152A 76% 153A 69% 154A 74% 75 PivO CO2Et NHBoc 148 86% HO CO2Et HO 156 65% NMR yield I. (Boc) 2O DMAP, Et 3N PivO II. TBAF, THF III. PivCl, Et 3N THF PivO NHBoc CO2Et 155 88% yield from 154A Before exploration of SES-deprotection of 153A, we turned our attention to the acetate cleavage problem in the samarium diiodide ring-opening process. This was solved by replacing the acetate groups with the bulky tert-butyl acyloxy (pivaloyl) groups. The catalytic asymmetric multicomponent aziridination worked smoothly with aldehyde 143 and afforded the aziridine 146 in 97% yield and 98% ee. Interestingly the MEDAM group could be removed with trifluoroacetic acid in anisole without cleave of the pivaloyl groups and then directly reacting the N-H aziridine with SESCl gave aziridine 151 in 86% yield. In addition to 146, we also considered aziridine 147 as a potential candidate for this synthesis. The aziridine 147 was readily prepared from the aldehyde 144 in high yield via the asymmetric aziridination reaction. However, the attempted cleavage of the MEDAM group in 147 with trifluoroacetic acid in anisole only led to decomposition. Formation of βamino ester 154A was smoothly achieved (74% yield) from the reductive ringopening reaction with no detection of cleavage of the pivolyl groups. The first attempt to remove the SES group from the amine function in 154A following a literature procedure19 involving heating with CsF in DMF at 95 °C resulted only in the formation of ethyl 3,4-dihydroxycinnamate 156 in 65% yield (NMR yield). This is probably due to a fluoride mediated deprotonation at the α-position of the carbonyl causing an elimination of the SES-amino group. Alternatively 156 could result from a fluoride mediated cleavage of the pivaloyl group followed by a phenoxide assisted elimination of the SES-amino group and a final rearomatization. A similar outcome was also observed for the SES protected βamino ester 153A. It has been previously reported that elimination of the SES 76 group from SES-protected α-amino carbonyl compounds can be a problem during the SES deprotection step.53 However, there is no example reported for the elimination of the SES-NH2 group from a β-amino ester during SES deprotection. It is known that N-acyl substituted SES groups are much more readily deprotected than simple SES groups.53 In light of the latter, we carried out the acylation of 154A by treating it with (Boc)2O and the crude mixture was treated with TBAF in THF at 25 °C for 1.5 h to afford the desired β-amino ester 155, the protected form of (R)-β3-DOPA, in 88% isolated yield from 154A. There was some cleavage of the pivaloyl groups by TBAF and thus a workup with pivaloyl chloride gives 155 as a pure compound. No purification was performed during any of the steps in the conversion of 154A to 155. Finally, the reductive ring-opening of aziridine 146 with palladium hydroxide catalyzed hydrogenation in the presence of (Boc)2O resulted in the formation of the α-amino ester 148, the protected form of L-DOPA, in 86% isolated yield. 3.8 Conclusion The reductive ring opening of 3-substituted aziridine-2-carboxylates with samarium diiodide can be controlled to proceed via C-N bond cleavage to give high yields of β−amino esters. The competing C-C bond cleavage gives rise to glycine derivatives. It is necessary to have an activating group on the aziridine nitrogen to achieve selective C-N bond cleavage. Aziridines with non-activating nitrogen substituents (hydrogen or benzhydryl) give exclusively the formation of glycine derivatives when there is a phenyl group in the 3-position and, when there is a cyclohexyl group in the 3-position, low yields of β−amino esters are 77 observed along with other decomposition products. The selectivity between C-N and C-C bond cleavage directly correlates with the electron-withdrawing power of the activating group on the nitrogen. Sulfonyl groups give higher selectivity than carbamate groups and this is especially noticeable with cis-aziridines that have a phenyl group in the 3-position. The lower selectivity with cis-aziridines is thought to be due to a steric release during the C-C bond cleavage leading to glycine products. The utility of this methodology is illustrated in the synthesis of a protected form of (R)-β3-DOPA by the reductive opening of aziridine 151 with samarium diiodide to give the β-amino ester 154A. Furthermore, this synthesis features the targeting of (R)-β3-DOPA and its regioisomer L-DOPA by ring opening of the same aziridine 146, the former by a reductive opening at the C-2 position and the latter by reductive opening at the C-3 position. 78 CHAPTER 4 STUDIES ON THE SYNTHESES OF TWO-HEADED SPHINGOID BASES 4.1 Introduction Sphingolipids are important components of eukaryotic cell membranes, which play important roles in various aspects of cell regulation including cell growth, differentiation, cell death, adhesion, neuronal repair and signal transduction.54 The core structure of a sphingolipid involves a sphingoid base backbone, which is a long-chain (mostly C18 chain) amino alcohol (Figure 4.1, a). Usually, the sphingoid base backbone involves a 2-amino-1,3-dihydroxy terminus, where an acyl group can be attached to the amino nitrogen and (or) a head group located on 1-OH, such as hydrogen, phosphate and glycoside. The three most common sphingoid bases found in mammalian cells include sphingosines, sphinganines and phytosphingosines (Figure 4.1, b).54b Figure 4.1 The general structure of sphingolipids and examples of sphingoid bases a) General structure of sphingolipids: R HN O Head group OH R = H, acyl sphingoid base backbone (eg. Sphingosine) b) Examples of sphingoid bases: OH * 12 * NH 2 Sphingosines OH OH OH * * * 12 NH 2 Sphinganines 79 OH 12 * OH * NH 2 OH Phytosphinganines In 1989, Rhizochalin (157) was isolated from a marine sponge as the first member of a new series of sphigolipids, whose sphingoid base backbone is a C28 chain and has both ends (α and ω terminus) functionalized (Figure 4.2).55 This special class of sphingolipids derived from the rare bis-α,ω-amino alcohols is called “two headed sphingolipids”, as their backbone is a formal “tail to tail” connection of two normal sphingoids. Some other members of this series include rhizochalin C (158)56 and D (160)56, calyxoside (162)57 and oceaninapiside (164),56, 58 with their sphingoid base aglycons being rhizochalinin C (159) and D (161), calyxinin (163) and oceanin (165) (Figure 4.2). In addition to their more complex structure, the two-headed sphingolipids were found to have high biological activity, including cytotoxic activity against carcinoma cells,55 antibacterial activity,55 antifungal activity,59,60 selective DNA-damaging activity57 and inhibition of protein kinase C.61 More interestingly, Molinski and coworkers discovered that the antifungal activity of the “two headed” sphingoid bases was ten times greater than the normal “one-headed” ones, which might be attributed to interaction with two receptor sites by one bifunctionalized “two-headed” base.62 80 Figure 4.2 The first member of the “two-headed” sphingolipids series R NH 2 O 18 26 2 3 27 OH O NH 2 157 rhizochalin R = !"D-galactopyranosyl OH OH O HO OH OH !"D-galactopyranosyl OH "two-headed" sphingoid base backbone HO HO O OH !"D-glucopyranosyl NH 2 OR OH 5 13 OH O NH 2 158 rhizochalin C R = !-D-galactopyranosyl 159 rhizochalinin C R = H NH 2 NH 2 OR 5 13 OH O NH 2 162 calyxoside R = !-D-glucopyranosyl 163 calyxinin R = H NH 2 OR 6 13 OH O NH 2 160 rhizochalin D R = !-D-galactopyranosyl 161 rhizochalinin D R = H OH OR OH 5 13 OH O NH 2 164 oceanapiside R = !-D-glucopyranosyl 165 oceanin R =H Despite the promising biological properties of the rare “two-headed” sphingolipids, the total synthesis of these sphingolipids or their sphingoid bases has not been explored much. Up till now, there has been only one example of a total synthesis of a two-headed sphingoid base, rhizochalinin C, reported by the Molinski’s group in 2013 (Scheme 4.1).63 In this synthesis, D-glucosamine was used from the chiral pool to generate the key intermediate threo-167a in 4 steps starting with an indium-mediated Barbier reaction (dr ~ 7:1). The subsequent protection of the diol, chain elongation by alkene metathesis and further functionalization provided the left half and right half pieces of the targeted molecule. Coupling of the two halves both derived from threo-167a by HornerEmmons-Wadsworth reaction and final hydrogenation completed the synthesis of rhizochalinin C (159). There have been no examples of an asymmetric synthesis of two-headed sphingoid bases by using a chiral catalyst reported to date. 81 Scheme 4.1 Total synthesis of rhizochalinin C from a chiral pool OH HO HO O H 2N OH 166 D-glucosamine a. In 0, Br 1,4-dioxane:H 2O (3:1) 100 °C NHPG + OH OH threo-167a b. Cbz-Cl or (Boc) 2O NaHCO 3, aq. c. NaIO4, H2O d. NaBH4, MeOH NH 2 OH OH NHPG OH OH 7 : 1 erythro-167b O 11 OH 5 159 rhizochalinin C NH 2 We have previously reported a catalytic asymmetric synthesis of all four diastereomers of the “one-headed” base sphinganines, where the correct stereochemistry of the amino alcohol terminus was accomplished via our catalytic asymmetric aziridination reaction.12a Based on these experiences, we became interested in applying the aziridination reaction to the synthesis of four of the “two-headed” sphingoid bases, which are rhizochalinin C (159) and D (161), calyxinin (163) and oceanin (165). Our ultimate goals of this project are twofold: 1) develop a versatile method where the catalytic asymmetric aziridination reaction can be used to provide access to four different marine-derived “two headed” sphingoid bases that are difficult to acquire; 2) confirm the structure and stereochemistry of the corresponding “two-headed” sphingolipids. This chapter will mainly focus on the studies of the synthesis of rhizochalinin C. 82 4.2 Synthetic Strategy towards the Four Two-Headed Sphingoids Our strategy to synthesize all four of the targeted “Two-headed” spingolipids involves the initial synthesis of three different “left heads” (168, ent168 and 171) and two different “right heads” (169 and 170) via the asymmetric catalytic aziridination reaction and then convergent late-stage coupling involving proper mix and match of the two “head pieces” (Scheme 4.2). By controlling the stereoselectivity of the aziridination, we can get access to all the requisite stereochemistries at the amino alcohol terminus. 83 Scheme 4.2 Proposed synthetic approach to the four sphingoid bases NH 2 OH OH 5 13 O rhizochalinin C (168+169) NH 2 OH NH 2 OH N O R 11 MEDAM N CONHR EtO 2C OTBS N 11 OH O oceanin (168+170) 13 R MEDAM CO2Et N O N BUDAM H 170 (right head) 5 NH 2 CO2Et N BUDAM N OH 13 O rhizochalinin D (169+171) O N MEDAM 169 (right head) H OBn 168 (left head) NH 2 6 OTBS MEDAM O OH MEDAM N MEDAM N OH NH 2 OBn 171 (left head) + EtO 2C OBn ent-168 (left head) NH 2 MeO R OH OMe 5 MEDAM = OH 13 O calyxinin (ent-168+170) OH NH 2 4.3 Retrosynthetic Analysis of Rhizochalinin C Rhizochalinin C (159) was chosen as the first targeted molecule. We envisioned that the skeleton of rhizochalinin C (159) could be constructed by a late-stage coupling of left head 168 and right head 169, which could be derived from compound 172 and 173, respectively, as shown in Scheme 4.3. The cis amino alcohol moiety in 172 and 173 would be achieved via ring an opening 84 reaction of cis-aziridines 174 and 175 by an oxygen nucleophile. Both aziridines could be prepared by the asymmetric aziridination reaction catalyzed by (R)VAPOL-BOROX 36 from corresponding aldehydes 176 and 177. Scheme 4.3 Retrosynthetic analysis for rhizochalinin C NH 2 OH OH 5 OH 13 O NH 2 159 rhizochalinin C OTBS CO2Et MEDAM N O + N OBn Left head 168 Reduction of ester Aziridine formation Protection of 2° alcohol MEDAM * EtO 2C 3 OH 172 Ring opening reaction MEDAM N EtO 2C 174 O 3 Right head 169 MEDAM NH 176 5 H 11 O 3 N N MEDAM Protection of 2° alcohol H R O O B O B O O O B O (R)-VAPOL BOROX catalyst (R)-36 MEDAM NH 2 144 + O + H OH O N CO2Et 11 O 173 H N O OEt N 2 145 MEDAM Ring opening reaction MEDAM N O O N 13 H 177 O N O CO2Et 11 175 4.4 Synthesis of Right Head 169 and Left Head 168 4.4.1 Synthesis of Right Head 169 The synthesis of right head 169 is shown in Scheme 4.4. Xin Zhang from our group performed the synthesis of 173 from 178. The aldehyde 179 was prepared from the commercially available lactone 178 by ring opening with 85 Weinreb’s amine and Swern oxidation in 69% yield over two steps. The catalytic asymmetric aziridination of aldehyde 179 afforded the desired aziridine in 72% yield with 95% ee, which was then treated with trifluoroacetic acid followed by basic hydrolysis to give the ring opened product 173 in high yield (84%). Protection of 173 was initially attempted with tert-butyldimethylsilyl chloride (TBSCl) in the presence of triethylamine, which resulted in low conversion after long reaction time (not shown). The silylated left head 169 was easily obtained in 81% yield by using the more reactive trimethylsilyl trifluoromethanesulfonate (TBSOTf). Scheme 4.4 Synthesis of right head 169 O O 1) Me 3Al O H N O O 2) (COCl) 2 DMSO N O 179 69% over two steps 178 1) CF 3CO2H 1 equiv 2) NaOH 1 equiv H 2O/EtOH N2 H 11 OH O N CO2Et O 11 173 H N MEDAM N OEt O 5 mol % (R)-VAPOL/B(OPh)3 MEDAMNH 2 toluene, - 10 °C, 16 h TBSOTf Et 3N O MEDAM O N CO2Et 11 O 175 72%, 95% ee OTBS CO2Et N O 11 H N MEDAM 169 81% 84% 4.4.2 Synthesis of Left Head 168 The synthesis of left head 168 involves several key steps similar to the right head 169, including asymmetric aziridination, ring opening reaction of the aziridine and protection of the resultant secondary alcohol. The requisite aziridine 174 was synthesized from aldehyde 17664 that can be prepared from the commercially available 3-octyl-1-ol. Initially, the 86 aziridination was carried out with VAPOL-BOROX catalyst prepared from B(OPh)3 (method A), which provided the aziridine 174 with 95% ee in 97% total yield. However, the difficult separation of aziridine 174 and phenol that was generated from the hydrolysis of BOROX catalyst led to only a 24% yield of 174 as a pure fraction and a 73% yield of 174 contaminated with phenol (Table 4.1, entry 1). It was found that if the phenol remained as an impurity in 174, it would interfere with the next ring-opening reaction (Table 4.2, entry 1). To solve this separation problem, a phenol derivative with a different polarity needs to be used instead of PhOH in the BOROX catalyst and this was prepared by method B. The aziridination with catalyst prepared by method B using p-methoxyphenol afforded the pure product 174 in 91-92% yield with the same asymmetric induction (Table 4.1, entries 2 and 3). Table 4.1 Catalytic asymmetric aziridination with aldehyde 176 O 176 1.05 equiv 5 mol % (R)-BOROX cat H MEDAM N 2.0 equiv EDA 145, 1.0 equiv MEDAM-NH 2 144 EtO 2C 174 toluene, –10°C, 4Å MS BOROX catalyst preparation: Method A: Ligand (5 mol %) B(OPh) 3 (15 mol %) MEDAMNH 2 144 (100 mol %) 80 °C (R)-BOROX catalyst toluene, 0.5 h MEDAMNH 2 144 100 °C Method B: Ligand (5 mol %) (100 mol %) (R)-BOROX catalyst BH 3·SMe2 (15 mol %) toluene, 1h H 2O (15 mol %) rt, 0.5 h p-methoxyphenol (10 mol %) 87 Table 4.1 (cont’d) entry[a] Scale (mmol) method ligand time (h) % ee[b] 174 % yield[c] 174 1 5 A (R)-VAPOL 16 95 (24+73)[d] 2 10 B (R)-VAPOL 15 95 92 3 2 B (S)-VAPOL 15 –95 91 [a] Unless otherwise specified, all reactions were carried out at 0.5 M in 144 in toluene for the indicated time with 5 mol % the catalyst prepared from method A or B. [b] Determined by HPLC. [c] Isolated yield after silica gel chromatography. [d] 24% pure aziridine was isolated and the other 73% aziridine contained phenol as an impurity (aziridine:phenol = 1:0.43). Next, the aziridine 174 was subjected to trifluoroacetic acid induced ring opening under the various conditions shown in Table 4.2. The ring opening reaction of 174 in the presence of PhOH was first investigated since it is difficult to separate PhOH from aziridine 174 prepared by method A (Table 4.1). Our group member Yubai Zhou found that the addition of AcOH could improve both the yield and the regioselectivity of the ring opening reaction of a related aziridine. However, both PhOH and AcOH had negative effects on the reaction yield when employed as additives (Table 4.2, entries 1-3 vs 4-5). The reaction at 40 °C gave mixtures of the regioisomers 172 and 180 in ratios that were scale dependent (Table 4.2, entries 4 and 5). When the temperature was lowered to 0°C, the ring opening reaction hardly proceeded determined by TLC after the first step (Table 4.2, entry 7). The reaction carried out at rt gave the product 172 in good yield with a regioselectivity of 16.7:1 (average of two runs) and thus it is the optimal condition for ring opening of 174 (Table 4.2, entry 6). 88 Table 4.2 Ring opening reaction of aziridine 174 1. TFA (1.0 equiv) Additive (x equiv) DCM, T °C MEDAM N EtO 2C 3 174 MEDAM 2. NaOH, H 2O/EtOH rt, 0.5 h MEDAM NH NH + EtO 2C EtO 2C OH 172 3 3 OH 180 Entry[a] conc. (M) temp (°C) additive time (h) ratio of 172:180 % yield[b] 172 1[d] 0.2 40 PhOH (0.43 equiv) 14 nd 28 2 0.2 40 AcOH (0.5 equiv) 18 nd 44 3 0.2 40 AcOH (1.0 equiv) 18 nd 66 4 0.2 40 – 15 10:1 83[c] 5[e] 0.2 40 – 15 4.5:1 70 6[g] 0.2 rt – 22 16.7:1 83 7[f] 0.4 0 – 22 nd nd [a] Unless otherwise specified, all reactions were carried out with 174 (0.2 mmol) in DCM for the indicated time with x equiv of the additive. [b] Isolated yield of pure 172 after silica gel chromatography. [c] 1H NMR yield determined with Ph3CH as an internal standard. [d] 22% (3,5-Me2-4-MeOC6H2)2CHOPh was isolated. [e] Reaction was carried out at 8.6 mmol scale. [f] Little product was formed in the first step as indicated by TLC. [g] Average of two runs at 0.2 mmol and 0.9 mmol scale. Protection of the 2° alcohol in compound 172 as the benzyl ether afforded compound 181 in 93% yield, which was then reduced by lithium aluminum hydride quantitatively to give compound 182 (Scheme 4.5). Conversion of the 1° alcohol in 182 into a tosylate was immediately followed by an intramolecular SN2 89 attack by the adjacent amino group to give an aziridine in the form of the left head 168 in 94% yield (Scheme 4.5). Scheme 4.5 Synthesis of 168 from 172 MEDAM MEDAM NH NaH, BnBr DMF, nBu 4NI EtO 2C 3 OH 172 MEDAM HO 3 OBn 182 100% 0 °C - rt, 1.5 h EtO 2C 0 °C —rt 3 OBn 181 93% MEDAM TsCl, DCM NH LiAlH 4, THF NH Et 3N, 0 °C 2 h, rt, 46 h N OBn 168 94% 3 4.5 Late-stage Coupling of Left Head 168 and Right Head 169 Followed by Removal of the TBS Group After several different conditions were screened, the coupling reaction of the left head 168 and right head 169 was achieved as shown in Scheme 4.6. Left head 168 was treated with the strong base ethylmagnesium bromide (EtMgBr) to form the corresponding acetylide which was then reacted with the right head 169 to give the desired product 183 in 81% isolated yield. Scheme 4.6 Coupling of 168 with 169 MEDAM N 1.EtMgBr (1 equiv), rt, THF MEDAM N OBn 168 OTBS CO2Et 3 2. O N 13 169 NHMEADM (1 equiv) THF, 65 °C O 90 OBn OTBS CO2Et 3 183 81% O 13 NHMEADM Next, different fluoride sources were screened to remove the silyl group in 183 (Table 4.3). Treatment of 183 with 2 equivalent of TBAF only led to complete decomposition (Table 4.3, entry 1), while decreasing the amount of TBAF to 1 equivalent resulted in a very slow reaction with decomposition also observed (Table 4.3, entry 2). The use of the less reactive HF·pyridine failed to provide any desired product. Finally, compound 183 was converted to the mono-protected diol 184 in quantitative yield by treatment with 25% aq HF. It is important to mention that the selective deprotection of the 2° alcohol in the right head provides an entry point to the natural product rhizochalin C via introduction of the carbohydrate unit to the mono-protected diol 184 (Scheme 4.7). Table 4.3 Removal of TBS group in 183 MEDAM N OBn OTBS CO2Et 3 O 13 MEDAM N X equiv [F] solvent NHMEADM OH OBn CO2Et 3 184 183 O 13 NHMEADM Entry floride source solvent equivalent(s) time (h) % yield[a] 183 1 TBAF THF 2.0 22 trace 2 TBAF THF 1.0 19 trace 3 HF·Pyr CH3CN/CH2Cl2 1.0 20 trace 4 aq HF CH3CN 1.0 5 90 [a] Isolated yield after silica gel chromatography. 91 Scheme 4.7 Entry point to rhizochalin C MEDAM MEDAM N 3 OBn N OTBS CO2Et O 183 13 OH HF OBn CH 3CN/H2O NHMEADM Using two different protecting groups allows for selective removal of the TBS group, which provide an entry point to the natural product, rhizochalin C, via introduction of the carbohydrate unit to the monoprotected diol. CO2Et 3 184 100% HO NH 2 OH HO 5 13 O NHMEDAM OH O O HO O 158 13 OH NH 2 rhizochalin C 4.6 Global Deprotection, Alkyne Reduction and Ring Opening of Aziridine 184 by Hydrogenation Followed by Hydrolysis We next investigated the hydrogenation reaction of 184. The optimized condition involves (Boc)2O as an additive to in situ protect the free amino group generated in the reaction. The hydrogenation catalyzed by Pd(OH)2 in the presence of (Boc)2O successfully reduced the triple bond, removed the Bn group and both MEDAM groups, and reductively opened the aziridine ring to give product 185 in 85% yield. After hydrolysis by LiOH, compound 186 was obtained in 92%. Scheme 4.8 Hydrogenation and hydrolysis MEDAM Boc N Pd(OH) 2, H 2 (1 atm) OH OBn CO2Et 3 13 O (Boc) 2O methanol, 62 h NHMEDAM Boc Dioxane/H 2O/THF rt, 4h OH CO2Et OH 5 O 185 85% 184 LiOH NH NH OH CO2H OH 5 13 O NHBoc 186 92% crude yield 92 13 NHBoc 4.7 Attempted Selective Reduction of the Carboxylic Acid in the Presence of a Ketone The last two steps that we planned for the synthesis of rhizochalinin C include selective reduction of the carboxylic acid in compound 186 to give compound 187 and then removal of the Boc groups. Different conditions reported for such a selective reduction include BH3·THF65, BH3·SMe266 or BH3·THF with B(OMe)3 as an additive67 and all have been examined with 186, but the reduction of the ketone functional group was always observed at either incomplete or 100% conversion. Scheme 4.9 Proposed final steps toward the synthesis of rhizochalinin C Boc NH Boc OH CO2H OH 5 13 O NHBoc [H] NH selective reduction 186 OH OH 5 O 13 OH NHBoc 187 NH 2 OH CH2OH OH 5 O 13 NH 2 159 rhizochalinin C deprotection 4.8 Attempted Selective Reduction of the Ethyl Ester in the Presence of a Ketone Inspired by two reported examples, which involve in situ masking the more reactive ketones to achieve reactions with the less reactive ester groups, we came up with a modified strategy toward the synthesis of rhizochalinin C as shown in Scheme 4.10. We turned our attention to the selective reduction of compound 188, which was synthesized by hydrogenation of 183 in high yield 93 (Scheme 4.9) under the same condition that is shown in Scheme 4.8. The two reported conditions for the selective reduction of an ester group in the presence of a ketone were explored with compound 188. One involves masking the ketone as an aminal (Scheme 4.11 a) and the other involves masking the ketone as a phosphonium salt (Scheme 4.11 b). Unfortunately, both reactions failed to give the desired product 189. This new strategy was abandoned at this point. Scheme 4.10 Modified strategy toward the synthesis of rhizochalinin C MEDAM N OBn OTBS CO2Et 3 O 13 NHMEADM Pd(OH) 2/C, H 2 Boc NH (Boc) 2O MeOH/EtOAc rt, 48 h OH 183 NH 2 Boc NH OH O O OTBS CH2OH CH2OH 13 5 13 NHBoc 188 OH 5 OTBS CO2Et NH 2 deprotection OH 159 rhizochalinin C 5 O 189 94 13 NHBoc selective reduction of the ester Scheme 4.11 Modified strategy toward the synthesis of rhizochalinin C a) Boc NH OTBS CO2Et OH Boc 5 O 188 13 NH Me 2Al O NHBoc 1) HN(OMe)Me!HCl nBuLi, Me 3 Al (all are 2.2 equiv) 13 N Me NHBoc Al OMe Me Me 13 NHBoc 5 PEt 3 OH NHBoc OTBS CO2Et 13 NHBoc OTf proposed in situ masking for reaction b OTBS 1) 0 °C, TMSOTf CO2Et Et 3N, 1h O 188 O 189 OTMS OTMS 13 5 NH 5O 5 OTBS OH Boc OTBS CO2Et NH OH NH 2) 3.5 equiv DIBAL-H THF, 0 °C proposed in situ masking for reaction a b) Boc Boc 2) PEt 3, TMSOTf, rt, 1h 3) DIBAL-H, 0 °C, 2h Boc NH OH OTBS 5 O 189 13 OH NHBoc 4.9 Conclusion The asymmetric synthesis of one of the four “two headed” sphingoid bases, rhizochalinin C, has been explored. The left head 168 and right head 169 were synthesized via asymmetric aziridination reaction, which highlighted the synthetic utility of the BOROX-catalyzed asymmetric aziridination in building chiral vincinal amino alcohol moieties. Late stage coupling of the two heads afforded the product with the complete carbon skeleton in high yield. The hydrogenation of 184 or 183 catalyzed by Pd(OH)2 in the presence of (Boc)2O successfully reduced the triple bond, deprotected the 2° alcohol, removed the MEDAM group, and reductively opened the aziridine ring. Finally, the selective reductions of the acid group in 186 and the ester group in 188 in the presence of a ketone functional group were attempted, both of which failed to provide the desired product. It is envisioned that the common strategy involving protection and 95 deprotection of the ketone will probably remove the obstacle in the final steps toward the targeted molecule, which will be investigated in the future. Once the asymmetric synthesis of rhizochalinin C is developed, the same strategy will be applied to the other three sphingoid bases. 96 CHAPTER 5 EXPERIMENTAL SECTION General information: Tetrahydrofuran (THF), diethyl ether and toluene were distilled from sodium under nitrogen. Dichloromethane was distilled from calcium hydride under nitrogen. Hexanes and ethyl acetate were ACS grade and used as purchased. Phenols were sublimed or recrystallized and stored in a dry desiccator. Solid aldehydes were either used as purchased from Aldrich or sublimed before use. Liquid aldehydes were distilled before use. Other reagents were used as purchased from Aldrich. VANOL and VAPOL were prepared according to literature procedures and were determined to be at least 99% optical purity.1 Preparation of phenols P-4268, P-4369, ligands (S)-7312c, (S)-7412c, (S)-7570, (S)-7770, and (S)-7970 have been previously reported. Melting points were determined on a Thomas Hoover capillary melting point apparatus and were uncorrected. IR spectra were taken on a Galaxy series FTIR-3000 spectrometer. 1H 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. CHCl3 was used as the internal standard for both 1H 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, by staining with phosphomolybdic acid in ethanol or with the aid of Iodine vapor. Column chromatography was performed with silica gel 60 (230 – 450 97 mesh). HPLC 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. 5.1 Experimental Part for Chapter 1 5.1.1 Preparation of Chiral Ligand (R)-76 and (R)-78 Preparation of (R)-76: Br Br 1. n-BuLi, Et 2O, - 78 °C Br I 2. I 2 in THF - 80 °C to rt Br 190 Br 191 95% crude yield 1,3-dibromo-5-iodobenzene 191: The reaction was carried out with an adaptation of a reported procedure.71 To a flame-dried 1 L round bottom flask was added 1,3,5-tribromobenzene 190 (25.2 g, 80.0 mmol, 1.00 equiv) and dry Et2O (620 mL). The solution was pre-cooled to – 78°C. Then n-BuLi (2.5 M in hexanes, 33 mL, 1.03 equiv) was added via syringe pump in 1.2 h. The reaction mixture was stirred at – 78°C for another 30 min. Then a solution of I2 (21.3 g in 46 mL THF, 84.0 mmol, 1.05 equiv) was quickly added to the mixture. After it was slowly warmed up to room temperature by removal of the cold bath (about 2 h), a solution of Na2S2O3 (8.5 g) in 160 mL H2O was added to the reaction flask and the resulting mixture was stirred for 20 min. The organic layer was separated 98 and the aqueous layer was extracted with Et2O (150 mL × 2). The combined organic layer was washed with H2O (100 mL × 2) and brine (100 mL), dried over Na2SO4, filtered and concentrated to afford a greenish solid (27.6 g, 76.3 mmol) in a crude yield of 95%, which was directly used in the next step without further purification. mp 120-121 °C (Lit.72 118 °C). Rf = 0.59 (hexane). Spectral data for 191: 1H NMR (500 MHz, CDCl3) δ 7.62 (t, 1H, J = 1.8 Hz), 7.78 (d, 2H, J = 1.8 Hz); 13C NMR (125 MHz, CDCl3) δ 94.42, 123.37, 133.64, 138.51. These spectral data match those previously reported for this compound.72 Br I Br 191 TMS TMS PdCl 2(PPh 3)2 , CuI Br Et 3N, THF Br 192 98% 1,3-Dibromo-5-(trimethylsilylethynyl)benzene 192: To a 250 mL flamedried round bottom flask filled with nitrogen was added 1,3-dibromo-5iodobenzene 191 (27.5 g, 76.0 mmol, 1.00 equiv), PdCl2(PPh3)2 (801 mg, 1.14 mmol, 1.5 mol %), CuI (218 mg, 1.14 mmol, 1.5 mol %), dry THF (115 mL) and Et3N (43 mL) under nitrogen. The reaction mixture was stirred at room temperature for 5 min and then trimethylsilyl acetylene (11.3 mL, 79.8 mmol, 1.05 mmol) was added slowly. The reaction mixture was stirred at room temperature for 27 h. After removal of the solvent by rotary evaporation, the residue was treated with NaHCO3 (sat. aq. 450 mL) and Et2O (450 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (150 mL × 3). The combined organic layer was washed with H2O (300 mL × 2), dried over Na2SO4, 99 filtered through Celite and concentrated to dryness. The crude product was purified by passing through a short column (50 mm × 150 mm, neutral Al2O3, hexanes as eluent) to give 192 as a light orange oil (24.6 g, 74.1 mmol) in 98% yield. Rf = 0.53 (hexane). Spectral data for 192: 1H NMR (500 MHz, CDCl3) δ 0.24 (s, 9H), 7.51 (d, 2H, J = 1.7 Hz), 7.58 (t, 1H, J = 1.7 Hz); 13 C NMR (125 MHz, CDCl3) δ 0.25, 97.55, 101.68, 122.48, 126.51, 133.31, 134.13. These spectral data match those previously reported for this compound.73 TMS Br PhB(OH) 2 Pd(PPh 3)4, K 2CO 3 K 2CO 3 THF MeOH,rt over night Br 192 Ph Ph 193 92% 1-(Ethynyl)-3,5-diphenylbenzene 193: This compound was prepared using a procedure that has been reported for a related compound.11 To a solution of 192 (4.99 g, 15.0 mmol, 1.00 equiv) in THF (100 mL) were added Pd(PPh3)4 (2.60 g, 2.25 mmol), K2CO3 (20.7 g, 150 mmol) and PhB(OH)2 (5.49 g, 45.0 mmol). After the mixture was stirred at 65 °C under nitrogen for 48 h, it was treated with NH4Cl (sat. aq. 65 mL) and then subjected to rotary evaporation to remove the organic solvent. Then 30 mL H2O was added to the residue and it was extracted with Et2O (100 mL × 3), dried over Na2SO4, filtered and concentrated to give an orange residue, which was passed through a short column (silica gel, 30 mm × 150 mm, hexanes) to give a yellow oil. The oil was then dissolved in MeOH (35 mL) and treated with K2CO3 (4.81 g, 34.8 mmol). The reaction mixture was stirred at room temperature for 25 h. To the resulting 100 reaction mixture was added H2O (95 mL) and this mixture was extracted with Et2O (60 mL × 3). The organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (40 mm × 200 mm, hexanes/EtOAc 10:1) gave 193 as a white solid (2.71 g, 10.7 mmol, 92%). mp 103-105 °C; Rf = 0.41 (1:10 EtOAc/hexanes). Spectral data for 193: 1H NMR (CDCl3, 500 MHz) δ 3.12 (s, 1H), 7.35-7.40 (m, 2H), 7.42-7.48 (m, 4H), 7.59-7.64 (m, 4H), 7.69 (d, 2H, J = 1.7 Hz), 7.77 (t, 1H, J = 1.7 Hz). 13 C NMR (125 MHz, CDCl3) δ 77.33, 83.58, 122.98, 126.68, 127.19, 127.79, 128.88, 129.66, 140.19, 142.00. IR (thin film) 3291(s), 3036(w), 1591(m), 1497(m) cm–1; HRMS (EI+) calcd for C20H14 m/z 254.1096 ([M]+), meas 254.1088. O OH SOCl2 O 90 °C, 1h O KOH O Ph 194 OH H 2O/THF/MeOH 100 °C Ph 190 °C 48 h 193 Ph Ph 195 54% 2-(3,5-diphenylphenyl)phenanthren-4-ol 195: A single-neck 100 mL round bottom flask equipped with a condenser was charged with 2-naphthaleneacetic acid 194 (1.44 g, 7.70 mmol, 1.00 equiv) and SOCl2 (2.0 mL, 28 mmol, 3.6 equiv). The top of the condenser was vented to a bubbler and then into a beaker filled with NaOH (sat. aq.) to trap acidic gases. The mixture was heated to reflux for 1 h in a 90 °C oil bath, and then all of the volatiles were carefully removed by swirling it under high vacuum (1 mm Hg) for 1 h with a 2nd liquid N2 trap to protect the pump. To the flask containing the acyl chloride was added 1-(Ethynyl)-3,5- 101 diphenylbenzene 193 (2.56 g, 10.1 mmol, 1.3 equiv) and (i-PrCO)2O (2.6 mL, 15.7 mmol, 2.0 equiv) under N2. The mixture was stirred at 190 °C for 48 h with a gentle nitrogen flow across the top of the condenser. The brown reaction mixture was cooled down to below 100 °C (ca. 40 °C, oil bath temperature) and THF (4.0 mL), MeOH (7.0 mL) and a solution of KOH (2.6 g, 46 mmol, 6.0 equiv) in 10 mL H2O were then added slowly. This mixture was stirred at 100 °C overnight. Upon completion, the reaction mixture was subjected to rotary evaporation to remove the organic solvents. Then EtOAc (20 mL) was added to the residue and it was stirred for 10 min at room temperature. The organic layer was separated and the aqueous layer was extracted with EtOAc (15 mL × 3). The combined organic layer was washed with brine (5 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (50 mm x 200 mm, CH2Cl2/hexanes 1:2 to 1:1 to 2:1) gave the product 195 as a light brown solid, which was recrystallized from CH2Cl2/hexane 2:1 (20 mL) to give 195 as an off-white solid (1.40 g, 3.31 mmol) in a yield of 43%. The mother liquor was concentrated to dryness and recrystallized from CH2Cl2/hexane 2:1 (3.5 mL) to give a second crop (247 mg, 0.58 mmol) in a yield of 7.6%. This was repeated one more time to give a third crop (118 mg, 0.28 mmol) in a yield of 3.6%. The total yield was 54%. mp 198199 °C; Rf = 0.25 (1:1 CH2Cl2/hexane). Spectral data for 195: 1H NMR (CDCl3, 500 MHz) δ 5.74 (s, 1H), 7.28 (d, 1H, J = 1.8 Hz), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 4H), 7.58-7.62 (m, 1H), 7.65-7.69 (m, 1H), 7.71-7.75 (m, 4H), 7.76 (s, 2H), 7.80-7.83 (m, 2H), 7.88-7.91 (m, 3H), 9.65 (d, 1H, J = 8.5 Hz); 102 13 C NMR (CDCl3, 125 MHz) δ 112.31, 118.73, 120.05, 125.19, 125.49, 126.07, 126.70, 127.22, 127.37, 127.63, 128.28, 128.46, 128.53, 128.89, 130.13, 132.63, 135.31, 139.02, 141.05, 141.17, 142.48, 154.69; IR (thin film) 3532(m), 3058(w), 1595(s), 1570(s), 1385(m), 1227(m) cm-1; HRMS (ESI–) m/z calculated for C32H21O (MH+) 421.1592, found 421.1590. Ph airflow Ph OH mineral oil 195 °C (+)-sparteine, CuCl DCM/MeOH (4:1) rt, overnight Ph Ph OH OH Ph Ph 195 (R)-76 33% over two steps Rac-76: To a 50 mL flame-dried three neck round bottom flask equipped with a cooling condenser was added 2-(3,5-diphenylphenyl)phenanthren-4-ol 195 (1.69 g, 4.0 mmol, 1.0 equiv) and mineral oil (5 mL). Airflow was introduced from one side neck via a needle located one inch above the mixture. The airflow rate was about one bubble per second. The mixture was stirred at 195 °C for 12 h. Upon completion, the crude mixture was purified by column chromatography on silica gel (dry loading, 50 mm x 200 mm, CH2Cl2/hexanes 1:2 to 1:1 to 2:1) to afford (±)-76 as an off-white solid (843 mg, 1.00 mmol) in a yield of 50%. (R)-76: To a 25 mL round bottom flask was added (+)-sparteine (170.6 mg, 0.728 mmol, 3.40 equiv), CuCl (36 mg, 0.36 mmol, 1.7 equiv) and MeOH (6.5 mL) under an atmosphere of air. The reaction mixture was stirred for 60 minutes with exposure to air. The flask was then sealed with a septum and 103 purged with nitrogen, which was introduced by a needle under the surface for 60 minutes. At the same time, to a 100 mL flame-dried round bottom flask was added racemic 76 (180.4 mg, 0.214 mmol, 1.00 equiv) and CH2Cl2 (26 mL). The resulting solution was purged with nitrogen for 45 minutes under the surface. The green Cu(II)-(+)-sparteine solution was then transferred via cannula to the solution of racemic 76 under nitrogen and then the combined mixture was stirred at room temperature for 42 h with an nitrogen balloon attached to the flask which was covered with aluminum foil. The reaction was quenched by slow addition of NaHCO3 (sat. aq. 4.2 mL) and H2O (4.2 mL) and most of the organic solvent was removed under reduced pressure. The residue was then extracted with CH2Cl2 (10 mL × 3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 25 mm × 200 mm, CH2Cl2/hexanes 1:2) to afford (R)76 as an off-white solid (119 mg, 0.141 mmol) in a yield of 66%. The optical purity was determined to be >99% ee by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL/min). Retention times: Rt = 6.29 min for (S)-76 (minor enantiomer) and Rt = 11.31 min for (R)-76 (major enantiomer). Mp 203-206 °C; Rf = 0.24 (1:2 CH2Cl2/hexane). Spectral data for 76: 1H NMR (CDCl3, 500 MHz) δ 6.82-6.92 (m, 10H), 6.94-7.02 (m, 8H), 7.047.09 (m, 4H), 7.10 (d, 4H, J = 1.7 Hz), 7.47 (t, 2H, J = 1.7 Hz), 7.64 (s, 2H), 7.717.79 (m, 6H), 7.90 (d, 2H, J = 8.8 Hz), 8.02-8.06 (m, 2H), 9.88 (dd, 2H, J = 8.3, 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 116.37, 118.62, 123.48, 124.60, 126.52, 126.65, 126.89, 127.03, 127.07, 127.33, 128.41, 128.48, 129.00, 129.67, 130.19, 104 133.00, 135.61, 140.33, 140.46, 141.12, 141.49, 154.08; IR (thin film) 3480(m), 3056(w), 1593(s) cm-1; HRMS (ESI–) m/z calculated for C64H41O2 (M-H+) 841.3107, found 841.3112. [α]!" ! = +357.5 (c 0.2, EtOAc) on >99% ee material. Preparation of (R)-78: OMe tBu tBu tBu + TMS PdCl 2(PPh 3), CuI K 2CO 3, MeOH Et 3N, reflux, 24.5h rt, overnight Br 196 OMe tBu 197 95% 1,3-di-tert-butyl-5-ethynyl-2-methoxybenzene 197: The first step was carried out with an adaptation of a procedure reported for a related compound.74 To a 500 mL round bottom flask filled with nitrogen was added 5-bromo-1,3-ditert-butyl-2-methoxybenzene 19612o (31.5 g, 105 mmol, 1.00 equiv), Pd(PPh3)2Cl2 (1.48 g, 2 mol, 2 mol %), CuI (400 mg, 2 mmol, 2 mol %) and dry Et3N (210 mL) under nitrogen. The flask was then sealed with a septum and purged for 10 minutes with nitrogen, which was introduced by a needle under the surface. Then trimethylsilyl acetylene (26.9 mL, 180 mmol, 1.80 equiv) was added slowly to the flask. After the mixture was refluxed (oil bath: 100 °C) for 24.5 h under nitrogen atmosphere, the solvent was removed by reduced pressure. The residue was dissolved in Et2O (600 mL) and treated with NaHCO3 (600 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (200 mL × 3). The combined organic layer was washed with H2O (200 mL), dried over Na2SO4, filtered and concentrated to give a black oil. The crude product was roughly purified by passing through a short column (50 mm × 150 mm, neutral Al2O3, hexanes as eluent) to give a yellow oil. This oil was then 105 dissolved in MeOH (300 mL) and treated with K2CO3 (43.5 g, 315 mmol). The reaction mixture was stirred at room temperature for 14 h. To the resulting reaction mixture was added H2O (800 mL) and this mixture was extracted with Et2O (500 mL × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (50 mm × 200 mm, hexanes) gave 197 as a light yellow oil (24.4 g, 99.8 mmol, 95%). Rf = 0.16 (hexanes). Spectral data for 197: 1 H NMR (CDCl3, 500 MHz) δ 1.40 (s, 18H), 2.98 (s, 1H), 3.66 (s, 3H), 7.37 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 31.90, 35.72, 64.37, 75.49, 84.52, 116.24, 130.60, 144.04, 160.47. These spectral data match those previously reported for this compound.75 t-Bu MeO SOCl2 O 90 °C, 1 h HO 194 t-Bu KOH H 2O/THF/MeOH 197 100 °C overnight O O O 190 °C, 48 h t-Bu OH MeO t-Bu 198 40% 2-(3,5-di-tert-butyl-4-methoxyphenyl)phenanthren-4-ol 198: The procedure for the preparation of 2-(3,5-diphenylphenyl)phenanthren-4-ol 195 was followed with 2-naphthaleneacetic acid 194 (16.8 g, 90.3 mmol, 1.00 equiv), SOCl2 (23.8 mL, 325 mmol, 3.60 equiv), 1,3-di-tert-butyl-5-ethynyl-2-methoxybenzene 197 (24.4g, 99.8 mmol, 1.10 equiv), (i-PrCO)2O (30.2 mL, 181 mmol, 2.00 equiv), THF (75 mL), MeOH (75 mL) and a solution of KOH (33.0 g, 588 mmol, 6.50 equiv) in H2O (130 mL). Purification of the crude product by column 106 chromatography on silica gel (50 mm x 250 mm, CH2Cl2/hexanes 1:3 to 1:1) gave 198 as a light yellow solid (14.84 g, 36.0 mmol) in a yield of 40%. mp 202203 °C; Rf = 0.21 (1:1 CH2Cl2/hexanes). Spectral data for 198: 1H NMR (CDCl3, 500 MHz) δ 1.50 (s, 18H), 3.75 (s, 3H), 5.69 (s, 1H), 7.18 (d, 1H, J = 2.0 Hz), 7.55-7.59 (m, 3H), 7.62-7.67 (m, 2H), 7.74 (d, 2H, J = 1.0 Hz), 7.87 (dd, 1H, J = 8.0, 1.5 Hz), 9.61 (d, 1H, J = 8.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 32.18, 35.99, 64.34, 112.41, 118.21, 119.69, 125.60, 125.86, 126.61, 127.27, 128.24, 128.32, 128.39, 130.26, 132.55, 134.37, 135.30, 139.99, 144.15, 154.52, 159.57; IR (thin film) 3521br m, 2961s, 1420s, 1227s cm-1; HRMS (ESI–) m/z calculated for C29H31O2 (M-H+) 411.2324, found 411.2312. tBu MeO airflow tBu OH MeO (+)-sparteine, CuCl mineral oil DCM/MeOH (4:1) 180 °C, 37 h rt, overnight tBu OH OH tBu MeO tBu tBu 198 (R)-78 69% over two steps Rac-78: The general procedure for oxidative phenol-coupling illustrated for 76 was followed with 2-(3,5-di-tert-butyl-4-methoxyphenyl)phenanthren-4-ol 198 (14.3 g, 34.7 mmol) and mineral oil (55 mL). The mixture was stirred at 180 °C for 37 h. After cooling down to room temperature, hexanes (83 mL) were added to the flask and the mixture was stirred until all large chunks had been broken up. The suspension was cooled in a freezer (–20 °C) overnight and then filtered through filter paper. The yellow powder was washed with chilled hexanes and 107 dried under vacuum to afford racemic 78 as an orange solid (10.3 g, 12.5 mmol) in a yield of 72%. (R)-78: Sonification was not employed in this procedure for deracemization. To a 100 mL round bottom flask was added CuCl (1.77 g, 17.9 mmol, 1.70 equiv), (+)-sparteine (8.61 g, 36.8 mmol, 3.5 equiv) and MeOH (60 mL) under an atmosphere of air. The mixture was stirred under air for 45 min. Then the flask was sealed with a septum and purged for 60 min with nitrogen, which was introduced by a needle under the surface of the solution. At the same time, to a flame-dried 1 L round bottom flask was added rac-78 (8.65 g, 10.5 mmol, 1.00 equiv) and dry CH2Cl2 (240 mL). The resulting solution was purged with nitrogen for 60 min. The green Cu(II)-(+)-sparteine suspension was then transferred via cannula to the solution of rac-78 under nitrogen and the combined mixture was stirred at room temperature for 16 h with a nitrogen balloon attached to the flask which was covered with aluminum foil. The reaction was quenched by slow addition of 125 mL NaHCO3 (aq. Sat.) and 400 mL H2O. Most of the organic solvent was removed by rotary evaporation. The residue was then extracted with CH2Cl2 (300 mL × 3). Then combined organic layer was dried with Na2SO4, filtered and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 55 × 230 mm, hexane: CH2Cl2 3:1) to afford (R)-78 as a light pink foamy solid (8.65 g, 10.5 mmol) in 100% isolated yield. The optical purity was determined to be 97.9% ee by HPLC analysis (Pirkle D-Phenylglycine column, 75:25 hexane/iPrOH at 254 nm, flow-rate: 2.0 mL/min). Retention times: Rt = 10.75 min (major enantiomer, (R)-78) and Rt = 21.60 min (minor enantiomer, 108 (S)-78). To enhance the optical purity, 13 mL of a mixture of hexane/CH2Cl2 (40:3) was added to the product and it was heated until a clear solution was obtained. After the solution was kept at room temperature for 2 h, a fine powder formed which made the solution slightly cloudy. The mixture was filtered through a filter paper and the original flask was rinsed with hexane (5 mL × 2). The rinse was also filtered. The combined filtrate was kept at room temperature for 1 h. It turned cloudy again. The above filtration procedure was repeated until the new filtrate did not turn cloudy after it was kept at room temperature for 1 h. The clear filtrate was concentrated to dryness to afford the product as a light yellow foamy solid (8.30 g, 10.1 mmol) in a yield of 96% with an optical purity of >99% ee determined by HPLC analysis (Pirkle D-phenylglycine column, 75:25 hexane/iPrOH at 254 nm, flow-rate: 2.0 mL/min). Retention times: Rt = 11.22 min for (R)-78 (major) and Rt = 22.90 min for (S)-78 (minor). mp 150-153 °C; Rf = 0.23 (hexane: CH2Cl2 3:1). Spectral data for 78: 1H NMR (500 MHz, CDCl3) δ 1.07 (s, 36H), 3.20 (s, 6H), 6.16 (s, 2H), 7.14 (s, 4H), 7.48-7.55 (m, 4H), 7.717.79 (m, 6H), 7.82-7.87 (m, 2H), 9.33-9.38 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 31.74, 35.46, 63.78, 116.54, 118.38, 122.27, 125.99, 126.57, 126.80, 127.04, 128.14, 128.59, 129.00, 130.17, 132.54, 133.59, 135.34, 140.81, 142.83, 153.19, 158.84; IR (thin film) 3486(br s), 2961(s), 1412(s), 1225(s), 1115(m) cm-1; HRMS (ESI–) m/z calculated for C58H62O4 822.4648, found 822.4680. [α]!" ! = +239.5 (c 1.0, CH2Cl2) on >99% ee material. 109 5.1.2 Preparation of Phenols Preparation of phenol P-39: OH Br Br (CH 3)SO4, KOH O Br Br 1,4-dioxane, 65 °c 6h P-40 199 77% 2,6-Dibromo-4-methylanisole 199: This compound was prepared using a procedure reported for related compounds.76 To a solution of 2,6-dibromo-4methylphenol P-40 (3.99 g, 15.0 mmol, 1.00 equiv) in 1,4-dioxane (15 mL) at 65 °C was added crushed commercial KOH (3.00 g, 53.5 mmol, 3.57 equiv). Then (CH3)2SO4 (1.43 mL, 15.1 mmol, 1.01 equiv) was added slowly to the orange reaction mixture over about 2 h. The resulting mixture was stirred for another 4 h at 65 °C. After it was cooled to rt, the reaction mixture was filtered. The filtrate was concentrated by rotary evaporation and then subjected to vacuum to remove 1,4-dioxane. Purification by column chromatography on silica gel (35 × 160 mm, hexanes as eluent) gave the product 199 as a colorless liquid (3.23 g, 11.5 mmol) in 77% yield. Rf = 0.26 (hexanes). Spectral data for 199: 1H NMR (300 MHz, CDCl3) δ 2.25 (t, 3H, J = 0.6 Hz), 3.83 (s, 3H), 7.29 (q, 2H, J = 0.6 Hz); 13C NMR (125 MHz, CDCl3) δ 20.20, 60.59, 117.60, 133.08, 136.53, 151.84. These spectral data match those previously reported for this compound.77 110 O O Br Br K 2CO 3, MeOH TMS PdCl 2(PPh 3)2, CuI Et 3N, 37h rt, overnight 199 200 94% 1,3-diethynyl-2-methoxy-5-methylbenzene 200: The first step was carried out with an adaptation of a procedure reported for a related compound.74 To a flame-dried 50 mL round bottom flask was added 2,6-dibromo-4-methylanisole 199 (2.24g, 8.00 mmol, 1.00 equiv), Pd(PPh3)2Cl2 (225 mg, 0.320 mmol, 0.0400 equiv) and CuI (61 mg, 0.32 mmol, 0.040 equiv) and dry NEt3 (16 mL). Then the flask was sealed with a septum and purged for 5 min with nitrogen, which was introduced by a needle under the surface of the solution. Then trimethylsilylacetylene (3.90 mL, 27.4 mmol, 3.42 equiv) was added to the flask via syringe. The mixture was refluxed for 37 h under a nitrogen atmosphere. After removal of the solvent, the residue was dissolved in 60 mL Et2O, followed by the addition of NaHCO3 (sat. aq. 60 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (20 mL x 3). The combined organic layer was washed with 20 mL H2O, 10 mL brine, dried with Na2SO4, filtered and concentrated to give a brown oil. It was roughly purified by passing through a short column (35 mm x 120 mm, neutral Al2O3, CH2Cl2 as eluent) to give the partially purified product as a yellow liquid, which was dissolved in 45 mL MeOH and treated with K2CO3 (6.30g, 45.6 mmol). The reaction mixture was stirred at room temperature overnight to give complete conversion. To the mixture was added 60 mL H2O and the mixture was extracted with Et2O (40 mL x 3). The 111 combined organic layer was dried with Na2SO4, filtered and concentrated to give the crude product as a light yellow liquid. Purification by silica gel chromatography (30 × 160 mm, hexane: EtOAc 20:1) afforded the product 200 (1.28 g, 7.52 mmol) as a light yellow liquid in 94% overall yield from 199. Rf = 0.32 (hexane: EtOAc 5:1). Spectral data for 200: 1H NMR (500 MHz, CDCl3) δ 2.24 (s, 3H), 3.25 (s, 2H), 4.00 (s, 3H), 7.24 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 20.20, 61.36, 79.37, 81.42, 115.96, 133.00, 135.19, 161.01. IR (thin film) 3289(w), 2955(w) cm–1; HRMS (EI+) calcd for C12H10O m/z 170.0732 ([M]+), meas 170.0744. O O NaBH 4, CH 3COOH 10 mol% Pd/C, iPrOH, 1.5h 201 80% 200 1,3-diethyl-2-methoxy-5-methylbenzene 201: This compound was prepared using a procedure reported for related compounds.21 To a 250 mL round bottom flask was added 1,3-diethynyl-2-methoxy-5-methylbenzene 200 (946 mg, 5.56 mmol, 1.00 equiv), Pd/C (594 mg, 10 mol%), iPrOH (55 mL) and acetic acid (1.27 mL, 22.2 mmol, 3.99 equiv). The flask was put into a room temperature water bath before the addition of powdered NaBH4 (1.68 g, 44.5 mmol, 8.00 equiv). Then the water bath was removed. After the reaction mixture was stirred at room temperature open to air for 90 min, 15 mL 0.1 M HCl was carefully added to the pre-cooled mixture at 0 °C. It was stirred until bubbles ceased coming out of solution. Then the pH of the solution was adjusted to 10 112 with aqueous NaOH. The mixture was filtered through a Celite pad and the Celite pad was washed with Et2O (20 mL x 3). The filtrate was washed with H2O (20 mL x 2). The organic layer was separated. The combined aqueous layer was subjected to rotary evaporation to remove iPrOH. Then it was extracted with Et2O (40 mL x 3). The combined organic layer was dried with Na2SO4, filtered and concentrated to give a yellow oil. Purification by column chromatography (35 × 160 mm, hexanes: EtOAc 40:1) gave the product 201 as a colorless oil (798 mg, 4.47 mmol) in 80% yield. Rf = 0.22 (hexanes: EtOAc 40:1). Spectral data for 201: 1 H NMR (500 MHz, CDCl3) δ 1.23 (t, 6H, J = 7.5 Hz), 2.28 (s, 3H), 2.64 (q, 4H, J = 7.5 Hz), 3.71 (s, 3H), 6.86 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 15.03, 20.91, 22.63, 61.19, 127.58, 133.36, 136.60, 153.88. IR (thin film) 2965(s), 2930(s), 1478(m), 1217(m), 1017(m) cm–1; HRMS (EI+) calcd for C12H18O m/z 178.1358 ([M]+), meas 178.1361. OH O BBr 3 DCM, 18.5h P-39 71% 201 2,6-diethyl-4-methylphenol P-39: To a 100 mL round bottom flask was added 1,3-diethyl-2-methoxy-5-methylbenzene 201 (798 mg, 4.47 mmol, 1.00 equiv) and dry CH2Cl2 (30 mL). The solution was pre-cooled to 0 °C, followed by the addition of BBr3 (1M in CH2Cl2, 9.0 mL, 9.0 mmol, 2.0 equiv). After the reaction mixture was stirred at room temperature for 18.5 h, 45 mL H2O was added to the flask. The organic layer was separated. The aqueous layer was 113 extracted with CH2Cl2 (25 mL x 3). The combined organic layer was dried with Na2SO4, filtered and concentrated to give a gray brown solid. Purification by column chromatography (25 × 180 mm, hexanes: EtOAc 16:1) gave product P-39 as white solid (524 mg, 3.19 mmol) in a yield of 71%; mp 47-48 °C; Rf = 0.28 (hexanes: EtOAc 10:1). Spectral data for P-39: 1H NMR (500 MHz, CDCl3) δ 1.22 (t, 6H, J = 7.5 Hz), 2.24 (s, 3H), 2.58 (q, 4H, J = 7.5 Hz), 4.46 (s, 1H), 6.79 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 14.07, 20.61, 23.04, 127.28, 128.99, 129.52, 148.87. IR (thin film) 3351(br, s), 2959(w), 1464(m) cm–1; HRMS (ESI–) m/z calculated for C11H15O (M-H+) 163.1123, found 163.1120. Preparation of phenol P-45: O OH Na 2S2O4 H 2O/Ether/MeOH O 202 OH 203 91% 2,6-Dimethyl-1,4-benzenediol 20378: Na2S2O4 (20.9 g, 120 mmol, 4.00 equiv) was dissolved in 145 mL H2O in a 500 mL round bottom flask filled with nitrogen. A solution of 2,6-dimethylbenzoquinone 202 (4.08 g, 30.0 mmol, 1.00 equiv) in a mixture of 65 mL ether and 40 mL MeOH was poured into the aqueous solution with stirring. Then a balloon filled with nitrogen was attached to the flask through a septum. After the reaction mixture was stirred at room temperature for 1h, the organic layer was separated and the aqueous layer was extracted with ether (60 mL x 4). The combined organic layer was washed with 50 mL H2O and 25 mL brine, dried over Na2SO4, filtered and concentrated to 114 afford the product as an off-white solid (3.77g, 27.3 mmol) in 91% yield. It was used without further purification; mp 150-151 °C (Lit.78 145-148 °C); Rf = 0.11 (hexanes: EtOAc 4:1). Spectral data for 203: 1H NMR (500 MHz, CDCl3) δ 2.18 (s, 6H), 4.19 (s, 1H), 4.23 (brs, 1H), 6.46 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 16.06, 115.00, 124.36, 146.08, 148.62. OH OAc Ac2O H 2SO 4 OH 203 OAc 204 97% 2,6-Dimethylphenylene-1,4-diacetate 204: This compound was prepared using a procedure reported for a related compound.79 To a oven-dried 50 mL round bottom flask filled with nitrogen was added 2,6-dimethyl-1,4-benzenediol 203 (3.77g, 27.2 mmol, 1.00 equiv), acetic anhydride (8.20 mL, 86.7 mmol, 3.19 equiv) and two drops of H2SO4 (conc.). After the solution was stirred at room temperature for 1.7 h, it was poured into 100 mL H2O and the mixture was stirred for 10 min to produce a white precipitate. The mixture was then filtered and the precipitate was washed with H2O several times and dried under vacuum to give the product 204 as a white solid (5.85 g, 26.3 mmol) in a 97% yield; mp 90-92 °C (Lit.80 91-93 °C). Rf = 0.27 (hexanes: EtOAc 3:1). Spectral data for 204: 1H NMR (500 MHz, CDCl3) δ 2.12 (s, 6H), 2.25 (s, 3H), 2.31 (s, 3H), 6.78 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 16.44, 20.42, 21.09, 121.28, 131.42, 145.68, 147.75, 115 168.70, 169.59. IR (thin film) 1759(s), 1370(m), 1215(s), 1169(s) cm–1; HRMS (ESI) calcd for C12H15O4 m/z 223.0970 ([M+H]+), meas 223.0969. OAc OAc NaOH, Na 2S2O4 H 2O, EtOH OH 205 82% OAc 204 4-hydroxy-2,6-dimethylphenyl acetate 205: This compound was prepared using a procedure reported for a related compound.81 To a 250 mL round bottom flask filled with nitrogen was added 2,6-dimethylphenylene-1,4-diacetate 204 (5.83 g, 26.2 mmol, 1.00 equiv) and EtOH (87 mL). A solution of NaOH (1.05 g, 26.2 mmol, 1.0 equiv) and Na2S2O4 (1.15 g, 6.6 mmol, 0.25 equiv) in 8.7 mL H2O was slowly added to the flask. After the mixture was stirred at room temperature for 40 min, 44 mL 1M HCl was added to the flask. The mixture was subjected to rotary evaporation to remove EtOH, during which the reaction mixture became cloudy. The residue was dissolved in 250 mL EtOAc. The organic layer was separated and washed with NH4Cl (aq. Sat. 25 mL), dried with Na2SO4, filtered and concentrated to give a yellow solid. It was crystallized from hexanes/EtOAc (8:1) to give an additional quantity of the product as white crystals (2.20 g, 12.2 mmol). The mother liquor was purified by column chromatography (silica gel, 40 × 200 mm, hexane:EtOAc 6:1è5:1è3:1) to give the product 205 as a white solid (1.65 g, 9.20 mmol). The combined yield was 82%. mp 108-110 °C (Lit. 82 105106 °C); Rf = 0.18 (hexanes: EtOAc 3:1). Spectral data for 205: 1H NMR (500 MHz, CDCl3) δ 2.04 (s, 6H), 2.31 (s, 3H), 5.78 (brs, 1H), 6.38 (s, 2H); 116 13 C NMR (125 MHz, CDCl3) δ 16.24, 20.43, 115.16, 130.80, 141.41, 153.19, 170.26. The 1 H NMR data match those previously reported for this compound.82 OAc OAc (Boc) 2O, LiClO 4 CH2Cl2 OH 205 OtBu 206 94% 4-(tert-butoxy)-2,6-dimethylphenyl acetate 206: This compound was prepared using a procedure reported for a related compound.83 To a flame-dried 25 mL round bottom flask filled with nitrogen was added 4-hydroxy-2,6dimethylphenyl acetate 205 (361 mg, 2.00 mmol, 1.00 equiv), Mg(ClO4)2 (45 mg, 0.20 mmol, 0.10 equiv) and dry CH2Cl2 (3 mL), followed by the addition of (Boc)2O (1.53 g, 7.00 mmol, 3.50 equiv). Then the flask was connected to a condenser with a nitrogen balloon attached on top of the condenser through a septum. The mixture was stirred at 40 °C for 24 h. Then another portion of (Boc)2O (300 mg, 1.37 mmol) was added to the reaction flask. The reaction mixture was stirred for another 23 h. The solvent was removed by slowly maintaining a nitrogen flow into the flask. The crude product was purified by column chromatography (silica gel, 25 × 200 mm, hexanesèhexane:EtOAc 5:1) to give the product 206 as a colorless oil (444 mg, 1.88 mmol) in a yield of 94%. Rf = 0.43 (hexanes: EtOAc 5:1). Spectral data for 206: 1H NMR (500 MHz, CDCl3) δ 1.31 (s, 9H), 2.08 (s, 6H), 2.29 (s, 3H), 6.66 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 16.43, 20.41, 28.83, 78.17, 123.77, 130.23, 143.97, 152.57, 117 168.85. IR (thin film) 2978(s), 1761(s), 1482(s), 1368(s), 1217(s), 1167(s) cm–1; HRMS (ESI) calcd for C14H21O3 m/z 237.1491 ([M+H]+), meas 237.1494. OH OAc K 2CO 3, MeOH OtBu P-45 85% OtBu 206 4-(tert-butoxy)-2,6-dimethylphenol P-45: This compound was prepared using a procedure reported for a related compound.84 To a 25 mL round bottom flask filled with nitrogen was added 4-(tert-butoxy)-2,6-dimethylphenyl acetate 206 (444 mg, 1.88 mmol, 1.00 equiv), K2CO3 (390 mg, 2.82 mmol, 1.50 equiv) and MeOH (9 mL). After the mixture was stirred at room temperature for 21 h, 15 mL H2O was added to the reaction flask. The pH of the solution was adjusted to 3-4 with 2N HCl. The mixture was concentrated to about 15 mL and extracted with Et2O (40 mL × 3). The combined organic layers were dried with Na2SO4, filtered and concentrated to afford a yellow solid, which was purified by column chromatography (silica gel, 30 × 200 mm, hexane:EtOAc 5:1) to give the product P-45 as an off-white solid (351 mg, 1.81 mmol) in a yield of 96%. It was recrystallized from 1 mL hexanes to give the first crop as white needles (270 mg, 1.39 mmol) in a yield of 74%. The second crop (39 mg, 0.20 mmol) was obtained from the residue. The combined yield was 85%. Mp 81-82 °C; Rf = 0.40 (hexanes: EtOAc 3:1). Spectral data for P-45: 1H NMR (500 MHz, CDCl3) δ 1.27 (s, 9H), 2.18 (s, 6H), 4.37 (s, 1H), 6.60 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 16.07, 28.77, 77.65, 123.06, 124.35, 147.76, 148.22. IR (thin film) 3407(s), 118 2978(m), 1485(s), 1167(m), 1138(m) cm–1; HRMS (ESI–) m/z calculated for C12H17O2 (M-H+) 193.1229, found 193.1227. Preparation of phenol P-46: OAc OAc NaH, EtOTf CH2Cl2 OEt 207 90% OH 205 4-(Ethoxy)-2,6-dimethylphenyl acetate 207: This compound was prepared using a procedure reported for a related compound.85 To a 100 mL flame dried round bottom flask filled with nitrogen was added the 4-hydroxy-2,6dimethylphenyl acetate 205 (541 mg, 3.00 mmol, 1.00 equiv) and dry CH2Cl2 (15 mL), followed by the addition of NaH (134 mg, 60% in mineral oil, 3.35 mmol. 1.10 equiv) with stirring. At the end of hydrogen evolution, EtOTf (0.47 mL, 3.63 mmol, 1.21 equiv) was added to the reaction flask. After the reaction mixture was stirred at room temperature for 7 h, NH4Cl (aq. sat. 8 mL) was added to the mixture. The organic layer was separated and the aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a yellow oil with some precipitate in it. The crude product was purified by column chromatography (silica gel, 25 × 200 mm, hexane:EtOAc 10:1) to give the product 207 as a colorless oil (562 mg, 2.70 mmol) in a yield of 90%. Rf = 0.37 (hexanes/EtOAc 10:1). Spectral data for 207: 1 H NMR (500 MHz, CDCl3) δ 1.36 (t, 3H, J = 7.0 Hz), 2.10 (s, 6H), 2.30 (s, 3H), 3.96 (q, 2H, J = 7.0 Hz), 6.57 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 14.88, 16.56, 119 20.43, 63.53, 114.16, 130.87, 141.68, 156.29, 169.26. IR (thin film) 2980(w), 2928(w), 1759(s), 1221(s), 1183(s) cm–1; HRMS (ESI+) calcd for C12H17O3 m/z 209.1178 ([M+H]+), meas 209.1180. OH OAc K 2CO 3, MeOH OEt P-46 81% OEt 207 4-Ethoxy-2,6-dimethylphenol P-46: To a 25 mL round bottom flask filled with nitrogen was added the 4-(ethoxy)-2,6-dimethylphenyl acetate 207 (560 mg, 2.69 mmol, 1.00 equiv) and EtOH (6 mL). Then a solution of KOH (377 mg, 6.72 mmol, 2.50 equiv) in H2O (6 mL) was added to the mixture. After the mixture was stirred at room temperature for 2 h, the pH of the solution was adjusted to ~3 with 2 M HCl. It was then concentrated to approximately 10 mL and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a brown oil, which was loaded onto a silica gel column (25 × 200 mm, hexane:EtOAc 10:1) and eluted to afford P-46 as a light brown solid (364 mg, 2.19 mmol) in a yield of 81%. Mp 43-44 °C; Rf = 0.29 (hexanes: EtOAc 3:1). Spectral data for P-46: 1H NMR (500 MHz, CDCl3) δ 1.36 (t, 3H, J = 7.0 Hz), 2.21 (s, 6H), 3.94 (q, 2H, J = 7.0 Hz), 4.26 (brs, 1H), 6.54 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 14.96, 16.24, 63.85, 114.54, 124.05, 146.02, 152.24. IR (thin film) 3449(s), 2978(m), 2923(w), 1491(s), 1196(s), 1059(s) cm–1; HRMS (ESI–) calcd for C10H13O2 m/z 165.0916 ([M-H]+), meas 165.0915. 120 Preparation of phenol P-47: OH OH H 2SO 4 (Conc.) MeOH, reflux 4h OH 203 OMe P-47 64% 4-methoxy-2,6-dimethylphenol P-47:86 To a 100 mL oven dried round bottom flask was added the 2,6-dimethyl-1,4-benzenediol 203 (4.61 g, 33.4 mmol, 1.00 equiv), MeOH (30 mL) and H2SO4 (conc., 12 mL). The mixture was refluxed for 4 h (oil bath: 100 °C). The mixture was then cooled to room temperature and poured into a 250 mL beaker containing 100 g ice. After the ice melted, the mixture was extracted with Et2O (100 mL x 4). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a brown oil. The crude product was purified by column chromatography (silica gel, 35 × 200 mm, hexane:EtOAc 8:1 to 6:1 to 5:1) and recrystallization from hexanes (43 mL) to afford white needles (3.24 g, 21.3 mmol) in a yield of 64%. mp 75-76 °C; Rf = 0.45 (hexanes: EtOAc 3:1). Spectral data for P-47: 1H NMR (500 MHz, CDCl3) δ 2.21 (s, 6H), 3.72 (s, 3H), 4.21 (s, 1H), 6.53 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 16.25, 55.65, 113.77, 124.08, 146.10, 152.99. The 1H NMR data match those previously reported for this compound.86 5.1.3 Preparation of Amines A-11 and A-12 NH 2 O2N 208 CHO NaBH 3CN + O2N 63b AcOH, CH 3CN 67.5 h 121 N H O2N A-11 35% NO 2 Bis-(4-nitrobenzyl)amine A-11: To an oven-dried 25 mL round bottom flask was added 4-nitrobenzaldehyde 63b (453 mg, 3.00 mmol, 1.00 equiv) and a solution of 4-nitrobenzylamine 208 (456 mg, 3.00 mmol, 1.00 equiv) in CH3CN (12 mL). After the mixture was stirred at room temperature for 1.5 h, NaBH3CN (566 mg, 9.00 mmol, 3.00 equiv) was added to the flask. After 20 min, acetic acid (0.86 mL, 15 mmol, 5.0 equiv) was added to the mixture. It was then stirred at room temperature for 67.5 h. The reaction mixture was diluted with CH2Cl2 (6 mL), washed with NaOH (1.0 M, 12 mL x 2), dried with Na2SO4, filtered and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 30 × 200 mm, hexane/EtOAc 1:1) and recrystallized from hexane/EtOAc (1:1) to give a yellow crystalline solid (302 mg, 1.05 mmol) in a yield of 35%. Mp 90-91 °C (Lit.87 90 °C); Rf = 0.13 (hexanes: EtOAc 1:1). Spectral data for A-11: 1H NMR (500 MHz, CDCl3) δ 1.76 (brs, 1H), 3.91 (s, 4H), 7.52 (d, 4H, J = 8.5 Hz), 8.18 (d, 4H, J = 8.5 Hz); 13 C NMR (125 MHz, CDCl3) δ 52.41, 123.71, 128.61, 147.18, 147.43. The 1H NMR data match previously reported for this compound.87 CHO + Si H N Si N H 1. LiClO 4, 50 °C 2. MeOH, NaBH 4 63r A-12 61% 209 Bis-(3,5-dimethylbenzyl)amine A-12: To a flame dried 25 mL round bottom flask filled with N2 was added 3,5-dimethylbenzaldehyde 63r (295 mg, 2.20 mmol, 1.00 equiv), LiClO4 (234 mg, 2.20 mmol, 1.00 equiv) and bis(trimethylsilyl)amine 209 (1.2 mL, 5.73 mmol, 2.60 equiv). The mixture was 122 stirred at 50 °C for 2 hours. After it was cooled to 0 °C, MeOH (5.5 mL) was added. Then NaBH4 (250 mg, 6.60 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 (5 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and filtered. The filtrate was concentrated. The crude product was dissolved in CH2Cl2 (5 mL) and aq HCl (6M, ~ 2.2 mL) was added dropwise until pH ~1. The resulting white precipitate was collected by filtration and suspended in EtOAc (10 mL). Then Na2CO3 (aq. sat. ~5 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 the product was purified by column chromatography (silica gel, 25 × 200 mm, hexane:EtOAc 3:1). The product A-12 was obtained as a colorless oil (171 mg, 0.675 mmol, 61%); Rf = 0.19 (Hexane:EtOAc 5:1). Spectral data for A-12: 1H NMR (500 MHz, CDCl3) δ 1.56 (brs, 1H), 2.34 (s, 12H), 3.77 (s, 4H), 6.92 (s, 2H), 6.99 (s, 4H); 13 C NMR (125 MHz, CDCl3) δ 21.21, 53.28, 125.93, 128.46, 137.81, 140.21. The 1H NMR data match previously reported for this compound.87 5.1.4 General Procedure A for Optimization of the Ugi-3CR A 25 mL Schlenk flask equipped with a stir bar was flame dried, cooled to rt under N2 and charged with 20 mol% ligand (0.050 mmol, 0.20 equiv), 40 mol% phenol (0.10 mmol, 0.40 equiv), dry toluene (1.5 mL), 60 mol% H2O (27 mg, 2.7 µL, 0.15 mmol, 0.60 equiv), and 60 mol% BH3·SMe2 (2M, 75 µL, 0.15 mmol, 0.60 123 equiv). The Teflon valve on the Schlenk flask was then closed, and the mixture heated at 100 °C for 1 h. After the flask was cooled to rt, the valve was carefully opened to gradually apply high vacuum (0.1 mm Hg) and the solvent and volatiles were removed. Then the flask was heated at 100 °C under high vacuum for 30 min. Dry reaction solvent (1 mL) was added to dissolve the residue in the flask after it was cooled to room temperature. To the resulting solution was added amine A (0.5 mmol, 2.0 equiv) under a N2 stream, followed by the addition of benzaldehyde 63a (26 µL, 0.25 mmol, 1.0 equiv) and then t-butyl isocyanide 64 (45 µL, 0.38 mmol, 1.5 equiv). The Teflon valve was then closed, and the resulting mixture was stirred at room temperature for a specified time 24-46 h. Upon completion, the reaction mixture was directly loaded onto a silica gel column (20 × 160 mm, hexanes:EtOAc 15:1) to afford the corresponding product 65. The optical purity was determined by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column or Chiralpak AD column). 5.1.5 Attempted Ugi Reaction with Amines A-1 and A-6 (Scheme 2.8) Attempted Ugi reaction with pyrrolidine A-1: 20 mol % BOROX catalyst O H 63a + N H A-1 + CN toluene, rt 64 N N 72 50% The general procedure A described in Part 5.1.4 was followed with (S)VAPOL ligand (27 mg, 0.050 mmol), phenol P-11 (9.6 mg, 0.10 mmol), pyrrolidine A-1 (42 µL, 0.51 mmol, 2.0 equiv) and d8-toluene (1 mL) as the 124 reaction solvent. After the reaction mixture was stirred at room temperature for 19 h, the crude NMR spectrum showed that the aminal 72 was formed in 50% yield (average of two runs) with the aid of Ph3CH as an internal standard. Aminal 72 was the only major species present in the crude reaction mixture other than the starting materials. The assignment of this major species as the aminal 72 was made based on the 1H NMR data of 72 that was prepared separately as described below. Separate preparation of aminal 72 from benzaldehyde 63a and prolidine A-1: O 3Å MS H 63a + N H toluene, reflux A-1 N N 72 85% α,α-Bis(pyrrolidinyl)toluene 72: An oven-dried 50 mL round bottom flask charged with 3Å powdered molecular sieves (3.0 g) and equipped with a magnetic stir bar was flame dried under high vacuum and cooled down under nitrogen. To the flask was then added 9.0 mL of dry toluene, pyrrolidine A-1 (0.82 mL, 10 mmol, 2.0 equiv) and benzaldehyde 63a (0.51 mL, 5.0 mmol, 1.0 equiv). After the mixture was heated to reflux for 16 h in an 80 °C oil bath, it was cooled to room temperature and filtered through a Celite pad. The pad was washed with dry CH2Cl2 (3 mL). The combined filtrate was concentrated to dryness to give 72 as a light yellow oil (980 mg, 4.25 mmol) in 85% yield. The crude product contains a very small amount of benzaldehyde 63a and pyrrolidine A-1. Spectral data for 72: 1H NMR (500 MHz, CDCl3) δ 1.60-1.69 (m, 8H), 2.41-2.50 (m, 8H), 125 3.89 (s, 1H), 7.23-7.33 (m, 5H); 1H NMR (500 MHz, d8-toluene) δ 1.50-1.64 (m, 8H), 2.43-2.60 (m, 8H), 3.89 (s, 1H), 7.17-7.31 (m, 5H). The 1H NMR data (CDCl3) match those reported for this compound.88 Attempted Ugi reaction with pyrrolidine A-6: 20 mol % BOROX catalyst O + H Ph Ph + CN N Ph toluene, rt NH 2 A-6 63a Ph 26Pa 100% 64 The general procedure A described in Part 5.1.4 was followed with (S)VAPOL ligand (27 mg, 0.050 mmol), phenol P-11 (9.6 mg, 0.10 mmol), benzhydrylamine A-6 (88 µL, 0.51 mmol, 2.0 equiv) and toluene (1 mL) as the reaction solvent. The crude NMR spectrum was taken after the reaction mixture had been stirred at room temperature for 18 h and for 89 h. In both cases, the crude NMR spectrum showed 100% formation of imine 412s with the aid of Ph3CH as an internal standard. 5.1.6 Ugi Reaction with Amines A-7—A-12 with General Procedure A (Part 5.1.4) and B (Part 5.1.7) O OMe H 63a MeO N H A-7 20 mol % (S)-BOROX catalyst + CN 64 mesitylene, rt MeO N OMe O 65r 126 H N (S)-2-(bis(4-methoxybenzyl)amino)-N-(tert-butyl)-2-phenylacetamide 65r: The general procedure A described in Part 5.1.4 was followed with ligand (S)-78 (41.5 mg, 0.0504 mmol), phenol P-36 (14 mg, 0.10 mmol), amine A-732 (98 mg, 0.50 mmol) and mesitylene (1 mL) with a reaction time of 39 h. After purification by column chromatography (silica gel, 20 × 160 mm, hexane:EtOAc 9:1), the product 65r was obtained as a yellow semi-solid (105 mg, 0.23 mmol, 92%). The optical purity was determined to be 85:15 er by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 7.04 min (major enantiomer) and Rt = 20.04 min (minor enantiomer). A reaction that was run according to general procedure B (described in Part 5.1.7) with (R)78 and phenol P-47 for 24 h at room temperature afforded the product 65r in 91% yield with 12:88 er. Rf = 0.30 (hexane:EtOAc 4:1). Spectral data for 65r: 1H 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, 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) cm–1; HRMS (ESI) calcd for C28H35N2O3 m/z 447.2648 ([M+H]+), meas 447.2631. [α]!" ! = +19.8 (c 1.0, CH2Cl2) on 85:15 er material. 127 O F H 63a F N H A-8 20 mol % (S)-BOROX catalyst + CN 64 mesitylene, rt F F N H N O 65s (S)-2-(bis(4-fluorobenzyl)amino)-N-(tert-butyl)-2-phenylacetamide 65s: The general procedure A described in Part 5.1.4 was followed with ligand (S)-78 (41.5 mg, 0.05 mmol), phenol P-36 (14 mg, 0.10 mmol), amine A-832 (119 mg, 0.51 mmol) and mesitylene (1 mL) as the solvent with a reaction time of 39 h. After purification by column chromatography (silica gel, 18 × 200 mm, hexane:EtOAc 15:1), the product 65s was obtained as a yellow foamy-solid (95.2 mg, 0.225 mmol, 88%). The optical purity was determined to be 86:14 er by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 98:2, 222 nm, flow 1 mL). Retention times: Rt = 10.25 min (major enantiomer) and Rt = 27.23 min (minor enantiomer); mp 105-107 °C; A reaction that was run according to general procedure B (described in Part 5.1.7) with (R)-78 and phenol P-47 for 24 h at room temperature afforded the product 65s in 85% yield with 10:90 er. Rf = 0.40 (hexane:EtOAc 4:1). Spectral data for 65s: 1H 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; IR (thin film) 3339(w), 2968(w), 1684(s), 1508(s) cm–1; HRMS (ESI) calcd for 128 C26H29F2N2O m/z 423.2248 ([M+H]+), meas 423.2268. [α]!" ! = +29.8 (c 1.0, CH2Cl2) on 86:14 er material. O Cl H 63a Cl N H A-9 20 mol % (S)-BOROX catalyst + CN 64 mesitylene, rt Cl N H N Cl O 65t (S)-2-(bis(4-chlorobenzyl)amino)-N-(tert-butyl)-2-phenylacetamide 65t: The general procedure A described in Part 5.1.4 was followed with ligand (S)-78 (41.5 mg, 0.05 mmol), phenol P-36 (14 mg, 0.10 mmol), amine A-932 (135 mg, 0.51 mmol) and mesitylene (1 mL) as the solvent with a reaction time of 39 h. After purification by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 15:1), the product 65t was obtained as a white foamy-solid (105 mg, 0.23 mmol, 90%). The optical purity was determined to be 85:15 er by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 98:2, 222 nm, flow 1 mL). Retention times: Rt = 9.35 min (major enantiomer) and Rt = 36.82 min (minor enantiomer); mp 105-106 °C, A reaction that was run according to general procedure B (described in Part 5.1.7) with (R)-78 and phenol P-47 for 24 h at room temperature afforded the product 65t in 80% yield with 12:88 er. Rf = 0.50 (hexane:EtOAc 4:1). Spectral data for 65t: 1H NMR (300 MHz, CDCl3) δ 1.40 (s, 9H), 3.44 (d, 2H, J = 14.2 Hz), 3.78 (d, 2H, J = 14.2 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, 129 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), 2966(w), 1668(s), 1491(s) cm–1; HRMS (ESI) calcd for C26H29Cl2N2O m/z 455.1657 ([M+H]+), meas 455.1680. [α]!" ! = +30.8 (c 1.0, CH2Cl2) on 85:15 er material. O Br H 63a Br N H A-10 20 mol % (S)-BOROX catalyst + CN 64 mesitylene, rt Br N H N Br O 65u (S)-2-(bis(4-bromobenzyl)amino)-N-(tert-butyl)-2-phenylacetamide 65u: The general procedure A described in Part 5.1.4 was followed with ligand (S)-78 (41.5 mg, 0.05 mmol), phenol P-36 (14 mg, 0.10 mmol), amine A-1032 (178 mg, 0.50 mmol) and mesitylene (1 mL) as the solvent with a reaction time of 37 h. After purification by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 15:1), the product 65u was obtained as a white foamy-solid (119 mg, 0.219 mmol, 86%). The optical purity was determined to be 83:17 ee by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 98:2, 222 nm, flow 1 mL); Retention times: Rt = 9.87 min (major enantiomer) and Rt = 45.29 min (minor enantiomer). Mp 108-109 °C; A reaction that was run according to general procedure B (described in Part 5.1.7) with (R)-78 and phenol P-47 for 24 h at room temperature afforded the product 65u in 79% yield with 13:87 er. Rf = 0.50 (hexane:EtOAc 4:1); Spectral data for 65u: 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 130 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), 1487(s) cm–1; HRMS (ESI) calcd for C26H2979Br2N2O m/z 543.0647 ([M+H]+), meas 543.0645. [α]!" ! = + 27.1 (c 1.0, CH2Cl2) on 83:17 er material. O NO 2 H 63a O2N N H A-11 20 mol % (S)-BOROX catalyst + CN 64 mesitylene, rt NO 2 O2N N H N O 65v (S)-2-(bis(4-nitrobenzyl)amino)-N-(tert-butyl)-2-phenylacetamide 65v: The general procedure A described in Part 5.1.4 was followed with ligand (S)-78 (41.5 mg, 0.05 mmol), phenol P-36 (14 mg, 0.10 mmol), amine A-11 (144 mg, 0.50 mmol) and mesitylene (1 mL) as the solvent with a reaction time of 37 h. After purification by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 3:1), the product 65v was obtained as a yellow oil (26 mg, 0.055 mmol, 22%). The optical purity was determined to be 67:33 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL); Retention times: Rt = 51.63 min (major enantiomer) and Rt = 65.73 min (minor enantiomer). A reaction that was run according to general procedure B (described in 5.1.7) with (R)-78 and phenol P-47 for 24 h at room temperature 131 afforded the product 65v in 22% 1 H NMR yield with 27:73 er. Rf = 0.18 (hexane:EtOAc 3:1); Spectral data for 65v: 1H NMR (500 MHz, CDCl3) δ 1.37 (s, 9H), 3.73 (d, 2H, J = 14.8 Hz), 3.98 (d, 2H, J = 14.8 Hz), 4.16 (s, 1H), 5.73 (s, 1H), 7.30-7.40 (m, 5H), 7.47 (d, 4H, J = 9.0 Hz), 8.16 (d, 4H, J = 9.0 Hz); Unfortunately, the product as obtained was contaminated with some impurities. Thus, a clean 13 C NMR could not be obtained. HRMS (ESI) calcd for C26H29N4O5 m/z 477.2138 ([M+H]+), meas 477.2134. O H 63a N H A-12 + 20 mol % (S)-BOROX catalyst CN 64 mesitylene, rt N H N O 65w (S)-2-(bis(3,5-dimethylbenzyl)amino)-N-(tert-butyl)-2-phenylacetamide 65w: The general procedure A described in Part 5.1.4 was followed with ligand (S)-78 (41.5 mg, 0.05 mmol), phenol P-36 (14 mg, 0.10 mmol), amine A-12 (130 mg, 0.51 mmol) and mesitylene (1 mL) as the solvent with a reaction time of 39 h. After purification by column chromatography (silica gel, 20 × 200 mm, hexane:EtOAc 15:1), the product 65w was obtained as a yellow oil (74 mg, 0.167 mmol, 65%). The optical purity was determined to be 61:39 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 95:5, 222 nm, flow 0.7 mL); Retention times: Rt = 39.43 min (major enantiomer) and Rt = 58.69 min (minor enantiomer). Rf = 0.17 (hexane:EtOAc 10:1); Spectral data for 65w: 132 1 H NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 2.31 (s, 12H), 3.14 (d, 2H, J = 14.0 Hz), 3.75 (d, 2H, 14.0 Hz), 4.32 (s, 1H), 6.90 (s, 2H), 6.94 (s, 4H), 7.22-7.28 (m, 2H), 7.29-7.34 (m, 1H), 7.35-7.40 (m, 2H), 7.59 (brs, 1H); 13 C NMR (125 MHz, CDCl3) δ 21.30, 28.80, 50.78, 54.59, 68.02, 126.49, 127.52, 127.96, 128.80, 130.58, 134.13, 137.92, 138.71, 170.81; IR (thin film) 3343(w), 2963(m), 2919 (m), 1684(s), 1507(s), 1453 (s) cm–1; HRMS (ESI) calcd for C30H39N2O m/z 443.3062 ([M+H]+), meas 443.3058. [α]!" ! = + 5.2 (c 1.0, CH2Cl2) on 61:39 er material. 5.1.7 Formation of α-Amino Amides 65a—65q with General Procedure B General procedure B for the catalytic asymmetric Ugi reaction – Illustrated for the synthesis of (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(phenyl)acetamide 65a (Table 2.8, entry 2): Ph O Ph H 63a + 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 4Å MS mesitylene, rt, 24 h 64 Ph N H N O 65a Preparation of catalyst stock solution: A 25 mL Schlenk flask equipped with a stir bar was flame dried, cooled to rt under N2 and charged with (R)-78 (128 mg, 0.156 mmol), P-47 (49 mg, 0.32 mmol), H2O (8.3 mg, 8.3 µL, 0.46 mmol), dry toluene (4.6 mL) and BH3·SMe2 (2M, 232.5 µL, 0.465 mmol). The Teflon valve on the Schlenk flask was then closed, and the mixture heated at 100 °C for 1 h. After the flask was cooled to rt, the valve was carefully opened to gradually apply high vacuum (0.1 mm Hg) and the solvent and volatiles were 133 removed. Then the flask was heated at 100 °C under high vacuum for 30 min. Dry mesitylene (3.04 mL) was added to dissolve the residue in the flask after it was cooled to room temperature. Catalytic asymmetric Ugi reaction with benzaldehyde 63a: A 25 mL Schlenk flask charged with 4Å powdered molecular sieves (13 mg) and equipped with a magnetic stir bar was flame dried under high vacuum and cooled down under nitrogen. To the flask was then added 1.0 mL of the catalyst stock solution (20 mol% catalyst, 0.05 mmol) via a plastic syringe fitted with a metallic needle. To the resulting solution was added dibenzylamine A-5 (0.10 mL, 0.52 mmol, 2.0 equiv) under a N2 stream, followed by the addition of benzaldehyde 63a (26.0 µL, 0.255 mmol, 1.00 equiv) and then t-butyl isocyanide (45 µL, 0.39 mmol, 1.5 equiv). The Teflon valve was then closed, and the resulting mixture was stirred at rt for 24 h. Upon completion, 8 µL H2O was added to the reaction flask. After the mixture was stirred vigorously at room temperature for another 5 min, it was directly loaded onto a silica gel column (20 mm x 160 mm) with a pipette. Purification by column chromatography (1st column, 20 × 160 mm, hexanes:EtOAc 15:1; 2nd column, 20 × 160 mm, hexanes/CH2Cl2 1:1 as eluent until all the phenol P-47 came out, then EtOAc/hexanes 1:5 as eluent) gave product 3a as a white solid (85 mg, 0.22 mmol) in 86% yield. The optical purity was determined to be 91:9 er by HPLC analysis (Pirkle Covalent (R,R) WHELKO1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL/min). Retention times: Rt = 12.77 min (minor enantiomer) and Rt = 16.45 min (major enantiomer). The product 65a (85 mg, 0.22 mmol) was recrystallized from hexanes/EtOAc (15:1, 134 0.8 mL) at room temperature to give colorless crystals of 65a (60.5 mg, 0.157 mmol) with >99.5:0.5 er and in 71% recovery. A reaction that was run at 40 °C for 7 h afforded the product 65a in 87% NMR yield with 86:14 er. A reaction that was run at 0 °C for 66 h afforded the product 65a (74 mg, 0.19 mmol) in 75% isolated yield with 92:8 er. mp 136-137 °C; Rf = 0.40 (hexane: EtOAc 4:1). Spectral data for 65a: 1H 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) cm–1; HRMS (ESI) calcd for C26H31N2O m/z 387.2431 ([M+H]+), meas 387.2461. [α]!" ! = – 34.5° (c 1.0, CH2Cl2) on >99.5:0.5 er material. Recovery of the ligand (R)-78: The fractions containing the ligand (R)-78 obtained from the purification of 65a were combined and concentrated to dryness to give an orange foamy solid (49 mg), the 1H NMR spectrum of which showed that the ligand was contaminated with a small amount of impurities that were not identified. This solid was purified by column chromatography on silica gel (20 × 150 mm, hexanes:EtOAc 30:1) to give (R)-78 as an off-white foamy solid (37 mg, 0.045 mmol) in 90% recovery with > 99% ee. If the fractions containing the ligand are allowed to stay at room temperature for several days before purification, a decrease in the ee of the recovered (R)-78 can be observed. 135 Ph O Ph H + N H O2N A-5 63b 20 mol % (R)-BOROX catalyst Ph + CN 64 4Å MS mesitylene, rt, 24 h Ph N O2N H N O 65b (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(4-nitrophenyl)acetamide 65b: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 4-nitrobenzaldehyde 63b (38.5 mg, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified by column chromatography on silica gel (1st column, 20 × 160 mm, hexanes:EtOAc 15:1; 2nd column, 20 × 160 mm EtOAc/hexanes 1:8 as eluent) to afford the product 65b as a yellow oil (91 mg, 0.21 mmol) in a yield of 83%. The optical purity was determined to be 93:7 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 23.87 min (minor enantiomer) and Rt = 31.55 min (major enantiomer); A reaction that was run at 0 °C for 66 h afforded the product 65b in 51% NMR yield with 92:8 er. Rf = 0.17 (hexane: EtOAc 8:1). Spectral data for 65b: 1H NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 3.27 (d, 2H, J = 14.0 Hz), 3.85 (d, 2H, J = 14.0 Hz), 4.39 (s, 1H), 7.09 (brs, 1H), 7.26-7.41 (m, 10H), 7.46 (d, 2H, J = 9.0 Hz), 8.23 (d, 2H, J = 9.0 Hz); 13 C NMR (125 MHz, CDCl3) δ 28.76, 51.29, 54.69, 67.17, 123.12, 127.65, 128.43, 128.75, 131.22, 137.99, 141.91, 147.40, 169.24; IR (thin film) 3351(w), 2969(w), 1680(s), 1520(s), 1348(s) cm–1; HRMS (ESI) calcd for C26H30N3O3 m/z 432.2287 ([M+H]+), meas 432.2283. [α]!" ! = – 92.3° (c 1.0, CH2Cl2) on 93:7 er material. 136 Ph O Ph H F 3C 63c + 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 64 4Å MS mesitylene, rt, 24 h Ph N F 3C H N O 65c (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(4-trifluoromethylphenyl)acetamide 65c: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 4-trifluoromethylbenzaldehyde 63c (35 µL, 0.256 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 15:1) to give pure product 65c as an off-white semi-solid (91.6 mg, 0.202 mmol) in a yield of 79% along with fractions containing a mixture of 65c and phenol P-47. This mixture was loaded onto a silica gel column (20 × 160 mm, hexanes:EtOAc 15:1) and eluted to give additional product 65c (7.40 mg, 0.016 mmol) in a yield of 6%. The combined yield of 65c was 85%. The optical purity was determined to be 91:9 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 9.70 min (minor enantiomer) and Rt = 13.94 min (major enantiomer); Rf = 0.43 (hexanes: EtOAc 3:1). Spectral data for 3c: 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 3.28 (d, 2H, J = 14.0 Hz), 3.83 (d, 2H, J = 14.0 Hz), 4.34 (s, 1H), 7.10 (brs, 1H), 7.25-7.37 (m, 10H), 7.39 (d, 2H, J = 8.0 Hz), 7.63 (d, 2H, J = 8.0 Hz); 13 C NMR (125 MHz, CDCl3) δ 28.81, 51.19, 54.69, 67.61, 124.15 (q, J = 271.8 Hz), 125.00 (q, J = 3.8 Hz), 127.53, 128.52, 128.70, 129.92 (q, J = 32.4 Hz), 130.73, 138.35, 138.44, 169.81; IR (thin film) 3343(w), 2969(w), 1682(s), 1325(s) cm–1; HRMS (ESI) calcd 137 for C27H30F3N2O m/z 455.2310 ([M+H]+), meas 455.2311. [α]!" ! = – 33.8° (c 1.0, CH2Cl2) on 91:9 er material. Ph O Ph H Br 63d + 20 mol % (R)-BOROX catalyst Ph N H A-5 + Ph N CN 4Å MS mesitylene, rt, 24 h 64 Br H N O 65d (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(4-bromophenyl)acetamide 65d: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 4-bromobenzaldehyde 63d (47.1 mg, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified on silica gel according to the standard procedure (1st column, 20 × 160 mm, hexanes:EtOAc 15:1; 2nd column, 20 × 160 mm, hexanes/CH2Cl2 1:1 as eluent untill all the phenol P-47 came out, then EtOAc/hexanes 1:5 as eluent) to afford the product 65d as a colorless oil (100.5 mg, 0.216 mmol) in a yield of 85%. The optical purity was determined to be 93:7 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 14.82 min (minor enantiomer) and Rt = 22.53 min (major enantiomer); Rf = 0.14 (hexane: EtOAc 15:1). A reaction that was run at 0 °C for 48 h afforded the product 65d (77.2 mg, 0.166 mmol) in a yield of 65% with 95:5 er. Spectral data for 65d: 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 3.27 (d, 2H, J = 14.0 Hz), 3.80 (d, 2H, J = 14.0 Hz), 4.25 (s, 1H), 7.11 (brs, 1H), 7.13-7.17 (m, 2H), 7.24-7.29 (m, 2H), 7.29-7.37 (m, 8H), 7.47-7.52 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 28.79, 51.07, 54.54, 67.37, 121.85, 127.43, 128.52, 128.64, 131.22, 132.04, 138 133.29, 138.46, 170.06; IR (thin film) 3345(w), 2967(w), 1684(s), 1507(s), 1453(m), 698(m) cm–1; HRMS (ESI) calcd for C26H3079BrN2O m/z 465.1542 ([M+H]+), meas 465.1540. [α]!" ! = – 68.3° (c 1.0, CH2Cl2) on 95:5 er material. Ph O Br Ph H 63e + 20 mol % (R)-BOROX catalyst Ph N H + CN A-5 4Å MS mesitylene, rt, 22 h 64 Ph N Br H N O 65e (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(3-bromophenyl)acetamide 65e: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 3-bromobenzaldehyde 63e (47.2 mg, 0.255 mmol, 1.00 equiv) with a reaction time of 22 h. The crude product was purified on silica gel according to the standard procedure (1st column, 20 × 160 mm, hexanes:EtOAc 15:1; 2nd column, 20 × 180 mm, hexanes/CH2Cl2 1:1 as eluent untill all the phenol P-47 came out, then EtOAc/hexanes 1:5 as eluent) to afford the product 65e as a colorless oil (98 mg, 0.21 mmol) in a yield of 82%. The optical purity was determined to be 93:7 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 13.57 min (minor enantiomer) and Rt = 17.64 min (major enantiomer); A reaction that was run at 0 °C for 66 h at 0.4 M afforded the product 65e (78.0 mg, 0.168 mmol) in a yield of 66% with 92:8 er. Rf = 0.28 (hexane: EtOAc 8:1). Spectral data for 65e: 1H NMR (500 MHz, CDCl3) δ 1.41 (s, 9H), 3.30 (d, 2H, J = 13.5 Hz), 3.82 (d, 2H, J = 13.5 Hz), 4.23 (s, 1H), 7.11 (brs, 1H), 7.20-7.39 (m, 12H), 7.41 (s, 1H), 7.46 (d, 1H, J = 7.5 Hz); 13 C NMR (125 MHz, CDCl3) δ 28.79, 51.09, 139 54.59, 67.49, 122.23, 127.45, 128.55, 128.65, 129.00, 129.59, 130.83, 133.30, 136.62, 138.41, 169.86; IR (thin film) 3345(w), 2967(w), 1682(s), 1506(s), 1453(s) cm–1; HRMS (ESI) calcd for C26H3079BrN2O m/z 465.1542 ([M+H]+), meas 465.1536. [α]!" ! = – 43.1° (c 1.0, CH2Cl2) on 93:7 er material. Ph O Cl Ph H Cl 63f + 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 4Å MS mesitylene, rt, 24 h 64 Ph N Cl Cl H N O 65f (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(3,4-dichlorolphenyl)acetamide 65f: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 3-bromobenzaldehyde 63f (44.5 mg, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified on silica gel according to the standard procedure (1st column, 20 × 160 mm, hexanes:EtOAc 15:1; 2nd column, 20 × 180 mm, hexanes/CH2Cl2 1:1 as eluent untill all the phenol P-47 came out, then EtOAc/hexanes 1:5 as eluent) to afford the product 65f as a colorless semi-solid (98.7 mg, 0.217 mmol) in a yield of 85%. The optical purity was determined to be 94:6 er by HPLC analysis (Pirkle Covalent (R,R) WHELKO1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 12.31 min (minor enantiomer) and Rt = 17.81 min (major enantiomer); Rf = 0.18 (hexane: EtOAc 10:1). A reaction that was run at 0 °C for 66 h afforded the product 3f with 95:5 er in a yield of 54% as determined by 1HNMR with the aid of an internal standard (Ph3CH). Spectral data for 65f: 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 3.28 (d, 2H, J = 13.5 Hz), 3.80 (d, 2H, J = 13.5 Hz), 4.23 (s, 1H), 140 7.05 (brs, 1H), 7.11 (dd, 1H, J = 8.3 Hz, 1.8 Hz), 7.25-7.39 (m, 11H) 7.43 (d, 1H, J = 8.0 Hz); 13 C NMR (125 MHz, CDCl3) δ 28.80, 51.19, 54.67, 67.02, 127.56, 128.52, 128.72, 129.71, 129.98, 131.93, 132.25, 132.28, 134.57, 138.25, 169.52; IR (thin film) 3349(w), 2969(w), 1682(s), 1509(s), 733(m), 698(m) cm–1; HRMS (ESI) calcd for C26H2935Cl2N2O m/z 455.1657 ([M+H]+), meas 455.1658. [α]!" ! = – 65.6° (c 1.0, CH2Cl2) on 94:6 er material. Ph O Ph H F 63g + 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 64 4Å MS mesitylene, rt, 24 h Ph N F H N O 65g (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(4-fluorophenyl)acetamide 65g: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 4-fluorobenzaldehyde 63g (31.7 mg, 28 µL, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified on silica gel according to the standard procedure (1st column, 20 × 160 mm, hexanes:EtOAc 15:1; 2nd column, 20 × 150 mm, hexanes/CH2Cl2 1:1 as eluent untill all the phenol P-47 came out, then EtOAc/hexanes 1:5 as eluent) to afford the product 65g as a colorless oil (89.7 mg, 0.22 mmol) in a yield of 87%. The optical purity was determined to be 91:9 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 11.97 min (minor enantiomer) and Rt = 15.26 min (major enantiomer); A reaction that was run at 0 °C for 67 h afforded the product 65g (63.9 mg, 0.158 mmol) in a yield of 62% with 94:6 er. Rf = 0.19 (hexanes: EtOAc 10:1). Spectral data for 141 65g: 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 3.29 (d, 2H, J = 13.8 Hz), 3.80 (d, 2H, J = 13.8 Hz), 4.27 (s, 1H), 7.02-7.09 (m, 2H), 7.12 (brs, 1H), 7.21-7.28 (m, 4H), 7.29-7.37 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 28.77, 51.01, 54.52, 67.22, 114.97 (d, J = 21.0 Hz), 127.38, 128.50, 128.60, 129.95 (d, J = 3.0 Hz), 131.98 (d, J = 7.9 Hz), 138.53, 162.28 (d, J = 245.8 Hz), 170.39; IR (thin film) 3345(w), 2967(w), 1682(s), 1509(s), 1227(s) cm–1; HRMS (ESI) calcd for C26H30FN2O m/z 405.2342 ([M+H]+), meas 405.2341. [α]!" ! = –21.0 ° (c 1.0, CH2Cl2) on 94:6 er material. O Ph H MeO 2C 63h Methyl + 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 4Å MS mesitylene, rt, 24 h 64 MeO 2C Ph Ph N H N O 65h (R)-4-(2-(tert-butylamino)-1-(dibenzylamino)-2-oxoethyl)benzoate 65h: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with methyl-4-formylbenzoate 63h (42.0 mg, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 15:1è7.5:1è5:1) to afford the product 65h as a colorless semisolid (90.7 mg, 0.204 mmol) in a yield of 80%. The optical purity was determined to be 93:7 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 75:25, 222 nm, flow 2 mL). Retention times: Rt = 7.84 min (minor enantiomer) and Rt = 11.73 min (major enantiomer); A reaction that was run at 0 °C for 67 h afforded the product 65h (70 mg, 0.157 mmol) in a yield of 62% with 93:7 er. Rf = 142 0.34 (hexanes: EtOAc 3:1). Spectral data for 65h: 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 3.28 (d, 2H, J = 13.8 Hz), 3.82 (d, 2H, J = 13.8 Hz), 3.91 (s, 3H), 4.33 (s, 1H), 7.07 (brs, 1H), 7.24-7.28 (m, 2H), 7.29-7.38 (m, 10H), 8.02-8.06 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 28.77, 51.11, 52.12, 54.56, 67.62, 127.45, 128.52, 128.63, 129.30, 129.44, 130.34, 138.35, 139.65, 166.90, 169.95; IR (thin film) 3370(w), 2963(w), 1725(s), 1680(s), 1281(s), 1111(m) cm–1; HRMS (ESI) calcd for C28H33N2O3 m/z 445.2491 ([M+H]+), meas 445.2486. [α]!" ! = – 64.3° (c 1.0, CH2Cl2) on 93:7 er material. Ph O Ph H AcO 63i + 20 mol % (R)-BOROX catalyst Ph N H A-5 + Ph N H N CN 4Å MS mesitylene, rt, 24 h 64 AcO (R)-4-(2-(tert-butylamino)-1-(dibenzylamino)-2-oxoethyl)phenyl O 65i acetate 65i: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 4-acetoxybenzaldehyde 63i (42.0 mg, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified by column chromatography on silica gel (1st column, 20 × 160 mm, hexanes:EtOAc 15:1è7.5:1è5:1; 2nd column, 2nd column, 20 × 150 mm, hexanes:EtOAc 4:1) to afford the product 65i as a yellow viscous oil (98.6 mg, 0.22 mmol) in a yield of 86%. The optical purity was determined to be 85:15 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 75:25, 222 nm, flow 2 mL). Retention times: Rt = 10.49 min (minor enantiomer) and Rt = 13.12 min (major enantiomer); Rf = 0.31 (hexanes: EtOAc 3:1). Spectral data for 65i: 1H 143 NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 2.29 (s, 3H), 3.35 (d, 2H, J = 13.8 Hz), 3.81 (d, 2H, J = 13.8 Hz), 4.28 (s, 1H), 7.06 (brs, 1H), 7.08-7.12 (m, 2H), 7.237.30 (m, 4H), 7.31-7.35 (m, 8H); 13 C NMR (125 MHz, CDCl3) δ 21.17, 28.80, 51.03, 54.50, 67.36, 121.13, 127.33, 128.56, 128.58, 131.30, 131.95, 138.70, 150.20, 169.26, 170.38; IR (thin film) 3374(w), 2965(w), 1763(s), 1680(s), 1505(s), 1202(s) cm–1; HRMS (ESI) calcd for C28H33N2O3 m/z 445.2491 ([M+H]+), meas 445.2490. [α]!" ! = – 31.6° (c 1.0, CH2Cl2) on 85:15 er material. Ph O Ph H AcHN 63j + 20 mol % (R)-BOROX catalyst Ph N H A-5 + Ph N CN 4Å MS mesitylene, rt, 24 h 64 AcHN H N O 65j (R)-2-(4-Acetamidophenyl)-N-(tert-butyl)-2-(dibenzylamino)acetamide 65j: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 4-acetaminobenzaldehyde 63j (41.6 mg, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 3:1è1:1) to afford the product 65j as a white solid (87.0 mg, 0.196 mmol) in a yield of 77%. The optical purity was determined to be 85:15 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 75:25, 254 nm, flow 2 mL). Retention times: Rt = 15.33 min (minor enantiomer) and Rt = 18.83 min (major enantiomer); The product was extracted with Et2O to give 65j as an off-white foamy solid with 96:14 er in 47% recovery. This material contains a very small amount of impurities. The precipitate that remained after the extraction was pure 144 rac-65j. Rf = 0.12 (hexanes: EtOAc 1:1). Spectral data for (±)-65j: 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 2.04(s, 3H), 3.19 (d, 2H, J = 13.9 Hz), 3.78 (d, 2H, J = 13.9 Hz), 4.23 (s, 1H), 7.05 (d, 2H, J = 7.5 Hz), 7.24-7.36 (m, 12H), 7.55 (s, 1H), 8.27 (s, 1H); 13 C NMR (125 MHz, CDCl3) δ 24.20, 28.81, 51.01, 54.60, 67.65, 119.85, 127.38, 128.55, 128.63, 129.14, 130.83, 137.72, 138.57, 168.62, 171.09; IR (thin film) 3312(m), 2969(w), 1663(s), 1514(s) cm–1; HRMS (ESI) calcd for C28H34N3O2 m/z 444.2651 ([M+H]+), meas 444.2654. Ph O Ph H 63k + 20 mol % (R)-BOROX catalyst Ph N H A-5 + Ph N CN 4Å MS mesitylene, rt, 24 h 64 (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(4-methyl)acetamide H N O 65k 65k: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with p-tolualdehyde 63k (30.6 mg, 30 µL, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified on silica gel according to the standard procedure (1st column, 20 × 160 mm, hexanes:EtOAc 15:1; 2nd column, 20 × 150 mm, hexanes/CH2Cl2 1:1 as eluent untill all the phenol P-47 came out, then EtOAc/hexanes 1:5 as eluent) to afford the product 65k as a colorless semi-solid (85.7 mg, 0.214 mmol) in a yield of 84%. The optical purity was determined to be 91:9 er by HPLC analysis (Pirkle Covalent (R,R) WHELKO1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 15.61 min (minor enantiomer) and Rt = 23.03 min (major enantiomer); Rf = 0.12 (hexanes: EtOAc 10:1). The product 65k (85.7 mg, 0.214 mmol) was 145 recrystallized from hexanes (0.5 mL) at room temperature to give colorless crystals of 65k (40.5 mg, 0.101 mmol) with 99.4:0.6 er and in 47% recovery. A reaction that was run at 0 °C for 66 h afforded the product 65k in 80% NMR yield with 92:8 er. Spectral data for 65k: 1H NMR (500 MHz, CDCl3) δ 1.41 (s, 9H), 2.36 (s, 3H), 3.37 (d, 2H, J = 14.0 Hz), 3.84 (d, 2H, J = 14.0 Hz), 4.28 (s, 1H), 7.09 (brs, 1H), 7.19 (s, 4H), 7.24-7.30 (m, 2H) 7.32-7.37 (m, 8H); 13 C NMR (125 MHz, CDCl3) δ 21.11, 28.79, 50.87, 54.50, 67.92, 127.20, 128.47, 128.59, 128.78, 130.17, 131.48, 137.28, 138.87, 170.79; IR (thin film) 3347(w), 2967(w), 1684(s), 1507(s), 1453(m) cm–1; HRMS (ESI) calcd for C27H33N2O m/z 401.2593 ([M+H]+), meas 401.2587. [α]!" ! = – 40.7° (c 1.0, CH2Cl2) on 91:9 er material. Ph O Ph H 63l + 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 4Å MS mesitylene, rt, 24 h 64 (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(2-methyl)acetamide Ph N H N O 65l 65l: The general procedure B for the catalytic asymmetric Ugi reaction described for 65A was followed with o-tolualdehyde 63l (30.6 mg, 30 µL, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified on silica gel according to the standard procedure (1st column, 20 × 160 mm, hexanes:EtOAc 15:1; 2nd column, 20 × 150 mm, hexanes/CH2Cl2 1:1 as eluent until all the phenol P-47 came out, then EtOAc/hexanes 1:5 as eluent) to afford the product 65l as a white solid (77.5 mg, 0.193 mmol) in a yield of 76%. The optical purity was determined to be 78:22 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 146 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 6.91 min (minor enantiomer) and Rt = 13.34 min (major enantiomer). The product (71.4 mg, 0.178 mmol) was recrystallized from 0.9 mL hexanes/EtOAc 20:1 at – 10°C to give a white solid (40 mg, 0.010 mmol) with > 99:1 er in 56% recovery. mp 104-105 °C. Rf = 0.16 (hexanes: EtOAc 10:1). Spectral data for 65l: 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 2.22 (s, 3H), 3.74 (d, 2H, J = 14.0 Hz), 3.83 (d, 2H, J = 14.0 Hz), 4.37 (s, 1H), 6.31 (brs, 1H), 7.15 (s, 3H), 7.19-7.25 (m, 6H) 7.26-7.31 (m, 4H), 7.39-7.45 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 19.87, 28.71, 51.07, 54.53, 65.93, 125.81, 127.03, 127.70, 128.22, 128.75, 129.04, 130.91, 135.52, 138.10, 138.99, 171.66; IR (thin film) 3337(w), 2967(w), 1671(s), 1509(s), 1453(s) cm–1; HRMS (ESI) calcd for C27H33N2O m/z 401.2593 ([M+H]+), meas 401.2589. [α]!" ! = –20.1° (c 1.0, CH2Cl2) on >99:1 er material. Ph O Ph H + tBu 63m 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 64 4Å MS mesitylene, rt, 24 h Ph N tBu (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(4-tert-butyl)acetamide H N O 65m 65m: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with tert-butylbenzaldehyde 65m (41.3 mg, 42.6 µL, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified by column chromatography on silica gel (1st column, 20 × 160 mm, hexanes:EtOAc 15:1; 2nd column, 20 × 150 mm, hexanes/CH2Cl2 1:1 as eluent untill all the phenol P-47 came out, then EtOAc/hexanes 1:5 as eluent) to afford the product 65m as 147 a white solid (93.7 mg, 0.212 mmol) in a yield of 83%. The optical purity was determined to be 84:16 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 10.99 min (minor enantiomer) and Rt = 16.16 min (major enantiomer); mp 48-51 °C. Rf = 0.52 (hexanes: EtOAc 3:1). Spectral data for 65m: 1H NMR (500 MHz, CDCl3) δ 1.31 (s, 9H), 1.39 (s, 9H), 3.37 (d, 2H, J = 14.0 Hz), 3.81 (d, 2H, J = 14.0 Hz), 4.25 (s, 1H), 7.10 (brs, 1H), 7.17-7.22 (m, 2H) 7.22-7.29 (m, 2H), 7.307.40 (m, 10H); 13 C NMR (125 MHz, CDCl3) δ 28.83, 31.33, 34.50, 50.93, 54.64, 67.99, 125.01, 127.21, 128.49, 128.63, 129.96, 131.42, 139.02, 150.41, 170.89; IR (thin film) 3341(w), 2965(s), 1682(s), 1507(s) cm–1; HRMS (ESI) calcd for C30H39N2O m/z 443.3062 ([M+H]+), meas 443.3063. [α]!" ! = – 40.9° (c 1.0, CH2Cl2) on 84:16 er material. Ph O Ph H MeO 63n + 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 64 4Å MS mesitylene, rt, 24 h Ph N MeO (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(4-methoxy)acetamide H N O 65n 65n: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 4-anisaldehyde 63n (34.7 mg, 31.0 µL, 0.255 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 10:1) to afford the product 65n as a semi-solid (74.4 mg, 0.179 mmol) in a yield of 70%. The optical purity was determined to be 89:11 er by HPLC analysis (Pirkle Covalent (R,R) 148 WHELK-O1 column, hexanes/2-propanol 75:25, 222 nm, flow 2 mL). Retention times: Rt = 5.91 min (minor enantiomer) and Rt = 8.80 min (major enantiomer); Rf = 0.34 (hexanes: EtOAc 3:1). A reaction that was run at 0 °C for 66 h afforded the product 65n (54.2 mg, 0.130 mmol) in a yield of 51% with 92:8 er. Spectral data for 65n: 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 3.32 (d, 2H, J = 14.0 Hz), 3.799 (d, 2H, J = 14.0 Hz), 3.802 (s, 3H), 4.24 (s, 1H), 6.87-6.93 (m, 2H), 7.11 (brs, 1H), 7.17-7.22 (m, 2H), 7.22-7.28 (m, 2H), 7.30-7.35 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 28.81, 50.90, 54.54, 55.23, 67.61, 113.54, 126.58, 127.24, 128.52, 128.60, 131.45, 138.89, 159.08, 170.88; IR (thin film) 3355(m), 2963(w), 1680(s), 1510(s), 1248(s) cm–1; HRMS (ESI) calcd for C27H33N2O2 m/z 417.2542 ([M+H]+), meas 417.2548. [α]!" ! = – 46.4° (c 1.0, CH2Cl2) on 92:8 er material. Ph O Ph H N + 20 mol % (R)-BOROX catalyst Ph N H + Ph N CN 4Å MS mesitylene, rt, 25 h N O 65o (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(pyridin-3-yl)acetamide 65o: 63o A-5 64 H N The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 3-pyridinecarboxaldehyde 63o (27.3 mg, 24.0 µL, 0.255 mmol, 1.00 equiv) with a reaction time of 25 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 15:1è5:1è1:1) to afford the product 65o as a solid (79.0 mg, 0.204 mmol) in a yield of 80%. The optical purity was determined to be 90:10 er by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention 149 times: Rt = 6.97 min (minor enantiomer) and Rt = 10.93 min (major enantiomer). The product (79.0 mg, 0.204 mmol) was crystallized from a mixture of hexanes/EtOAc (8:1) at room temperature to give 48 mg of 65o as colorless crystals in >99:1 er and 61% recovery. mp 123-124 °C. Rf = 0.29 (hexanes: EtOAc 1:2). Spectral data for 65o: 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 3.22 (d, 2H, J = 13.7 Hz), 3.83 (d, 2H, J = 13.7 Hz), 4.34 (s, 1H), 7.21 (brs, 1H), 7.25-7.30 (m, 2H) 7.30-7.38 (m, 9H), 7.65-7.70 (m, 1H), 8.48 (s, 1H), 8.57 (d, 1H, J = 4.6 Hz); 13 C NMR (125 MHz, CDCl3) δ 28.77, 51.17, 54.63, 65.40, 123.12, 127.61, 128.48, 128.76, 129.75, 138.09, 138.43, 148.60, 151.08, 169.46; IR (thin film) 3349(w), 2969(w), 1680(s) cm–1; HRMS (ESI) calcd for C25H30N3O m/z 388.2389 ([M+H]+), meas 388.2384. [α]!" ! = –17.1° (c 1.0, CH2Cl2) on >99:1 er material. Ph O Ph H N 63p + 20 mol % BOROX catalyst Ph N H A-5 + CN 4Å MS mesitylene 64 Ph N N (R)-N-(tert-butyl)-2-(dibenzylamino)-2-(pyridin-4-yl)acetamide H N O 65p 65p: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with 4-pyridinecarboxaldehyde 63p (27.3 mg, 24.0 µL, 0.255 mmol, 1.00 equiv) except that the reaction time is 70 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 3:1è1:1) to afford the product 65p as a semi-solid (65.2 mg, 0.168 mmol) in a yield of 66%. The optical purity was determined to be 89:11 er by HPLC analysis 150 (Chiralpak AD column, hexanes/2-propanol 95:5, 222 nm, flow 0.7 mL). Retention times: Rt = 18.38 min (minor enantiomer) and Rt = 22.86 min (major enantiomer). Rf = 0.30 (hexanes/EtOAc 1:2). Spectral data for 65p: 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 3.26 (d, 2H, J = 13.8 Hz), 3.82 (d, 2H, J = 13.8 Hz), 4.27 (s, 1H), 7.07 (brs, 1H), 7.20-7.22 (m, 2H), 7.25-7.30 (m, 2H), 7.30-7.38 (m, 8H), 8.59-8.64 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 28.75, 51.24, 54.61, 66.74, 125.41, 127.60, 128.44, 128.73, 138.04, 143.18, 149.42, 169.10; IR (thin film) 3341(w), 3258(w), 3031(w), 2967(w), 1680(s) cm–1; HRMS (ESI) calcd for C25H30N3O m/z 388.2389 ([M+H]+), meas 388.2382. [α]!" ! = –11.9° (c 1.0, CH2Cl2) on >89:11 er material. Ph O Ph H 63q + 20 mol % (R)-BOROX catalyst Ph N H A-5 + Ph N CN 4Å MS mesitylene, rt, 24 h 64 (R)-N-(tert-butyl)-2-cyclohexyl-2-(dibenzylamino)acetamide H N O 65q 65q: The general procedure B for the catalytic asymmetric Ugi reaction described for 65a was followed with cyclohexanecarboxaldehyde 63q (28.7 mg, 31.0 µL, 0.256 mmol, 1.00 equiv) with a reaction time of 24 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 15:1) to afford the product 65q as an off-white solid (45.1 mg, 0.115 mmol) in a yield of 45%. A second run gave 65q (49.2 mg, 0.125 mmol) in 49% isolated yield. The optical purity was determined to be 50.5:49.5 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 151 mL). Retention times: Rt = 4.59 min (minor enantiomer) and Rt = 5.06 min (major enantiomer). mp 97-100 °C. Rf = 0.25 (hexanes/EtOAc 10:1). Spectral data for 65q: 1H NMR (500 MHz, CDCl3) δ 0.67-0.79 (m, 1H), 0.80-0.92 (m, 1H), 1.011.14 (m, 1H), 1.14-1.31 (m, 2H), 1.37 (s, 9H), 1.53-1.67 (m, 3H), 1.72 (d, 1H, J = 13.3 Hz), 1.90-2.01 (m, 1H), 2.27 (d, 1H, J = 13.3 Hz), 2.46 (d, 1H, J = 10.3 Hz), 3.45 (d, 2H, J = 14.5 Hz), 4.06 (d, 2H, J = 14.5 Hz), 5.02 (s, 1H), 7.22 (t, 2H, J = 13 7.5 Hz), 7.31 (t, 4H, J = 7.5 Hz), 7.40 (d, 4H, J = 7.5 Hz); C NMR (125 MHz, CDCl3) δ 25.97, 26.00, 26.62, 28.98, 29.83, 30.53, 36.14, 51.49, 54.37, 68.75, 126.82, 128.30, 128.37, 140.16, 170.17; IR (thin film) 3430(w), 2926(s), 2851(s), 1676(s), 1503(s), 1453(s) cm–1; HRMS (ESI) calcd for C26H37N2O m/z 393.2906 ([M+H]+), meas 393.2904. 5.1.8 Intramolecular Interception of the Nitrilium Cation O Ph H OH 63r + N H A-5 + O 20 mol % (R)-BOROX catalyst Ph NH tBu CN 4Å MS mesitylene, rt, 44 h N Bn Bn 64 93 N3,N3-dibenzyl-N2-(tert-butyl)benzofuran-2,3-diamine: The general procedure B for the catalytic asymmetric Ugi reaction described in Part 5.1.7 was followed with salicylaldehyde 63r (31.1 mg, 27.0 µL, 0.255 mmol, 1.00 equiv) with a reaction time of 44 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 20:1) to afford the product 93 as a yellow solid (21.5 mg, 0.0559 mmol) in a yield of 22%. The product was assigned as 93 on the basis of its 1H and 13 C NMR spectra. A reaction that was run at 0 °C for 66 h afforded the product 93 (20 mg, 0.052 152 mmol) in a yield of 20%. Rf = 0.24 (hexanes/EtOAc 20:1). Spectral data for 93: 1H NMR (500 MHz, CDCl3) δ 1.06 (s, 9H), 3.80 (s, 1H), 4.16 (s, 4H), 6.96-7.02 (m, 1H), 7.12 (t, 1H, J = 7.5 Hz), 7.18-7.30 (m, 11H), 7.40-7.44 (m, 1H); 13 C NMR (125 MHz, CDCl3) δ 29.99, 52.33, 58.60, 106.83, 110.38, 117.01, 119.44, 122.08, 127.07, 127.69, 128.21, 129.11, 139.60, 149.26, 155.28. 5.1.9 Formation of α -Amino Amides with Different Isocyanides O Ph H + 63a 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 4Å MS mesitylene, rt, 68 h 80a Ph Ph N H N O 81a (R)-2-(dibenzylamino)-2-phenyl-N-(2,4,4-trimethylpentan-2-yl)acetamide 81a: The general procedure B for the catalytic asymmetric Ugi reaction described in Part 5.1.7 was followed with isocyanide 80a (67 µL, 0.38 mmol, 1.5 equiv) with a reaction time of 68 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 15:1) to afford the product 81a as a colorless semi-solid (62.2 mg, 0.141 mmol) in a yield of 55%. The optical purity was determined to be 87:13 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 9.78 min (minor enantiomer) and Rt = 11.13 min (major enantiomer); Rf = 0.25 (hexanes: EtOAc 6:1). Spectral data for 81a: 1H NMR (500 MHz, CDCl3) δ 0.94 (s, 9H), 1.43 (s, 3H), 1.48 (s, 3H), 1.64 (d, 1H, J = 15.3 Hz), 1.94 (d, 1H, J = 15.3 Hz), 3.25 (d, 2H, J = 13.5 Hz), 3.86 (d, 2H, J = 13.5 Hz), 4.30 (s, 1H), 7.23-7.42 (m, 16H); 153 13 C NMR (125 MHz, CDCl3) δ 29.27, 29.38, 31.42, 31.49, 51.28, 54.46, 54.91, 68.02, 127.31, 127.63, 128.02, 128.55, 128.63, 130.63, 133.86, 138.55, 170.28; IR (thin film) 3351(w), 2955(m), 1684(s), 1507(s), 1453(w) cm–1; HRMS (ESI) calcd for C30H39N2O m/z 443.3062 ([M+H]+), meas 443.3060. [α]!" ! = – 15.2° (c 1.0, CH2Cl2) on 87:13 er material. Ph O Ph H 63a + 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 4Å MS mesitylene, rt, 24 h 80b Ph N H N O 81b (R)-N-cyclohexyl-2-(dibenzylamino)-2-phenylacetamide 81b: The general procedure B for the catalytic asymmetric Ugi reaction described in Part 5.1.7 was followed with isocyanide 80b (47.5 µL, 0.382 mmol, 1.50 equiv) with a reaction time of 24 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 15:1) to afford the product 81b as a white solid (78.8 mg, 0.191 mmol) in a yield of 75%. The optical purity was determined to be 67:33 er by HPLC analysis (CHIRALCEL OD-H column, hexanes/2propanol 98:2, 222 nm, flow 1 mL). Retention times: Rt = 8.00 min (minor enantiomer) and Rt = 9.18 min (major enantiomer); mp 129-132 °C. Rf = 0.33 (hexanes: EtOAc 3:1). Spectral data for 81b: 1H NMR (500 MHz, CDCl3) δ 1.121.30 (m, 3H), 1.32-1.46 (m, 2H), 1.57-1.77 (m, 3H), 1.85-2.01 (m, 2H), 3.35 (d, 2H, J = 14.0 Hz), 3.82 (d, 2H, J = 14.0 Hz), 3.80-3.91 (m, 1H), 4.35 (s, 1H), 7.06 (d, 1H, J = 8.4 Hz), 7.23-7.39 (m, 15H); 13 C NMR (125 MHz, CDCl3) δ 24.67,24.73, 25.55, 33.02, 33.35, 47.81, 54.50, 67.72, 127.26, 127.74, 128.13, 128.52, 128.64, 130.16, 134.71, 138.73, 170.28; IR (thin film) 3318(w), 2930(s), 154 2853(m), 1663(s), 1506(s), 1453(m) cm–1; HRMS (ESI) calcd for C28H33N2O m/z 413.2593 ([M+H]+), meas 413.2591. [α]!" ! = – 5.8° (c 1.0, CH2Cl2) on 67:33 er material. Ph O Ph H 63a + 20 mol % (R)-BOROX catalyst Ph N H A-5 + Ph N H N 4Å MS mesitylene, rt, 39 h CN O 80c 81c (R)-N-butyl-2-(dibenzylamino)-2-phenylacetamide 81c: The general procedure B for the catalytic asymmetric Ugi reaction described in Part 5.1.7 was followed with isocyanide 80c (40 µL, 0.38 mmol, 1.5 equiv) with a reaction time of 39 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 15:1 to 5:1) to afford the product 81c as an off-white solid (47.3 mg, 0.122 mmol) in a yield of 48%. The optical purity was determined to be 52:48 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 90:10, 222 nm, flow 1 mL). Retention times: Rt = 30.04 min (major enantiomer) and Rt = 33.40 min (minor enantiomer); mp 83-85 °C. Rf = 0.26 (hexanes: EtOAc 3:1). Spectral data for 81c: 1H NMR (500 MHz, CDCl3) δ 0.93 (t, 3H, J = 7.3 Hz), 1.31-1.41 (m, 2H), 1.53 (pentet, 2H, J = 7.3 Hz), 3.263.42 (m, 2H), 3.34 (d, 2H, J = 13.5 Hz), 3.84 (d, 2H, J = 13.5 Hz), 4.39 (s, 1H), 7.14 (br, t, 1H, J = 5.8 Hz), 7.22-7.42 (m, 15H); 13 C NMR (125 MHz, CDCl3) δ 13.70, 20.08, 31.73, 38.91, 54.48, 67.66, 127.27, 127.76, 128.13, 128.53, 128.58, 130.18, 134.39, 138.62, 171.25; IR (thin film) 3310(m), 2957(m), 155 2930(m), 1655(s), 1495(m), 1453(m) cm–1; HRMS (ESI) calcd for C26H31N2O m/z 387.2436 ([M+H]+), meas 387.2433. O Ph H + 63a 20 mol % (R)-BOROX catalyst Ph N H A-5 + Ph N 4Å MS mesitylene, rt, 29 h CN H N O 81d 80d (R)-N-benzyl-2-(dibenzylamino)-2-phenylacetamide Ph 81d: The general procedure B for the catalytic asymmetric Ugi reaction described in Part 5.1.7 was followed with isocyanide 80d (47 µL, 0.39 mmol, 1.5 equiv) with a reaction time of 29 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 6:1) to afford the product 81d as a light yellow solid (49.4 mg, 0.117 mmol) in a yield of 46%. The optical purity was determined to be 51:49 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 85:15, 222 nm, flow 1 mL). Retention times: Rt = 34.61 min (major enantiomer) and Rt = 39.08 min (minor enantiomer); mp 104-105 °C. Rf = 0.11 (hexanes: EtOAc 6:1). Spectral data for 81d: 1H NMR (500 MHz, CDCl3) δ 3.33 (d, 2H, J = 14.0 Hz), 3.86 (d, 2H, J = 14.0 Hz), 4.48 (s, 1H), 4.51 (dd, 1H, J = 14.5 Hz, J = 6.0 Hz), 4.61 (dd, 1H, J = 14.5 Hz, J = 6.0 Hz), 7.24-7.45 (m, 20H), 7.52 (t, 1H, J = 5.8 Hz); 13 C NMR (125 MHz, CDCl3) δ 43.47, 54.51, 67.66, 127.29, 127.52, 127.76, 127.88, 128.19, 128.53, 128.68, 128.73, 130.29, 134.06, 138.25, 138.43, 171.31; IR (thin film) 3310(m), 3029(m), 1662(s), 1495(m), 1453(m) cm–1; HRMS (ESI) calcd for C29H29N2O m/z 421.2280 ([M+H]+), meas 421.2278. 156 Ph O Ph H + 63a 20 mol % (R)-BOROX catalyst Ph N H A-5 + CN 4Å MS mesitylene, rt, 44 h 80e Ph N H N O 81e (R)-2-(dibenzylamino)-N-(2,6-dimethylphenyl)-2-phenylacetamide 81e: The general procedure B for the catalytic asymmetric Ugi reaction described in Part 5.1.7 was followed with isocyanide 80e (50 mg, 0.38 mmol, 1.5 equiv) with a reaction time of 44 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 6:1) to afford a mixture of phenol P47 and the product 81e which contained the product 81e (32 mg, 0.074 mmol) in a yield of 29%. The optical purity was determined to be 85:15 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 75:25, 222 nm, flow 2 mL). Retention times: Rt = 4.84 min (major enantiomer) and Rt = 10.60 min (minor enantiomer); Rf = 0.16 (hexanes: EtOAc 6:1). Spectral data for 81e: 1H NMR (600 MHz, CDCl3) δ 2.17 (s, 6H), 3.34 (d, 2H, J = 14.0 Hz), 4.02 (d, 2H, J = 14.0 Hz), 4.67 (s, 1H), 7.05-7.12 (m, 3H), 7.25-7.30 (m, 2H), 7.32-7.45 (m, 13H), 8.83 (s, 1H); 13 C NMR (125 MHz, CDCl3) δ 18.76, 54.59, 67.74, 127.17, 127.54, 128.00, 128.22, 128.29, 128.70, 128.73, 130.68, 133.45, 133.92, 135.38, 138.11, 169.71; HRMS (ESI) calcd for C30H31N2O m/z 435.2436 ([M+H]+), meas 435.2435. 157 NC O Ph H + 63a Ph N H A-5 + OMe 80f Ph 20 mol % (R)-BOROX catalyst 4Å MS mesitylene, rt, 24 h Ph N H N O 81f OMe (R)-2-(dibenzylamino)-N-(4-methoxyphenyl)-2-phenylacetamide 81f: The general procedure B for the catalytic asymmetric Ugi reaction described in Part 5.1.7 was followed with isocyanide 80f (51 mg, 0.38 mmol, 1.5 equiv) with a reaction time of 24 h. The crude product was purified by column chromatography on silica gel (20 × 160 mm, hexanes:EtOAc 6:1) to afford the product 81f as a yellow solid (72.2 mg, 0.165 mmol) in a yield of 65%. The optical purity was determined to be 88:12 er by HPLC analysis (Pirkle Covalent (R,R) WHELK-O1 column, hexanes/2-propanol 75:25, 222 nm, flow 2 mL). Retention times: Rt = 14.25 min (major enantiomer) and Rt = 30.58 min (minor enantiomer); mp 54-55 °C. Rf = 0.13 (hexanes: EtOAc 6:1). Spectral data for 81f: 1H NMR (500 MHz, CDCl3) δ 3.33 (d, 2H, J = 14.0 Hz), 3.79 (s, 3H), 3.95 (d, 2H, J = 14.0 Hz), 4.57 (s, 1H), 6.87-6.92 (m, 2H), 7.26-7.46 (m, 15H), 7.50-7.55 (m, 2H), 9.30 (s, 1H); 13 C NMR (125 MHz, CDCl3) δ 54.67, 55.48, 68.17, 114.22, 120.83, 127.50, 128.03, 128.24, 128.63, 128.74, 130.59, 131.06, 133.25, 138.21, 156.22, 169.31; IR (thin film) 3322(w), 3029(w), 1682(m), 1514(s), 1246(m) cm–1; HRMS (ESI) calcd for C29H29N2O2 m/z 437.2229 ([M+H]+), meas 437.2227. [α]!" ! = + 67.4° (c 1.0, CH2Cl2) on 88:12 er material. 158 5.1.10 Determination of the Absolute Configuration of the Ugi Product 65a (Scheme 2.10) Removal of the benzyl groups of 65a: Ph Ph N H N O (R)-65a 90:10 er Pd(OH) 2/C H 2 (1 atm) EtOH, 25 °C 90% NH 2 H N O (R)-82 91.5:8.5 (R)-2-amino-N-(tert-butyl)-2-phenylacetamide 82: To a flame-dried 25 mL round bottom flask filled with nitrogen was added 65a (70.0 mg, 0.181 mmol, 90:10 er), Pd(OH)2 (20.0 mg, 0.028 mmol) (Pd(OH)2 on carbon 20%, moisture ≤ 50%). The flask was sealed with a rubber septum and a needle connected to a vacuum line was used to apply vacuum in the flask through the septum. The vacuum was applied for a few seconds. Then the vacuum was stopped and a hydrogen balloon was connected to the flask by a needle through the septum. This process was repeated four times. Then 5.0 mL EtOH was added to the flask via a needle through the septum. The suspension was stirred at room temperature under hydrogen for 18 hours and then filtered through a pad of Celite. The filter cake was washed with MeOH (5 mL) and DCM (5 mL × 3). The combined filtrate was concentrated to give a light yellow oil. Purification of the crude product by column chromatography on silica gel (20 mm × 160 mm, CH2Cl2/MeOH 20:1) gave the product 82 as a colorless oil (33.4 mg, 0.162 mmol, 90%). The optical purity was determined to be 91.5:8.5 er by HPLC analysis (Chiralpak AS column, hexanes/2-propanol 85:15, 222 nm, flow 1 mL). Retention times: Rt = 8.55 min (minor enantiomer) and Rt = 13.56 min (major enantiomer). 159 The retention times appear to be dependent on the concentration of the sample. Rf = 0.28 (CH2Cl2/MeOH 12:1). Spectral data for 82: 1H NMR (500 MHz, CDCl3) δ 1.31 (s, 9H), 1.83 (brs, 2H), 4.36 (s, 1H), 6.92 (brs, 1H), 7.22-7.28 (m, 1H) 7.287.36 (m, 4H); 13 C NMR (125 MHz, CDCl3) δ 28.64, 50.69, 60.27, 126.79, 127.76, 128.74, 141.54, 172.04; IR (thin film) 3310(m), 2969(m), 1653(s), 1522(m) cm–1; HRMS (ESI+) calcd for C12H19N2O m/z 207.1497 ([M+H]+), meas 207.1498. [α]!" ! = –23.1° (c 1.0, CH2Cl2) on >91.5:8.5 er material. Preparation of (S)-2-amino-N-(tert-butyl)-2-phenylacetamide 82 from L-(+)-αphenylglycine: NH 2 OH Ph O (S)-83 (Boc) 2O Dioxane/H 2O 2:1 1M NaOH, NaHCO 3 tBuNH2 DCC DCM BocHN Ph H N O (S)-84 51% over two steps tert-Butyl (S)-(2-(tert-butylamino)-2-oxo-1-phenylethyl)carbamate 84: To a 100 mL round bottom flask was added L-(+)-α-phenylglycine 83 (756 mg, 5.00 mmol, 1.00 equiv), a mixture of dioxane/water (2:1, 10 mL) and 1M NaOH (5 mL). After the mixture was cooled in an ice-bath for 5 min, (Boc)2O (1.64 g, 7.50 mmol, 1.50 equiv) and NaHCO3 (420 mg, 5.00 mmol, 1.00 equiv) were added to the flask. The mixture was stirred at room temperature for 18 h. Then EtOAc (30 mL) was added to the reaction mixture and then it was cooled in an ice bath for 5 min. The pH of the mixture was adjusted to 2-3 with 1M HCl. The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was transferred to a 50 mL round bottom flask and 160 dissolved in CH2Cl2 (15 mL). After the solution was cooled to 0 °C, N,N’dicyclohexylcarbodiimide (1.05 g, 5.09 mmol, 1.02 equiv) was added to the flask, followed by the addition of tert-butylamine (0.51 mL, 4.9 mmol, 0.98 equiv). The reaction mixture was warmed up to room temperature and stirred for 18 h. Then the white precipitate that formed in the reaction was removed by filtration through a Celite pad. The pad was washed with CH2Cl2 (5 mL x 4). The combined filtrate was concentrated and the product was purified by column chromatography on silica gel (30 mm × 160 mm, hexanes/EtOAc 5:1) to give the product 84 as a white solid (774 mg, 2.53 mmol) in a 51% yield over two steps. mp 144-146 °C. Rf = 0.24 (hexanes/EtOAc 3:1). Spectral data for 84: 1H NMR (500 MHz, CDCl3) δ 1.26 (s, 9H), 1.38 (s, 9H), 4.99 (brs, 1H), 5.45 (brs, 1H), 5.81 (brs, 1H), 7.257.36 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 28.26, 28.52, 51.64, 58.71, 79.81, 127.12, 128.13, 128.92, 138.95, 155.15, 169.11; IR (thin film) 3360(w), 3283(m), 2975(w), 1692(s), 1645(s), 1364(m) cm–1; HRMS (ESI+) calcd for C17H27N2O3 m/z 307.2022 ([M+H]+), meas 307.2018. [α]!" ! = + 102.5° (c 1.0, CH2Cl2). BocHN Ph H N O (S)-84 NH 2 TFA DCM Ph H N O (S)-82 100% > 99:1 er (S)-2-amino-N-(tert-butyl)-2-phenylacetamide 82: To an oven-dried 10 mL round bottom flask was added tert-butyl (S)-(2-(tert-butylamino)-2-oxo-1phenylethyl)carbamate 84 (92.0 mg, 0.300 mmol, 1.00 equiv), dry CH2Cl2 (0.80 mL) and trifluoroacetic acid (0.82 mL). After the mixture was stirred at room 161 temperature for 3 h, it was concentrated and diluted with 1 mL H2O. The pH of the mixture was adjusted to ~10 with sat. aq. NaHCO3 (ca. 35 mL). Then the mixture was extracted with CH2Cl2 (30 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give 82 as a colorless oil (62 mg, 0.30 mmol, 100%). [α]!" ! = +27.1° (c 1.0, CH2Cl2) on >99:1 er (by HPLC) material. 5.1.11 Preparation of the Aminal 85a Ph O Ph H 63a + Ph N H A-5 3Å MS toluene, reflux 24 h rt, 12 h Ph N N 85a 30% Ph Ph α,α-Bis(N,N-dibenzylamino)toluene 85a: An oven-dried 100 mL round bottom flask charged with 3Å powdered molecular sieves (10.0 g) and equipped with a magnetic stir bar was flame dried under high vacuum and cooled down under nitrogen. To the flask was then added 9.0 mL of dry toluene, dibenzylamine A-5 (0.60 mL, 3.0 mmol, 1.0 equiv) and benzaldehyde 63a (0.46 mL, 4.5 mmol, 1.5 equiv). After the mixture was heated to reflux for 24 h in an 80 °C oil bath, it was cooled to room temperature and stirred for another 12 h. The mixture was filtered through a Celite pad. The pad was washed with dry CH2Cl2 (3 mL). The combined filtrate was concentrated to dryness to give a light yellow viscous oil. After this oil was kept at room temperature for 7 days, a solid separated from the oil, which was filtered off and washed with hexanes to give 85a as colorless crystals (434 mg, 0.899 mmol) in 30% yield. Mp 142-144 °C (Lit.33 138-140 °C); Spectral data for 85a: 1H NMR (500 MHz, CDCl3) δ 3.54 (d, 162 4H, J = 14.0 Hz), 3.96 (d, 4H, J = 14.0 Hz), 4.47 (s, 1H), 7.13-7.22 (m, 20H), 7.30-7.36 (m, 1H), 7.37-7.42 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 52.67, 79.64, 126.53, 127.67, 127.74, 128.04, 129.09, 129.69, 135.09, 139.47; HRMS (ESI) calcd for C35H35N2 m/z 483.2800 ([M+H]+), meas 483.2803. The 1H NMR data match those reported for this compound.33 5.1.12 1H NMR Study of the Reaction Progress (Figures 2.2-2.4) Ugi-3CR with different aldehydes: O Ph H R 63 + N H A-5 Ph 20 mol % (S)-BOROX catalyst Ph + Ph N CN H N d8-toluene, rt R 64 O 65 Preparation of pre-catalyst stock solution: A 25 mL Schlenk flask equipped with a stir bar was flame dried, cooled to rt under N2 and charged with (S)-L-8 (145.3 mg, 0.1765 mmol), P-36 (49 mg, 0.36 mmol), H2O (9.5 mg, 9.5 µL, 0.53 mmol), dry toluene (5.3 mL) and BH3·SMe2 (2M, 262.5 µL, 0.525 mmol). The Teflon valve on the Schlenk flask was then closed, and the mixture heated at 100 °C for 1 h. After the flask was cooled to rt, the valve was carefully opened to gradually apply high vacuum (0.1 mm Hg) and the solvent and volatiles were removed. Then the flask was heated at 100 °C under high vacuum for 30 min. Dry d8-toluene (3.5 mL) was added to dissolve the residue in the flask after it was cooled to room temperature. 1 H NMR study of the Ugi-3CR with aldehyde 63a, 63d and 63n: A 25 mL Schlenk flask equipped with a magnetic stir bar was flame dried under high vacuum and cooled to 25 °C under nitrogen. To the flask was then added Ph3CH 163 as an internal standard and the pre-catalyst stock solution (1.0 mL, 0.050 mmol (S)-78) via a plastic syringe fitted with a metallic needle. To the resulting solution was added dibenzylamine A-5 (0.10 mL, 0.52 mmol, 2.0 equiv) under a N2 stream, followed by the addition of benzaldehyde 63a (26.0 µL, 0.255 mmol, 1.00 equiv) and then t-butyl isocyanide (45 µL, 0.39 mmol, 1.5 equiv). Then to an oven-dried NMR tube filled with nitrogen was added 0.7 mL of the reaction mixture and the tube was sealed with a rubber cap. The 1H NMR spectrum was taken at certain intervals. The NMR yields of 65a at different time points were determined by comparing the methine proton of Ph3CH and the methine proton of 65a. This procedure was repeated with aldehyde 63d (47.1 mg, 0.255 mmol, 1.00 equiv) and 63n (34.7 mg, 31.0 µL, 0.255 mmol, 1.00 equiv). The combined results are presented in Figure 2.2. In each case, there is an intitial build-up of aminal 85 and then it slowly disappears as the product grows in and is gone at the end of the reaction. The rates of the reaction with para- methoxylbenzaldehyde 63n and para-bromobenzaldehyde 63d are essentially the same and both are slower than benzaldehyde 63a. Ugi-3CR with different amounts of 4Å MS or H2O as an additive: O Ph H 63a + 20 mol % (S)-BOROX catalyst Ph N H A-5 + CN Ph Ph N d8-toluene, rt, additive 64 H N O 65a The general procedure A described in Part 5.1.4 was followed with (S)-78 164 ligand (41.5 mg, 0.0504 mmol), phenol P-36 (14 mg, 0.10 mmol) and 1 mL d8toluene as the reaction solvent. A certain amount of 4Å MS was added to the pre-catalyst solution right before the addition of dibenzylamine A-5. In the case of H2O as an additive, it was added right after the addition of benzaldehyde 63a, followed by the addition of tert-butyl isocyanide 64. The results are shown in Figures 2.3 and 2.4. 5.1.13 Effect of PhCOOH on the Ugi-3CR O Ph H 63a + Ph 20 mol % (S)-BOROX catalyst (LAP 30-5-36) N H A-5 O CN OH 64 4Å MS toluene Ph Ph N O 65a Ph H N + Ph N N O O 90 89 The pre-catalyst was prepared according to the general procedure A described in Part 5.1.4 with (S)-VAPOL ligand (27 mg, 0.050 mmol) and phenol P-36 (14 mg, 0.10 mmol). Dry toluene (1 mL) was added to the flask to dissolve the pre-catalyst, followed by the addition of dibenzylamine A-5 (0.10 mL, 0.52 mmol, 2.0 equiv) and a certain amount of benzoic acid 89. This mixture was stirred at 60 °C for 0.5 h. After it was cooled to room temperature, benzaldehyde 63a (26.0 µL, 0.255 mmol, 1.00 equiv) and tert-butyl isocyanide 64 (45 µL, 0.38 mmol, 1.5 equiv) were added in sequence. The reaction mixture was stirred at room temperature for 36-42 h and the crude product was purified by column chromatography on silica gel (20 x 160 mm, hexanes/EtOAc 15:1). The results are shown in Table 5.1. 165 Table 5.1 Ugi-3CR with PhCOOH as an additive. a Entry Time (h) PhCOOH (mol %) Ratio of 65a:90 65aa %Yield/er 90 %Yield/er 1 36 0 1:0 72/70:30 nd 2 39 20 1:0.27 78b/65:35 21b/nd 3c 42 100 1:0.60 60b/nd 36b/52:48 4c,d 42 100 1:0.88 nd nd Isolated yield after chromatography on silica gel. b NMR yield with the aid of Ph3CH. c 100 mg 4 Å MS was added before the addition of benzaldehyde 3a. d The mixture of pre-catalyst, dibenzylamine and PhCOOH was stirred at rt for 5 min instead of at 60 °C for 0.5 h 5.1.14 Four-Component Ugi Reaction O Ph H N H A-5 2.0 equiv 63a 1.0 equiv + CN 64 1.5 equiv Ph O OH 20 mol % (S)-BOROX catalyst (LAP 78-5-36) mesitylene 25 °C, 2 h 4 Å MS Ph Ph N N O O 90 75% (0% ee) 89 1.6 equiv N-(tert-butyl)-N-(2-(dibenzylamino)-2-phenylacetyl)benzamide 90: The pre-catalyst was prepared according to the general procedure A (Part 5.1.4) with (S)-78 (41.5 mg, 0.050 mmol), P-36 (14.0 mg, 0.10 mmol), H2O (2.7 mg, 2.7 µL, 0.15 mmol), dry toluene (1.5 mL) and BH3·SMe2 (2M, 75 µL, 0.15 mmol). After the pre-catalyst was cooled to room temperature, 4 Å MS (250 mg) was added to 166 the flask, followed by the addition of dry toluene (0.5 mL) to dissolve the precatalyst. Then dibenzylamine A-5 (0.1 mL, 0.5 mmol, 2 equiv) and benzoic acid 89 (50 mg, 0.41 mmol, 1.6 equiv) were added to the solution, followed by addition of another portion of toluene (0.5 mL). After the mixture was stirred for 5 min at room temperature, benzaldehyde 63a (26.0 µL, 0.255 mmol, 1.00 equiv) and tert-butyl isocyanide 64 (45 µL, 0.38 mmol, 1.5 equiv) were added in sequence. After the mixture was stirred at room temperature for 2 h, the crude 1H NMR spectrum showed that the reaction was complete and that the ratio of 90:65a was about 16:1. Then the reaction mixture was directly loaded onto a silica gel column (20 x 160 mm, hexanes/EtOAc 15:1) to afford a mixture of the product 90 and phenol P-36. The yield of product 90 was calculated to be 75% with the aid of Ph3CH as an internal standard. The optical purity was determined to be 50.1:49.9 er by HPLC analysis (Chiralpak AD column, hexanes/2-propanol 98:2, 222 nm, flow 1 mL). Retention times: Rt = 4.91 min and Rt = 12.49 min. Spectral data for 90: 1H NMR (500 MHz, CDCl3) δ 1.56 (s, 9H), 3.75 (d, 2H, J = 14.5 Hz), 3.84 (d, 2H, J = 14.5 Hz), 4.18 (s, 1H), 6.92-7.06 (m, 4H), 7.10-7.29 (m, 16H); 13 C NMR (125 MHz, CDCl3) δ 28.61, 54.59, 59.44, 66.95, 126.63, 127.58, 127.98, 128.03, 128.20, 128.49, 129.48, 129.86, 133.47, 135.21, 136.72, 140.22, 171.54, 174.82; HRMS (ESI+) calcd for C33H35N2O2 m/z 491.2699 ([M+H]+), meas 496.2696. 167 5.2 Experimental Part for Chapter 3 5.2.1 Preparation of Protected Aziridines H N NaHCO 3 CO 2Et O Cl trans-117a O Acetone:H2O = 3:1 rt, 48 h O O N CO 2Et 72% trans-96a Trans-N-9-fluorenylmethyl-carbamate-2-carboxyethyl-3-phenylaziridine 96a: To a 100 mL round bottom flask was added racemc trans-2-carboxyethyl-3phenylaziridine 117a89 (0.296 g, 1.5 mmol, 1.0 equiv.), NaHCO3 (0.252 g, 3.0 mmol, 2.0 equiv.), 30 mL of a mixture of acetone and H2O (3:1). The mixture was stirred at room temperature for 5 min and then 9-fluorenylmethylchloroformate (0.388 g, 1.5 mmol, 1.0 equiv.) was added. Then the reaction mixture was stirred at room temperature for 48 hours. The acetone was removed by rotary evaporation and the aqueous residue was extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with sat aq NaCl, dried over MgSO4 and concentrated by rotary evaporation to afford a yellow oil. Purification twice by silica gel chromatography (the first column: 18 mm × 250 mm, 4:1:1 hexanes/diethyl ether/CH2Cl2 as eluent; the second column: 18 mm × 250 mm, CH2Cl2 as eluent) afforded trans-96a as a colorless oil in 72% isolated yield, which solidified upon standing (white solid, mp 93-95 °C). Spectral data for trans-96a: 1H NMR (500 MHz, CDCl3) δ 1.25 (t, 3H, J = 7.2 Hz), 3.20 (d, 1H, J = 2.4 Hz), 3.90 (d, 1H, J = 2.4 Hz), 4.18 (q, 2H, J = 7.2 Hz), 4.24 (t, 1H, J = 7.2 Hz), 168 4.33 (dd, 1H, J = 10.5, 7.8 Hz), 4.48 (dd, 1H, J = 10.5, 7.2 Hz), 7.25-7.31 (m, 2H), 7.32-7.42 (m, 7H), 7.55-7.61 (m, 2H), 7.74 (d, 2H, J = 7.5 Hz); 13 C NMR (150 MHz, CDCl3) δ 14.05, 44.15, 45.09, 46.80, 62.19, 68.77, 119.96, 119.97, 125.15, 125.28, 126.43, 127.05, 127.06, 127.73, 127.77, 128.57, 128.66, 134.94, 141.25, 141.26, 143.57, 143.68, 159.67, 167.31; IR (thin film) 1744(vs), 1179(s) cm-1; HRMS calcd (MH+) C26H24NO4+ 414.1705, found 414.1731. H N O NaHCO 3 CO 2Et O Cl trans-117b O O N Acetone:H2O = 3:1 rt, 48 h CO 2Et 91% trans-96b Trans-N-9-fluorenylmethyl-carbamate-cis-2-carboxyethyl-3cyclohexylaziridine 96b: This aziridine was prepared according to the procedure described above for trans-96a starting with racemic trans-2-carboxyethyl-3cyclohexylaziridine trans-117b47a (296 mg, 1.50 mmol). Purification by silica gel chromatography (column: 15 mm × 250 mm, 8:1 hexanes/EtOAc as eluent) afforded trans-96b as a colorless oil in 91% isolated yield (572 mg, 1.36 mmol). Rf = 0.28 (5:1 hexanes/EtOAc); Spectral data for trans-96b: 1H NMR (600 MHz, CDCl3) δ 1.16-1.28 (m, 6H), 1.22 (t, 3H, J = 7.2 Hz), 1.62-1.68 (m, 1H), 1.69-1.78 (m, 3H), 1.81 (d, 1H, J = 12 Hz), 2.66 (dd, 1H, J = 7.2, 2.7 Hz), 2.96 (d, 1H, J = 2.7 Hz), 4.08-4.16 (m, 2H), 4.22 (t, 1H, J = 6.9 Hz), 4.32 (dd, 1H, J = 10.5, 7.5 Hz), 4.46 (dd, 1H, J = 10.2, 7.2 Hz), 7.27-7.31 (m, 2H), 7.38 (t, 2H, J = 7.5 Hz), 7.60 (t, 2H, 1H, J = 7.8 Hz), 7.74 (d, 2H, 1H, J = 7.8 Hz); 169 13 C NMR (150 MHz, CDCl3) δ 14.03, 25.47, 25.57, 26.05, 29.69, 29.91, 39.18, 39.45, 46.90, 48.96, 61.81, 68.34, 119.90, 119.91, 125.06, 125.19, 127.01, 127.03, 127.66, 127.70, 141.27, 141.29, 143.67, 143.82, 160.23, 168.29; IR (thin film) 2928(s), 2853(w), 1743(vs), 1451(m), 1310(m), 1177(s) cm-1; mass spectrum, m/z (% rel intensity) 419 M+ (0.07), 346 (0.15), 178 (100), 165 (62), 84 (34), 49 (56). HRMS calcd (MH+) C26H30NO4+ 420.217, found 420.216. H N CO 2Et + (Boc) 2O NaHCO 3, MeOH rt, 4 days 71% trans-117a Boc N CO 2Et trans-100a Trans-N-Boc-2-carboxyethyl-3-phenylaziridine 100a: To a 25 mL flamedried round bottom flask filled with argon was added trans-2-carboxyethyl-3phenylaziridine 117a89 (150 mg, 0.784 mmol) and 5 mL MeOH followed by the addition of NaHCO3 (197 mg, 0.450 mmol, 3.00 equiv.). The flask was put in an ultrasonic bath for 5 minutes and then (Boc)2O (428 mg, 1.96 mmol, 2.50 equiv.) was added. The mixture was left in the ultrasonic-bath for 4 hours with a needle in the rubber septum to release the generated CO2 gas. After 4 h, a second portion of NaHCO3 and (Boc)2O was added in equal amounts to the first addition. Then the reaction mixture was stirred for 4 days. The reaction mixture was filtered through Celite and the solid residue was washed with Et2O. The cloudy filtrate was filtered again through Celite and then concentrated by rotary evaporation to afford the crude product as a colorless liquid. Purification by silica gel chromatography (15 mm × 250 mm, hexanes and then 1:9 ethyl acetate/ 170 hexanes as eluent) afforded trans-100a as a colorless oil in 71% isolated yield (163 mg, 0.56 mmol). Rf = 0.36 (hexanes/EtOAc = 4:1); Spectral data for trans100a: 1H NMR (300 MHz, CDCl3) δ 1.30 (t, 3H, J = 7.0 Hz), 1.44 (s, 9H), 3.07 (d, 1H, J = 2.6 Hz), 3.79 (d, 1H, J = 2.6 Hz), 4.14-4.36 (m, 2H), 7.24-7.36 (m, 5H); 13 C NMR (150 MHz, CDCl3) δ 14.16, 27.88, 44.02, 44.92, 61.82, 82.04, 126.43, 128.27, 128.48, 135.33, 158.29, 167.40. The 1H and 13 C NMR data match those previously reported for this compound.42c H N CO 2Et + (Boc) 2O NaHCO 3, MeOH rt, 22 h 89% trans-117b Boc N CO 2Et trans-100b Trans-N-Boc-2-carboxyethyl-3-cyclohexylaziridine 100b: To a flame-dried 25 mL round bottom flask filled with argon was added racemic trans-2carboxyethyl-3-cyclohexylaziridine 117b47a (198 mg, 1.0 mmol, 1.0 equiv), MeOH (6.5 mL) and NaHCO3 (0.84 g, 10 mmol, 10 equiv.). The flask was put in an ultrasonic bath for 5 min and then (Boc)2O (1.09 g, 5.00 mmol, 5.00 equiv) was added. The mixture was left in the ultrasonic-bath for 4 hours with a needle in the rubber septum to release the generated CO2 gas and then it was stirred at room temperature for another 18 h. The reaction mixture was filtered through Celite and the filter cake was washed with diethyl ether. The cloudy filtrate was filtered again through Celite and then concentrated by rotary evaporation to afford the crude product as a light yellow liquid. Purification by silica gel chromatography (15 mm × 250 mm, 45:1 hexanes/EtOAc as eluent until the first fraction came out 171 and then 15:1 hexanes/EtOAc as eluent) afforded trans-100b as a colorless oil in 89% isolated yield (265 mg, 0.89 mmol). Rf = 0.42 (5:1 hexanes/EtOAc); Spectral data for trans-100b: 1H NMR (500 MHz, CDCl3) δ 1.04-1.25 (m, 6H), 1.28 (t, 3H, J = 7.2 Hz), 1.43 (s, 9H), 1.60-1.65 (m, 1H), 1.66-1.76 (m, 3H), 1.80-1.86 (m, 1H), 2.60 (dd, 1H, J = 6.8, 3.0 Hz), 2.83 (d, 1H, J = 3.0 Hz), 4.11-4.28 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 14.19, 25.47, 25.60, 26.09, 27.95, 29.71, 30.01, 39.27, 39.45, 48.73, 61.54, 81.47, 159.04, 168.42; IR (thin film) 2980(w), 2930(s), 2855(w), 1744(vs), 1728(s), 1154(s) cm-1; mass spectrum, m/z (% rel intensity) 224 (M+ - 73) (5.6), 196 (21), 124 (85), 95 (73), 57 (100); Anal calcd for C16H27NO4: C, 64.62; H, 9.15; N, 4.71. Found: C, 64.88; H, 9.27; N, 4.72. H N Et 3N CO 2Et TsCl CH 2Cl 2, rt 94h 54% trans-117a Ts N CO 2Et trans-101a Trans-N-Tosyl-2-ethoxycarbonyl-3-phenylaziridine trans-101a: To a flamedried 50 mL round bottom flask filled with argon was added racemic trans-2carboxyethyl-3-phenylaziridine 117a89 (0.335g, 1.75 mmol, 1.0 equiv.) and CH2Cl2 (14 mL, freshly distilled). The solution was cooled to 0 °C in an ice-bath followed by the addition of Et3N (0.7 mL, 5.03 mmol, 2.9 equiv., freshly distilled). After the reaction mixture was stirred for 5 min at 0 °C, TsCl (0.534 g, 2.8 mmol, 1.6 equiv) was added to the mixture at 0 °C. Thereafter, the ice-bath was removed and the mixture was stirred at room temperature for 94 hours. The reaction was quenched by the addition of 26 mL sat aq NH4Cl and 5 mL H2O. 172 The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (30 mL × 3). The combined organic layer was washed with the following reagents in the indicated sequence: 5 mL H2O, 10 mL aq citric acid, 5 mL H2O, 10 mL sat aq NaHCO3 and 20 mL sat aq NaCl. The combined organic layer was dried over MgSO4 and concentrated by rotary evaporation to afford the crude product as an orange oil. Purification by silica gel chromatography (the first column: 15 mm × 250 mm, 40:9 hexanes/EtOAc as eluent; the second column: 15 mm × 250 mm, 16:4:1 hexanes/ CH2Cl2/EtOAc as eluent) afforded trans-101a as a light yellowish oil in 54% yield (0.326 g, 0.94 mmol); Rf = 0.24 (4:1 hexanes/EtOAc); Spectral data for trans-101a: 1H NMR (300 MHz, CDCl3) δ 1.32 (t, 3H, J = 7.0 Hz), 2.39 (s, 3H), 3.49 (d, 1H, J = 3.9 Hz), 4.20-4.39 (m, 2H), 4.41 (d, 1H, J = 3.9 Hz), 7.19-7.31 (m, 7H), 7.71-7.80 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 13.95, 21.58, 47.08, 47.68, 62.41, 127.32, 127.46, 128.55, 128.86, 129.52, 132.68, 137.17, 144.25, 165.73. The 1H and 13 C NMR data match those previously reported for this compound.42c H N Et 3N CO 2Et + TsCl CH 2Cl 2/CHCl3 (1:1) rt, 72 h 70% trans-117b Ts N CO 2Et trans-101b Trans-N-Tosyl-2-ethoxycarbonyl-3-cyclohexylaziridine 101b: This aziridine was prepared according the same procedure used for trans-101a. Racemic trans-2-carboxyethyl-3-cyclohexylaziridine 117b47a (197 mg, 1.0 mmol, 1.0 equiv) was reacted with tosyl chloride (0.305 g, 1.6 mmol, 1.6 equiv), Et3N (freshly 173 distilled, 0.42 mL, 3.0 mmol, 3.0 equiv) in 1:1(v) CH2Cl2/CHCl3 (8 mL) for 72 h. Purification by silica gel chromatography (first column: 15 mm × 250 mm, 10:1 hexanes/EtOAc, second column: 15 mm × 250 mm, 6:1:16 CH2Cl2/diethyl ether/hexanes as eluent) and recrystallization from hexanes afforded trans-101b as white crystals (mp: 71-73 °C) in 70% isolated yield (246 mg, 0.70 mmol). Rf = 0.26 (5:1 hexanes/EtOAc); Spectral data for trans-101b: 1H NMR (300 MHz, CDCl3) δ 1.00-1.35 (m, 8H), 1.58-1.79 (m, 5H), 1.95 (d, 1H, J = 10.5 Hz), 2.41 (s, 3H), 3.02 (dd, 1H, J = 9.0, 4.2 Hz), 3.18 (d, 1H, J = 4.2 Hz), 4.15 (q, 2H, J = 6.9 Hz), 7.24-7.32 (m, 2H), 7.79-7.83 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 13.90, 21.58, 25.19, 25.40, 25.87, 30.59, 31.13, 37.53, 43.71, 53.66, 61.86, 127.52, 129.50, 137.10, 144.20, 166.70. IR (thin film) 2930(s), 2855(m), 1745(s), 1331(s), 1101(s) cm-1; mass spectrum, m/z (% rel intensity) 306 (M+ - 45) (2.3), 278 (3.2), 197 (34), 196 (100), 168 (29), 122 (88), 67 (83); Anal calcd for C18H25NO4S: C, 61.51; H, 7.17; N, 3.99. Found: C, 61.60; H, 7.22; N, 3.96. This compound has been reported as a cis/trans mixture.90 H N Et 3N CO 2Et + SESCl CH 2Cl 2 rt, 69 h 83% cis-117a SES N CO 2Et cis-102a Cis-ethyl (2R, 3R)-3-phenyl-1-((2-(trimethylsilyl)ethyl)sulfonyl)aziridine-2carboxylate 102a: To a 10 mL flame-dried round bottom flask was added 2(trimethylsilyl)ethanesulfonyl chloride (SESCl, 82.5 µl, 0.639 mmol, 1.28 equiv), Et3N (0.7 mL, 5 mmol, 10 equiv) and CH2Cl2 (2 mL, freshly distilled). The mixture 174 was pre-cooled in an ice-bath for 5 min. Cis-(2R, 3R)-2-carboxyethyl-3phenylaziridine 117a12q (95.6 mg, 0.5 mmol, 1 equiv, 98% ee) was dissolved in 0.5 mL CH2Cl2 and the solution was added dropwise to the 10 mL round bottom flask containing 2-(trimethylsilyl)ethanesulfonyl chloride. Then the ice-bath was removed and the reaction mixture was stirred at room temperature for 45 hours. Thereafter, another portion of 2-(trimethylsilyl)ethanesulfonyl chloride (160 ml, 1.26 mmol, 2.5 equiv) and Et3N (0.7 mL, 5 mmol, 10 equiv) was added to the reaction mixture. After the mixture was stirred for 24 hours at room temperature, the reaction was quenched with 2 mL sat aq NH4Cl and 1 mL H2O. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (4 mL × 3). The combined organic layer was dried with Na2SO4, filtered and concentrated to give a dark brown oil. Purification by silica gel chromatography (15 mm × 180 mm, 9:1 hexanes/EtOAc as eluent) afforded cis-102a as a light yellow oil in 83 % yield (0.147 g, 0.413 mmol). Rf = 0.19 (9:1 hexanes/EtOAc); Spectral data for cis-102a: 1H NMR (500 MHz, CDCl3) δ 0.04 (s, 9H), 1.00 (t, 3H, J = 7.0 Hz), 1.131.24 (m, 2H), 3.16-3.26 (m, 2H), 3.67 (d, 1H, J = 7.5 Hz), 3.93-4.05 (m, 2H), 4.07 (d, 1H, J = 7.5 Hz), 7.26-7.34 (m, 3H), 7.37-7.41 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ -2.05, 9.73, 13.86, 43.67, 44.31, 49.51, 61.63, 127.52, 128.30, 128.66, 131.36, 164.49; IR (thin film) 2955 s, 1755 vs cm-1; HRMS calcd (MH+) C16H26NO4SSi+ 356.1352, found 356.1351; [α]!" ! = –38.0° (c 1.0, CH2Cl2) on 98% ee material (the optical purity was assumed to be unchanged from 117a). 175 5.2.2 Reductive Ring Opening of Aziridines-2-Carboxylates with SmI2 O O N SmI 2, DMEA CO 2Et HN Boc CO 2Et THF, 0 oC 104a + N CO 2Et Boc 108a cis-100a General procedure for the reductive ring opening of aziridines-2carboxylates with SmI2 (illustrated for cis-100a): To a flame-dried 10 mL round bottom flask filled with argon was added Sm (180 mg, 1.20 mmol, 6.00 equiv) and dry THF (1.8 mL, freshly distilled). Thereafter, the vacuum adapter was changed to a rubber septum and the suspension was purged with nitrogen under the surface of the solution for 5 min by a needle through the septum. Another needle was used as an outlet for the nitrogen gas. Then CH2I2 (92.5 µL, 1.15 mmol, 5.7 equiv) was added to the reaction flask and the reaction mixture was purged with nitrogen for another 1 min. The needle as an outlet was removed and the one for nitrogen flow was lifted above the surface of the solution. The reaction mixture was stirred at room temperature for 2 hours, resulting in a dark blue slurry. The slurry was then pre-cooled to 0 °C in an ice-bath. To another flame-dried 5 mL round bottom flask filled with nitrogen was added cis-(2R, 3R)100a12q (78% ee, 60 mg, 0.2 mmol, 1.0 equiv.), dry THF (1.5 mL, freshly distilled) and N,N-dimethylethanolamine (0.24 mL, 2.4 mmol, 12.0 equiv.). The solution was purged with nitrogen under the surface of the solution for 2 min and transferred to the flask containing the SmI2 slurry dropwise via cannula. Vigorous stirring was maintained during the addition of the aziridine to the SmI2 slurry. The 5 mL flask was washed with 0.3 mL degassed THF and the rinse was also 176 transferred to the reaction flask containing SmI2. The reaction mixture was stirred at 0 °C for 40 min to 1 h and then quenched by the addition of sat aq NaHCO3 (5 mL) at 0 °C. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL × 4). The combined organic layer was dried with Na2SO4 and filtered. The solvent was removed by rotary evaporation to give a light yellow solid. The 1H NMR spectrum of the crude reaction mixture showed that it was a mixture of 104a and 108a in a ratio of 1.4:1. Purification by silica gel chromatography (18 × 250 mm, 1:1:4.6 diethyl ether/hexanes/CH2Cl2 as eluent) afforded (S)-104a as a white solid (mp 75-77 °C) in 55% isolated yield (33.6 mg, 0.11 mmol) and 108a as colorless oil in 32% isolated yield (19.2 mg, 0.065 mmol). The optical purity of (S)-104a was determined to be 78% ee by HPLC analysis (Chiralcel OD-H column, 98:2 hexanes/iPrOH at 222nm, flow-rate: 1.0 ml/min); retention times: Rt = 6.24 min (minor enantiomer (R)-104a) and Rt = 7.08 min (major enantiomer (S)-104a). TLC and Spectral data for (S)-104a: Rf = 0.24 (5:1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ 1.14 (t, 3H, J = 7.1 Hz), 1.40 (s, 9H), 2.70-2.90 (m, 2H), 4.05 (q, 2H, J = 7.1Hz), 5.09 (brs, 1H), 5.46 (brs, 1H), 7.19-7.35 (m, 5H); 13 C NMR (CDCl3, 150 MHz) δ 14.03, 28.31, 41.00, 51.21, 60.63, 79.61, 126.12, 127.43, 128.56, 141.19, 154.99, 170.88;  [α]!" ! = –31.6 (c 1.0, EtOAc) on 78% ee (S)-104a.91 TLC and Spectral data for 108a (mixture of rotamers): Rf = 0.34 (5:1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ 1.219 and 1.224 ( 2 x t, 3H, J = 7.1 Hz), 1.447 and 1.452 (2 x s, 9H), 3.75 and 3.89 ( 2 x s, 2H), 4.13 and 4.14( 2 x q, 2H, J = 7.1Hz), 4.49 and 4.52 (2 x s, 2H), 7.187.35 (m, 5H); 13 C NMR (CDCl3, 150 MHz) δ 14.12, 14.21, 28.25, 28.32, 47.71, 177 48.13 51.04, 51.50, 60.91, 60.96, 80.42, 80.59, 127.37, 127.43, 127.48, 128.12, 128.53, 137.36, 137.60, 155.59, 155.77, 169.90, 169.94.92 Fmoc N CO 2Et SmI 2, DMEA HN Fmoc CO 2Et + THF, 0 oC 97a N CO 2Et Fmoc 98a trans-96a Reductive ring opening of trans-96a: The reaction was carried out according to the general procedure described above starting with aziridine trans96a (racemic, 62.1 mg, 0.15 mmol, 1.0 equiv), SmI2 (5.5 equiv), N,Ndimethylethanolamine (0.17 mL, 1.7 mmol, 11.0 equiv) and dry THF (1.5 mL for SmI2 and 1.5 mL for aziridine, freshly distilled) at 0 °C for 1 hour. The 1H NMR spectrum of the crude reaction mixture showed that 97a12q and 98a12q were obtained in a ratio of 16.7:1. The NMR yield of 97a was determined to be 82% with the aid of Ph3CH as an internal standard. Fmoc N CO 2Et SmI 2, DMEA HN Fmoc CO 2Et THF, 0 oC 97b + N CO 2Et Fmoc 98b trans-96b Reductive ring opening of trans-96b: This reaction was carried out according to the general procedure described above starting with aziridine trans96b (racemic, 62.7 mg, 0.15 mmol, 1.0 equiv.), SmI2 (6.0 equiv.), N,Ndimethylethanolamine (0.18 mL, 1.8 mmol, 12.0 equiv.) and dry THF (1.5 mL for SmI2 and 1.5 mL for aziridine, freshly distilled) at 0 °C for 1 hour. The NMR yield 178 of 97b12q was determined to be 73% with the aid of Ph3CH as an internal standard. Boc N HN SmI 2, DMEA CO 2Et Boc CO 2Et N CO 2Et Boc + THF, 0 oC 104a 108a trans-100a Reductive ring opening of trans-100a: The reaction was carried out according to the general procedure described above starting with trans-100a (racemic, 58.3 mg, 0.2 mmol, 1.0 equiv), SmI2 (6.0 equiv), N,N- dimethylethanolamine (0.24 mL, 2.4 mmol, 12.0 equiv) and dry THF (1.8 mL for SmI2 and 1.8 mL for aziridine, freshly distilled) at 0 °C for 1 hour. The 1H NMR spectrum of the crude reaction mixture showed that 104a and 108a were present in a ratio of 6.7:1. Purification by silica gel chromatography (18 × 250 mm, 1:1:4.6 diethyl ether/hexanes/CH2Cl2 as eluent) afforded 104a as a white solid (mp 75-77 °C) in 85% isolated yield (50.1 mg, 0.17 mmol) and 108a as colorless oil in 10% isolated yield (5.9 mg, 0.02 mmol). The spectral data for 104a and 108a are the same as those obtained in the in the reductive ring-opening of cis-100a. Boc N CO 2Et SmI 2, DMEA HN Boc CO 2Et THF, 0 oC 104b + N CO 2Et Boc 108b trans-100b Reductive ring opening of trans-100b: The reaction was carried out according to the general procedure described above starting with trans-100b 179 (racemic, 59.5 mg, 0.2 mmol, 1.0 equiv.), SmI2 (6.0 equiv.), N,N- dimethylethanolamine (0.24 mL, 2.4 mmol, 12.0 equiv.) and dry THF (1.8 mL for SmI2 and 1.8 mL for aziridine, freshly distilled) at 0 °C for 1 hour. The β-amino ester 104b12d was obtained in 84% NMR yield with the aid of Ph3CH as an internal standard. The 1H NMR spectrum of the crude reaction mixture showed that the ratio of 104b : 108b >99:1. Ts N HN SmI 2, DMEA CO 2Et Ts CO 2Et N Ts + THF, 0 oC 105a CO 2Et 109a trans-101a Reductive ring opening of trans-101a: The reaction was carried out according to the general procedure described above starting with trans-101a (racemic, 51.9 mg, 0.15 mmol, 1.0 equiv), SmI2 (6.0 equiv.), N,N- dimethylethanolamine (0.18 mL, 1.8 mmol, 12.0 equiv) and dry THF (1.5 mL for SmI2 and 1.5 mL for aziridine, freshly distilled) at 0 °C for 1 hour. Purification by silica gel chromatography (18 × 250 mm, 5:1 hexanes/EtOAc as eluent) afforded 105a as a colorless liquid in 88% isolated yield (45.9 mg, 0.132 mmol). Rf = 0.25 (1:3 EtOAc/Hexanes); Spectral data for 105a: 1H NMR (CDCl3, 500 MHz) δ 1.10 (t, 3H, J = 7.2Hz), 2.35 (s, 3H), 2.72 (dd, 1H, J = 16, 6.0 Hz), 2.81 (dd, 1H, J = 16, 6.0 Hz), 3.94-4.05 (m, 2H), 4.70 (q, 1H, J = 6.7 Hz), 5.67 (d, 1H, J = 7.5 Hz), 7.06-7.11 (m, 2H), 7.12-7.19 (m, 5H), 7.56-7.60 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.97, 21.45, 41.18, 54.31, 60.88, 126.44, 127.11, 127.73, 128.52, 129.44, 137.48, 139.34, 143.22, 170.63. These data match that previously 180 reported for this compound.42c The 1H NMR spectrum of the crude reaction mixture showed that the ratio of 105a : 109a >99:1. Ts N SmI 2, DMEA CO 2Et HN Ts CO 2Et THF, 0 oC 105b + N Ts CO 2Et 109b cis-101b Reductive ring opening of cis-101b: The general procedure for the reductive ring opening described above was followed starting with aziridine (2R,3R)-101b12q (82% ee, 53.4 mg, 0.15 mmol, 1.0 equiv.), SmI2 (5.0 equiv.), N,N-dimethylethanolamine (0.15 mL, 1.5 mmol, 10.0 equiv.) and dry THF (1.5 mL for SmI2 and 1.5 mL for aziridine, freshly distilled) at 0 °C for 1 hour. Purification by silica gel chromatography (18 × 250 mm, 5:1 hexanes/EtOAc as eluent) afforded (S)-105b as a colorless oil in 97% isolated yield (52.1 mg, 0.147 mmol); Rf = 0.17 (4:1 hexanes/EtOAc). The optical purity of (S)-105b was determined to be 84% ee by HPLC analysis (Chiralcel OD-H column, 98:2 hexanes/iPrOH at 222nm, flow-rate: 1.0 ml/min); retention times: Rt = 12.73 min (major enantiomer (S)-105b) and Rt = 16.94 min (minor enantiomer (R)-105b). The 1H NMR spectrum of the crude reaction mixture showed that the ratio of 105b : 109b >99:1 Spectral data for (S)-105b: 1H NMR (CDCl3, 600 MHz) δ 0.78 (qd, 1H, J = 12.0, 3.2 Hz), 0.87 (qd, 1H, J = 12.0, 3.2), 1.00-1.17 (m, 3H), 1.18 (t, 3H, J = 7.1 Hz), 1.37-1.45 (m, 1H), 1.54-1.61 (m, 2H), 1.63-1.70 (m, 2H), 1.73-1.81 (m, 1H), 2.25 (dd, 1H, J = 16.0, 5.6 Hz), 2.37 (dd, 1H, J = 16.0, 5.6 Hz), 2.39 (s, 3H), 3.26-3.34 (m, 1H), 4.01 (m, 2H), 5.24 (d, 1H, J = 9.3 Hz), 7.26 (d, 2H, J = 8.1 181 Hz), 7.72 (d, 2H, J = 8.1 Hz); 13 C NMR (CDCl3, 150 MHz) δ 14.06, 21.48, 25.87, 25.93, 26.07, 29.10, 29.33, 35.92, 41.24, 55.52, 60.63, 127.02, 129.55, 138.21, 143.15, 171.61. IR (thin film) 3292 m, 2928 vs, 2854 m, 1734 vs, 1718 s, 1456 m, 1324 s, 1161 vs cm-1; mass spectrum, m/z (% rel intensity) 354 (MH+) (6.4), 271 (31), 270 (100), 224 (50), 198 (42), 155 (86), 91 (86), 41 (12); Anal calcd for C18H27NO4S: C, 61.16; H, 7.70; N, 3.96. Found: C, 61.30; H, 8.12; N, 3.88. [α]!" ! = –10 (c 0.4, EtOAc) on 84% ee (S)-105b. The reported spectrum data for the compound 3c (105b in this thesis) in this reference does not match our data or the structure of 3c 93 Ts N HN SmI 2, DMEA CO 2Et Ts CO 2Et N Ts + THF, 0 oC 105b CO 2Et 109b trans-101b Reductive ring opening of trans-101b: The reaction was carried out according to the general procedure described above starting with trans-101b (racemic, 53.3 mg, 0.15 mmol, 1.0 equiv), SmI2 (6.0 equiv), N,N- dimethylethanolamine (0.18 mL, 1.8 mmol, 12.0 equiv) and dry THF (1.5 mL for SmI2 and 1.5 mL for aziridine, freshly distilled) at 0 °C for 1 hour. Purification by silica gel chromatography (18 × 250 mm, 5:1 hexanes/EtOAc as eluent) afforded 105b as a colorless oil in 95% isolated yield (51.0 mg, 0.144 mmol). The spectral data of 105b are the same as the product obtained from the reductive ring-opening of cis-101b. The 1H NMR spectrum of the crude reaction mixture showed that the ratio of 105b : 109b >99:1. 182 SES N SmI 2, DMEA CO 2Et THF, 0 HN SES HN SES N SES CO 2Et + oC CO 2Et + 110a 106a 211 cis-102a Reductive ring opening of cis-102a: The general procedure for the reductive ring opening described above was followed with aziridine cis-102a (53.4 mg, 0.15 mmol, 1.0 equiv), SmI2 (4.0 equiv), N,N-dimethylethanolamine (0.12 mL, 1.2 mmol, 8.0 equiv) and dry THF (2.0 mL for SmI2 and 1.5 mL for aziridine, freshly distilled) at 0 °C for 1 hour. The 1H NMR spectrum of the crude reaction mixture showed that 106a, 110a and 221 were present in a ratio of 23:1:1.6. Purification by silica gel chromatography (18 × 250 mm, 5:1 hexanes/EtOAc as eluent) afforded (S)-106a as a white solid (mp 60-61 °C) in 84% isolated yield (45.2 mg, 0.126 mmol), 110a as a colorless oil in 4% isolated yield (2.0 mg, 0.0056 mmol) and 211 as a white solid (mp 91-62 °C, Lit.94 98 °C) in 5% yield (2.0 mg, 0.0075 mmol). Spectral data for 106a: 1H NMR (500 MHz, CDCl3): δ –0.14 (s, 9H), 0.75 (td, 1H, J = 14, 4.5 Hz), 0.84 (td, 1H, J = 14, 4.0 Hz), 1.17 (t, 3H, J = 7 Hz), 2.52 (td, 1H, J = 14, 4.5 Hz), 2.63 (td, 1H, J = 14, 4.0 Hz), 2.79-2.90 (m, 2H), 4.08 (qd, 2H, J = 7.2, 1.5 Hz), 4.81-4.90 (m, 1H), 5.57 (d, 1H, J = 8 Hz), 7.24-7.30 (m, 1H), 7.30-7.39 (m, 4H); 13 C NMR (CDCl3, 125 MHz) δ -2.17, 10.25, 14.03, 41.91, 49.92, 54.52, 60.96, 126.63, 128.20, 128.87, 140.34, 170.53; IR (thin film) 3277 br s, 2955 w, 1736 s, 1144 s cm-1 HRMS calcd (MH+) C16H28NO4SiS+ 358.1508, found 358.1509; [α]!" ! = –21.7 (c 0.87, CH2Cl2) on 98% ee (S)-106a. Spectral data for 110a: 1H NMR (500 MHz, CDCl3): δ 0.05 183 (s, 9H), 1.11-1.16 (m, 2H), 1.24 (t, 3H, J = 7.2 Hz), 3.05-3.10 (m, 2H), 3.90 (s, 2H), 4.16 (q, 2H, J = 7.2 Hz), 4.53 (s, 2H), 7.27-7.36 (m, 5H); 13 C NMR (CDCl3, 125 MHz) δ –1.97, 10.30, 14.15, 46.94, 50.04, 51.76, 61.32, 128.13, 128.51, 128.78, 135.51, 169.64; IR (thin film) 2955 w, 1746 s, 1333 s, 1142 s cm-1; HRMS calcd (MH+) C16H28NO4SiS+ 358.1508, found 358.1530. Spectral data for 211: 1H NMR (500 MHz, CDCl3): δ -0.04 (s, 9H), 0.89-0.96 (m, 2H), 2.76-2.83 (m, 2H), 4.29 (d, 2H, J = 10.0 Hz), 4.42 (t, br, 1H, J = 10.5 Hz), 7.25-7.38 (m, 5H); 13 C NMR (CDCl3, 125 MHz) δ -2.06, 10.57, 47.37, 49.67, 127.98, 128.13, 128.91, 137.11. HRMS calcd (MH+) C12H22NO2SiS+ 272.1141, found 272.1164. The 1H and 13C NMR data match those previously reported for this compound.94 Ph Ph N Ph HN SmI 2, DMEA CO 2Et THF, 0 oC Ph CO 2Et 119b cis-118b Reductive ring opening of cis-118b: + Ph Ph NH 2 A-6 The general procedure for the reductive ring opening described above was followed with cis-118b12r (44 mg, 0.12 mmol). Purification of the product by silica gel chromatography (18 mm x 300 mm, 1:5 EtOAc/hexanes as eluent) gave a 1:1.4 mixture of the β-amino ester 119b (22% NMR yield) and unreacted cis-118b (31% NMR yield). The 1H NMR spectrum of the crude reaction mixture indicated the formation of the amine A-6 in 39% yield. Extending the reaction time for the ring opening reaction of cis118b (42 mg, 0.12 mmol) at room temperature from 40 min to 2 h gave 119b (8.6 mg, 0.024 mmol) in 22% isolated yield and the amine A-6 in 52% isolated yield. 184 The unreacted cis-118b was isolated with a 20% recovery. Spectral data for 119b: 1H NMR (600 MHz, CDCl3) δ 0.90-1.04 (m, 2H), 1.05-1.23 (m, 2H), 1.20 (t, 3H, J = 7.1 Hz), 1.45-1.54 (m, 1H), 1.60-1.80 (m, 6H), 2.34 (dd, 1H, J = 14.5, 7.0 Hz), 2.47 (dd, 1H, J = 14.5, 5.3 Hz), 2.77 (dt, 1H, J = 7.0, 5.3 Hz), 4.03-4.14 (m, 2H), 4.94 (s, 1H), 7.15-7.19 (m, 2H), 7.23-7.28 (m, 4H), 7.35-7.41 (m, 4H) (N-H proton not located); 13 C NMR (150 MHz, CDCl3) δ 14.21, 26.52, 26.59, 26.69, 28.43, 29.53, 36.02, 40.86, 56.78, 60.21, 64.13, 126.89, 126.91, 127.42, 127.55, 128.33, 128.34, 144.24, 144.45, 172.90; HRMS calcd for (MH+) C24H32NO2 366.2433, found 366.2431. Spectral data for A-6: 1H NMR (600 MHz, CDCl3) δ 1.84 (bs, 2H), 5.20 (s, 1H), 7.18-7.23 (m, 2H), 7.26-7.32 (m, 4H), 7.33-7.37 (m, 4H); 1 13 C NMR (150 MHz, CDCl3) δ 59.74, 126.88, 126.92, 128.45, 145.58. The H and 13 C NMR spectral data for A-6 match those provided by Aldrich for this compound. Boc N Me CO2Et 123 Boc SmI 2 DMEA THF, 0 oC NH Boc O NH O OEt + OEt + Me Boc O N OEt Me syn-124 anti-124 125 Reductive ring opening of 123: The general procedure for the reductive ring opening described above was followed with the tri-substituted aziridine 12346 (76 mg, 0.25 mmol, 99% ee) and 5.0 equiv SmI2. The 1H NMR spectrum of the crude reaction mixture indicated a mixture of anti-124, syn-124 and 125 was present in a ratio of 1.28:0.28:1. Purification of the products by silica gel chromatography (18 mm x 200 mm, 1:10 to 1:6 EtOAc/hexanes as eluent) gave 185 anti-124 as a white solid (mp 53-55 °C) in 43% isolated yield (32.7 mg, 0.106 mmol), syn-124 as a white solid (mp 89-91 °C) in 9% isolated yield (6.6 mg, 0.021 mmol) and 125 as a colorless oil in 30% isolated yield (23.2 mg, 0.0755 mmol). Spectral data for anti-124: 1H NMR (300 MHz, CDCl3) δ 1.09 (t, 3H, J = 7.1 Hz), 1.20 (d, 3H, J = 7.0 Hz), 1.39 (s, 9H), 2.87 (brt, 1H, J = 6.5 Hz), 4.01 (q, 2H, J = 7.1 Hz), 4.81 (brs, 1H), 5.81 (brs, 1H), 7.16-7.33 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 14.00, 15.37, 28.33, 45.27, 56.69, 60.55, 79.39, 126.25, 127.25, 128.40, 141.01, 155.44, 174.92; IR (thin film) 3355 br w, 2978 m, 1721 s, 1171 s cm-1; HRMS calcd (MH+) C17H26NO4+ 308.1862, found 308.1860; [α]!" ! = – 40.1 (c 0.5, CH2Cl2) on 99% ee material. Spectral data for syn-124: 1H NMR (600 MHz, CDCl3) δ 1.11 (t, 3H, J = 7.2 Hz), 1.13 (d, 3H, J = 7.2 Hz), 1.39 (s, 9H), 2.87 (brs, 1H), 3.96-4.08 (m, 2H), 4.97 (brs, 1H), 5.27 (brs, 1H), 7.19-7.25 (m, 3H), 7.267.31 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 13.11, 13.99, 28.33, 45.43, 56.52, 60.61, 79.59, 126.76, 127.45, 128.40, 140.17, 155.10, 173.70; IR (thin film) 3380 s, 2980 m, 1728 s, 1686 s, 1520 s, 1173 s cm-1; HRMS calcd (MH+) C17H26NO4+ 308.1862, found 308.1855; [α]!" ! = – 26.0 (c 0.5, CH2Cl2) on 99% ee material. Spectral data for 125 (compound 125 appeared to be a mixture of two rotamers at room temperature in a ratio of 1.2:1): colorless oil 1H NMR (600 MHz, CDCl3) δ 1.21 (t, 3H, J = 7.2 Hz), 1.27-1.50 (m, 12H), 3.82-4.64 (m, 5H), 7.16-7.37 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 14.10, 15.38, 15.75, 28.29, 49.74, 50.81, 54.83, 55.40, 60.94, 80.42, 80.58, 126.95, 127.18, 127.30, 127.97, 128.29, 128.58, 138.25, 139.20, 155.38, 155.51, 172.08, 172.27. The 1H NMR data match those previously reported for this compound.95 186 5.2.3 Determination of the Relative Stereochemistry of anti-124 Boc NH O TFA OEt Me CH2Cl2 NH 2 O OEt Me anti-126 anti-124 Anti-ethyl 3-amino-2-methyl-3-phenylpropanoate 126: To a solution of anti-124 (27 mg, 0.088 mmol, 1.0 equiv) in CH2Cl2 (0.24 mL) was added trifluoroacetic acid (0.240 mL, 357 mg, 3.13 mmol, 35.6 equiv). After the reaction mixture was stirred at room temperature under nitrogen overnight, it was concentrated and diluted with 0.3 mL H2O. The pH of the mixture was adjusted to ~10 with sat aq NaHCO3 (ca. 10 mL) and then the mixture was extracted with CH2Cl2 (10 mL × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated. Purification of the product by silica gel chromatography (18 mm x 150 mm, 1:1 EtOAc/hexanes as eluent) gave ethyl 3-amino-2-methyl-3phenylpropanoate 126 as a colorless oil in 74% isolated yield (13.5 mg, 0.065 mmol). Spectral data for ethyl 3-amino-2-methyl-3-phenylpropanoate 126: 1H NMR (500 MHz, CDCl3) δ 0.93 (d, 3H, J = 7.2 Hz), 1.26 (t, 3H, J = 7.2 Hz), 1.64 (brs, 2H), 2.60-2.72 (m, 1H), 4.00 (d, 1H, J = 9.4 Hz), 4.17 (q, 2H, J = 7.2 Hz), 7.21-7.34 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 14.2, 15.4, 48.1, 59.1, 60.4, 127.0, 127.5, 128.5, 143.6, 175.9. The 1H NMR data match those previously reported for the anti-isomer but not those of the syn-isomer.96 187 5.2.4 Formation of Aziridines 145-147 O O AcO AcO H + MEDAM NH 2 44 142 MeO + H OEt N2 45 MEDAM 5 mol% (R)-VAPOL BOROX toluene 25 °C, 20 h N CO2Et AcO AcO OMe 145 MEDAM 4-((2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3(ethoxycarbonyl)aziridin-2-yl)-1,2-phenylene diacetate 145: To a 25 mL flamedried Schlenk flask equipped with a stir bar and filled with nitrogen was added (R)-VAPOL (54 mg, 0.10 mmol), B(OPh)3 (87 mg, 0.30 mmol), amine 4412j (599 mg, 2.00 mmol) and dry toluene (4 mL) to dissolve the reagents. The flask was then sealed and the reaction mixture was stirred at room temperature for 1 h. Thereafter, 4Å powdered Molecular Sieves (600 mg, freshly flame-dried) was added to the reaction flask followed by the addition of the aldehyde 14297 (467 mg, 2.10 mmoL, 1.05 equiv). To this solution was rapidly added ethyl diazoacetate (EDA) 45 (0.30 mL, 2.4 mmoL, 1.2 equiv). After the resulting mixture was stirred for 20 h at room temperature, it was dilluted by addition of hexane (12 mL). The reaction mixture was then filtered through a Celite pad into a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (6 mL × 3) and the rinse was filtered through the same Celite pad. The combined filtrate was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) to afford the crude aziridine as a yellow oil. Purification of the aziridine by 188 silica gel chromatography (40 mm × 210 mm column, 2:1 hexanes/EtOAc as eluent) afforded pure cis-aziridine 145 as a white solid (mp 65-67 °C on >98.5% ee material) in 98 % isolated yield (1.15 g, 1.95 mmol). The optical purity of 145 was determined to be >98.5 % ee by HPLC analysis (CHIRALCEL OD-H column, 85:15 hexane/2-propanol at 222 nm, flow-rate: 1 mL/min). Retention times: Rt = 7.18 min (minor enantiomer, ent-145) and Rt = 8.46 min (major enantiomer, 145). Rf = 0.19 (1:2 EtOAc/hexane); Spectral data for 145: 1H NMR (500 MHz, CDCl3) δ 1.02 (t, 3H, J = 7.1 Hz), 2.21 (s, 6H), 2.25 (s, 3H), 2.26 (s, 6H), 2.27 (s, 3H), 2.59 (d, 1H, J = 6.8 Hz), 3.09 (d, 1H, J = 6.8 Hz), 3.65 (s, 3H), 3.68 (s, 1H), 3.69 (s, 3H), 3.91-4.03 (m, 2H), 7.04-7.10 (m, 3H), 7.17 (s, 2H), 7.24-7.29 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 13.97, 16.15, 16.22, 20.59, 20.60, 46.39, 47.15, 59.51, 59.57, 60.76, 76.85, 122.60, 122.87, 126.02, 127.27, 127.66, 130.63, 130.76, 134.21, 137.53, 137.59, 141.17, 141.45, 155.90, 156.15, 167.70, 168.01, 168.25; IR (thin film) 2932 m, 1773 vs, 1746 s, 1213 vs cm-1; HRMS calcd (MH+) C34H40NO8+ 590.2754, found 590.2769; [α]!" ! = – 28.2° (c 1.0, CH2Cl2) on >98.5% ee (by HPLC) material. O O PivO PivO H 143 + MEDAM NH 2 44 + H OEt N2 45 MEDAM 5 mol% (R)-VAPOL BOROX toluene 25 °C, 20 h N CO2Et PivO PivO 146 4-((2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3(ethoxycarbonyl)aziridin-2-yl)-1,2-phenylene bis(2,2-dimethylpropanoate) 146: The procedure for the synthesis of aziridine 145 was followed starting with 189 aldehyde 14398 (643 mg, 2.10 mmoL, 1.05 equiv). Purification of the aziridine by silica gel chromatography (40 mm × 210 mm column, 5:1 hexanes/EtOAc as eluent) afforded pure cis-aziridine 146 as a white solid (mp 64-66 °C on 98% ee material) in 97 % isolated yield (1.31 g, 1.94 mmol). The optical purity of 146 was determined to be 98 % ee by HPLC analysis (Chiralpak AD column, 95:5 hexane/2-propanol at 222 nm, flow- rate: 0.7 mL/min). Retention times: Rt = 8.68 min (minor enantiomer, ent-146) and Rt = 10.23 min (major enantiomer, 146). Rf = 0.21 (1:5 EtOAc/hexane); Spectral data for 146: 1H NMR (500 MHz, CDCl3) δ 1.04 (t, 3H, J = 7.0 Hz), 1.30 (s, 9H), 1.32 (s, 9H), 2.20 (s, 6H), 2.24 (s, 6H), 2.56 (d, 1H, J = 6.8 Hz), 3.08 (d, 1H, J = 6.8 Hz), 3.64 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H), 3.90-4.03 (m, 2H), 6.98 (d, 1H, J = 8.0 Hz), 7.07 (s, 2H), 7.11 (d, 1H, J = 1.5 Hz), 7.16 (s, 2H), 7.25 (dd, 1H, J = 8.5, 1.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 14.04, 16.18, 16.22, 27.18, 27.23, 39.03, 39.06, 46.18, 47.31, 59.51, 59.56, 60.74, 76.88, 122.60, 122.82, 125.63, 127.27, 127.66, 130.62, 130.71, 133.71, 137.55, 137.61, 141.70, 141.88, 155.88, 156.14, 167.82, 175.57, 175.79; IR (thin film) 2977 s, 1761 vs, 1482 s, 1119 vs cm-1; HRMS calcd (MH+) C40H52NO8+ 674.3693, found 674.3694; [α]!" ! = – 34.2° (c 1.0, CH2Cl2) on 98% ee (by HPLC) material. O O H 3CO H 3CO H 144 + MEDAM NH 2 44 + H OEt N2 45 MEDAM 5 mol% (R)-VAPOL BOROX N H 3CO 190 CO2Et toluene 25 °C, 20 h H 3CO 147 ethyl-(2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(3,4dimethoxyphenyl)aziridine-2-carboxylate 147: The procedure for the synthesis of aziridine 145 was followed starting with aldehyde 144 (88.0 mg, 0.525 mmoL, 1.05 equiv), amine 44 (150 mg, 0.500 mmol, 1.00 equiv), ethyl diazoacetate (EDA) 45 (0.08 mL, 0.6 mmoL, 1.2 equiv), (R)-VAPOL (13.5 mg, 0.0250 mmol) and B(OPh)3 (22 mg, 0.075 mmol). Purification of the aziridine by silica gel chromatography (25 mm × 160 mm column, 3:1 hexanes/EtOAc as eluent) afforded pure cis-aziridine 147 as a yellow semi-solid in 90 % isolated yield (240 mg, 0.450 mmol). Rf = 0.17 (1:3 EtOAc/hexane); Spectral data for 147: 1H NMR (500 MHz, CDCl3) δ 1.05 (t, 3H, J = 7.2 Hz), 2.20 (s, 6H), 2.25 (s, 6H), 2.55 (d, 1H, J = 6.8 Hz), 3.09 (d, 1H, J = 6.8 Hz), 3.63 (s, 3H), 3.67 (s, 1H), 3.68 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 3.90-4.04 (m, 2H), 6.72 (d, 1H, J = 8.2 Hz), 6.83-6.92 (m, 2H), 7.12 (s, 2H), 7.19 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.10, 16.19, 45.94, 48.03, 55.61, 55.77, 59.47, 59.54, 60.54, 76.92, 110.40, 111.06, 115.31, 119.81, 120.05, 127.30, 127.82, 127.84, 129.44, 130.55, 130.58, 137.66, 138.04, 148.07, 148.22, 155.81, 156.02, 168.25, (one sp3 carbon and one sp2 carbon not located); IR (thin film) 2940 m, 1746 m, 1518 s, 1223 vs cm-1; HRMS calcd (MH+) C32H40NO6+ 534.2856, found 534.2869. [α]!" ! = – 24.5° (c 1.0, CH2Cl2) 5.2.5 Synthesis of Protected Forms of L-DOPA MEDAM N H 2, Pd(OH) 2 PivO CO2Et PivO PivO (Boc) 2O MeOH 146 191 CO2Et NHBoc PivO 148 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)-1,2phenylene bis(2,2-dimethylpropanoate) 148: To a oven-dried 25 mL round bottom flask equipped with a stir bar and filled with nitrogen was added aziridine 146 (67.4 mg, 0.100 mmol, 98% ee), Pd(OH)2 (28.0 mg, 0.020 mmol, Pd(OH)2 on carbon 20%, moisture ≤ 50%), di-tert-butyl dicarbonate (33 mg, 0.15 mmol) and methanol (10 mL). The flask was sealed with a rubber septum and a needle connected to a vacuum line was used to apply vacuum in the flask through the septum. The vacuum was applied for a few seconds with vigorous stirring of the reaction mixture. Then the vacuum was stopped and a hydrogen balloon was connected to the flask by a needle through the septum. This process was repeated four times. Then the suspension was stirred at room temperature under hydrogen for 17 hours and then filtered through a pad of Celite. The filter cake was washed with EtOAc (5 mL) and DCM (3 mL × 3). The combined filtrate was concentrated to give a light yellow oil. Purification of the crude product by column chromatography on silica gel (20 mm × 160 mm, hexanes/EtOAc 5:1) gave the αamino ester 148 as a colorless oil (42.2 mg, 0.0855 mmol, 86%). Rf = 0.20 (1:5 EtOAc/hexane); Spectral data for 148: 1H NMR (500 MHz, CDCl3) δ 1.20 (t, 3H, J = 7.0 Hz), 1.30 (s, 18H), 1.41 (s, 9H), 3.06 (d, 2H, J = 6.0 Hz), 4.07-4.18 (m, 2H), 4.50 (dt, 1H, J = 7.5, 6.0 Hz), 5.01 (d, 1H, J = 7.5 Hz), 6.87 (s, 1H), 6.97 (d, 1H, J = 8.2 Hz), 7.02 (d, 1H, J = 8.2 Hz); 13 C NMR (CDCl3, 125 MHz) δ 14.07, 27.19, 28.27, 37.50, 39.06, 39.09, 54.27, 61.49, 79.90, 123.24, 124.25, 127.05, 134.53, 141.52, 142.31, 155.00, 171.48, 175.63, 175.79, (one sp3 carbon not located); IR (thin film) 2977 s, 1761 vs, 1482 s, 1119 vs cm-1; HRMS calcd (M+H+) 192 C26H40NO8+ 494.2754, found 494.2751; [α]!" ! = + 27.8° (c 1.0, CH2Cl2) on 98% ee material (The optical purity was assumed to be unchanged from 146). 5.2.6 Formation of Aziridines 149-151 MEDAM Ts N N i TFA/anisole CO2Et AcO AcO ii TsCl, Et 3N, DCM CO2Et AcO AcO 145 149 4-((2S,3S)-3-(ethoxycarbonyl)-1-tosylaziridin-2-yl)-1,2-phenylene diacetate 149: To a flame-dried 100 mL round bottom flask equipped with a stir bar and filled with nitrogen was added aziridine 145 (467 mg, 0.792 mmol) and anisole (4.1 mL) at room temperature. The resulting solution was cooled to 0 °C in an ice-bath and trifluoroacetic acid (4.1 mL) was rapidly added. The ice-bath was then removed and the reaction mixture was stirred for 40 minutes at room temperature. The reaction mixture was quenched by careful addition of saturated aq Na2CO3 (30 mL) and H2O (10 mL) followed by addition of Et2O (30 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (30 mL × 3). The combined organic layer was dried with Na2SO4, filtered and concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 4 h to give a yellow oil, to which was added 6.5 mL CH2CI2/CHCl3 (1:1) and Et3N (0.33 mL, 2.4 mmol). The resulting solution was cooled to 0 °C followed by the addition of tosyl chloride (228 mg, 1.20 mmol). The mixture was then stirred at 0 °C for 15 h. Thereafter, another portion of tosyl chloride (228 mg, 1.20 mmol) and Et3N (0.33 mL, 2.4 mmol) was added to the reaction mixture at room 193 temperature. After the mixture was stirred for 26 hours at room temperature, the reaction was quenched with 12 mL sat aq NH4Cl and 2.5 mL H2O. The aqueous layer was extracted with CH2Cl2 (15 mL × 3) and the combined organic layer was dried with Na2SO4, filtered and concentrated to give a dark brown oil. Purification by silica gel chromatography (25 mm × 160 mm, 2:1 hexanes/EtOAc as eluent) afforded cis-149 as a light yellow oil in 70 % yield (258 mg, 0.559 mmol). Rf = 0.14 (1:2 EtOAc/hexane); Spectral data for 149: 1H NMR (500 MHz, CDCl3) δ 0.96 (t, 3H, J = 7.1 Hz), 2.236 (s, 3H), 2.240 (s, 3H), 2.43 (s, 3H), 3.66 (d, 1H, J = 7.5 Hz), 3.89-4.02 (m, 2H), 4.03 (d, 1H, J = 7.5 Hz), 7.07 (d, 1H, J = 8.3 Hz), 7.13 (d, 1H, J = 2.0 Hz), 7.17 (dd, 1H, J = 8.3, 2.0 Hz), 7.34 (d, 2H, J = 8.0 Hz), 7.88 (d, 2H, J = 8.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.71, 20.55, 20.60, 21.71, 43.40, 44.32, 61.86, 122.72, 123.28, 125.81, 128.12, 129.94, 129.97, 133.71, 141.83, 142.27, 145.39, 164.13, 167.85, 168.01; IR (thin film) 2986 w, 1773 vs, 1734 m, 1210 vs, 1165 s cm-1; HRMS calcd (MH+) C22H24NO8S+ 462.1223, found 462.1234; [α]!" ! = + 15.6° (c 1.0, CH2Cl2) on >98.5% ee material (The optical purity was assumed to be unchanged from 145). MEDAM SES N N i TFA/anisole CO2Et AcO AcO CO2Et ii SESCl, Et 3N, DCM AcO AcO 145 150 4-((2S,3S)-3-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethyl)sulfonyl)aziridin-2yl)-1,2-phenylene diacetate 150: To a flame-dried 100 mL round bottom flask equipped with a stir bar and filled with nitrogen was added aziridine 145 (366 mg, 194 0.621 mmol) and anisole (3.1 mL) at room temperature. The resulting solution was cooled to 0 °C in an ice-bath and trifluoroacetic acid (3.1 mL) was rapidly added. The ice-bath was then removed and the reaction mixture was stirred for 40 minutes at room temperature. The reaction mixture was quenched by careful addition of saturated aq Na2CO3 (25 mL) and H2O (10 mL) followed by addition of Et2O (30 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (30 mL × 3). The combined organic layer was dried with Na2SO4, filtered and concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 4 h to give a yellow oil, which was then dissolved in a mixture of CH2Cl2 (2 mL) and Et3N (0.9 mL). After the solution was cooled to 0 °C in an ice-bath, 2-(trimethylsilyl)ethanesulfonyl chloride (0.12 mL, 0.93 mmol) was added dropwise to the reaction mixture at 0 °C. Then the ice-bath was then removed and the reaction mixture was stirred at room temperature for 17 hours. Thereafter, another portion of 2-(trimethylsilyl)ethanesulfonyl chloride (0.12 ml, 0.93 mmol) and Et3N (0.9 ml) was added to the reaction mixture at room temperature. After the mixture was stirred for 23 hours at room temperature, the reaction was quenched with 2.5 mL sat aq NH4Cl and 1 mL H2O. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (4 mL × 3). The combined organic layer was dried with Na2SO4, filtered and concentrated to give a dark brown oil. Purification by silica gel chromatography (25 mm × 160 mm, 3:1 hexanes/EtOAc as eluent) afforded cis-150 as a light yellow oil in 78% yield (0.228 g, 0.483 mmol). Rf = 0.20 (1:3 EtOAc/hexane); Spectral data for 150: 1 H NMR (500 MHz, CDCl3) δ 0.05 (s, 9H), 1.03 (t, 3H, J = 7.0 Hz), 1.12-1.20 (m, 195 2H), 2.26 (s, 6H), 3.16-3.24 (m, 2H), 3.66 (d, 1H, J = 7.5 Hz), 3.97-4.09 (m, 2H), 4.02 (d, 1H, J = 7.5 Hz), 7.15 (d, 1H, J = 8.2 Hz), 7.25 (d, 1H, J = 1.9 Hz), 7.30 (dd, 1H, J = 8.2 Hz, J = 1.9 Hz); 13 C NMR (125 MHz, CDCl3) δ –2.06, 9.53, 13.81, 20.57, 20.62, 43.50, 43.60, 49.51, 61.99, 122.79, 123.42, 125.84, 130.06, 141.98, 142.42, 164.21, 167.87, 168.00; IR (thin film) 2955 m, 1777 s, 1208 s, 1177 s cm-1; HRMS calcd (MH+) C20H30NO8SiS+ 472.1461, found 472.1449; [α]!" ! = +27.5° (c 1.0, CH2Cl2) on >98.5% ee material (The optical purity was assumed to be unchanged from 145). MEDAM SES N N i TFA/anisole CO2Et PivO PivO CO2Et ii SESCl, Et 3N, DCM PivO PivO 146 151 4-((2S,3S)-3-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethyl)sulfonyl)aziridin-2yl)-1,2-phenylene bis(2,2-dimethylpropanoate) 151: To a flame-dried 100 mL round bottom flask equipped with a stir bar and filled with nitrogen was added aziridine 146 (674 mg, 1.00 mmol) and anisole (8.9 mL) at room temperature. The resulting solution was cooled to 0 °C in an ice-bath and trifluoroacetic acid (8.9 mL) was rapidly added. The ice-bath was removed and the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was quenched by careful addition of saturated aq Na2CO3 (68 mL) and H2O (35 mL) followed by addition of Et2O (50 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (100 mL × 3). The combined organic layer was dried with Na2SO4, filtered and concentrated in vacuo followed by 196 exposure to high vacuum (0.05 mm Hg) for 4 h to give a yellow oil, which was then dissolved in a mixture of CH2Cl2 (3.5 mL) and Et3N (1.5 mL). After the solution was cooled to 0 °C, 2-(trimethylsilyl)ethanesulfonyl chloride (0.20 mL, 1.5 mmol) was added dropwise to the reaction mixture at 0 °C. Then the ice-bath was removed and the reaction mixture was stirred at room temperature for 14 hours. Thereafter, another portion of 2-(trimethylsilyl)ethanesulfonyl chloride (0.20 mL, 1.5 mmol) and Et3N (1.5 mL) was added to the reaction mixture at room temperature. After the mixture was stirred for 22 hours at room temperature, the reaction was quenched with 4 mL sat aq NH4Cl and 1.5 mL H2O. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (6 mL × 3). The combined organic layer was dried with Na2SO4, filtered and concentrated to give a dark brown oil. Purification by silica gel chromatography (25 mm × 160 mm, 5:1 hexanes/EtOAc as eluent) afforded cis151 as a light yellow oil in 86 % yield (0.475 g, 0.855 mmol). Rf = 0.20 (1:5 EtOAc/hexane); Spectral data for 151: 1H NMR (500 MHz, CDCl3) δ 0.05 (s, 9H), 1.06 (t, 3H, J = 7.1 Hz), 1.11-1.21 (m, 2H), 1.31 (s, 9H), 1.32 (s, 9H), 3.17-3.26 (m, 2H), 3.66 (d, 1H, J = 7.5 Hz), 3.98-4.07 (m, 2H), 4.02 (d, 1H, J = 7.5 Hz), 7.09 (d, 1H, J = 8.3 Hz), 7.18 (d, 1H, J = 1.8 Hz), 7.27 (dd, 1H, J = 8.3 Hz, J = 1.8 Hz); 13 C NMR (125 MHz, CDCl3) δ –2.13, 9.50, 13.81, 27.10, 27.14, 39.03, 39.06, 43.23, 43.70, 49.39, 61.87, 122.68, 123.32, 125.36, 129.54, 142.40, 142.89, 164.18, 175.37, 175.55; IR (thin film) 2977 m, 1761 vs, 1117 s cm-1; HRMS calcd (M+NH4+) C26H45N2O8SiS+ 573.2666, found 573.2675; [α]!" ! = + 197 26.9° (c 1.0, CH2Cl2) on 98% ee material (The optical purity was assumed to be unchanged from 146). 5.2.7 Reductive Ring Opening of Aziridines 149-151 Ts N I. SmI2, DMEA CO2Et II. Ac O, Et N 2 3 AcO AcO Ts NH AcO O AcO OEt + AcO AcO 152A 149 Ts N CO2Et 152B Reductive ring opening of 149: The general procedure for the reductive ring opening described in Part 6.2.2 was followed with aziridine 149 (228 mg, 0.494 mmol), 2.5 equiv SmI2 and 5 equiv DMEA. The 1H NMR spectrum of the crude reaction mixture indicated a complex mixture of several products due to partial cleavage of the acetate group on the benzene ring. To this mixture was added Ac2O (0.2 mL) and Et3N (0.16 mL). After the reaction was stirred at room temperature for 30 minutes, it was quenched by the addition of EtOH (0.1 mL) and H2O (2.5 mL). The resulting mixture was extracted with EtOAc (3 mL × 3). The combined organic layer was dried with Na2SO4, filtered and concentrated to give a yellow oil. Purification by silica gel chromatography (20 mm × 160 mm, 1:1.5 EtOAc/hexanes as eluent) gave 152A as a colorless oil in 76% isolated yield (173 mg, 0.373 mmol) and 152B as a light yellow oil in 8% isolated yield (17.5 mg, 0.0377 mmol). Spectral data for 152A (Rf = 0.23 (1:1.5 EtOAc/hexane)): 1H NMR (500 MHz, CDCl3) δ 1.11 (t, 3H, J = 7.1 Hz), 2.22 (s, 6H), 2.33 (s, 3H), 2.68 (dd, 1H, J = 16.2, 6.2 Hz), 2.75 (dd, 1H, J = 16.2, 6.4 Hz), 3.99 (q, 2H, J = 7.1 Hz), 4.70 (dt, 1H, J = 7.5, 6.2 Hz), 5.97 (d, 1H, J = 7.8 Hz), 198 6.90-6.98 (m, 3H), 7.14 (d, 2H, J = 8.0 Hz), 7.54 (d, 2H, J = 8.0 Hz); 13 C NMR (125 MHz, CDCl3) δ 13.88, 20.51, 20.56, 21.37, 40.96, 53.57, 61.04, 121.79, 123.28, 124.47, 126.93, 129.50, 137.07, 138.01, 141.38, 141.82, 143.39, 167.82, 167.90, 170.40; IR (thin film) 3279 m, 2984 w, 2930 w, 1773 s, 1734 s, 1211 s, 1161 s cm-1; HRMS calcd (MH+) C22H26NO8S+ 464.1379, found 464.1381; [α]!" ! = + 45.2° (c 1.0, CH2Cl2) on >98% ee material (The optical purity was assumed to be unchanged from 145). Spectral data for 152B (Rf = 0.38 (1:1.5 EtOAc/hexane)): 1H NMR (500 MHz, CDCl3) δ 1.13 (t, 3H, J = 7.1 Hz), 2.26 (s, 6H), 2.42 (s, 3H), 3.93 (s, 2H), 3.99 (q, 2H, J = 7.1 Hz), 4.46 (s, 2H), 7.09 (s, 1H), 7.12 (s, 2H), 7.30 (d, 2H, J = 8.2 Hz), 7.73 (d, 2H, J = 8.2 Hz); 13 C NMR (125 MHz, CDCl3) δ 13.96, 20.60, 20.65, 21.57, 46.78, 50.48, 61.24, 123.49, 123.64, 126.51, 127.44, 129.60, 134.05, 136.68, 141.88, 142.23, 143.64, 168.06, 168.16, 168.57; IR (thin film) 2984 w, 2934 w, 1773 vs, 1213 s cm-1; HRMS calcd (MH+) C22H26NO8S+ 464.1379, found 464.1381. SES N I. SmI2, DMEA CO2Et II. Ac O, Et N 2 3 AcO AcO SES NH AcO O AcO OEt + AcO AcO 153A SES N CO2Et 153B 150 Reductive ring opening of 150: The general procedure for the reductive ring opening described above was followed with aziridine 150 (236 mg, 0.500 mmol), 4 equiv SmI2 and 8 equiv DMEA. The 1H NMR spectrum of the crude reaction mixture indicated a complex mixture of several products due to partial cleavage of the acetate group on the benzene ring. To this mixture was added 199 Ac2O (0.63 mL) and Et3N (0.5 mL). After the reaction was stirred at room temperature for 40 minutes, it was quenched by the addition of EtOH (0.32 mL) and H2O (9 mL). The resulting mixture was extracted with EtOAc (10 mL × 3). The combined organic layer was dried with Na2SO4, filtered and concentrated to give a yellow oil. Purification by silica gel chromatography (20 mm × 160 mm, 1:2 EtOAc/hexanes as eluent) gave 153A as a colorless oil in 69% isolated yield (164 mg, 0.346 mmol) and 153B as a light yellow oil in 19% isolated yield (45 mg, 0.095 mmol). Spectral data for 153A (Rf = 0.21 (1:2 EtOAc/hexane)): 1H NMR (500 MHz, CDCl3) δ -0.09 (s, 9H), 0.78-0.93 (m, 2H), 1.19 (t, 3H, J = 7.1 Hz), 2.26 (s, 6H), 2.59-2.78 (m, 2H), 2.80-2.89 (m, 2H), 4.06-4.13 (m, 2H), 4.87 (dt, 1H, J = 8.1, 6.4 Hz), 5.70 (d, 1H, J = 8.1 Hz), 7.16 (d, 1H, J = 8.7 Hz), 7.197.28 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ –2.23, 10.18, 13.97, 20.575, 20.584, 41.57, 50.11, 53.57, 61.15, 121.89, 123.71, 124.60, 139.08, 141.73, 142.23, 167.85, 167.97, 170.48; IR (thin film) 3283 m, 2955 m, 1773 vs, 1734 vs, 1211 s, 1143 s cm-1; HRMS calcd (M+NH4+) C20H35N2O8SiS+ 491.1883, found 491.1894; [α]!" ! = +27.0° (c 1.0, CH2Cl2) on >98.5% ee material (The optical purity was assumed to be unchanged from 145). Spectral data for 153B (Rf = 0.27 (1:2 EtOAc/hexane)): 1H NMR (500 MHz, CDCl3) δ 0.04 (s, 9H), 1.08-1.16 (m, 2H), 1.24 (t, 3H, J = 7.1 Hz), 2.26 (s, 6H), 3.04-3.11 (m, 2H), 3.93 (s, 2H), 4.15 (q, 2H, J = 7.1 Hz), 4.52 (s, 2H), 7.12-7.21 (m, 3H); 13 C NMR (125 MHz, CDCl3) δ -2.02, 10.19, 14.08, 20.59, 20.63, 46.82, 50.00, 50.91, 61.43, 123.24, 123.68, 126.28, 134.44, 141.87, 142.29, 168.07, 168.15, 169.51; IR (thin film) 2955 w, 2930 w, 200 1773 s, 1742 s, 1211 s cm-1; HRMS calcd (M+NH4+) C20H35N2O8SiS+ 491.1883, found 491.1897. SES SES NH N SmI2, DMEA PivO + PivO PivO PivO PivO OEt CO2Et PivO O 154A SES N CO2Et 154B 151 Reductive ring opening of 151: The general procedure for the reductive ring opening described above was followed with aziridine 151 (111 mg, 0.200 mmol, 98% ee) and 4.0 equiv SmI2. The 1H NMR spectrum of the crude reaction mixture indicated a mixture of C-N cleavage product 154A and C-C cleavage product 154B was obtained with a ratio of 4.3:1. Purification by silica gel chromatography (20 mm × 160 mm, 1:3 EtOAc/hexanes as eluent) gave 154A as a yellow oil in 74% isolated yield (81.8 mg, 0.147 mmol) and 154B as a light yellow oil in 16% isolated yield (18.2 mg, 0.0326 mmol). Spectral data for 154A (Rf = 0.25 (1:3 EtOAc/hexane)): 1H NMR (500 MHz, CDCl3) δ – 0.11 (s, 9H), 0.75-0.90 (m, 2H), 1.18 (t, 3H, J = 7.2 Hz), 1.29 (s, 9H), 1.30 (s, 9H), 2.55-2.75 (m, 2H), 2.82 (d, 2H, J = 6.5 Hz), 4.07 (q, 2H, J = 7.1 Hz), 4.84 (dt, 1H, J = 8.0, 6.5 Hz), 5.70 (d, 1H, J = 8.0 Hz), 7.09 (d, 1H, J = 8.4 Hz), 7.13 (d, 1H, J = 2.0 Hz), 7.19 (dd, 1H, J = 8.4, 2.0 Hz); 13 C NMR (125 MHz, CDCl3) δ –2.25, 10.15, 13.98, 27.11, 27.13, 39.05, 39.06, 41.65, 50.04, 53.67, 61.07, 121.83, 123.66, 124.30, 138.65, 142.22, 142.64, 170.40, 175.38, 175.47; IR (thin film) 3283 m, 2977 s, 1763 vs, 1736 s, 1117 s cm-1; HRMS calcd (M+NH4+) C26H47N2O8SiS+ 575.2822, found 575.2842; [α]!" ! = +26.0° (c 1.0, CH2Cl2) on 98% ee material 201 (The optical purity was assumed to be unchanged from 146). Spectral data for 154B (Rf = 0.39 (1:3 EtOAc/hexane)): 1H NMR (500 MHz, CDCl3) δ 0.04 (s, 9H), 1.09-1.16 (m, 2H), 1.24 (t, 3H, J = 7.1 Hz), 1.31 (s, 18H), 3.04-3.13 (m, 2H), 3.92 (s, 2H), 4.15 (q, 2H, J = 7.1 Hz), 4.52 (s, 2H), 7.06-7.11 (m, 2H), 7.17 (dd, 1H, J = 8.4, 1.8 Hz); 13 C NMR (125 MHz, CDCl3) δ –2.01, 10.20, 14.08, 27.18, 27.21, 39.10, 39.13, 46.73, 49.95, 50.88, 61.39, 123.35, 123.68, 126.12, 133.87, 142.43, 142.75, 169.54, 175.68, 175.81; IR (thin film) 2977 s, 1761 vs, 1507 m, 1337 m, 1256 m, 1117 vs cm-1; HRMS calcd (M+NH4+) C26H47N2O8SiS+ 575.2822, found 575.2834. SES NH PivO PivO O OEt 154A I. (Boc) 2O, DMAP, Et 3N PivO II. TBAF, THF III. PivCl, Et 3N, THF PivO NHBoc CO2Et 155 (R)-4-(1-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)-1,2phenylene bis(2,2-dimethylpropanoate) 155: To a oven-dried 10 mL Schlenk flask equipped with a stir bar and filled with nitrogen was added 154A (38 mg, 0.068 mmol, 1.0 equiv), 4-dimethylaminopyridine (0.9 mg, 0.007 mmol, 0.1 equiv), Et3N (19 µL, 14 mg, 0.14 mmol, 2.0 equiv) and CH2Cl2 (0.32 mL). The flask was sealed and the reaction mixture was stirred for 2 h at room temperature and then at 40 °C for 15 h. After the reaction mixture was cooled to room temperature, 0.5 mL of 1 N HCl was added to the flask followed by the addition of EtOAc (5 mL). The organic layer was separated, washed with brine (0.3 mL × 2), dried with Na2SO4 and concentrated to give a yellow oil, which was then 202 dissolved in THF (0.65 mL) in a 10 mL Schlenk flask filled with nitrogen. To this solution was added TBAF (0.31 mL, 1 M in THF, 0.31 mmol) dropwise at room temperature. After the reaction mixture was stirred at room temperature under nitrogen for 1.5 h, it was concentrated by rotary evaporation and then high vacuum (0.5 mm Hg) to give a bright yellow oil. This oil was dissolved in a mixture of THF (0.2 mL) and Et3N (0.2 mL). Then trimethylacetyl chloride (0.05 mL, 0.4 mmol) was added to the solution at room temperature. After the resulting reaction mixture was stirred for 15 minutes at room temperature under nitrogen, it was quenched by the addition of EtOH (0.1 mL) and H2O (1.5 mL). The resulting mixture was extracted with EtOAc (2 mL × 3). The combined organic layer was dried with Na2SO4, filtered and concentrated to afford a yellow oil. Purification by silica gel chromatography (20 mm × 120 mm, 1:3 EtOAc/hexanes as eluent) gave 155 as a light yellow oil in 88% isolated yield (29.5 mg, 0.0598 mmol). Rf = 0.27 (1:3 EtOAc/hexane); Spectral data for 155: 1H NMR (500 MHz, CDCl3) δ 1.16 (t, 3H, J = 7.2 Hz), 1.30 (s, 9H), 1.31 (s, 9H), 1.39 (brs, 9H), 2.62-2.92 (m, 2H), 4.06 (q, 2H, J = 7.2 Hz), 5.06 (brs, 1H), 5.47 (d, 1H, J = 7.5 Hz), 7.03 (d, 1H, J = 1.6 Hz), 7.06 (d, 1H, J = 8.4 Hz), 7.14 (dd, 1H, J = 8.4 Hz, J = 1.6 Hz); 13 C NMR (125 MHz, CDCl3) δ 14.04, 27.20, 27.22, 28.30, 39.10, 39.12, 40.72, 50.62, 60.86, 79.83, 121.37, 123.46, 124.04, 139.73, 141.80, 142.50, 154.89, 170.69, 175.61, 175.80; IR (thin film) 3387 m, 2978 s, 2936 m, 2874 w, 1761 vs, 1739s, 1723 s, 1713 s, 1256 s, 1119 vs cm-1; HRMS calcd (MH+) C26H40NO8+ 494.2754, found 494.2758; [α]!" ! = + 23.6° (c 1.0, CH2Cl2) on 98% ee material (The optical purity was assumed to be unchanged from 146). 203 5.3 Experimental Part for Chapter 4 5.3.1 Preparation of Left Head 169 OH O N CO2Et O 11 173 H N MEDAM TBSOTf O Et 3N THF OTBS CO2Et N O 11 169 H N MEDAM Compound 169: To an oven dried 100 mL round bottom flask filled with nitrogen was added compound 173 (2.35 g, 3.36 mmol, 1.00 equiv) and dry THF (30 mL) followed by the addition of Et3N (0.90 mL, 6.5 mmol, 1.9 equiv). After the solution was cooled to 0 °C, trimethylsilyl trifluoromethanesulfonate (TBSOTf, 0.80 mL, 3.5 mmol, 1.0 equiv) was added to the reaction flask and the resulting mixture was stirred at 0 °C under nitrogen for 1.5 h. The reaction mixture was then concerntrated by rotary evaporator. The product was purified by column chromatography (silica gel, 40 × 180 mm, hexane:EtOAc 3:1) to afford the product 169 as a colorless oil (2.22 g, 2.73 mmol) in 81% yield. Rf = 0.19 (hexane:EtOAc 3:1). Spectral data for 169: 1H NMR (500 MHz, CDCl3) δ -0.10 (s, 3H), -0.02 (s, 3H), 0.81 (s, 9H), 0.95-1.43 (m, 29H), 1.55-1.65 (m, 2H), 1.902.00 (m, 1H), 2.22 (s, 12H), 2.39 (t, 2H, J = 7.4 Hz), 3.08 (d, 1H, J = 2.1 Hz), 3.16 (s, 3H), 3.65 (s, 3H), 3.656 (s, 3H), 3.661 (s, 3H), 3.85-3.92 (m, 1H), 4.10-4.20 (m, 2H), 4.63 (s, 1H), 7.00 (s, 4H); 13 C NMR (125 MHz, CDCl3) δ -5.07, -4.29, 14.30, 16.18, 16.20, 17.95, 24.64, 25.75, 25.83, 29.44, 29.46, 29.52, 29.63, 29.66, 29.68, 29.74, 29.86, 31.88, 34.08, 59.53, 59.56, 60.41, 61.16, 61.78, 63.97, 74.48, 127.38, 128.12, 130.38, 130.51, 138.16, 140.34, 155.68, 155.85, 174.13, (one sp2 carbon and two sp3 carbons not located); IR (thin film) 2926(vs), 2855(s), 1740(m), 1670(m), 1458(m), 1221(m), 1152(m), 1017(m) cm–1; HRMS 204 calcd for C47H81N2O7Si (M+H, ESI+) m/z 813.5813, meas 813.5804; [α]!" ! = – 15.5° (c 1.0, CH2Cl2) on 95% ee material. 5.3.2 Procedures for Catalytic Azymmetric Aziridination of Aldehyde 176 (Table 4.1) Method A: Ligand (5 mol %) B(OPh) 3 (15 mol %) MEDAMNH 2 144 (1 equiv) 80 °C toluene, 0.5 h 4Å MS aldehyde 176 (1.05 equiv) EDA 145 (2 equiv) –10 °C, 15 h MEDAM N EtO 2C 174 3 To a 50 mL flame-dried Schlenck flask equipped with a stir bar and filled with N2 was added (R)-VAPOL (135 mg, 0.251 mmol), B(OPh)3 (218 mg, 0.751 mmol) and amine 144 (1.5 g, 5.0 mmol). Dry toluene (10 mL) was added under an N2 atmosphere to dissolve the reagents and the flask was sealed. After the reaction mixture was stirred at 80 °C for 0.5 h, it was first cooled to rt and 4Å Molecular Sieves (1.5 g, freshly flame-dried) were added to the flask. After the reaction mixture was cooled to – 10 °C, the aldehyde 17664 (652 mg, 5.25 mmol) was added followed by the addition of ethyl diazoacetate (EDA) 145 (1.3 mL, 10 mmol). The resulting mixture was stirred for 16 h at – 10 °C. The reaction was dilluted by addition of hexane (15 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (6 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine 174 as a viscous yellow oil. The product was purified by column chromatography (silica 205 gel, 40 × 210 mm, hexane:EtOAc 9:1) to afford the pure product 174 as a light yellow oil (0.600 g, 1.22 mmol, 24%) and a mixture of product 174 and PhOH (1.8 g, 174 : PhOH = 1 : 0.43). The optical purity of 174 was determined to be 95% ee by HPLC analysis (Chiralcel OD-H column, 99:1 hexane/2-propanol at 222 nm, flow-rate 0.7 mL/min); Retention times: Rt = 5.70 min (minor enantiomer, ent-174) and Rt = 7.15 min (major enantiomer, 174). Rf = 0.34 (hexane:EtOAc 3:1). Spectral data for 174: 1H NMR (500 MHz, CDCl3) δ 0.93-1.04 (m, 1H), 1.06-1.16 (m, 1H), 1.17-1.28 (m, 5H), 1.29-1.38 (m, 2H), 1.40-1.55 (m, 2H), 1.88 (t, 1H, J = 2.6 Hz), 1.94 (q, 1H, J = 6.6 Hz), 2.04 (td, 2H, J = 7.2 Hz, J = 2.2 Hz), 2.19 (d, 1H, J = 6.8 Hz), 2.215 (s, 6H), 2.220 (s, 6H), 3.38 (s, 1H), 3.657 (s, 3H), 3.665 (s, 3H), 4.10-4.25 (m, 2H), 6.99 (s, 2H), 7.07 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 14.35, 16.14, 16.18, 18.16, 26.69, 27.72, 28.15, 28.38, 43.56, 46.77, 59.59, 59.62, 60.72, 68.12, 77.33, 84.49, 127.32, 128.10, 130.47, 130.50, 137.68, 138.14, 155.76, 156.12, 169.63; IR (thin film) 3289(w), 2934(s), 2861(m), 1744(s), 1719(m), 1483(s), 1221(s), 1184(s), 1144(m), 1015(m) cm–1; HRMS calcd for C31H42NO4 (M+H, ESI+) m/z 492.3114, meas 492.3108; [α]!" ! = –85.5° (c 1.0, CH2Cl2) on 95% ee material. Method B: (R)-VAPOL (5 mol %) 100 °C BH 3·SMe 2 (15 mol %) H 2O (15 mol %) toluene p-methoxyphenol (10 mol %) 1h MEDAMNH 2 144 (1 equiv) rt, 0.5 h 4Å MS aldehyde 176 (1.05 equiv) EDA 145 (2 equiv) –10 °C, 15 h MEDAM N EtO 2C 174 3 A 50 mL Schlenk flask equipped with a stir bar was flame dried, cooled to rt under N2 and charged with (R)-VAPOL (270 mg, 0.501 mmol), p- 206 methoxylphenol (125 mg, 1.01 mmol), dry toluene (10 mL), H2O (27 mg, 27.0 µL, 1.50 mmol), and BH3·SMe2 (2M, 0.75 mL, 1.5 mmol). The Teflon valve on the Schlenk flask was then closed, and the mixture heated at 100 °C for 1 h. After the flask was cooled to rt, amine 144 (10 mmol, 1.0 equiv) and dry toluene (10 mL) was added to the mixture under a N2 stream and the resulting mixture was stirred at rt for 30 min. After the mixture was cooled to – 10 °C, 4Å Molecular Sieves (3.0 g, freshly flame-dried) and the aldehyde 176 (1.30 g, 10.5 mmol) were added to the flask followed by the addition of ethyl diazoacetate (EDA) 145 (85%, 2.6 mL, 20 mmol). The Teflon valve was then closed, and the resulting mixture was stirred at room temperature for 15 h. Upon completion, the reaction was dilluted by addition of hexane (25 mL). The reaction mixture was then filtered through a Celite pad to a 250 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine 174 as a viscous yellow oil. The product was purified by column chromatography (silica gel, 40 × 250 mm, hexane:EtOAc 9:1) to afford compound 174 as a light yellow oil (4.5 g, 9.2 mmol, 92%, 95% ee). 5.3.3 Procedure for Ring Opening Reaction of Aziridine 174 (Table 4.1, illustrated for entry 5) 1. TFA (1.0 equiv) Additive (x equiv) DCM, T °C MEDAM N EtO 2C 174 3 2. NaOH, H 2O/EtOH rt, 0.5 h MEDAM NH + EtO 2C EtO 2C OH 172 207 MEDAM NH 3 OH 180 3 To an oven-dried 100 mL Schlenk flask flask filled with nitrogen was added the aziridine 174 (4.24 g, 8.63 mmol, 1.00 equiv), dry DCM (40 mL) and trifluoroacetic acid (TFA) (0.69 mL, 9.01 mmol, 1.04 equiv). The Teflon valve on the Schlenk flask was then closed, and the mixture was stirred at 40 °C for 15 h. Then the reaction mixture was concentrated by rotary evaporator. To the residue was added a solution of NaOH (345 mg, 8.63 mmol, 1.00 equiv) in EtOH/H2O (v/v 15:2). After the resulting mixture was stirred at rt for 30 min, it was concentrated under reduced pressure and dissolved in a mixture of H2O (5 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL x 2). The combined organic layer was dried with Na2SO4, filtered and concentrated. The crude 1H NMR showed that the ratio of the isomers 172 and 180 is 4.5:1. Purification by column chromatography (35 × 180 mm, hexanes:EtOAc 4:1) gave the desired product 172 as a colorless oil (3.08 g, 6.04 mmol) in 70% yield, Rf = 0.20 (hexane:EtOAc 3:1), and its isomer 180 as a colorless oil (440 mg, 0.863 mmol) in 10 yield, Rf = 0.32 (hexane:EtOAc 3:1). Spectral data for 172: 1H NMR (500 MHz, CDCl3) δ 1.21-1.31 (m, 1H), 1.26 (t, 3H, J = 7.1 Hz), 1.33-1.55 (m, 7H), 1.91 (brt, 1H, J = 2.6 Hz), 2.15 (td, 2H, J = 7.0 Hz, 2.6 Hz), 2.225 (s, 6H), 2.233 (s, 6H), 3.04 (d, 1H, J = 6.1 Hz), 3.11 (brs, 1H), 3.57-3.65 (m, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 4.17 (q, 2H, J = 7.1 Hz), 4.56 (s, 1H), 6.94 (s, 2H), 6.98 (s, 2H), one proton not located (N-H or O-H); 13 C NMR (125 MHz, CDCl3) δ 14.23, 16.10, 16.19, 18.23, 25.01, 28.28, 28.58, 33.51, 59.45, 59.48, 60.84, 63.58, 64.69, 68.14, 72.18, 84.43, 127.30, 127.73, 130.62, 130.70, 137.22, 139.10, 155.91, 155.95, 173.91; IR (thin 208 film) 3484(w), 3291(w), 2938(vs), 2861(m), 1730(s), 1483(s), 1221(s), 1142(s), 1017(s) cm–1; HRMS calcd for C31H44NO5 (M+H, ESI+) m/z 510.3219, meas 510.3206; [α]!" ! = –28.3° (c 1.0, CH2Cl2) on 95% ee material. Spectral data for 180: 1H NMR (500 MHz, CDCl3) δ 1.13 (t, 3H, J = 7.1 Hz), 1.20-1.50 (m, 7H), 1.60-1.72 (m, 1H), 1.91 (brt, 1H, J = 2.5 Hz), 2.12 (td, 2H, J = 6.8 Hz, 2.5 Hz), 2.24 (2s, 12H), 3.677 (s, 3H), 3.682 (s, 3H), 3.88-4.01 (m, 2H), 4.07-4.16 (m, 1H), 4.60 (d, 1H, J = 9.0 Hz), 5.19 (s, 1H), 6.85 (s, 2H), 6.87 (s, 2H), two protons not located (N-H and O-H); 13 C NMR (125 MHz, CDCl3) δ 13.80, 16.16, 16.19, 18.16, 24.67, 28.03, 28.31, 30.92, 54.63, 59.48, 59.57, 61.91, 68.32, 75.82, 81.08, 84.22, 127.10, 127.52, 130.67, 130.76, 136.36, 136.90, 156.29, 156.46, 169.20; IR (thin film) 3434(w), 3291(w), 2940(s), 2863(w), 1734(vs), 1221(s), 1171(s) 1017(m) cm–1; HRMS calcd for C31H44NO5 (M+H, ESI+) m/z 510.3219, meas 510.3209; [α]!" ! = – 24.2° (c 1.0, CH2Cl2) on 95% ee material. The reaction carried out at rt afforded the product 180 in 83% isolated yield. The diastereoselectivity (172:180) is 17:1 indicated by 1H NMR spectrum. 5.3.4 Procedure for Converting Compound 172 to Left Head 168 MEDAM MEDAM NH DMF, nBu 4NI EtO 2C OH 172 MEDAM NaH, BnBr 3 HO OBn 182 3 0 °C - rt, 1.5 h EtO 2C 0 °C —rt OBn 181 93% 3 MEDAM TsCl, DCM NH LiAlH 4, THF NH Et 3N, 0 °C 2 h, rt, 46 h N OBn 168 94% 209 3 Compound 181: To a flame-dried 100 mL round bottom flask filled with nitrogen was added compound 172 (2.27 g, 4.44 mmol, 1.00 equiv), dry DMF (13 mL), tetra-n-butylammonium iodide (nBu4NI) (333 mg, 0.900 mmol, 0.200 equiv) and benzyl bromide (BnBr) (0.90 mL, 7.6 mmol, 1.7 equiv). After the mixture was stirred at 0 °C for 10 min, NaH (198 mg, 60% dispersion in mineral oil, 4.89 mmol, 1.10 equiv) was added to the flask. The resulting suspension was stirred at 0 °C for 2 h which became viscous gel-like mixture. Then it was warmed up to rt and stirred at rt for 15 h. After the reaction mixture was cooled to 0 °C, H2O (50 mL) was slowly added to the mixture. It was then extracted with DCM (50 mL x 3). The combined organic layer was dried with Na2SO4, filtered and concentrated. Purification by column chromatography (35 × 200 mm, hexanes:EtOAc 9:1) gave the desired product 181 as a colorless oil (2.48 g, 4.13 mmol) in 93% yield. Rf = 0.29 (hexane:EtOAc 9:1). Spectral data for 181: 1H NMR (500 MHz, CDCl3) δ 1.05-1.31 (m, 5H), 1.35-1.53 (m, 4H), 1.67-1.88 (m, 2H), 1.93 (t, 1H, J = 2.6 Hz), 2.16 (td, 2H, J = 7.0 Hz, 2.6 Hz), 2.223 (s, 6H), 2.225 (s, 6H), 2.29-2.39 (m, 1H), 3.18 (d, 1H, J = 2.5 Hz), 3.64-3.70 (m, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 4.06-4.19 (m, 2H), 4.41 (d, 1H, J = 11.6 Hz), 4.47 (d, 1H, J = 11.6 Hz), 4.63 (s, 1H), 7.026 (s, 2H), 7.034 (s, 2H), 7.21-7.32 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 14.29, 16.19, 16.27, 18.36, 25.39, 28.42, 28.83, 30.79, 59.54, 59.58, 60.63, 61.00, 64.63, 68.23, 72.03, 80.66, 84.51, 127.44, 127.57, 127.84, 127.95, 128.23, 130.49, 130.57, 138.17, 138.27, 139.98, 155.82, 155.89, 174.07; IR (thin film) 3293(w), 2938(s), 2861(m), 1736(s), 1483(m) 1456(m), 1221(m), 1144(m), 210 1017(m) cm–1; HRMS calcd for C38H50NO5 (M+H, ESI+) m/z 600.3689, meas 600.3696; [α]!" ! = – 24.6° (c 1.0, CH2Cl2) on 95% ee material. Compound 168: To an ovendried 25 mL round bottom flask filled with nitrogen was added LiAlH4 (115 mg, 3.02 mmol, 1.60 equiv) and THF (7 mL). After the suspension was cooled to 0 °C, a solution of compound 181 (1.13 g, 1.89 mmol, 1.00 equiv) in THF (5 mL) was added dropwise into the reaction flask at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then rt for 1 h. It was quenched by addition of H2O (0.115 mL), followed by addition of aq NaOH (15%, 0.115 mL) and then another two portions of H2O (0.35 mL x 2). After the mixture was vigorously stirred at rt for 30 min, it became a white emulsion, which was filtered through a Celite pad. The Celite pad was washed with ethyl acetate several times until TLC indicated there was no product in the rinse. The combined organic solution was concentrated to give the crude product 182 as an opaque oil which was then dissolved in DCM (9.5 mL) in an oven-dried 50 mL round bottom flask. After the solution was cooled to 0 °C, Et3N (290 µL, 2.08 mmol, 1.10 equiv) and tosyl chloride (396 mg, 2.08 mmol, 1.10 equiv) were added to the reaction flask. The reaction mixture was stirred at 0 °C for 5 h and then rt for 24 h, which was then added another portion of Et3N (1.77 mL, 12.7 mmol, 6.72 equiv) and tosyl chloride (540 mg, 2.83 mmol, 1.50 equiv). After the mixture was stirred for another 24 h at rt, it was quenched by the addition of NaHCO3 (28 mL). The organic layer was separated and the aqueous layer was extracted with DCM (30 mL x 3). The combined organic layer was dried with Na2SO4, filtered and concentrated. Purification by column chromatography (35 × 211 180 mm, hexanes:EtOAc 9:1) gave the desired product 168 as a colorless oil (956 mg, 1.77 mmol) in 94% yield. Rf = 0.24 (hexane:EtOAc 9:1). Spectral data for 168: 1H NMR (500 MHz, CDCl3) δ 1.20-1.58 (m, 9H), 1.68 (d, 1H, J = 3.6 Hz), 1.79 (td, 1H, J = 6.8 Hz, 3.5 Hz), 1.90 (t, 1H, J = 2.6 Hz), 2.12 (td, 2H, J = 7.2 Hz, 2.7 Hz), 2.17 (s, 6H), 2.25 (s, 6H), 3.00-3.06 (m, 1H), 3.25 (s, 1H), 3.53 (s, 3H), 3.68 (s, 3H), 4.08 (d, 1H, J = 12.0 Hz), 4.12 (d, 1H, J = 12.0 Hz), 6.99-7.05 (m, 4H), 7.07 (s, 2H), 7.15-7.25 (m, 3H); 13 C NMR (125 MHz, CDCl3) δ 16.17, 16.20, 16.22, 16.24, 18.31, 25.10, 28.35, 28.63, 30.58, 33.26, 44.58, 59.41, 59.45, 59.57, 59.62, 68.10, 70.91, 78.21, 78.22, 80.69, 84.64, 127.06, 127.34, 127.40, 128.01, 128.48, 130.42, 130.54, 138.55, 138.64, 139.15, 155.63, 156.15; IR (thin film) 3293(w), 2938(vs), 2861(m), 1483(s), 1221(s), 1144(s), 1017(s) cm–1; HRMS calcd for C36H46NO3 (M+H, ESI+) m/z 540.3478, meas 540.3484; [α]!" ! = – 16.7° (c 1.0, CH2Cl2) on 95% ee material. 5.3.5 Procedure for Coupling Reaction of Left Head 168 and Right Head 169 MEDAM N 1.EtMgBr (1 equiv), rt, THF MEDAM N OBn 168 OTBS CO2Et 3 2. O N 13 169 NHMEADM (1 equiv) THF, 65 °C O OBn OTBS CO2Et 3 183 81% O 13 NHMEADM Compound 183: The reaction was carried out with an adaptation of a procedure reported for a similar transformation.99 To a solution of compound 168 (236 mg, 0.437 mmol, 1.00 equiv) in THF (1.2 mL) was added ethylmagnesium bromide (3 M in diethyl ether, 145 µL, 0.435 mmol, 1.00 equiv) dropwise at 0 °C. After this solution was stirred at 0 °C for 20 min, it was transferred via a syringe 212 to a solution of compound 169 (355 mg, 0.437 mmol, 1.00 equiv) in THF (0.65 mL) at 0 °C. The mixture was then heated up to 65 °C and stirred for 5 h. After it was cooled to rt, the mixture was treated with aq NaH2PO4 (1 M, 2.2 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (4 mL x 3). The combined organic layer was dried with Na2SO4, filtered and concentrated. Purification by column chromatography (25 × 160 mm, hexanes:EtOAc 5:1) gave the desired product 183 as a colorless oil (460 mg, 0.356 mmol) in 81% yield. Rf = 0.20 (hexane:EtOAc 5:1). Spectral data for 183: 1 H NMR (500 MHz, CDCl3) δ -0.09 (s, 3H), 0.00 (s, 3H), 0.82 (s, 9H), 0.98- 1.67 (m, 38H), 1.69 (d, 1H, J = 3.7 Hz), 1.79 (td, 1H, J = 6.8 Hz, 3.7 Hz), 1.922.02 (m, 1H), 2.17 (s, 6H), 2.23 (2s, 12H), 2.26 (s, 6H), 2.29 (t, 2H, J = 7.2 Hz), 2.49 (t, 2H, J = 7.2 Hz), 3.00-3.07 (m, 1H), 3.09 (s, 1H), 3.26 (s, 1H), 3.53 (s, 3H), 3.66 (s, 3H), 3.67 (s, 3H), 3.69 (s, 3H), 3.87-3.93 (m, 1H), 4.09 (s, 2H), 4.124.20 (m, 2H), 4.65 (s, 1H), 6.99-7.05 (m, 8H), 7.08 (s, 2H), 7.16-7.25 (m, 3H); 13C NMR (125 MHz, CDCl3) δ -5.08, -4.29, 14.29, 16.17, 16.19, 16.21, 17.94, 18.83, 24.06, 25.02, 25.74, 25.82, 27.61, 28.74, 28.96, 29.35, 29.46, 29.60, 29.65, 29.67, 29.73, 29.86, 30.56, 33.19, 34.07, 44.49, 45.51, 59.39, 59.52, 59.53, 59.56, 60.40, 61.76, 63.95, 70.89, 74.47, 78.20, 80.60, 80.88, 93.96, 127.07, 127.31, 127.36, 127.37, 127.99, 128.10, 128.47, 130.36, 130.40, 130.50, 130.52, 138.15, 138.52, 138.58, 139.10, 140.33, 155.63, 155.67, 155.83, 156.14, 174.12, 188.49, (2 sp3 carbons not located); IR (thin film) 2928(s), 2855(s), 2213(w), 1740(m), 1674(m), 1483(m), 1221(m), 1144(m), 1017(m) cm–1; HRMS calcd for 213 C81H119N2O9Si (M+H, ESI+) m/z 1291.8685, meas 1291.8682; [α]!" ! = – 16.8° (c 1.0, CH2Cl2). 5.3.6 Procedure for Removal of TBS Group in 183 MEDAM MEDAM N OBn OTBS CO2Et 3 O 183 13 NHMEADM N OH HF CH 3CN/H2O OBn CO2Et 3 184 100% O 13 NHMEDAM Compound 184: The reaction was carried out with an adaptation of a procedure reported for a similar transformation.100 To a 50 mL Teflon round bottom flask was added a solution of compound 183 (180 mg, 0.139 mmol) in acetonitrile (18 mL) followed by the addition of aqueous HF (25%, 0.73 mL). After the reaction mixture was stirred at rt for 5 h, it was quenched with careful addition of aq NaHCO3 (30 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (40 mL x 3). The combined organic layer was dried with Na2SO4, filtered and concentrated. Purification by column chromatography (25 × 160 mm, hexanes:EtOAc 3:1) gave the desired product 184 as a colorless oil (164 mg, 0.139 mmol) in 100% yield. Rf = 0.18 (hexane:EtOAc 3:1). Spectral data for 184: 1H NMR (500 MHz, CDCl3) δ 1.181.66 (m, 39H), 1.67 (d, 1H, J = 3.5 Hz), 1.78 (td, 1H, J = 6.8 Hz, 3.5 Hz), 2.16 (s, 6H), 2.22 (s, 6H), 2.23(s, 6H), 2.25 (s, 6H), 2.28 (t, 2H, J = 7.1 Hz), 2.48 (t, 2H, J = 7.5 Hz), 2.97-3.09 (m, 3H), 3.25 (s, 1H), 3.52 (s, 3H), 3.57-3.63 (m, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 3.68 (s, 3H), 4.08 (s, 2H), 4.17 (q, 2H, J = 7.2 Hz), 4.55 (s, 1H), 6.94 (s, 2H), 6.97 (s, 2H), 6.99-7.04 (m, 4H), 7.06 (s, 2H), 7.15-7.24 (m, 3H); 13 C NMR (125 MHz, CDCl3) δ 14.33, 16.19, 16.20, 16.24, 16.28, 18.87, 214 24.10, 25.06, 25.63, 27.65, 28.78, 28.99, 29.36, 29.47, 29.60, 29.62, 29.63, 29.64, 29.67, 30.59, 33.22, 33.76, 44.52, 45.54, 59.44, 59.58, 59.59, 59.61, 60.92, 63.69, 64.75, 70.92, 72.41, 76.75, 78.23, 80.64, 80.91, 94.02, 127.10, 127.34, 127.39, 127.41, 127.81, 128.03, 128.50, 130.44, 130.56, 130.71, 130.81, 137.29, 138.55, 138.61, 139.13, 139.21, 155.66, 155.99, 156.03, 156.18, 174.08, 188.56 (one sp3 carbons not located); IR (thin film) 3474 (vw), 2926(vs), 2855(s), 1734(m), 1670(m), 1483(m), 1221(s) cm–1; HRMS calcd for C75H105N2O9 (M+H, ESI+) m/z 1177.7820, meas 1177.7784; [α]!" ! = – 14.3° (c 1.0, CH2Cl2). 5.3.7 Preparation of 185 and 188 by Hydrogenation MEDAM Boc N Pd(OH) 2, H 2 (1 atm) OH OBn CO2Et 3 184 O 13 NHMEDAM (Boc) 2O methanol, 62 h NH OH CO2Et OH 5 O 185 85% 13 NHBoc Compound 185: To a oven-dried 50 mL round bottom flask equipped with a stir bar and filled with nitrogen was added compound 184 (77 mg, 0.065 mmol, 1.0 equiv), Pd(OH)2 (Pd(OH)2 on carbon 20%, moisture ≤ 50%, 28.0 mg, 0.020 mmol, 0.30 equiv), di-tert-butyl dicarbonate (72 mg, 0.33 mmol, 5.0 equiv) and methanol (6.5 mL). The flask was sealed with a rubber septum and a needle connected to a vacuum line was used to apply vacuum in the flask through the septum. The vacuum was applied for a few seconds with vigorous stirring of the reaction mixture. Then the vacuum was stopped and a hydrogen balloon was connected to the flask by a needle through the septum. This process was repeated four times. Then the suspension was stirred at room temperature under hydrogen for 62 hours and then filtered through a pad of Celite. The filter cake 215 was washed with EtOAc (5 mL × 3). The combined filtrate was concentrated to give a colorless oil. Purification by column chromatography on silica gel (20 mm × 160 mm, hexanes/EtOAc 4:2.5) gave compound 185 as a colorless oil (40.3 mg, 0.0553 mmol, 85%). Rf = 0.30 (1:1.5 EtOAc/hexane); Spectral data for 185: 1 H NMR (500 MHz, CDCl3) δ 1.13 (d, 3H, J = 6.8 Hz), 1.18-1.34 (m, 31H), 1.35- 1.57 (m, 28H), 2.21 (brs, 2H), 2.34 (t, 4H, J = 7.3 Hz), 3.39-3.48 (m, 1H), 3.60 (brs, 1H), 3.99-4.09 (m, 1H), 4.19 (q, 2H, J = 7.1 Hz), 4.25 (d, 1H, J = 9.0 Hz), 4.59-4.80 (m, 1H), 5.30 (d, 1H, J = 9.1 Hz); 13 C NMR (125 MHz, CDCl3) δ 14.08, 18.21, 23.70, 23.78, 25.47, 25.53, 28.21, 28.31, 29.07, 29.15, 29.22, 29.30, 29.32, 29.35, 29.39, 29.40, 29.48, 29.52, 33.72, 33.99, 42.67, 42.73, 50.09, 57.59, 61.40, 71.97, 74.67, 79.14, 79.75, 156.05, 156.16, 171.75, 211.82. (three sp3 carbons not located); IR (thin film) 3440(m, br), 2928(s), 2855(s), 1717(s), 1507(m), 1368(m), 1167(m) cm–1; HRMS calcd for C40H77N2O9 (M+H, ESI+) m/z 729.5629, meas 729.5626; [α]!" ! = + 3.9° (c 1.0, CH2Cl2). MEDAM N OBn Pd(OH) 2/C, H 2 OTBS CO2Et 3 183 O 13 NHMEADM (Boc) 2O MeOH/EtOAc rt, 48 h Boc NH OH OTBS CO2Et 5 O 188 13 NHBoc Compound 188: The reaction was carried out according to the procedure described above for hydrogenation of 184 with compound 183 (527 mg, 0.408 mmol, 1.00 equiv), Pd(OH)2 (Pd(OH)2 on carbon 20%, moisture ≤ 50%, 115 mg, 0.0819 mmol, 0.200 equiv), di-tert-butyl dicarbonate (356 mg, 1.63 mmol, 4.0 equiv), methanol (25 mL) and ethyl acetate (15 mL). Purification by column chromatography (30 × 180 mm, hexanes:EtOAc 3:1) gave the desired product 216 188 as a colorless oil (300 mg, 0.356 mmol) in 87% yield. Rf = 0.45 (hexane:EtOAc 3:1). Spectral data for 188: 1H NMR (500 MHz, CDCl3) δ –0.10 (s, 3H), –0.03 (s, 3H), 0.77 (s, 9H), 1.09 (d, 3H, J = 6.8 Hz), 1.12-1.27 (m, 32H), 1.32-1.54 (m, 27H), 2.30 (t, 4H, J = 7.4 Hz), 2.64 (brs, 1H), 3.39 (brs, 1H), 3.56 (brs, 1H), 4.00-4.17 (m, 3H), 4.21 (d, 1H, J = 9.9 Hz), 4.73-4.85 (m, 1H), 5.06 (d, 1H, J = 9.9 Hz); 13C NMR (125 MHz, CDCl3) δ -5.24, -4.35, 13.98, 17.80, 18.28, 23.66, 23.75, 25.22, 25.44, 25.54, 25.61, 28.13, 28.21, 28.27, 29.03, 29.14, 29.18, 29.29, 29.31, 29.36, 29.41, 29.43, 29.49, 29.52, 34.05, 34.43, 42.63, 42.70, 50.01, 56.72, 61.13, 72.89, 74.58, 78.98, 79.56, 156.03, 156.07, 171.61, 211.64; IR (thin film) 3447(w), 2928(s), 2855(m), 1717(s), 1499(m), 1169(m) cm–1; HRMS calcd for C46H91N2O9Si (M+H, ESI+) m/z 843.6494, meas 843.6503; [α]!" ! = – 1.6° (c 1.0, CH2Cl2). 5.3.8 Preparation of 186 by Hydrolysis of 185 Boc NH Boc OH CO2Et OH 5 O 185 13 NHBoc LiOH Dioxane/H 2O/THF rt, 4h NH OH CO2H OH 5 13 O NHBoc 186 92% crude yield Compound 186: To a 10 mL round bottom flask equipped with a stir bar was added compound 185 (40 mg, 0.055 mmol, 1.0 equiv), a mixture of dioxane/THF/H2O (2:2:1, 0.5 mL) and a solution of LiOH (1.4 M, 0.10 mL, 0.14 mmol, 2.5 equiv). After the mixture was stirred at rt for 4 h, it was acidified with aq HCl (0.5 M) to pH ~5 and extracted with ethyl acetate (1 mL x 3). The combined organic layer was dried with Na2SO4, filtered and concentrated to give the cude product 186 as a semi-solid in 92% yield. Spectral data for 186: 1H 217 NMR (500 MHz, CDCl3) δ 1.13 (d, 3H, J = 6.9 Hz), 1.16-1.33 (m, 30H), 1.41 (brs, 20H), 1.46-1.57 (m, 6H), 2.35 (t, 4H, J = 7.5 Hz), 3.44 (brs, 1H), 3.60 (brs, 1H), 4.03-4.19 (m, 1H), 4.26 (d, 1H, J = 8.5 Hz), 4.80 (brs, 1H), 5.24 (brs, 2H), 5.60 (d, 1H, J = 8.5 Hz), one proton not located (COOH); Unfortunately, a clean 13 C NMR could not be obtained; IR (thin film) 3370(m, br), 2926(s), 2855(m), 1715(s), 1169(m) cm–1; HRMS calcd for C38H73N2O9 (M+H, ESI+) m/z 701.5316, meas 701.5325; [α]!" ! = + 6.1° (c 1.0, CH2Cl2). 218 REFERENCES 219 REFERENCES 1. Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471-5569. 2. Erkkila, A.; Majander, I.; Pihko, P. M. Chem. 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