CONSTRUCTION OF A VAULTED BIARYL LIGAND LIBRARY FOR THE AZIRIDINATION REACTION By Yong Guan A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chemistry 2012 ABSTRACT CONSTRUCTION OF A VAULTED BIARYL LIGAND LIBRARY FOR THE AZIRIDINATION REACTION By Yong Guan A highly enantioselective asymmetric catalytic synthesis of alkynyl aziridines can be achieved from alkynyl imines with diazo compounds mediated by a chiral boroxinate (BOROX) catalyst generated from VANOL or VAPOL ligand. In contrast to the aziridination reaction (AZ reaction) with aryl and alkyl substituted imines, alkynyl imines react to give cis-substituted aziridines with both diazo esters and diazo acetamides. Unexpectedly, the two diazo compounds afford different enantiomers of the cis-aziridine from the same enantiomer of the catalyst. The (S)-BOROX catalyst promotes the reaction of ethyl diazoacetate such that reaction occurs with the Si-face of the imine and the Si-face of the diazo compound. However, in the case of a diazo acetamide, the (S)-BOROX catalyst switches the facial selectivity for reaction of both substrates from Si-face to Re-face. A diverse family of chiral boroxinate Brønsted acids is generated from a library of thirty-one VANOL derivatives that are substituted in the 7,7’-positions. A direct and convergent synthetic access to the ligand library is made viable by a cycloaddition/electrocylization cascade from various p-substituted phenyl acetic acids. The family of ligands is used to screen the catalytic asymmetric AZ reaction of two different benzhydryl imines, one from an aryl aldehyde and the other from an aliphatic aldehyde. Remarkably, the highest asymmetric induction for each substrate was recorded with the same ligand, 7,7’-di-t-butylVANOL. This ligand was in turn screened with a set of 10 different benzhydryl imines to find that this ligand gives an average of 97% ee over all ten imines whereas the corresponding unsubstituted ligand VANOL gives an average of 87% ee and the VAPOL ligand gives an average of 86% ee. Three sets of VANOL ligands: 1) naphthalene skeleton modified; 2) C3-aryl group modified; 3) C1-symmetric VANOL derivatives were synthesized and evaluated in the AZ reaction. Those modifications lead to complicated outcomes. Generally, 7,7’-substituents are beneficial to the AZ reaction, whereas 4,4’- or 8,8’-substituents are detrimental to the AZ reaction. Modification of the C3-aryl effects the enantioselectivity to some extent. Four VAPOL derivatives were prepared and evaluated in the AZ reaction. In addition to the AZ reaction, those VANOL and VAPOL derivatives were evaluated in the reduction of 2-quinolines and VAPOL was found to be the optimal ligand. A novel DMAP-squaramide catalyst was prepared from BINAM and evaluated in the Michael addition of a nitroalkane to a nitroalkene. To my dearest parents iv ACKNOWLEDGEMENTS As I am approaching the end of my PhD journey, it’s the time to give my sincere thanks to those who help and support me in the past six years. Amongst all the people that I want to thank, my PhD advisor – Dr. William D. Wulff is the first and the most important person. I would like to thank him for his patience, understanding and support. It’s my fortune to find a advisor who is so enthusiastic about research and knowledgable about chemistry and many other things. He provides me the unique freedom and opportunity to work on these interesting and exciting projects, and is always available whenever I need help. I really appreciate his trust on my ability and encouragement when I am frustrated. The post group meetings – the wine parties gives me the unprecedented chance to have a taste of wine and its knowledge as well. I would also like to thank professor Robert E. Maleczka, Jr. As the second reader in my committee members, he offered insightful discussions during my second year oral exam and he also organized the Wednesday night mechanism clubs that were very helpful to my education. I want to thank professors Babak Borhan, and Milton R. Smith for being my committee members and for their valuable teaching in CEM 845, 956 and 820. I owe my thanks to Daniel Holmes and Kermit Johnson for their help on the NMR analysis. I would also like to acknowledge Rui Huang for the help on the GC-Mass and elemental analyses. v Thanks Ms Lijun Chen and professor Daniel Jones for their help in acquiring high resolution mass spectrometry. The friendly working environment could not exist without all my colleagues in Wulff’s group. I want to thank Gang Hu for his help when I first entered the lab, and thank Zhenjie Lu for helping me get familiar with the experimental skills. Special thanks to Zhensheng Ding for being a good guider and chatting-mate. His humor and drawings contribute to my unforgettable life in room 529. Many thanks to Desai Aman for his always “yes” whenever I need help. He was always optimistic and enthusiastic about research and life as a whole. Thanks Alex Predeus for bringing funny things and talks, as well as helpful suggestions. Thanks Prutyanov Victor for his suggestions and discussions. I would like to thank Li Huang specially for being a really good labmate and study mate. We took several courses together and she helped me a lot through those tough courses. I want to thank Anil Kumar Gupta for his help and being an entertainment star during the parties, thank Mummun Mukherjee for her helpful suggestions when I brought questions to her, thank Dima Berbasov for being a considerate and warmhearted labmate, and thank Nilanjana Majumdar for her lovely smiles. Hong Ren, Wynter E. G. Osminski, Mathew Vetticatt, Wenjun Zhao, Xin Zhang, Yubai Zhou, Xiaopeng Yin are friendly group members to whom I am deeply indebted. Life is always colorful with these friends around. Many thanks from the bottom of my heart to Weihan Wang, Xiaojie Dong, Naiguang Lei, Wenjing Wang, Peisong Han, Hui Zhao, Quanxuan vi Zhang, Heyi Hu, Hao Li, Luis Mori-Quiroz, Roozbeh Yousefi … (a long list). Thousands of pictures recorded the colorful moments I spent with my friends. Finally, I would like to thank my parents for their selfless love and support. They are the most important persons in my life and this thesis is a dedication to them. vii TABLE OF CONTENTS LIST OF TABLES …………………………………………………………………………….....xi LIST OF SCHEMES …………………………………………………………………………...xiv ABBREVIATIONS …………………………………………………………………………….xxi CHAPTER ONE VANOL/VAPOL: A NEW CLASS OF PRIVILEGED LIGAND ……………………………….1 1.1 Background ………………………………………………………………………...........1 1.2 BINOL vs VANOL/VAPOL ……………………………………………………………4 1.3 VANOL/VAPOL in asymmetric catalysis ………………………………………………6 1.4 VANOL/VAPOL derivatives in asymmetric catalysis …………………………...........19 1.5 Conclusion ……………………………………………………………………………..26 CHAPTER TWO REAGENT-DEPENDENT CATALYTIC ENANTIODERVEGENT SYNTHESIS OF ALKYNYL AZIRIDINES ………………………………………………………………………27 2.1 Introduction …………………………………………………………………………….27 2.1.1 Utility of alkynyl aziridines in organic transformations ………………………..27 2.1.2 Utility of alkynyl aziridines in natural products synthesis ……………………...34 2.1.3 Previous study on the synthesis of alkynyl aziridines ………………………….37 2.2 Background …………………………………………………………………………….43 2.3 Results and discussion …………………………………………………………………47 2.3.1 Aziridinations with ethyl diazoacetate ………………………………………….47 2.3.2 Aziridinations with diazoactamide ……………………………………………..57 2.4 Future plan ……………………………………………………………………………..67 2.5 Conclusion ……………………………………………………………………………..68 CHAPTER THREE CONVERGENT SYNTHESIS OF 7,7’-DISUBSTITUTED VANOL LIGANDS AND A CONCENSUS IN THE AZIRIDINATION REACTION ………………………………………69 3.1 Introduction …………………………………………………………………………….69 3.2 Background …………………………………………………………………………….72 3.3 Results and discussion …………………………………………………………………80 3.3.1 Preparation of 4-substituted phenylacetic acids …………………………….......80 viii 3.3.2 Preparation of 7-substituted 3-phenyl-1-naphthols ……………………………..81 3.3.3 Oxidative coupling and deracemization …………………………………….......85 3.3.4 Synthesis of 7,7’-VANOL derivatives via Suzuki coupling ……………………87 3.3.5 Synthesis of 7,7’-VANOL derivatives via Stille coupling ……………………..90 3.3.6 Synthesis of 7,7’-VANOL derivatives via Kumada coupling ………………….92 3.3.7 Synthesis of 7,7’-VANOL derivatives via Sonogashira and Ullman coupling reactions ……………………………………………………………………………..92 3.3.8 Screen of 7,7’-VANOL derivatives in the Wulff cis-aziridination reaction ……94 3.3.9 Utility of 7,7’-di-t-butylVANOL in the Wulff trans-aziridination reaction …..105 3.4 Future plan ……………………………………………………………………………107 3.5 Conclusion ……………………………………………………………………………110 CHAPTER FOUR SYSTEMATIC EXPLORATION OF SINGLE-POINT AND DOUBLE-POINT CHANGES TO VANOL BOROX CATALYST: STRUCTURE-ACTIVITY RELATIONSHIP STUDY ON VANOL DERIVATIVES………………………………………………………………………111 4.1 Introduction ……………………………………………………………………...........111 4.2 Background ……………………………………………………………………...........116 4.2.1 Effect of N-substituent on the imine …………………………………………..116 4.2.2 Effect of diazo compounds ……………………………………………………118 4.2.3 Effect of phenols ………………………………………………………………120 4.2.4 Effect of C3 aryl group ………………………………………………………..124 4.3 Results and discussion ………………………………………………………………..128 4.3.1 Effect of substitution on the naphthalene core ………………………………...128 4.3.2 Effect of C3-aryl substituents …………………………………………………136 4.3.3 C1-symmetric VANOL derivatives ……………………………………….......147 4.4 Future plan ……………………………………………………………………………160 4.5 Conclusion ……………………………………………………………………………162 CHAPTER FIVE STUDY OF VAPOL DERIVATIVES AND OTHER ORGANOCATALYSTS ……………..163 5.1 Synthesis of VAPOL derivatives and their applications in asymmetric catalysis ……163 5.1.1 Background ……………………………………………………………………163 5.1.2 Synthesis of novel VAPOL derivatives ……………………………………….166 5.1.3 VAPOL derivatives in asymmetric catalysis ………………………………….170 5.2 The CAEC cascade: scope and limitations ……………………………………...........173 5.3 Reduction of 2-quinoline ……………………………………………………………..178 5.4 Synthesis of a novel DMAP-squaramide catalyst and its applications in catalysis ………………………………………………………………………………....180 5.5 One-pot imine formation-AZ reaction ………………………………………………..182 ix CHAPTER SIX EXPERIMENTAL PART ……………………………………………………………...............189 6.1 Experimental for chapter two …………………………………………………………190 6.1.1 Preparation of propynols ………………………………………………………190 6.1.2 Preparation of propynals ………………………………………………………194 6.1.3 Preparation of alkynyl imines …………………………………………………202 6.1.4 Preparation of diazoacetamide 148 ……………………………………………222 6.1.5 Catalytic asymmetric aziridination of alkynyl imines with ethyl diazoacetate …………………………………………………………………………223 6.1.6 Catalytic asymmetric aziridination of alkynyl imines with diazoacetamides …237 6.1.7 Detemination of the absolute configurations of cis-aziridines from diazoacetamides ……………………………………………………………………..255 6.2 Experimental for chapter three ………………………………………………………..260 6.2.1 Preparation of boronic acids …………………………………………………..260 6.2.2 Preparation of 4-substituted-phenylacetic acids ………………………………261 6.2.3 Preparation of 7-substituted-3-phenyl-1-naphthols ……………………….......264 6.2.4 Preparation of 7,7’-disubstituted VANOL ligands ……………………………281 6.2.5 Catalytic asymmetric aziridination of benzhydryl imines with ethyl diazoacetate mediated by a catalyst prepared from 7,7’-di-t-butylVANOL 174m ………………………………………………………………………...............324 6.3 Experimental for chapter four …………………………………………………...........340 6.3.1 Preparation of alkynes …………………………………………………………340 6.3.2 Preparation of VANOL monomer derivatives …………………………….......345 6.3.3 Preparation of C2-VANOL derivatives ……………………………………….359 6.3.4 Preparation of C1-VANOL derivatives ……………………………………….390 6.4 Experimental for chapter five …………………………………………………...........402 6.4.1 Preparation of aryl alkyne 331x ……………………………………………….402 6.4.2 Preparation of aryl acetic acids ………………………………………………..403 6.4.3 Preparation of monomers ………………………………………………….......409 6.4.5 Functionalization of VANOL monomer ………………………………………426 6.4.6 Asymmetric transfer hydrogenation of 2-pentylquinoline …………………….430 6.4.7 Preparation of squaramide-DMAP-BINAM …………………………………..432 6.4.8 Asymmetric addition of 1-nitropropane to nitrostyrene ………………………435 6.4.9 One-pot imine formation-AZ reaction …………………………………….......436 REFERENCES ………………………………………………………………………...............439 x LIST OF TABLES Table 1.1 Diels-Alder reaction of methacrolein and cyclopentadiene ……………………………6 Table 1.2 Aza Diels-Alder reaction with Danishesky’s diene ……………………………………8 Table 1.3 Imino aldol reaction with silyl ketene acetal 13 ……………………………………….9 Table 1.4 Baeyer-Villiger reactionm of 3-phenylcyclobutanone ……………………….............10 Table 1.5 Desymmetrization of meso-epoxide ………………………………………………….10 Table 1.6 Petasis reaction catalyzed by chiral diols …………………………………………….11 Table 1.7 Aza-Cope rearrangement ……………………………………………………………..13 Table 1.8 Ugi-type reaction ……………………………………………………………………..14 Table 1.9 Cis-selective aziridination reaction …………………………………………...............15 Table 1.10 Asymmetric synthesis of trisubstituted aziridine from Boc imine ………………….16 Table 2.1 Synthesis of ynals: Route I …………………………………………………...............48 Table 2.2 Synthesis of ynals: Route II …………………………………………………………..49 Table 2.3 Optimization of the catalytic asymmetric aziridination of silyl substituted alkynyl imines …………………………………………………………………………............................50 Table 2.4 Optimization of the catalytic asymmetric aziridination of imine 136b ………………52 Table 2.5 Optimization of the catalytic asymmetric aziridination of phenylpropynyl imines ……………………………………………………………………………………………53 Table 2.6 Catalytic asymmetric synthesis of alkynyl aziridines with ethyl diazoacetate ……….56 Table 2.7 Optimization of the catalytic asymmetric aziridination of phenylpropynyl imines with diazoacetate 148 …………………………………………………………………………………60 xi Table 2.8 Catalytic asymmetric synthesis of alkynyl aziridines with diazo acetamide 148 ……………………………………………………………………………………………….62 Table 2.9 Catalytic asymmetric aziridination of alkynyl imines with N-n-butyl diazoacetamide 154 ……………………………………………………………………………………………….64 Table 3.1 Directed mono lithiation-substitution of protected VANOL …………………………73 Table 3.2 Synthesis of 7-substituted 3-phenyl-1-naphthol ……………………………...............82 Table 3.3 Synthesis of optically pure 7,7'-disubstituted VANOL derivatives …………………..86 Table 3.4 Suzuki couplings of 7,7'-dibromo VANOL …………………………………………..88 Table 3.5 Ligand screen on the cis-aziridination reaction of phenyl imine 9i .………………….96 Table 3.6 Ligand screen on the cis-aziridination reaction of phenyl imine 9d .………………..100 Table 3.7 Substrate scope comparison of di-t-Bu-VANOL with VANOL and VAPOL ………………………………………………………………………………………...103 Table 3.8 Cis-aziridination reaction of imines 201 with VANOL and di-t-Bu-VANOL...........................................................................................................................105 Table 3.9 Trans-aziridination reaction of imine 203 with VANOL and di-t-Bu-VANOL ………………………………………………………………………………..106 Table 4.1 Aziridination reaction of different diazo acetates …………………………...............118 Table 4.2 Aziridination reaction catalyzed by ligand BOROX catalyst ……………………….126 Table 4.3 Ligand screen in the aziridination of benzhydryl imines ……....................................134 Table 4.4 Synthesis of 7,7-dibromo VANOL ligands …………………………………………140 Table 4.5 Synthesis of 7,7-diaryl VANOL ligands …………………………………………….141 Table 4.6 Synthesis of 7,7-diaryl VANOL ligands via Suzuki coupling ………………………142 Table 4.7 Synthesis of C3-aryl-1-naphthol …………………………………………………….142 xii Table 4.8 Synthesis of C3-aryl VANOL derivatives …………………………………………..143 Table 4.9 Ligand screen in the aziridination of benzhydryl imines: C3-aryl effect …...............145 Table 4.10 Synthesis of C1-symmetric VANOL derivatives ………………………………….152 Table 4.11 Ligand screen on the aziridination of benzhydryl imines: C1-symmetric VANOL ligands ………………………………………………………………………………………….156 Table 4.12 Ligand screen in the aziridination of benzhydryl imines: C1- vs C2-symmetric ligands ...………………………………………………………………………………………..157 Table 5.1 Synthesis of 2-aryl-4-phenanthrols ………………………………………………….167 Table 5.2 Synthesis of 2-aryl-7-bromo-4-phenanthrols ..............................................................168 Table 5.3 Synthesis of optically pure C2-aryl VAPOL derivatives ……………………………168 Table 5.4 VAPOL Ligand screen on the aziridination of benzhydryl imines …………………170 Table 5.5 Ugi-type reaction mediated with VAPOL derivatives ………………………………171 Table 5.6 Scope of acetylene in the CAEC cascade …………………………………...............173 Table 5.7 Scope of acetic acid in the CAEC cascade ………………………………………….175 Table 5.8 Synthesis of 2-aryl-4-phenanthrols via the CAEC cascade …………………………176 Table 5.9 Michael addition of nitroalkane to nitroalkene with DMAP catalysts ……...............181 Table 5.10 Optimization on the one-pot imine generation-aziridination reactions ……………183 Table 5.11 Procedure III of the aziridination of benzhydryl imines …………………………...185 Table 5.12 Procedure IV of the aziridination of benzhydryl imines …………………...............186 Table 5.13 Optimization on the one-pot imine generation-aziridination reaction ……………..187 Table 5.14 One-pot imine generation-aziridination reactions with aldehyes and benzhydryl amine …………………………………………………………………………………………...188 xiii LIST OF SCHEMES Scheme 1.1 Privileged ligand ……………………………………………………………..3 Scheme 1.2 BINOL vs VANOL/VAPOL ………………………………………………...............5 Scheme 1.3 Diels-Alder reaction of methyl acrylate and cyclopentadiene ………………………6 Scheme 1.4 Aza Diels-Alder reaction of Bh imines ……………………………………...............7 Scheme 1.5 Imino Aldol reaction ………………………………………………………………9 Scheme 1.6 Baeyer-Villiger reaction ……………………………………………………………10 Scheme 1.7 Petasis reaction ……………………………………………………………………..11 Scheme 1.8 Aminoallylation of aldehyde ……………………………………………………….13 Scheme 1.9 Wulff universal aziridination reactions …………………………………………….15 Scheme 1.10 Asymmetric synthesis of trisubstituted aziridines ………………………...............16 Scheme 1.11 Propargylation of acetophenone …………………………………………………..17 Scheme 1.12 Asymmetric hydrogenation of (Z)-methyl-2-acetamido-3-phenylacrylate ……….18 Scheme 1.13 Various reactions catalyzed by VAPOL phosphoric acid ………………...............20 Scheme 1.14 Hydrogenolysis of racemic 3-substituted 3-hydroxyisoindolin-1-ones …………..21 Scheme 1.15 Utility of VAPOL phosphoric acid in the total synthesis of hopeahainol A and hopeanol …………………………………………………………………………………………21 Scheme 1.16 Aza-Darzens reactions …………………………………………………………….22 Scheme 1.17 Reactions of oxindoles ……………………………………………………………23 Scheme 1.18 Hydroacylation of pent-4-enal ……………………………………………………24 xiv Scheme 1.19 Cycloaddition of alkene …………………………………………………………..24 Scheme 1.20 Hydroarylation of alkene ………………………………………………………….25 Scheme 2.1 Nucleophilic addition of alkynyl aziridines ………………………………………..27 Scheme 2.2 Organocopper-mediated ring opening of 2-ethynylaziridines ……………………..28 Scheme 2.3 Ring opening of 2-ethynylaziridines with hydride …………………………………28 Scheme 2.4 Ring opening of trisubstituted ethynylaziridines with various nucleophiles ……………………………………………………………………………………..29 Scheme 2.5 Ring opening of 2-ethynylaziridines with H2O ……………………………………30 Scheme 2.6 Cyclization/ring expansion of ethynylaziridines with isocyanates ………...............31 Scheme 2.7 Synthesis of 1,3-amino alcohols ……………………………………………………31 Scheme 2.8 Counterion effects in the Au(I) catalyzed synthesis of pyrroles …………...............32 Scheme 2.9 Pt(II) catalyzed synthesis of pyrroles from disubstituted ethynylaziridines ……….33 Scheme 2.10 Au(I) catalyzed synthesis of pyrroles from trisubstituted ethynylaziridines ………………………………………………………………………………...33 Scheme 2.11 Pt(II) catalyzed synthesis of 1,4,5,6-tetrahydropenta[b]pyrroles …………………33 Scheme 2.12 Ag(I)-single vs Au(I)-double cyclizations of aryl alkynyl aziridines …………….34 Scheme 2.13 Total synthesis of (+)-lysergic acid, (+)-isolysergol and (+)-lysergol ……………35 Scheme 2.14 Towards total synthesis of mitomycin C ………………………………………….36 Scheme 2.15 Total synthesis of decarbamoyl α-saxitoxinol …………………………………….36 Scheme 2.16 Total synthesis of ustiloxin D ……………………………………………………..37 Scheme 2.17 Reaction of sulfonium yilde with imines …………………………………………38 xv Scheme 2.18 Reaction of guanidinium ylide with aldehydes …………………………...............38 Scheme 2.19 Dehydrohalogenation of α-bromoalkenyl aziridines ……………………...............39 Scheme 2.20 Amination of chiral bromoallenes ………………………………………...............40 Scheme 2.21 Addition of alkynyl cerium reagent to α-chloroinmine …………………...............40 Scheme 2.22 Addition of alkynylzinc reagent to imines ………………………………………..41 Scheme 2.23 Synthesis of chiral alkynyl aziridines from rac allenylzinc reagent ……...............41 Scheme 2.24 Catalytic asymmetric aziridination of 1-phenyl-3-buten-1-yne …………………..42 Scheme 2.25 Brønsted acid catalyzed aziridination of imine and ethyl diazoacetate …………..42 Scheme 2.26 Wulff cis-aziridination reaction …………………………………………………..44 Scheme 2.27 Proposed catalytic cycle of Wulff cis-aziridination reaction ……………………..46 Scheme 2.28 Wulff cis-aziridination reaction of imine …………………………………………47 Scheme 2.29 Synthesis of BUDAM-NH2 ……………………………………………………….48 Scheme 2.30 Preparation of imines ……………………………………………………………..49 Scheme 2.31 Transformations of BUDAM alkynyl aziridine 139b …………………………….53 Scheme 2.32 Control experiment of alkynyl aziridine ………………………………………….55 Scheme 2.33 Formation of the [3+2] adduct ……………………………………………………55 Scheme 2.34 A universal catalyst system for both cis- and trans-aziridines ……………………58 Scheme 2.35 Aziridinations of alkynyl imines with diazo acetate and acetamide ……...............59 Scheme 2.36 Absolute configuration of alkynyl aziridines 152c and 138c ……………………..66 Scheme 2.37 Facial selectivities in the aziridination reactions ………………………………….66 Scheme 2.38 Proposed synthetic route of sphinosine analogues ………………………………..67 xvi Scheme 3.1 BINOL and BINOL derivatives ……………………………………………………69 Scheme 3.2 Synthesis of 3,3'-BINOL derivatives ………………………………………………70 Scheme 3.3 Synthesis of 4,4'-dinitroVANOL …………………………………………………..72 Scheme 3.4 Attempted directed lithiation-substitution of unprotected VANOL ……………….73 Scheme 3.5 Retrosynthetic analysis of 7,7'-disubstituted VANOL ……………………………..74 Scheme 3.6 Various routes for the synthesis of 3-phenyl-1-naphthol …………………………..76 Scheme 3.7 Mechanism of the CAEC cascade ………………………………………………….77 Scheme 3.8 Synthesis of rac-VANOL …………………………………………………………..77 Scheme 3.9 Resolution of rac-VANOL/VAPOL ……………………………………………….78 Scheme 3.10 Deracemization of rac-VANOL/VAPOL ………………………………………...79 Scheme 3.11 Synthesis of 4-iodophenylacetic acid ……………………………………………..80 Scheme 3.12 Synthesis of 4-tert-butyl-phenylacetic acid ……………………………………….81 Scheme 3.13 Synthesis of 7-substituted 3-phenyl-1-naphthols via the CAEC cacade ………….81 Scheme 3.14 Synthesis of 7-silyl 3-phenyl-1-naphthol 175n …………………………...............83 Scheme 3.15 Synthesis of 7-trifluoromethyl-3-phenyl-1-naphthol 175f ………………………..84 Scheme 3.16 Synthesis of 7-nitro-3-phenyl-1-naphthol 175ai ………………………………….85 Scheme 3.17 Synthesis of aryl boronic acids ……………………………………………………88 Scheme 3.18 Synthesis of 7,7'-diaryl VANOLs via Suzuki coupling …………………………..90 Scheme 3.19 Synthesis of 7,7'-disubstituted VANOL via Stille coupling ……………...............91 Scheme 3.20 Synthesis of 7,7'-di-n-butylVANOL ……………………………………...............91 xvii Scheme 3.21 Synthesis of 7,7'-dialkyl VANOL via Kumada coupling …………………………92 Scheme 3.22 Synthesis of 7,7'-disubstituted VANOL via Sonogashira and Ullman coupling ………………………………………………………………………………………….93 Scheme 3.23 The library of 7,7'-disubstituted VANOL derivatives …………………………….94 Scheme 3.24 Wulff cis-aziridination reaction …………………………………………………..95 Scheme 3.25 Synthesis of polymer networks of BINOL derivatives ………………………….108 Scheme 3.26 Proposed polymer network of VANOL derivative 174aa ………………………109 Scheme 4.1 VAPOL BOROX catalyst complexed with the phenyl MEDAM imine …………………………………………………………………………………………...112 Scheme 4.2 VANOL ligand BOROX catalyst complexed with the phenyl MEDAM imine …………………………………………………………………………………………...114 Scheme 4.3 CH-π interaction …………………………………………………………………..115 Scheme 4.4 Aziridination reaction of different N-substituted imines ………………………….117 Scheme 4.5 Aziridination reaction of 3° diazoacetamide ……………………………...............119 Scheme 4.6 Effect of phenols on the aziridination of the phenyl imine 9d ……………………122 Scheme 4.7 Effect of phenols on the aziridination of the phenyl imine 9i …………………….123 Scheme 4.8 Synthetic routes of C3-aryl VANOL derivatives 223 …………………………….125 Scheme 4.9 Substituents on naphthalene core …………………………………………………128 Scheme 4.10 CAEC cascade reactions of 2-, 3- and 4-bromo phenylacetic acids …………….129 Scheme 4.11 Synthesis of dibromo VANOL ligands ………………………………………….129 Scheme 4.12 Synthesis of diaryl VANOL ligands …………………………………………….130 Scheme 4.13 Synthesis of 4,4'-disubstituted VANOL ligands ………………………...............131 xviii Scheme 4.14 Synthesis of 8,8'-disubstituted VANOL ligands ………………………...............132 Scheme 4.15 Synthesis of 8,8'-diphenyl VANOL ligands ……………………………………..133 Scheme 4.16 Synthesis of H8-VANOL ………………………………………………………..133 Scheme 4.17 Aziridination of benzhydryl imines catalyzed by H8-VANOL BOROX ……….135 Scheme 4.18 Ligands for C3 aryl effect study …………………………………………………137 Scheme 4.19 Synthesis of aryl alkynes ………………………………………………...............138 Scheme 4.20 Synthesis of C3 aryl substituted 7-bromo-1-naphthols ………………………….139 Scheme 4.21 Synthesis of C3-aryl VANOL ligand via Suzuki coupling ……………...............144 Scheme 4.22 Cycloaddition of trimethylenemethane and aldehydes ………………………….148 Scheme 4.23 Synthesis of C1-symmetric BINOLs via direct modification of BINOL ………..148 Scheme 4.24 Synthesis of C1-symmetric BINOLs via asymmetric oxidative cross coupling ………………………………………………………………………………...............149 Scheme 4.25 Retro synthetic analysis of C1-symmetric VANOLs ……………………………150 Scheme 4.26 Attempted bromination of 3-phenyl-1-naphthol ………………………...............151 Scheme 4.27 Attempted oxidative cross coupling of 3-aryl-1-naphthols ……………...............152 Scheme 4.28 Attempted oxidative cross coupling ……………………………………………..154 Scheme 4.29 Synthesis of C1-symmetric VANOL derivatives via Suzuki coupling ………….155 Scheme 4.30 Proposed synthetic route of polymer-supported VANOL derivative ……………161 Scheme 5.1 Synthesis of 6,6'-disubstituted VAPOL ligands …………………………………..164 Scheme 5.2 Synthesis of 7,7'-dimethyl VAPOL ligand ………………………………………..165 Scheme 5.3 Synthesis of aryl alkyne …………………………………………………………..166 xix Scheme 5.4 Synthesis of 6-bromo-2-naphthaleneacetic acid ………………………………….166 Scheme 5.5 Synthesis of 7,7'-di-silyl VAPOL derivative ……………………………………..169 Scheme 5.6 Synthesis of 2-phenanthreneacetic acid …………………………………………..177 Scheme 5.7 Functionalization of 3-phenyl-1-naphthol ………………………………..............177 Scheme 5.8 Ligand screen on the asymmetric hydrogenation of 2-quinoline …………………179 Scheme 5.9 Synthesis of DMAP catalysts derived from BINAM ……………………………..180 xx ABBREVIATIONS AZ : aziridination Bh : benzhydryl BINAP : 2,2’-bis(diphenylphosphino)-1,1’-binapthyl BINOL : 1,1’-binaphthol Boc : tert-butyloxycarbonyl BUDAM : bis(3,5-di-tert-butyl-4-methoxylphenyl)methyl DCM : dichloromethane DIBAL : diisopropyl aluminum hydride DME : 1,2-dimethoxy ethane DMAP : 4-N,N’-dimethylaminopyridine DMF : N,N-dimethylformamide EDA : ethyl diazoacetate ee : enantiomeric excess EI : electron ionization ESI : electrospray ionization HRMS : high resolution mass spectrometry MALDI : matrix-assisted laser desorption Ionization MS : mass spectrometry MEDAM : bis(3,5-di-methyl-4-methoxylphenyl)methyl xxi NBS : N-bromosuccinimide TBAF : tetrabutylammonium fluoride TBDPS : tert-butyldiphenylsilyl TfOH : trifluoromethanesulfonic acid THF : tetrahydrofuran TIPS : triisopropylsilyl TLC : thin layer chromatography TMS : trimethylsilyl VANOL : vaulted 2,2’-binaphthol VAPOL : vaulted 2,2’-biphenanthrol xxii CHAPTER ONE VANOL/VAPOL: A NEW CLASS OF PRIVILEGED LIGAND 1.1 Background The demand to develop synthetic methods for optically active compounds in an efficient way is increasing dramatically due to the inherent relationship between biological activity and absolute configuration of stereogenic centers.1 Compared to nature, which makes utility of enzymes, the most efficient and elaborate devices to generate optically enriched molecules, organic chemists with limited tools were struggling until the 1980s with the advances in the 2,3 asymmetric epoxidation of alkenes and asymmetric hydrogenation reactions. On one hand, enzymes normally have a limited substrate scope, while synthetic asymmetric catalysts possess a broader substrate scope. On the other hand, enzymes can sense subtle differences, whereas synthetic asymmetric catalysts can hardly achieve that high level of distinction. One of the ultimate goals for today’s organic chemist is to unveil or generate a catalyst that is suitable for all substrate and at the same time demonstrates excellent enantioselectivity for a given type of transformation. Diversity in catalysis is crucial and essential: 1) a flexible collection of catalysts (i.e. Buchwald ligand kit) enhances the possibility that reactivity and selectivity can be optimized for 4 an individual substrate; 2) the evolutionary development of ligands enables the realization of 5 new transformations (i.e. nitration of aryl chlorides with t-BuBrettPhos); 3) The performance of a ligand library could shed an insightful light on the transition states. Consequently, continuous development of ligands is one the main themes in organic chemistry. 1 Traditionally, asymmetric catalysts have been metal complexes bearing chiral ligands. While the metal dominates the reactivity, the chiral ligand modifies the reactivity and selectivity of the metal center in such a way that one enantionmer is formed preferentially over the other. As a result, the key to obtaining efficient asymmetric catalysis lies in the generation of robust chiral catalysts by properly pairing chiral ligands with a metal core. Rigid and stable ligands with tunable steric and electronic properties are the ideal choices. 6 Since the pioneering development of DIOP by Kagan, many C2 symmetric ligands have been synthesized and investigated. A few classes, which are designated as “privileged” ligands 7 by Jacobsen and coworkers, have been found to be truely general in scope. The important members are shown in Scheme 1.1. The majority of the successes in asymmetric catalysis have been accomplished with these ligands. 2 3 1.2 BINOL vs VANOL/VAPOL Listed as one of the “privileged” ligands, BINOL (short for 1,2’-bi-2-naphthol) was first prepared as a racemate by von Richter in 1873 and the enantiopure version was made by 8,9 Pummerer in 1926. It was not until 1979 that Noyori discovered the potential of BINOL as a useful chiral ligand in his report on the asymmetric reduction of aromatic ketones and 10 aldehydes. Since then, tremendous work has been put into developing the catalytic potential of 11 BINOL and its derivatives. In spite of its efficacy in asymmetric catalysis, a major limitation of BINOL is that the chiral pocket (major groove) formed by the two naphthyl rings is far away from the diols, the bidentate chelating site (minor groove) (Scheme 1.2). One of the solutions to gain increased enantioselection is to introduce substituents at the 3,3’-positions. However, the rotation of the C-C or C-X single bonds between the 3,3’-groups and the binaphthyl motif increases the flexibility of the skeletal backbone, leading to more conformational isomers in transition states and decreased enantioselectivity. 12 Inspired by the structural topology of gossypol, a naturally occurring compound found in cotton seeds, our group designed and synthesized vaulted 2,2'-binaphthol (VANOL) and vaulted 13 3,3'-biphenanthrol (VAPOL) a new class of biaryl ligands (Scheme 1.2). The major feature of VANOL and VAPOL is that annulated benzene ring is extended in the direction of the nascent active site of the phenol units. Therefore, a much deeper chiral pocket is formed and the chelating site is in the major groove. Another feature is that the bulkiness of the adjacent phenyl groups constrains the rotation of the C-C single bond connecting the two naphthyl rings. The 4 choice of phenyls on the 3,3’-positions of VANOL and the 2,2’-positions of VAPOL was made out of concern for synthetic convenience. 5 1.3 VANOL/VAPOL in asymmetric catalysis Since the debut of VANOL and VAPOL, our gourp as well as other research groups initiated extensive investigations on the applications of these new ligands and this will be reviewed below. entry ligand % yield exo/endo % ee 1 (S)-BINOL 99 32.3 23 2 (S)-3,3’-(SiPh3)2-BINOL 69 11.5 20 3 (S)-VANOL 84 13.3 5 4 (S)-VAPOL 100 49.0 91 5 (S)-6,6’-Br2-VAPOL >95 8.3 18 6 (S)-6,6’-Me2-VAPOL >95 14.4 30 7 (S)-6,6’-Ph2-VAPOL 76 11.7 -41 8 (S)-6,6’-(3,5-(t-Bu)2-C6H3)2-VAPOL >95 8.4 62 6 The Diels-Alder reaction of methyl acrylate and cyclopentadiene was investigated in our group. Catalysts generated from various biaryl ligands and Et2AlCl were examined, and significant asymmetric induction was achieved with VAPOL as the ligand along with the 14 addition of a carbonyl mimic (Scheme 1.3). A dramatic phenomenon from this study is the occurrence of an autoinduction resulting from a coordination complex between the product and the catalyst. A similar study on the Diels-Alder reaction of methacrolein and cyclopentadiene was also carried out (Table 1.1). 14,15 Among the ligands BINOL, 3,3’-disubstitued BINOL and VANOL, VAPOL stands out as the optimal ligand, giving 91% ee. A number of 6,6’-disubstituted VAPOL derivatives were also prepared and evaluated. However, none of these were found to exceed VAPOL in terms of asymmetric induction. Dr. Newman from our group developed a protocol for the aza-Diels-Alder reactions of N-benzhydryl imines and Danishefsky’s diene with a catalyst derived from VAPOL and 16 B(OPh)3 (Scheme 1.4). A similar catalyst derived from BINOL and B(OPh)3 does not provide any turnover while the catalyst generated from VAPOL and B(OPh)3 furnishes good turnover, giving excellent enantioselectivity and yield (Table 1.2). 7 entry ligand % yield % ee 1 BINOL 0 - 2 VAPOL 94 94 An asymmetric imine aldol reaction of silyl ketene acetals and aryl imines provides an important method for access to chiral β-amino esters. Kobayashi and coworkers reported the first useful catalytic asymmetric version of this transformation with a zirconium complex derived from 6,6’-Br2-BINOL. 17 Our group also became interested in the same reaction and published a 18 temperature independent and highly catalytic asymmetric version (Scheme 1.5). The VAPOL derived catalyst gives a much higher asymmetric induction than does either BINOL or 3,3’-Br2-BINOL derived catalysts. Later on, 7,7’-Me2-VAPOL prepared by Dr. Rampalakos from our group was demonstrated to give an even more efficient catalyst and this confirmed the 19 model proposed for the intermediates in this reaction (Table 1.3). 8 entry ligand % yield % ee 1 VAPOL 94 89 2 BINOL 100 28 3 3,3’-Br2-BINOL 87 48 4 7,7’-Me2-VAPOL 97 86 The utility of VANOL and VAPOL has been extended to the Baeyer-Villiger reaction 20 producing g-butyrolactones (Scheme1.6). Bolm and coworkers reported that VANOL is superior to VAPOL and BINOL with respect to asymmetric induction for a catalyst generated from VANOL and Me2AlCl (Table 1.4). The enantioselectivies are claimed to be among the best for those simple substrates. 9 entry ligand % ee 1 BINOL 68 2 VAPOL 14 3 VANOL 80 A collaboration project on catalytic asymmetric ring opening reactions of rac-epoxides with 21 alcohols was initiated by Prof. Nyugen and coworkers at Northwestern University. suggested that VAPOL was the best ligand for the transformation (Table 1.5). 10 Their study Table 1.5 (cont’d) entry ligand % yield % ee 1 BINOL 51 59 2 3,3’-Ph2-BINOL 19 63 3 VAPOL 69 81 4 VANOL - 20 Schaus and coworkers developed the asymmetric Petasis reaction between alkenyl 22 boronates, secondary amines and glyoxylates to generate a-amino esters (Scheme 1.7). BINOL and 3,3’-disubstituted BINOL derivatives provide low to modest asymmetric inductions, while VANOL and VAPOL produce products in good yields with excellent enantioselectivities (Table 1.6). 11 Table 1.6 (cont’d) entry ligand % yield % ee 1 BINOL 45 20 2 3,3’-Br2-BINOL 65 50 3 3,3’-Ph2-BINOL 51 40 4 3,3’-(3,5-Me2-C6H3)2-BINOL 25 18 5 3,3’-(SO2CF3)2-BINOL 70 10 6 VANOL 77 70 7 VAPOL 80 74 Asymmetric aminoallylation of aldehydes is a good way to synthesize chiral homoallylic amines. Rueping and coworkers demonstrated the first asymmetric version of this transformation 23 catalyzed by a Brønsted acid. Hong Ren from our group developed a highly enantioselective aminoallylation of aldehyde which is synergistically catalyzed by a chiral Brønsted acid derived 24 from VANOL and a non-chiral Brønsted acid (Scheme 1.8). Good to excellent inductions and yields for both aryl and alkyl aldehydes were obtained. During the optimization of aza-Cope rearrangement, catalysts derived from BINOL derivatives or VAPOL could not compete with VANOL (Table 1.7). 12 entry ligand % yield % ee 1 (R)-BINOL 78 36 2 (R)-3,3’-Ph2-BINOL 62 –7 3 (R)-VAPOL 84 9 4 (R)-VANOL 89 78 13 The applications of the VANOL/VAPOL ligands have been extended to the Ugi reactions, for which no successful catalytic asymmetric version has yet been realized. Dr. Huang from our group has made great efforts on the Ugi-type reactions of an aldehyde, secondary amine and t-Bu isocyanide. Various biaryl ligands have been evaluated and a boroxinate catalyst prepared from 25 VAPOL turned out to be the optimal at this early stage (Table 1.8). entry ligand % yield % ee 1 (R)-VAPOL 76 –18 2 (S)-VANOL 60 6 3 (R)-3,3’-Ph2-BINOL 37 –11 4 (R)-3,3’-Br2-BINOL 30 –11 5 (R)-3,3’-(SiPh3)2-BINOL trace - Aziridination is one of the most important applications of the VANOL/VAPOL ligands. Our group first developed a protocol for the highly enantioselective cis-selective aziridination reactions of imines and ethyl diazoacetate (Scheme 1.9).26 This transformation is catalyzed by a self-assembled boroxinate derived from VANOL/VAPOL and B(OPh)3. Later on, Dr. Desai from our group realized the highly enantioselective trans-selective aziridination reactions of 14 imines and diazoacetamides catalyzed by 15 the same boroxinate 27 catalyst. In case of the cis-selective aziridination reactions, a number of BINOL derivatives were evaluated by our group and Wipf’s group, and low to moderate asymmetric inductions were 25,28 observed (1-78% ee) (Table 1.9). Installation of proper steric can improve the induction from 17% ee (BINOL, Table 1.9, entry 1) to 76% ee (3,3’-Ph2-BINOL, Table 1.9, entry 2). If the substituent in the 3,3’-positions of BINOL is too big (Table 1.9, entry 4 and 5), racemic product was obtained. With the success of universal catalytic asymmetric aziridination protocol established, Dr. Huang from our group developed the first procedure for the catalytic asymmetric synthesis of trisubstituted aziridines from Boc-imines and diazo 29 diastereoselectivities and enantioselectivities (Scheme 1.10). compounds excellent Catalysts prepared from BINOL derivatives could not compete with those generated from VANOL. 16 with Table 1.10 (cont’d) entry ligand % conv. % yield % ee 1 (S)-VANOL 100 80 94 2 (S)-VAPOL 66 21 –8 3 (S)-BINOL 92 56 40 4 (S)-3,3’-Br2-BINOL 100 79 53 5 (S)-3,3’-Ph2-BINOL 65 14 0 Schaus and coworkers demonstrated that VANOL and VAPOL could catalyze the asymmetric propargylation of acetophenone with allenylboronate, giving medium to good 30 enantioselectivities (Scheme 1.11). Van Leeuwen and coworkers reported that supermolecular complex assembled from Ti(Oi-Pr)4, [Rh(nbd)2]BF4, achiral ditopic ligand 40 and VAPOL could catalyzed the asymmetric hydrogenation of (Z)-methyl-2-acetamido-3-phenylacrylate 38, giving 83.6% ee 31 (Scheme 1.12). 17 18 1.4 VANOL/VAPOL derivatives in asymmetric catalysis The last decade has witnessed the flourishing of organocatalysis in synthesis, the third pillar of asymmetric catalysis after biocatalysis and metal catalysis. In this new trend, Akiyama and 32 Terada pioneered the BINOL based chiral phosphoric acid catalyzed reactions. The phosphoric 33 acid center activates substrates by either protonation or H-binding. Antilla and coworkers have successfully employed VANOL/VAPOL phosphoric acids in a 34a number of reations, such as imine amidation 34c a-amino esters, 34b and imidation reduction of a-imino esters to 34d as well as the desymmetrization of meso-aziridines with azide 34e or thiols (Scheme 1.13). Almost At the same time, Della Sala and coworkers reported a similar desymmetrization of meso-aziridines with Me3SiSPh. 35a Later on, they extended the nucleophile 35b in this transformation to selenium nucleophiles. Zhou and coworkers developed an asymmetric synthesis of 3-substituted isoindolin-1-ones via the VAPOL phosphoric acid catalyzed transfer hydrogenolysis of racemic 3-substituted 36 3-hydroxyisoindolin-1-ones with a Hantzsch ester (Scheme 1.14). 19 20 Snyder and coworkers applied VAPOL phosphoric acid in the total synthesis of hopeahainol 37 and hopeanol (Scheme 1.15). One critical step is the VAPOL phosphoric acid mediated pinocal rearrangement of intermediate 42 to 43 with high diastereoselectivity. 21 In addition to VAPOL phosphoric acid, Antilla and coworkers also utilized the corresponding metal salts in several asymmetric transformations. They developed an asymmetric aza-Darzens reaction in which trisubstituted aziridines was obtained via the nucleophilic addition 38 of a-chloro-1,3-diketones to N-benzoyl imines (Scheme 1.16). This was claimed to be the first example of an enantioselective Mannich-type reaction catalyzed by a magnesium salt of a chiral phosphoric acid. Chiral 3,3’-disubstituted oxindoles are important structural units in alkaloids and pharmaceuticals. Antilla and coworkers realized a highly enantioselective chlorination of 39 3-substituted oxindoles catalyzed by a chiral calcium VAPOL phosphate salt (Scheme 1.17). The same calcium phosphate salt was also found to be an efficient catalyst in the asymmetric 39 Michael addition of 3-aryloxindoles to methyl vinyl ketone, 40 benzoyloxylation of 3-aryloxindoles. 22 as well as the asymmetric Phosphoramidites derived from VANOL/VAPOL also demonstrated potential in some asymmetric catalytic reactions. Carreira and coworkers showed that intramolecular hydroacylation of pent-4-enals affording β-substituted cyclopentanones could be catalyzed by cationic rhodium complexes prepared from VANOL phosphoramidite-alkene ligand and an 41 achiral phosphine ligand (Scheme 1.18). 23 Toste and coworkers explored the potential of VANOL/VAPOL phosphoramidite ligands in 42 the Au(I)-catalyzed asymmetric intramolecular [2+2] cycloaddtion of allenenes (Scheme 1.19). 24 Ellman and coworkers found that the enantioselective catalytic intramolecular hydroarylation of alkenes via imine directed C-H activation could be promoted by rhodium complexes which are prepared from VANOL/VAPOL phosphoramidite ligands 57 and 58 43 (Scheme 1.20). 25 1.5 Conclusion The advent of VANOL and VAPOL, a new ligand class, opens a new door to a number of catalytic asymmetric reactions. More and more attention on VANOL/VAPOL has been drawn by the chemical community, as we have seen a rapid increasing demand for VANOL and VAPOL from other research groups and commercial suppliers (i.e. Sigma-Aldrich). Inspired by the big library of existing BINOL derivatives currently in service, we initiated the project on constructing a library of VANOL/VAPOL derivatives. With the library in hand, a number of reactions could be further optimized. The first highly enantioselective catalytic synthesis of cis-alkynyl aziridine-2-carboxylate esters or amides was developed (Chapter 2). This protocol features an unprecedented reagent-dependent catalytic enantiodivergent synthesis of alkynyl aziridines. A large diverse library of 7,7’-disubstituted VANOL derivatives were designed, synthesized and evaluated in the Wulff aziridination reactions of imines and ethyl diazoacetate (Chapter 3). 7,7’-tBu2-VANOL turned out to be the best and is superior to VANOL/VAPOL for 14 different substrates. Ligands with various substitution patterns on different positions of the VANOL backbone were successfully prepared and evaluated in the Wulff aziridination reactions of imines and ethyl diazoacetate (Chapter 4). This study could shed some light on the critical non-covalent binding interactions between the substrate and the catalyst in the transition states. The synthesis and evaluation of several VAPOL derivatives, the examination of VANOL derivatives in reduction of 2-quinoline, and the synthesis and application of a novel bifunctional squaramide catalyst based on BINAM as a chiral scaffold will also be discussed (Chapter 5). 26 CHAPTER TWO REAGENT-DEPENDENT CATALYTIC ENANTIODERVEGENT SYNTHESIS OF ALKYNYL AZIRIDINES 2.1 Introduction The last decade has seen the development of plethora of development of application of the chemistry of alkynyl aziridine. Like other aziridines, alkynyl aziridines with 3-membered cores are of importance for ring opening reactions, and are used in natural products synthesis. 2.1.1 Utility of alkynyl aziridines in organic transformations 44 Ring opening of alkynyl aziridines could occur in three ways (Scheme 2.1). The most common attack occurs at the propargylic position (path a) due to activation from the alkyne. A mixture of regioisomers could be obtained with nucleophilic attack on the alkyne carbon to afford an allene (path b) or attack occurring at the homopropargylic carbon (path c). Many variations of the 27 conjugate SN2’ ring opening reactions of alkynyl aziridines with various nucleophiles provide diverse motifs and useful building blocks. Ohno and coworkers reported that the 3-alkyl-2-ethynylaziridines could be converted to N-protected amino allenes stereospecifically via an anti-SN2’ ring opening with organocopper species (Scheme 2.2). (S,R)-amino allenes, 45 While treatment of (2S,2S)-2,3-cis-3-alkyl-2-ethynylaziridines gives reaction of (2R,2S)-2,3-trans-3-alkyl-2-ethynylaziridines (S,S)-isomers. 28 generates Yudin and coworkers showed that unprotected α-amino allenes could be accessed via a SN2’ scission of N-H alkynyl aziridines with a boron hydride (Scheme 2.3). 46 A syn hydride transfer was suggested following the pre-coordination of boron to the aziridine nitrogen atom. In general, ring opening occurs at the more substituted carbon when a trisubstituted ethynylaziridines is employed. Joullié and coworkers demonstrated that ring opening of a 29 trisubstituted alkynyl aziridines could provide 1,2-diamines in a complete regio- and stereoselective way. They found that the nucleophile could be extended to phenols, thiols, azide and chloride, affording diverse building blocks (Scheme 2.4). 47 Ferreira and coworkers developed a protocol for the synthesis of acetylenic α-amino alcohols via ring opening of 2,3-disubstituted ethynyl N-tert-butanesulfinylaziridines with p-toluenesulfonic 48 acid (Scheme 2.5). Cis and trans aziridines furnish syn and anti α-amino alcohols, respectively. High regio- (>20:1) and diastereoselectivities (>20:1) were achieved. Ohno and coworkers developed a Pd(0) catalyzed domino cyclization/ring expansion of 2-ethynylaziridines bearing a N-protected 2-aminoethyl group (Scheme 2.6). N-protected 2-(4-aminobut-1-ynyl)aziridine derivatives and aryl isocyanates 49 The reaction of (1 equiv) at room temperature generates 4-(4,5-dihydropyrrol-2yl)imidazolidin-2-one derivatives 69. Interestingly, the reaction of the same substrates with excess isocyanates (5 equiv) at –40 °C affords bis-adducts 70 as the major products. 30 Ohno and coworkers found that allenylindium reagents with a protected amino group could be synthesized via a Pd(0) catalyzed ring opening of optically pure N-protected 3-alkyl-2-ethynylaziridines by treatment with InI in the presence of H2O (Scheme 2.7). 50 The subsequent stereoselective addition of allenylindium reagent to aldehydes yields chiral 1,3-amino alcohols. While 2,3-trans-aziridines give syn,syn-1,3-amino alcohols, 2,3-cis-aziridines give anti,syn-1,3-amino alcohols. 51 That pyrroles can be prepared from alkynyl aziridines has drawn substantial interest. Davies and coworkers showed that 2,5-substituted pyrroles are formed when OTs is present as the 31 counterion of Au(I) catalyst (Scheme 2.8). 51a While with OTf as the counterion, 2,4-substituted pyrroles are obtained via a ring expansion and rearrangement. At the same time, Hou and 51c coworkers reported similar results. Yoshida and coworkers demonstrated that 2,5-substituted pyrroles could be obtained via a Pt(II) catalyzed cyclization of alkynyl aziridines in aqueus media (Scheme 2.9). 51b Treatment of the 51j same substrates with I2 and NaHCO3 leads to 3-iodo-2,5-substituted pyrroles. 32 Pale and coworkers found that acyloxylated ethynylaziridines could be efficiently converted into 51e pyrroles catalyzed by Au(I) in the presence of MeOH or EtOH (Scheme 2.10). Yoshida and coworkers revealed that 1,4,5,6-tetrahydropenta[b]pyrroles could be accessed from 2-alkyl-1-azaspiro[2.3]hexanes with the aid of the Au(I) catalyst (Scheme 2.11). 33 51i Pale and coworkers showed that alkynyl aziridines with an aryl group could be transformed into aminoallenylidene isochromns, isoquinolines or tetrahydonaphtalenes by Ag(I) and into 1-azaspiro[4.5]decane derivatives by Au(I) (Scheme 2.12). 52 Both reactions went through a Friedel-Crafts type intramolecular reaction leading to an allene intermediate. This first cyclization was suggested to be an anti-SN2’ reaction. Au(I) also catalyzed a second intramolecular cyclization of the allene intermediate to the spiro species. 2.1.2 Utility of alkynyl aziridines in natural products synthesis A number of research groups have taken advantages of the established useful transformations of alkynyl aziridines in the total synthesis of natural products. 34 Ohno and coworkers synthesized chiral 1,3-amino alcohol 82 from the Pd(0)-and InI(I)-mediated reductive coupling of the L-serine derived 2-ethynylaziridine 81 and formaldehyde (Scheme 2.13). 50c From this intermediate, indole alkaloids (+)-lysergic acid, (+)-isolysergol and (+)-lysergol were synthesized enantioselectively. 35 Johnston and coworkers are working on the synthesis of mitomycin natural products. An aminomercuration/coupling sequence on alkynyl amine 86 with quinone 87 gave an advanced intermediate 88 towards the total synthesis of the antitumor agent mitomycin C (Scheme 2.14). 53 Saxitoxin is a potent and specific blocker of voltage-gated sodium channels. Nishikawa and coworkers completed the total synthesis of decarbamoyl α-saxitoxinol (Scheme 2.15). 36 54 One of the key reactions is the ring opening of guanidino ethynylaziridine 90 with NaN3 to afford intermediate 91. With their previous studies on the chemistry of ethynylaziridines, Joullié and coworkers 47c accomplished the total synthesis of ustiloxin D (Scheme 2.16). One of the featured steps is that of a Cu(I) promoted ring opening of an ethynylaziridine with a phenol to yield an alkyl aryl ether in 90% yield. In addition to ustiloxin D, they were able to synthesize ustiloxin F and eight analogues of this family. 47e By employing the same chemistry, Wandless and coworkers 47b finished the total synthesis of antimitotic phomposin B. 2.1.3 Previous study on the synthesis of alkynyl aziridines 37 In 1997, Dai and coworkers reported the first asymmetric synthesis of an ethynylaziridine which involves the reaction of N-tosylimines with D-(+)-camphor derived chiral sulfionium ylide (Scheme 2.17). 55 Moderate to good enantioselectivities and excellent cis/trans selectivities were obtained. Ishikawa and coworkers showed that reaction of a chiral guanidinium ylide with 3-phenylprop-2-ynal gave an ethynylaziridine with excellent asymmetric induction, though the trans/cis ratio was low (Scheme 2.18). 56 Ibuka and coworkers demonstrated that dehydrohalogenation of α-bromoalkenyl aziridines yielded 2,3-cis- and 2,3-trans-N-arylsulfonyl-2-ethynylaziridine with high enantiomeric purity (>99% ee) (Scheme 2.19). 57 Though the details of the dehydrobromination reactions are not clear, they proposed two pathways which were depicted in Scheme 2.19. If the 38 dehydrobromination goes by path A, it will generate the 2,3-trans-ethynylaziridine and if it proceeds by path B, it will provide either only 2,3-trans-ethynylaziridine or 2,3-cis-ethynylaziridine or a mixture of both. Ohno and coworkers reported that stereoselective synthesis of 2,3-cis-2-ethynylaziridines can be achieved from chiral amino allenes mediated by NaH (Scheme 2.20). 58 Both (4S,aS)-4-alkyl-[N-(arylsulfonyl)amino]-1-bromobuta-1,2-dienes and their (4S,aR)-isomers give a mixture of 2,3-cis- and 2,3-trans-2-ethynylaziridines with the former product predominating. The amination of (4S,aR)-bromoallenes affords better selectivities. 39 Hodgson and coworkers showed that addition of alkynyl cerium reagent to N-(2-chloroethylidene)-tert-butylsulfinamide provided alkynyl aziridine 105 in 82% yield with good diastereoselectivity (85:15) (Scheme 2.21). 59 This was the only example of an ethynylaziridine generated by their protocol. Chemla and coworkers demonstrated that reactions of allenylzinc carbenoid 106 with various imines 2.22). afforded 60a,60b 2,3-trans-ethynylaziridines with excellent stereoselectivities (Scheme While the reactions of N-benzylaldimines 107 gave N-benzyl aziridines, the reactions of N-(trimethylsilyl)imines 109 gave N-H aziridines. 40 Ferreira and coworkers showed that enantiopure ethynyl N-tert-butanesulfinylaziridines could be prepared from the condensation of the rac allenylzinc carbenoid 106 onto enantiopure N-tert-butanesulfinylaldimines and ketimines 111 in good to excellent yields (Scheme 2.23). 60c,d,e Katsuki and coworkers reported that the (R,R)-Ru(salen)(CO) complex 115 can catalyze the asymmetric aziridination of 1-phenyl-3-buten-1-yne, yielding ethynylaziridine 116 in 85% yield and 95% ee (Scheme 2.24). 61 This was the only example of an ethynylaziridine produced by this catalyst. 41 In their effort towards the total synthesis of mitomycin C, Johnston and coworkers found that the Brønsted acid TfOH will catalyze the aziridination of the imine 134x and ethyl diazoacetate, providing 2,3-cis-2-ethynylaziridine137x in 70% yield (Scheme 2.25). 53b Although great effort has been put into the synthesis of ethynylaziridines, there is no reported procedure that features an asymmetric catalyst that gives high enantioselectivity, high diastereoselectivity and a broad substrate scope. 42 2.2 Background Our group has developed an enantioselective catalytic cis-aziridination reaction (Wulff cis-aziridination) involves imines and diazo compounds. 26 Since the first report from our group in 1999, we have put a lot of effort into the continuous study of this transformation (Scheme 2.26). The catalyst in the Wulff cis-aziridination was originally believed to be a Lewis acid. Later on we obtained the crystal structure of the complex of the catalyst and the imine which 26i,26l revealed that the actual catalyst is a Brønsted acid. The Brønsted acid is a boroxinate which is self-assembled from VANOL or VAPOL, B(OPh)3 and imine. Imines with various substituents, such as aryl, heteroaryl, 1°, 2°, 3° alkyl, will proceed successfully under the reaction condition. Recently, we have developed a muti-component process from an aldehyde, an 26p amine and a diazo compound. As a result, the substrate scope was further broadened. 43 The initial reaction was developed with imines prepared from commercially available benzhydryl amine. Dr. Zhang and Dr. Lu undertook an investigation to extensively probe the effects of changes in the conformation, electronics, and sterics of the two phenyl groups in the 26h,j N-benzhydryl substituent. The study provided a clearer picture of important non-covalent interactions between the catalyst and the imine. In addition, two useful N-substituents, tetra-methyldianisylmethyl (MEDAM) and 3,5-di-tert-butyldianisylmethyl (BUDAM), were identified from their study. Subsequently, the reaction scope was defined for the MEDAM group 44 by Dr. Mukherjee. Clean and high yielding reactions with high enantioselectivties for both aryl and alkyl imines became possible with the Wulff cis-aziridination reaction. The proposed catalytic cycle is shown in Scheme 2.27. VANOL/VAPOL, B(OPh)3 and H2O, upon heating generate meso-monoborate (B1) and pyroborate (B2). After addition of the imine substrate, a spiroboroxinate catalyst-imine complex, BOROX (B3) is formed. The diazo compound, upon coordinating with the BOROX catalyst, reacts with the imine to afford the aziridine. The imine will replace the aziridine and regenerate the loaded BOROX catalyst, thus releasing the aziridine product. 45 46 2.3 Results and discussion 2.3.1 Aziridinations with ethyl diazoacetate Dr. Patwardhan was the first to examine the Wulff cis-aziridination of alkynyl imine derived from 3-phenyl propynal and the result was not promising, giving only moderate yields and asymmetric induction. Dr. Lu found that the yield but not the asymmetric induction could be improved with tri-isopropyl silyl imine 134a (91% yield and 32% ee) (Scheme 2.28). As had proven to be the case with aryl and alkyl imines it was thought that imines from BUDAM-NH2 or MEDAM-NH2 might increase the low induction. BUDAM-NH2 128 was prepared according the published procedure (Scheme 2.29) in a large 26h scale. 26j MEDAM-NH2 129 was prepared in a similar fashion. Since very few alkynyl aldehydes are commercially available, two practical routes were employed. Each route has its own advantages and shortcomings. 47 62 The first route involves the formylation of acetylides with DMF (Table 2.1). entry R % yield 1 C6H5 85 2 3-MeC6H4 75 3 2-MeC6H4 69 4 cyclohexyl 74 5 n-butyl 56 6 t-Bu 50 7 i-Pr3Si 78 48 The second route consists of a two-step sequence (Table 2.2). 63 Sonogashira coupling of aryl iodides with propargyl alcohols and subsequent oxidation with MnO2 furnishes the preparation of ynals. Compared with the alkynes used in Route I, aryl iodides are cheaper and available in greater variety. However, Route I is more straightforward. entry R % yield (coupling) % yield (oxidation) 1 4-BrC6H4 82 66 2 4-NO2C6H4 93 70 3 4-MeOC6H4 59 67 4 4-MeO2CC6H4 87 67 5 1-naphthyl 55 72 With the ynals and amines in hand, the imines were prepared with a known procedure (Scheme 2.30). Most imines were obtained as a mixture of trans and cis isomers, which is different from aryl and alkyl imines where only the trans isomer is observed. 49 entry R P ligand imine cis/trans AZ imine % yield b AZ % ee AZ c 1 Bh (S)-VAPOL 134a 1.3:1 137a 91 32 2 i-Pr3Si Bh (R)-VANOL 134a nd 137a 87 -21 3 Me3Si Bh (S)-VAPOL 134b nd 137b 78 32 4 i-Pr3Si MEDAM (S)-VAPOL 135a 1.5:1 138a 87 44 5 i-Pr3Si MEDAM (R)-VANOL 135a nd 138a 89 -40 6 i-Pr3Si BUDAM (S)-VAPOL 136a nd 139a 97 7 i-Pr3Si BUDAM (S)-VANOL 136a nd 139a 97 8 Me3Si BUDAM (S)-VAPOL 136b 19:1 e 139b 93 9 Me3Si BUDAM (S)-VAPOL 136b 1.6:1 139b 86 10 Me3Si BUDAM (R)-VANOL 136b 19:1 e 139b 91 11 a i-Pr3Si Me3Si BUDAM (S)-VAPOL 136b 19:1 e 139b 87 d 83 d 78 f d,f 85 84 –74 80 Unless otherwise specified, all reactions were performed at 0.5 M in ether with 1.1 equiv of EDA for 24 h with 10 mol% catalyst. The catalyst was prepared from 1 equiv VAPOL or 50 Table 2.3 (cont’d) VANOL, 4 equiv B(OPh)3 and 1 equiv H2O at 80 °C in toluene for 1 h, followed by removal of volatiles under vacuum (0.5 mm Hg) at 80 °C for 0.5 h. No trans-aziridine was detected in any reaction. b Isolated yield of cis-aziridine 137, 138, 139 after chromatography on silica gel. c Determined by HPLC on a Chiralcel OD-H column. The induction in all entries was determined after conversion of 139b to the N-H aziridine 141. d e 2 mol% catalyst. The isomer ratio was f enhanced by crystallization from EtOAc/hexane. Overall yield of 141 from 136b. Dr. Zhang and Dr. Lu performed optimization experiments on the catalytic asymmetric 64 aziridination of silyl substituted alkynyl imines (Table 2.3). The focus was on the N-substituent and the difference between VANOL and VAPOL. VAPOL gives a better enantioselectivity than VANOL. For example, the reaction of Bh imine with VAPOL gave 32% ee, while with VANOL as ligand, the reaction yielded 21% ee (Table 2.3, entry 1 vs 2). With the same silyl substituent, same ligand, BUDAM was the optimal N-substituent (83% ee, entry 6), followed by MEDAM (44% ee, Table 2.3, entry 4) and benzhydryl (32% ee, Table 2.3, entry 1). TMS and TIPS substituted alkynyl imines gave similar results. Another interesting finding is that the enantioselectivities are independent of the geometry of the imine, since both 1.6:1 and 19:1 mixtures of imine 136b gave the same asymmetric induction (Table 2.3, entries 8 & 9). Dr. Lu and Dr. Lopez-Alberca undertook a further optimization of the temperature and solvent 64 (Table 2.4). The optimal temperature was found to be –20 °C in terms of both asymmetric induction and yield (Table 2.4, entries 1-4). Solvent screening revealed that ether was the best 51 (Table 2.4, entries 5-7). With the optimal conditions, the aziridine 139b could be obtained in 86% yield and 95% ee (Table 2.4, entry 7). b entry temp (°C) solvent 1 4 25 toluene 81 4 0 toluene 86 83 3 4 –20 toluene 90 87 4 4 –40 toluene 69 75 5 10 –20 toluene 90 90 6 10 –20 CCl4 86 74 7 10 –20 Et2O 86 c 80 2 a mol% catalyst 95 % yield AZ % ee AZ Unless otherwise specified, all reactions were performed at 0.5 M in ether with 1.1 equiv of EDA for 24 h with 10 mol% catalyst. The catalyst was prepared as described in Table 2.3. Isolated yield after chromatography on silica gel. c b Determined by HPLC on a Chiralcel OD-H column. The induction in all entries was determined after conversion of to the N-H aziridine 141. The ee of aziridine 139b was measured by chiral HPLC after the removal of BUDAM (Scheme 2.31). Treatment of BUDAM aziridine 139b with 5 equivalents of triflic acid in anisole for 1 h at 52 room temperature gave the N-H aziridine 141 in 83% yield. Orthogonal removal of TMS could be achieved with tetra-butylammonium fluoride, affording ethynyl aziridine 140 in 89% yield. The reaction of imines from phenylpropynal gave an unexpected side product in addition to the desired alkynyl aziridine (Table 2.5). Analysis of the purified side product revealed that it resulted from both a [3+2] and a [2+1] cycloaddition with two molecules of ethyl diazoacetate. Based on the structures of reported [3+2] adducts of ethyl diazoacetate with α,β-unsaturated alkynyl esters, ketones and aldehydes, the regiochemistry of this [3+2] adduct was assumed by 65 analogy. Again, BUDAM imine was superior to MEDAM or benzhydryl imines in terms of asymmetric induction and reaction conversion under the same conditions (Table 2.5, entries 1-6). Ether was a superior solvent to toluene (Table 2.5, entry 9 vs 6) and VAPOL was a better ligand than VANOL (Table 2.5, entry 9 vs 10). 53 Table 2.5 (cont’d) entry P ligand solvent temp % (°C) conv % yield b c AZ % ee AZ d % yield , e 142-144 1 Bh (S)-VAPOL toluene 25 39 21 17 2 2 Bh (R)-VANOL toluene 25 47 30 0 1 3 MEDAM (S)-VAPOL toluene 25 22 14 49 <1 4 MEDAM (R)-VANOL toluene 25 21 14 -25 <1 5 BUDAM (S)-VAPOL toluene 25 100 61 87 4 6 BUDAM (S)-VAPOL toluene –20 100 67 92 11 7 BUDAM (S)-VAPOL ether 25 100 52 93 15 8 BUDAM (S)-VAPOL ether 0 100 61 96 10 9 BUDAM (S)-VAPOL ether –20 100 66 97 18 10 BUDAM (R)-VANOL ether –20 100 49 -85 17 f BUDAM (S)-VAPOL ether –20 100 56 95 14 g BUDAM (S)-VAPOL ether –20 100 32 h nd 6 i BUDAM (S)-VAPOL ether –20 100 58 h nd 3 BUDAM (S)-VAPOL ether –40 100 98 23 11 12 13 14 a 57 Unless otherwise specified, all reactions were performed at 0.5 M in ether with 1.2 equiv of EDA for 24 h with 10 mol% catalyst. The catalyst was prepared as described in Table 2.3. nd = b not determined. No trans-aziridine was detected in any reaction. Determined from 1H NMR 54 Table 2.5 (cont’d) spectrum of the crude reaction mixture. c Isolated yield after chromatography on silica gel. Determined on purified cis-aziridine by HPLC. e d 1 Determined from H NMR spectrum of the f g crude reaction mixture and based on isolated yield of cis-aziridine. 5 mol% catalyst. Reaction h with 0.9 equiv of EDA. Determined from 1H NMR spectrum of the crude reaction mixture with i j Ph3CH as internal standard. Reaction with 4.0 equiv of EDA. A third product is produced in 14% yield and is tentatively assigned as the regioisomer of 144. When 4.0 equivalents of ethyl diazoacetate was used, the yield of the alkynyl aziridine didn’t increase (Table 2.5, entry 13). A control experiment was performed with alkynyl aziridine 139c, ethyl diazoacetate and VAPOL-BOROX catalyst generated from VAPOL, B(OPh)3, H2O and benzhydryl imine 9d, but no [3+2] pyrrazole side product was formed. 55 entry R imine ligand AZ % yield AZ b % ee AZ c % yield 1 Me3Si 136b (S)-VAPOL 139b 86 95 - 2 C6H5 136c (S)-VAPOL 139c 66 97 18 3 C6H5 136c (R)-VANOL 139c 49 –85 4 4-MeOC6H4 136d (S)-VAPOL 139d 45 96 5 4-MeOC6H4 136d (R)-VANOL 139d 24 –83 6 4-BrC6H4 136e (S)-VAPOL 139e 54 97 7 4-BrC6H4 136e (R)-VANOL 139e 25 –53 8 4-MeO2CC6H4 136f (S)-VAPOL 139f 57 94 9 4-MeO2CC6H4 136f (R)-VANOL 139f 30 –54 56 e 17 27 e 11 24 e 5 19 e 5 d Table 2.6 (cont’d) 10 136g (S)-VAPOL 139g 35 88 11 4-NO2C6H4 136g (R)-VANOL 139g 8 –41 12 n-butyl 136k (S)-VAPOL 139k nd f nd nd 13 a 4-NO2C6H4 22 cyclohexyl 136l (S)-VAPOL 139l nd f nd nd e 3 Unless otherwise specified, all reactions were performed at 0.5 M in ether with 1.2 equiv EDA at –20 °C for 24 h with 10 mol% catalyst. The catalyst was prepared as described in Table 2.3. nd = not determined. No trans-aziridine was detected in any reaction. chromatography on silica gel. c b Isolated yield after Determined on purified cis-aziridine 139 by HPLC. d Determined from 1H NMR spectrum of the crude reaction mixture and based on isolated yield of cis-aziridine. e f Enantiomer of 139 is formed. Complex mixture of products was formed. The ratio of 139:144 was ~ 1:1 but neither was the major species. Based on those observations, we believe that the [3+2] cycloaddtion should occur before the aziridination (Scheme 2.33). With the optimal condition established, the scope of the transformation was developed (Table 2.6). VAPOL gave uniformly superior performance in terms of both asymmetric induction and yield. Excellent enantioselectivities and good yields were obtained with aryl and silyl substituted alkynyl imines. In the case of aryl substituted alkynyl imines, pyrrazoles were obscerved in small amounts. However, no such side product was observed with silyl substituted alkynyl imines. 57 Aliphatic substituted alkynyl imines gave complicated reaction mixtures which were not characterized (Table 2.6, entries 12 and 13). 2.3.2 Aziridinations with diazoactamide Recently, we reported that trans-aziridines could be obtained from the same imines and same 27a BOROX catalyst by switching from a diazo ester to a diazoacetamide (Scheme 2.34). Computational studies suggest that in case of cis-aziridine formation, the protonated imine is 27b H-bonded to O-1 of the boroxinate core and ethyl acetate is H-bonded to O-2. While in the course of trans-aziridine formation, the protonated imine is H-bonded to O-3 and diazo acetamide is H-bonded to O-1 and O-2. The reversed binding sequence contributes to the opposite diastereochemical outcome. 58 It was originally expected that the azidination of the same alkynyl imines with diazoacetamide would lead to trans-alkynyl aziridines. However, very little amounts of aziridines were observed (Scheme 2.35) under the conditions that were optimized for the ethyl diazoacetate 30 (Table 2.6). The reaction of alkynyl imine 136c with diazoacetamide 148 under the identical condition with 1 ethyl diazoactate 30 gave the cis-aziridine 153c in 4% yield ( H NMR yield) and the 1 trans-aziridine 153c in 1% yield ( H NMR yield), and no starting imine remained. VANOL gave a better result (16% cis-aziridine 153c and 13% trans-aziridine 153c) under the same conditions (Table 2.7, entry 12 vs 13). When switching the N-substituent of the imine from BUDAM to benzhydryl and MEDAM, promising results were obtained. Benzhydryl alkynyl aziridine 151c was produced in 77% yield and 90% ee (Table 2.7, entry 2) and the MEDAM alkynyl aziridine 152c was obtained in 77% yield and 90% ee (Table 2.7, entry 4). VANOL is a better ligand than either VAPOL or 59 7,7’-di-t-butylVANOL (Table 2.7, entry 3 vs 4 and 5). Further optimization on temperature, catalyst loading, reaction time and solvent was carried out. The optimal conditions are with 5 mol% catalyst in toluene at –40 °C with a reaction time of 4 h, from which the aziridine 152c could be obtained in 91% yield and 97% ee (cis/trans = 50:1) (Table 2.7, entry 16). entry ligand P temp mol% time % (°C) cat (h) conv cis/ b trans % yield b c AZ % ee AZ d 1 (S)-VANOL Bh 0 10 24 100 25:1 77 89 2 (R)-VAPOL Bh 0 10 24 100 20:1 77 -90 3 (S)-VANOL MEDAM 0 10 24 100 12:1 78 94 4 (R)-VAPOL MEDAM 0 10 24 100 20:1 77 -90 5 (S)-tBu2- MEDAM 0 10 24 100 14:1 84 59 34 -VANOL e 6 (S)-VANOL BUDAM 0 10 24 100 2:1 7 (R)-VAPOL BUDAM 0 10 24 100 2:1 8 (S)-VANOL MEDAM –20 10 24 100 20:1 60 nd f 71 f,g nd 84 96 Table 2.7 (cont’d) 9 MEDAM –20 5 24 100 20:1 86 96 10 (S)-VANOL MEDAM –20 5 1 100 17:1 82 97 11 (S)-VANOL MEDAM –20 2 1 100 >100:1 44 98 12 (S)-VANOL BUDAM –20 10 24 100 1.2:1 16 13 (R)-VAPOL BUDAM –20 10 24 100 4:1 4 14 (S)-VANOL Bh –40 5 4 22 >100:1 nd nd 15 (R)-VAPOL Bh –40 5 4 46 20:1 nd nd 16 (S)-VANOL MEDAM –40 5 4 100 50:1 91 97 17 (S)-VANOL MEDAM –40 5 4 100 17:1 18 (S)-VANOL BUDAM –40 5 4 12 2:1 nd nd 19 (R)-VAPOL BUDAM –40 5 4 0 - - - 20 a (S)-VANOL (S)-VANOL MEDAM –78 5 4 14 >100:1 nd nd h,i nd h,i nd 83 h 92 Unless otherwise specified, all reactions were performed on 0.2 mmol in toluene at 0.2 M imine with 1.4 equiv of diazoacetamide for 4 h and went to 100% conversion. The catalyst was prepared by heating a mixture of 1 equiv of the ligand, 3 equiv BH3•SMe2, 2 equiv phenol, 3 equiv H2O in toluene at 100 °C for 1 h. The volatiles were then removed under vacuum (0.1 mm Hg) at 100 °C for 1 h. nd = not determined. reaction mixture. c b 1 Determined from H NMR spectrum of the crude Yield of isolated pure cis-aziridine after silica gel chromatography. e f Determined by HPLC on pure cis-aziridine. 7,7’-di-t-butylVANOL. A number of other 61 d Table 2.7 (cont’d) unidentified products formed in this reaction. entry 6. h g The amount of cis-aziridine is much less than in i 1 Reaction performed in ether. Determined from H NMR spectrum of the crude reaction mixture with Ph3CH as internal standard. The optimal conditions were then examined with twelve additional alkynyl imines (Table 2.8). In all cases, high asymmetric inductions were achieved. The reactions of aryl substituted alkynyl imines went to completion with 5 mol% catalyst at –40 °C within 4 h. All gave 96-99% ee, regardless of various functional groups at different positions on the aryl ring (Table 2.8, entries 5 to 19). The reactions of n-butyl and cyclohexyl substituted alkynyl imines needed a higher temperature (–20 °C) to finish in 4 h and also went with excellent enantioselectivities (Table 2.8, entries 20 to 24). The reaction of the t-butyl substituted alkynyl imine 135k was slower and needed 24 h to go to completion. Lower induction (91%) and lower cis/trans ratio (4:1) were obtained (Table 2.8, entries 25 to 26). The reaction of the trimethylsilyl substituted alkynyl imine 135b also gave lower induction (83%) and lower cis/trans ratio (5:1) (Table 2.8, entries 3 & 4). Fortunately, the reaction of the triisopropylsilyl substituted alkynyl imine 135a gave 86% yield and 98% ee with an excellent cis/trans ratio (50:1) (Table 2.8, entries 1 & 2). 62 entry R Ligand imine temp cis/ (°C) trans AZ b % yield AZ c % ee AZ 1 i-Pr3Si (S)-VANOL 135a –20 50:1 152a 86 98 2 i-Pr3Si (R)-VANOL 135a –20 100:1 152a 87 98 3 Me3Si (S)-VANOL 135b –20 5:1 152b 80 83 4 Me3Si (R)-VANOL 135b –20 5:1 152b 80 86 5 C6H5 (S)-VANOL 135c –40 50:1 152c 91 97 6 4-MeOC6H4 (S)-VANOL 135d –40 >100:1 152d 90 99 7 4-MeOC6H4 (R)-VANOL 135d –40 >100:1 152d 89 99 8 4-BrC6H4 (S)-VANOL 135e –40 >100:1 152e 93 98 9 4-BrC6H4 (R)-VANOL 135e –40 >100:1 152e 92 99 10 4-MeO2CC6H4 (S)-VANOL 135f –40 25:1 152f 90 96 11 4-MeO2CC6H4 (R)-VANOL 135f –40 20:1 152f 89 95 12 4-NO2C6H4 (S)-VANOL 135g –40 25:1 152g 91 95 13 4-NO2C6H4 (R)-VANOL 135g –40 25:1 152g 89 96 14 3-MeC6H4 (S)-VANOL 135h –40 33:1 152h 89 96 63 d Table 2.8 (cont’d) 15 3-MeC6H4 (R)-VANOL 135h –40 33:1 152h 90 96 16 2-MeC6H4 (S)-VANOL 135i –40 33:1 152i 95 95 17 2-MeC6H4 (R)-VANOL 135i –40 33:1 152i 94 98 18 1-naphthyl (S)-VANOL 135j –40 33:1 152j 95 97 19 1-naphthyl (R)-VANOL 135j –40 25:1 152j 94 99 20 n-butyl (S)-VANOL 135k –20 25:1 152k 82 98 21 n-butyl (R)-VANOL 135k –20 >100:1 152k 81 98 22 cyclohexyl (S)-VANOL 135l 0 9:1 152l 73 91 23 cyclohexyl (S)-VANOL 135l –20 25:1 152l 84 97 e cyclohexyl (S)-VANOL 135l –40 >100:1 152l 78 99 f t-butyl (S)-VANOL 135m –20 4:1 152m 77 91 f t-butyl (R)-VANOL 135m –20 4:1 152m 78 91 24 25 26 a Unless otherwise specified, all reactions were performed on 0.2 mmol in toluene at 0.2 M imine with 1.4 equiv of diazoacetamide 148 for 4h and went to 100% conversion. The catalyst was prepared as described in Table 2.7. reaction mixture. c b 1 Determined from H NMR spectrum of the crude Yield of isolated pure cis-aziridine after silica gel chromatography. e f d Determined by HPLC on pure cis-aziridine. Reaction went to 81% completion. Reaction time was 24 h. 64 When the more soluble N-n-butyl diazoacetamide 154 was employed, slightly lower yield (86%) and lower induction (95%) were observed with imine 135c (Table 2.9), compared to the results from N-phenyl diazoacetamide 148 under the identical conditions (Table 2.8, entry 5). Table 2.9 (cont’d) b c entry ligand 1 (S)-VANOL 33:1 84 2 (R)-VANOL 50:1 86 d 94 95 a cis/trans % yield AZ % ee AZ Unless otherwise specified, all reactions were performed on 0.2 mmol in toluene at 0.2 M imine with 1.4 equiv of diazoacetamide 154 for 4 h and went to 100% conversion. The catalyst was prepared as described in Table 2.7. mixture. c b 1 Determined from H NMR spectrum of the crude Yield of isolated pure cis-aziridine after silica gel chromatography. d Determined by HPLC on pure cis-aziridine. After transforming amide 152c into ester 138c, it was found that this counpound had an optical rotation that had a sign opposite to that for cis-aziridine 138c synthesized from imine 135c with ethyl diazoacetate 30 with the same enantiomer of the ligand (Table 2.5). In other words, by using a ligand with the same chirality, the reaction of diazoacetamide 148 gave the 65 pseudoenantiomer of the product from the reaction of diazoacetate 30. Thus, the chirality of the products from the aziridination reaction are reagent dependent. Pearlman’s catalyst promoted hydrogenation of cis-aziridine 138c prepared from amide 152c afforded the known aziridine 156 the facial selectivities of the Wulff aziridination reactions can be summarized as shown in Scheme 2.37. With the (S)-ligand, Si-face addition of diazoacetates to the imine is observed while Re-face addition of diazoacetamides to the imine is preferred. In the case of 2° diazoacetamides, akynyl imines give cis-aziridines while aryl and alkyl imines afford trans-aziridines. 66 2.4 Future plan One potential application of the above chemistry is the synthesis of sphingosine and its analogues. The proposed synthetic route is shown in Scheme 2.38. 67 2.5 Conclusion We have successfully developed the first highly enantioselective catalytic synthesis of cis-alkynyl aziridine-2-carboxylate esters or amides in excellent yields with very high diasetreoselectivities. Several important features of this work are: a) the induction of the aziridine is independent of the geometry of the imine; b) the reactions of alkynyl imines with ethyl diazoacetate give cis-aziridines with excellent asymmetric inductions but in moderate yields due in part to the competing formation of [3+2] pyrrazole side products; c) In contrast to previous trans-aziridinations from aryl or alkyl imines, the reactions of alkynyl imines with diazoacetamides afford cis-aziridines in excellent yields with excellent enantioselectivities; d) cis-aziridines obtained with diazoacetates and diazoacetamides are opposite enantiomers when the same enantiomer of the catalyst is used. 68 CHAPTER THREE CONVERGENT SYNTHESIS OF 7,7’-DISUBSTITUTED VANOL LIGANDS AND A CONCENSUS IN THE AZIRIDINATION REACTION 3.1 Introduction In the general introduction in Chapter 1, we have learned that VANOL and VAPOL are the members of the vaulted biaryls which is a new class of “privileged ligands” as judged by their increasing new applications in asymmetric catalysis. The substrates in an organic reaction may possess an enormous molecular diversity that drives the demand for structurally diverse catalysts. Chiral ligands, which serve an important role in tuning the electronics of the active site and in defining the chiral environment of the catalysts, should be of a collection flexible enough to offer the maximum potential of discovering the optimal platform for transforming a given substrate. The chemistry of BINOL is has been extensively developed not only due to the early recognition of its catalysis potential but also the ease and flexibility with which it was possible to form a 69 library of BINOL derivatives. The vast majority of BINOL derivatives are those that have 11 substituents in the 3- and 3’-positions (Scheme 3.1). And from those 3,3’-BINOL derivatives, functionalization of the phenol substituents leads to the phosphate derivatives, as well as to the 65-69 phosphoramidite derivatives. Some of the most common methods for the introduction of different groups in the 3- and 3’-positions are outlined in Scheme 3.2. Different functional groups (i.e. Me, CH(OH)Ph, SPh, Br, Cl, I, SiR3) could be accessed through ortho lithiation of 2,2’-oxygen-based directed 70 metalation groups followed by electrophile quench. Treatment of 3,3’-dibromo or 3,3’-iodo BINOL derivatives with various boronic acids under Suzuki cross coupling conditions furnishes 70 3,3’-diaryl BINOL derivatives. Trifluoromethylation can be achieved with FSO2CF2CO2Me 71 mediated by CuI. 71 3.2 Background Compared to the well-established methods for preparing BINOL derivatives, the approaches to VANOL and VAPOL derivatives are limited and not well explored. There are two general ways to modify VANOL/VAPOL: 1) by replacing a certain hydrogen atom(s) in one of the rings in an existing molecule of VANOL/VAPOL or 2) by synthesizing substituted monomers prior to dimerization followed by resolution or deracemization. The first approach appears to be more direct and convenient. The easiest way is via electrophilic aromatic substitution reactions. 4,4’-Dinitro VANOL was prepared by Dr. Hu from our group via nitration of the naphthol rings which are activated and directed by the phenol groups (Scheme 3.3). 72 72 + entry E solvent E conditions TMEDA (eq) % yield 1 CH3I ether CH3 25 °C, 35 h 0 nd 2 CH3I ether CH3 45 °C, 2 h 0 40 3 CH3I ether CH3 50 °C, 24 h 0 100 4 CH3I ether CH3 25 °C, 24 h 2.5 5 CH3I hexanes CH3 25 °C, 24 h 2.5 6 BrCH2CH2Br ether Br 25 °C, 3 h 2.5 a nd = not detected, 171 was recovered. b c a b b b 44.2 (100 ) nd a d 31.5 (65 ) 1 conversion based on H NMR spectrum of the crude c d reaction mixture. isolated yield by chromatography on silica gel. 171 (34.8%) was recovered. 73 Due to the close proximity of the 8 and 8’ positions to the hydroxyl functions, an ortho-lithiation/electrophile quench sequence was investigated by Dr. Ding from our group 73 (Scheme 3.4). However, only starting material was recovered. The same sequence was then carried out on VANOL protected as its bis-methyl ether. With MeI as the electrophile, 8-methylated VANOL 172 was obtained (Table 3.1). Similarly, bromination 73 led to 8-bromo VANOL upon treatment with 1,2-dibromoethane. However, introduction of substituents in the 8,8’-positions leads to decreased yields and inductions (Chapter 4). Therefore, the second route seemed to be the method of choice to introduce substituents in the 7,7’-positions (Scheme 3.5). There are a number of ways to synthesize 3-phenyl-1-naphthol as VANOL monomer. Dr. Ding instigated the investigations into several ways to prepare this key intermediate (Scheme 3.6). 13f,13g,73 The first route is benzannulation pathway. Benzannulation of the phenyl carbene complex with phenylacetylene, followed by exposure to EtSH in the presence of AlCl3, affords the monomer 175 in 73% overall yield. The second route involves Michael addition of a benzyl 74 Grignard to methyl cinnamate, followed by intramolecular Friedel-Craft reaction. Dehydrogenation of the resulting tetralone yields the monomer 175 in 54% overall yield. The third route is a Reformatsky reaction/cycloacylation sequence, giving the monomer 175 in 48% overall yield. The fourth route features a dienone-phenol rearrangement of a 4-aryl-1-tetralenone generated in-situ from the reaction of a chlorination product of 1-naphthol with AlCl3 and benzene. The overall yield is 74%. The last route is ketene pathway. The key step is a cycloaddition/electrocyclic ring-opening/electrocyclic ring closure/tautomerization (CAEC) cascade. This last route tolerates more function groups and many phenyl acetic acid derivatives are commercially available. Therefore, the CAEC cascade is the method of choice. 75 The mechanism of the CAEC cascade is presented in Scheme 3.8. Pyrolyis of phenylacyl chloride gives ketene 181, which undergoes [2+2] cycloaddition with phenylacetylene. Electrocyclic ring-opening of the adduct 182, followed by electrocyclic ring closure and subsequent tautomerization, gives the monomer 175 in a one-pot fashion. 76 The first synthesis of racemic VANOL was performed by heating 175 (1 g scale) in a test tube in 13a the presence of air at 190 °C to give an 87% yield of racemic VANOL. The major drawback of this method is that VANOL solidifies during the process and traps the monomer which results in incomplete conversion. Dr. Ding optimized the coupling step by choosing various solvents and temperatures with different concentrations and found that by heating the monomer as a 0.92 M solution in mineral oil at 165 °C for 17 h, the pure racemate was obtained in 89% yield 73 (Scheme 3.9). Thus, this optimal procedure for the oxidative coupling is method of choice for the work in this thesis. 77 There are two general ways of preparing optical pure VANOL and VAPOL from the racemates. The first way is by resolution (Scheme 3.9). 13a,13g,73 The resolution of VANOL is based on the separation of diastereomeric salts formed from the reaction of its racemic VANOL hydrogen phosphate with (–)-brucine. The resolution of VAPOL is related to that of VANOL but employs (–)-cinchonidine instead of (-)-brucine. Resolution is good for large scale synthesis. However, it might not be a facile way to synthesis a large number of VANOL derivatives. The second way for securing optical pure VANOL and VAPOL is by deracemization. Dr. Hu developed a more reliable procedure for the deracemizaion of VANOL/VAPOL mediated by 13c copper (II)/diamine complexes (Scheme 3.10). While the use of a copper complex of (–)-sparteine gives (S)-enantiomers of BINOL, VANOL and VAPOL, the use of a copper 78 complex of (+)-O’Brien diamine gives the (R)-enantiomeric series. This process may be more suitable for small scale synthesis and fast access to a library of VANOL derivatives. 79 3.3 Results and discussion 3.3.1 Preparation of 4-substituted phenylacetic acids From the above discussion, the optimized route to the optical pure VANOL has already been developed. This route is short, efficient, cost effective and capable of generating a large number of VANOL derivatives in a convergent manner. The best and easiest position for diversity proliferation is in the 7- and 7’-positions of VANOL. Though most of the required 4-substituted phenylacetic acids are commercially available, two acids were prepared from relative inexpensive starting materials. Sandmeyer reaction of 4-aminophenylacetic acid with NaNO2 and H2SO4, followed by KI yields 4-iodophenylacetic 74 acid in 61% yield (Scheme 3.11). Friedel-Crafts acylation of t-butylbenzene with acetyl chloride in the presence of AlCl3 afforded 75 4-t-butylacetophenone in 91% yield (Scheme 3.12). Willgerodt-Kindler reaction of 4-t-butylacetophenone and subsequent hydrolysis gave 4-tert-butyl-phenylacetic acid in 88% 76,77 yield in a one-pot process. This sequence involves only one column chromatography separation of the final product 191m. 80 3.3.2 Preparation of 7-substituted 3-phenyl-1-naphthols 13g The synthesis of various monomers was carried out via the CAEC cascade (Scheme 3.13). The iso-butyric anhydride is used to trap the product naphthols to prevent them from reacting with phenyl ketene, which in its absence would necessarily result in a much lower yield. It was pleased to find that various halogen groups, 1°, 2°, 3° alkyls, and OMe survive the CAEC cascade (Table 3.2). The reactions with phenyl acetic acids bearing CF3, NMe2 or NO2 groups in the para-position gave non-separable mixtures. 81 entry R 1 b F c Cl 71 3 d Br 67 4 e I 52 5 g OMe 50 6 h Me 56 7 k i-Pr 61 8 m t-Bu 51 9 ag Ph 65 10 aj NMe2 nd 11 f CF3 nd 12 ai NO2 a 65 2 a series nd % yield isolated yield by chromatography on silica gel. nd = not determined Lithiation of the protected bromo naphthol 82 195d, and then quenched with tert-butyl(chloro)diphenylsilane, followed by deprotection afforded silyl-substituted naphthol 15 175n in 63% yield (Scheme 3.14). Treatment of the protected bromo naphthol 195d by the Shechter modification of the Rosenmund-Van Braun reaction gave insoluble mixture of products 78 that was not further characterized. Coupling of the MOM protected iodonaphthol 196e with the phenanthroline complex of trifluoromethyl copper developed by Hartwig and coworkers, followed by deprotection 79 generated the trifluoromethyl naphthol 175f in 97% yield (Scheme 3.15). 83 The nitro naphthol 175ai was successfully accessed by employing a process developed by 5 Buchwald and coworkers (Scheme 3.16). Pd and t-buBrettPhos could promote the conversion of protected chloro naphthol 195c or 196c to the nitro naphthol 195ai or 196ai. Demethylation of the nitroaromatic methyl ether 195ai with BBr3 failed to give a clean product, which was disappointing. To our delight, removal of the MOM group of 196ai with Amberlyst 15 gave the desired nitro naphthol 175ai in 90% yield. 84 3.3.3 Oxidative coupling and deracemization The oxidative coupling procedure was then applied to the 7-substituted-3-phenyl-1-naphthols described above (Table 3.3). Different halogen groups, alkyl groups, and a silyl group survived the coupling conditions and the resulting racemic VANOL derivatives were available for the deracemization process. The racemic 7,7’-dimethoxyl VANOL 174g has low solubility that 85 obstructs purification and further processing. The oxidative couplings of 7-nitro- and 7-phenyl-3-phenyl-1-naphthol failed, giving complicated mixtures. It was delightful to find that all of the new VANOL derivatives could be brought to >99% ee in the (S)-enantiomer with the (–)-sparteine-copper complex which isomerizes the (R)-enantiomer in good to excellent yield. (R)-VANOL derivatives with >99% ee were obtained when the (+)-sparteine-copper complex was used. entry series R % yield % yield % ee (±)-174 (S)-174 (S)-174 91 45 >99 83 >99 >99 1 b F 2 c Cl 3 d Br 84 83 4 d Br 84 98 5 e I 86 76 6 f CF3 51 7 g OMe 86 73 86 a c 79 d - >99 b >99 >99 - b Table 3.3 (cont’d) 8 Me 9 k i-Pr 82 10 m t-Bu 72 11 n SiPh2t-Bu 84 12 ag Ph - 13 a h ai NO2 - phenol coupling for 48 h. b d 54 55 >99 c 72 e 77 >99 80 >99 >99 b c (R)-174 obtained upon deracemization with (+)-sparteine. phenol e coupling at 160 °C for 48 h. low solubility. phenol coupling at 150 °C. 3.3.4 Synthesis of 7,7’-VANOL derivatives via Suzuki coupling The convergent synthesis of various 7,7’-VANOL derivatives could in principle be realized by a number of different types of coupling reactions. The Suzuki coupling of different aryl boronic acids with the enantiopure 7,7’-dibromoVANOL could lead to a variety of 7,7’-diaryl VANOL derivatives. The two aryl boronic acids 198s and 198x were synthesized via lithiation of the corresponding aryl bromides and then borylation. Hydrolysis gave the corresponding aryl 80,81 boronic acids in decent yields (Scheme 3.17). 87 Several Suzuki conditions with the unprotected 7,7’-dibromoVANOL (S)-174d were screened 15 and the optimal conditions were established (Table 3.4, entry 2). 88 Table 3.4 (cont’d) entry Pd cat base solvent % yield (S)-174s 1 Pd(PPh3)4 Na2CO3 DME/H2O 42 2 Pd(PPh3)4 Na2CO3 benzene/EtOH/H2O 60 DME 42 3 a a PdCl2•dppf•CH2Cl2 K3PO4•2H2O isolated yield by chromatography on silica gel. Three different protocols were employed in the Suzuki coupling reactions (Scheme 3.18). Higher overall yields were obtained with a protection/Suzuki coupling/deprotection sequence than with a one-step method in which no protection is employed. For instance, 7,7’-bis-(para-t-butylphenyl)VANOL (S)-174g could be generated in 41% yield by direct Suzuki coupling, while the three-step method gave a 73% overall yield. However, the one-step method is simple, direct and fast. Homocoupling of the boronic acids and the formation of a considerable amount of base-line material might be the cause of the relatively lower yields of the one-step method. Polyaromatics (1-naphthyl, 2-naphthyl and 9-anthracenyl) and heterocycles (3-thiophenyl and 3-furyl) were successfully introduced by Suzuki couplings as well. 89 3.3.5 Synthesis of 7,7’-VANOL derivatives via Stille coupling 90 The convergent synthesis of VANOL derivatives could also employ the Stille coupling 82 reaction. The Stille coupling of 7,7’-dibromoVANOL with various stannanes was used to produce 7,7’-divinylVANOL, 7,7’-bis-(2-thiophenyl)VANOL and 7,7’-bis-(2-furyl)VANOL in good to excellent yields (Scheme 3.19). Hydrogenation of 7,7’-bis-(2-thiophenyl)VANOL (R)-174y with Raney Ni and H2 at room 83 temperature afforded 7,7’-di-n-butylVANOL (R)-174j in 45% yield (Scheme 3.20). 91 3.3.6 Synthesis of 7,7’-VANOL derivatives via Kumada coupling The Kumada coupling reaction also adds to the convergent synthesis of VANOL derivatives. Reactions of the protected 7,7’-dibromoVANOL (S)-199d with the proper Grignard reagents (1° or 2° alkyls) catalyzed by NidppeCl2, followed by deprotection gave 7,7-diethyl- or 15 7,7-dicyclohexylVANOL in good yields (Scheme 3.21). The Kumada couplings of the unprotected 7,7’-dibromoVANOL (S)-174d with the Grignard reagents under the same conditions failed, leading to the recovery of the starting material. 3.3.7 Synthesis of 7,7’-VANOL derivatives via Sonogashira and Ullman coupling reactions Direct Sonogashira couplings of the 7,7’-diiodoVANOL (S)-174e were of highly efficiency as well. The coupling with trimethylsilyl acetylene afforded (S)-174ae in 83% yield and that with 63c t-butylacetylene afforded (S)-174af in 89% yield (Scheme 3.22). Removal of the trimethylsilyl group in the former with TBAF gave the alkynyl ligand (S)-174ad in 80% yield. Since the deracemization of racemic 7,7’-dimethoxylVANOL failed, conversion of 92 7,7’-diiodoVANOL (S)-174e to the 7,7’-dimethoxylVANOL (S)-174g was investigated with several protocols. The phenol functions in the 7,7’-diiodoVANOL were protected as methoxylmethyl ethers in order to realize orthogonal functionalization of the two pairs of the four phenols in the coupling product. The copper mediated coupling with sodium methoxide was successful in introducing the methoxy functions in the 7,7’-positions of VANOL. 84 Removal of the MOM groups with Amberlyst 15 gave the desired 7,7’-dimethoxylVANOL (S)-174g in 54% yield over three steps. Thus, a direct and convergent synthesis of 7,7’-disubstituted VANOL derivatives has been accomplished, resulting in the successful construction of a library of 31 ligands (Scheme 3.23). 93 3.3.8 Screen of 7,7’-VANOL derivatives in the Wulff cis-aziridination reaction Our group reported the first highly diastereoselective and enantioselective catalytic asymmetric 26 synthesis of aziridines (Wulff cis-aziridination reaction) in 1999 (Scheme 3.24). The reactions of aryl imines prepared from aryl aldehydes and benzhydryl amine give aziridines in 79-94% ee with both VANOL and VAPOL derived catalysts, and those from aliphatic aldehydes give aziridines in 77-87% ee. Of all the substituted benzhydyl imines exmined, MEDAM imines are 94 the optimal, giving 96-99% ee for aryl aziridines and 86-92% ee for alkyl aziridines. However, MEDAM-NH2 is not commercially available. Thus, it would be important to improve the asymmetric inductions with simple benzhydryl imines from commercially available benzyhydryl amine. In addition, it would be of mechanistic interest to investigate the effect of the different substituents in each of the 31 ligands on the Wulff cis-aziridination reaction with benzhydryl imines. The first round of screening of the 31 ligands was performed with the imine 9i, synthesized from cyclohexane carboxaldehyde, since this imine only gives 81% ee with VANOL derived BOROX catalyst, leaving much room for improvement (Table 3.5). It was found that catalysts from most of the ligands gave a higher asymmetric induction than that from the parent VANOL ligand. The halogen groups have generally small positive effects (F, 82% ee; Br, 85% ee; I, 88% ee) except 95 for Cl which has a small negative effect (78% ee) and it seems that size rather an inductive electron-withdrawing effect predominates the asymmetric induction. That OMe gives a higher induction than 1° or 2° alkyl groups indicates that there is a positive component to an electron-releasing effect. The series of aryl groups reveals that the interplay between sterics and electronics of the aryl group is quite delicate and complicated. The 4-methylphenyl groups gives 90% ee and the 4-t-butylphenyl group gives 93% ee, big jumps from 81% ee with VANOL. However, the increase is more than negated by a 4-trifluoromethylphenyl group (78% ee). A similar trend is observed where the 3,5-dimethylphenyl group gives 92% ee, a jump from 81% ee with VANOL, whereas this increase is again negated by a 3,5-bis-trifluromethylphenyl group (80% ee). The advantage of a phenyl group is lost when ortho-groups are introduced on the phenyl ring. For example the 2,6-dimethylphenyl group gives 82% ee, the 2-naphthyl group gives 81% ee and the 9-anthracenyl group gives 63% ee. Most of the 1° and 2° alkyl groups give similar asymmetric inductions (Me, 87% ee; Et, 87% ee; n-Bu, 89% ee; i-Pr, 89% ee; Cy, 87% ee). The t-Bu group gives 94% ee and turns out to be the optimal among all of the 31 ligands entry ligand R 1 3 H % yield 78 96 b % ee 82 c VAPOL Table 3.5 (cont’d) 2 174a H 77 3 174b F 76 82 4 174c Cl 83 78 5 174d Br 78 85 6 174e I 80 88 7 174f CF3 88 85 8 174g OMe 88 92 9 174h Me 83 87 10 174i Et 91 87 11 174j n-Bu 91 89 12 174k i-Pr 91 89 13 174l Cy 90 87 14 174m t-Bu 88 94 15 174n SiPh2t-Bu 72 79 16 174o 4-MeC6H4 89 90 17 174p 4-CF3C6H4 93 78 18 174q 4-t-BuC6H4 83 93 19 174r 3,5-Me2C6H3 88 92 20 174s 3,5-(t-Bu)2-4-MeOC6H2 77 86 97 81 VANOL Table 3.5 (cont’d) 21 3,5-(CF3)2C6H3 90 80 22 174u 2,6-Me2C6H3 72 82 23 174v 1-naphthyl 87 81 24 174w 2-naphthyl 94 90 25 174x 9-anthracenyl 72 63 26 174y 2-C4H3S 90 88 27 174z 2-C4H3O 77 76 28 174aa 3-C4H3S 91 90 29 174ab 3-C4H3O 90 89 30 174ac -CH=CH2 90 82 31 174ad -CCH 85 84 32 174ae -CCSiMe3 79 88 33 a 174t 174af -CC-t-Bu 87 87 unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 1.2 equiv EDA at 25 °C for 24 h and went to 100% completion with 5 mol% catalyst. The catalyst was prepared from 1 equiv ligand, 4 equiv B(OPh)3 and 1 equiv H2O at 80 °C in toluene for 1 h, followed by removal of volatiles under vacuum (0.5 mm Hg) at 80 °C for 0.5 h. yield of isolated cis-aziridine by chromatography on silica gel. Chiralcel OD-H column. 98 c b determined by HPLC on a The second round of screening of the 31 ligands was performed with the imine 9d synthesized from benzaldehyde (Table 3.6). Many of the trends in asymmetric induction observed for the cyclohexyl imine 9i were also observed for the phenyl imine 9d. Electron releasing groups generally give increased inductions (OMe, 96% ee) compared to VANOL (92% ee) while electron withdrawing substituents lead to decrease inductions (F, 83% ee; Cl, 89% ee; Br, 89% ee; CF3, 86% ee). The 4-methylphenyl group gives 96% ee and 4-t-butylphenyl group gives 97% ee. The increase is again more than negated by a 4-trifluoromethylphenyl group (84% ee). One contrast is that the 3,5-bis-trifluoromethylphenyl group gives an increased induction (95% ee) for the phenyl imine 9d but a decreased induction (78% ee) for the cyclohexyl imine 9i, compared to VANOL. The advantage of a phenyl group is again lost when ortho-groups are introduced on the phenyl ring. Et, n-Bu and Cy groups give the same asymmetric induction (94%) but the i-Pr group gives 97% ee and the t-Bu group gives 98% ee. The best ligand for the cyclohexyl imine is also the best ligand for the phenyl imine. All reactions were carried out for 24 h in order to ensure that any differences in rates for the different ligands could be accommodated. The reaction of the phenyl imine 9d with the catalyst from 7,7’-di-t-butylVANOL (5 mol%) was repeated and stopped after 4 h. The reaction was complete and gave aziridine 31d in 89% yield with 97.4% ee. The sample of the ligand used in this reaction has been stored in the refrigerator under N2 for two years subsequent to the first run indicated in Table 3.6. 99 b c entry ligand R 1 3 H 76 93 VAPOL 2 174a H 84 92 VANOL 3 174b F 80 83 4 174c Cl 91 89 5 174d Br 6 174e I 85 92 7 174f CF3 96 86 8 174g OMe 86 96 9 174h Me 10 174i Et 90 94 11 174j n-Bu 95 94 12 174k i-Pr 93 97 13 174l Cy 94 94 14 174m t-Bu 82 15 174n SiPh2t-Bu 77 % yield 89 82 100 d e f % ee 89 86 98 d e f 94 Table 3.6 (cont’d) 16 4-MeC6H4 94 96 17 174p 4-CF3C6H4 92 84 18 174q 4-t-BuC6H4 85 97 19 174r 3,5-Me2C6H3 82 95 20 174s 3,5-(t-Bu)2-4-MeOC6H2 85 97 21 174t 3,5-(CF3)2C6H3 94 95 22 174u 2,6-Me2C6H3 77 91 23 174v 1-naphthyl 92 92 24 174w 2-naphthyl 91 95 25 174x 9-anthracenyl 88 84 26 174y 2-C4H3S 96 95 27 174z 2-C4H3O 95 96 28 174aa 3-C4H3S 96 96 29 174ab 3-C4H3O 98 95 30 174ac -CH=CH2 91 93 31 174ad -CCH 86 93 32 174ae -CCSiMe3 86 92 33 a 174o 174af -CC-t-Bu 94 94 unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 1.2 equiv EDA at 25 °C for 24 h and went to 100% completion with 5 mol% catalyst. 101 The catalyst was prepared as indicated in Table 3.5. b yield of isolated cis-aziridine by c d chromatography on silica gel. determined by HPLC on a Chiralcel OD-H column. a repeat of this reaction on 1.0 mmol scale gave 80% yield and 88% ee. e a repeat of this reaction on 1.0 f mmol scale gave 87% yield and 86% ee. a repeat of this reaction revealed that it was complete in 4 h to give 89% yield and 97.4% ee. Given the fact that the 7,7’-di-t-butylVANOL was the best ligand for both of the benzhydryl imines 9d and 9i, ten benzhydryl imines were then examined with the catalyst generated from 7,7’-di-t-butylVANOL (Table 3.7). All of these imines have been previously examined with 26g catalysts prepared from VANOL and VAPOL. For all the ten imines, 7,7’-di-t-butylVANOL gives higher asymmetric inductions and yields than either VANOL or VAPOL. For aryl imines, 7,7’-di-t-butylVANOL gives 95-99% ee, while VAPOL gives 79-94% ee and VANOL gives 87-94% ee. For 1°, 2° and 3° alkyl imines, 7,7’-di-t-butylVANOL gives 94-96% ee, while VAPOL gives 81-87% ee and VANOL gives 77-85% ee. 7,7’-Di-t-butylVANOL gives both a much higher average yield and asymmetric induction (85% yield, 97% ee) than VANOL (74% yield, 87% ee) or VAPOL (65% yield, 86% ee). The improvement on some challenging subtrates is much more obvious. For instance, the reaction of the 2-bromophenyl imine 9c with the VAPOL catalyst gives a 1.6:1 mixture of cis and trans isomers (82% ee for the cis isomer), and the VANOL catalyst gives a 1.9:1 mixture of cis and trans isomers (82% ee for the cis isomer), whereas, the 7,7’-di-t-butylVANOL catalyst gives an 8:1 mixture of cis and trans isomers (95% ee for the cis isomer). Improved diastereoselectivity is also observed for the 2-methylphenyl 102 imine 9f with cis:trans ratios increasing from 10:1 to 12: 1 to >100:1 for the VAPOL, VANOL and 7,7’-di-t-butylVANOL catalysts, respectively. A decrease in the amount of enamine side-products and an increase in the cis:trans ratio together account for the increase in efficiency in the formation of the cis-aziridine. The 7,7’-di-t-butylVANOL catalyst solves several of the long-standing problems in the Wulff cis-aziridination reactions of benzhydryl imines, providing excellent diastereoselectitivties and enantioselectivities. Table 3.7 Substrate scope comparison of di-t-Bu-VANOL with VANOL and VAPOLa Ph N Ph O Ph + BOROX cat (5 mol%) OEt tolunene, rt, 24 h N2 R 9 R N R 30 CO2Et 31 VAPOL catalyst series Ph % yield c AZ % ee AZ d b VANOL catalyst % yield c AZ % ee AZ d b t-Bu2VANOL catalyst % yield c AZ % ee AZ a 4-NO2C6H4 79 79 86 89 96 98 b 4-BrC6H4 78 90 86 94 90 98 c 2-BrC6H4 37 82 43 f 82 d C6H5 82 94 87 93 82 98 e 1-naphthyl 76 93 80 93 91 99 f 2-MeC6H4 91 67 i 90 92 j 97 g 4-MeOC6H4 51 86 67 87 71 98 h n-propyl 40 81 54 77 77 94 63 e h 103 78 g 95 d Table 3.7 (cont’d) i 73 81 79 82 88 94 j t-butyl 72 87 89 85 89 96 average a cyclohexyl 65 86 74 87 85 97 unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 1.2 equiv EDA at 25 °C for 24 h and went to 100% completion with 5 mol% catalyst. b c The catalyst was prepared as indicated in Table 3.5. data taken from ref 26g. yield of isolated cis-aziridine by chromatography on silica gel. column. e d determined by HPLC on a Chiralcel OD-H f plus 23% yield trans-31c (cis/trans = 1.6:1). plus 23% yield trans-31c (cis/trans = g h 1.9:1). plus 10% yield trans-31f (cis/trans = 8:1). plus 6% yield trans-31f (cis/trans = 10:1). i j plus 6% yield trans (cis/trans = 12:1). cis/trans > 100:1. Given the success of with benzhydryl imines, 7,7’-di-t-butylVANOL was then examined with MEDAM imines (Table 3.8). The reaction of the 4-bromophenyl imine 201b with the VANOL catalyst affords aziridine 202b in 95% yield and 97% ee and the reaction with the 7,7’-di-t-butylVANOL catalyst affords aziridine 202b in 95% yield and 99% ee. The reaction of the cyclohexyl imine 201i with the VANOL catalyst affords aziridine 202i in 95% yield and 91% ee and with 7,7’-di-t-butylVANOL catalyst aziridine 202b is obtained in 92% yield and 97% ee. Thus 7,7’-di-t-butylVANOL can further improve the performance of MEDAM imines in term of asymmetric induction. 104 Table 3.8 Cis-aziridination reaction of imines 201 with VANOL and di-t-Bu-VANOLa OMe MeO O + N R OEt OMe BOROX cat (5 mol%) N tolunene, rt, 24 h N2 R OMe 201b, R = 4-BrC6H4 201i, R = Cy 30 CO2Et 202 VANOL catalyst c b t-Bu2VANOL catalyst d c entry 1 4-BrC6H4 95 97 95 cyclohexyl 95 91 92 d 99 2 a R 97 % yield AZ % ee AZ % yield AZ % ee AZ unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 1.2 equiv EDA at 25 °C for 24 h and went to 100% completion with 5 mol% catalyst. b c The catalyst was prepared as indicated in Table 3.5. data taken from ref 26j. yield of isolated d cis-aziridine by chromatography on silica gel. determined by HPLC. 3.3.9 Utility of 7,7’-di-t-butylVANOL in the Wulff trans-aziridination reaction It was found that 7,7’-di-t-butylVANOL catalyst outperforms that from VANOL in the Wulff trans-aziridination reaction as well at least for the two substrates shown in Table 3.9. The reaction of the ethyl imine 203k with the VANOL catalyst affords aziridine 204k in 67% yield and 85% ee and that with the 7,7’-di-t-butylVANOL catalyst affords aziridine 204k in 65% yield and 90% ee. The reaction of the n-propyl imine 203l with the VANOL catalyst affords aziridine 105 204l in 70% yield and 71% ee and that with the 7,7’-di-t-butylVANOL catalyst affords aziridine 204l in 69% yield and 85% ee. Though the reaction of the phenyl imine 204d with the 7,7’-di-t-butylVANOL catalyst affords no desired trans-aziridines. Table 3.9 Trans-aziridination reaction of imine 203 with VANOL and di-t-Bu-VANOLa OMe t-Bu t-Bu N R t-Bu OMe t-Bu 203d, R = Ph 203k, R = Et 203k, R = n-Pr O + NHPh BUDAM N BOROX cat (10 mol%) N2 tolunene, 0 °C, 24 h NHPh R O 148 204 VANOL catalyst c b t-Bu2VANOL catalyst d c entry % yield AZ 1 Ph 75 91 nd Et 67 82 65 90 3 n-Pr 70 71 69 d nd 2 a R 85 % ee AZ % yield AZ % ee AZ Unless otherwise specified, all reactions were performed on 0.2 mmol scale in toluene at 0.2 M imine with 1.4 equiv of diazoacetamide for 24 h at 0 °C and went to 100% conversion. The catalyst was prepared by heating a mixture of 1 equiv of the ligand, 3 equiv BH3•SMe2, 2 equiv phenol, 3 equiv H2O in toluene at 100 °C for 1 h. The volatiles were then removed under b c vacuum (0.1 mm Hg) at 100 °C for 1 h. nd = not determined. data taken from ref 27a. yield of d isolated trans-aziridine by chromatography on silica gel. determined by HPLC. 106 3.4 Future plan With the set of thirty-one VANOL derivatives in hands, it would be of synthetic benefit to find a superior ligand to further improve the Wulff trans-aziridination developed by Dr. Desai and the 27a,29 catalytic asymmetric systhesis of trisubstituted aziridines developed by Dr. Huang. Blechert and coworkers introduced a new concept to immobilize an organocatalyst (Scheme 3.25). 85 They obtained several polymer networks 206 or 208 via the oxidative coupling of thienyl-functionalized BINOL derivatives in the form of the structure-directing monomers 205 or 207. Microporosity, chirality and active centers are introduced in the polymer network. Those polymers can catalyze transfer hydrogenation of dihydro-2H-benzoxazine 209 with decent to excellent enantioselectivities. The catalysts could be recovered by centrifugation and reused for 10 runs without any loss in activity or selectivity. The reactions catalyzed by the heterogenous catalysts show increased enantioselectvity compared to the homogenous reactions. Inspired by their concept, we might be able to prepare a polymer network 211 from 7,7’-bis-(3-thienyl)VANOL 174aa, a ligand from the 31 member VANOL library (Scheme 3.26). This homogenous catalyst could be used in the Wulff aziridination reactions, as well as other reactions catalyzed by VANOL. 107 108 109 3.5 Conclusion The family of 7,7’-disubstituted VANOL ligands can be quickly and efficiently prepared in three steps from p-substituted phenylacetic acids and phenylacetylene via a cycloaddition/electrocyclic ring-opening/electrocyclic ring closure/tautomerization cascade, a phenol homo-coupling reaction and finally deracemization. A convergent synthesis of additional members of the family can be achieved via 7,7’-dibromoVANOL or 7,7’-diiodoVANOL via Suzuki, Stille, Kumada, Sonogashira, Hartwig and Ullman coupling reactions. A set of 31 7,7’-disubstituted VANOL ligands was then used to screen the cis-aziridination reaction of benzhydryl imines and ethyl diazoacetate. Phenyl and cyclohexyl imines were treated with boroxinate catalysts prepared from all 31 of the VANOL ligands. Asymmetric inductions varied from 63-98% ee. The best induction for the two imines was obtained with the same ligand: 7,7’-di-t-butylVANOL. This ligand was applied to the aziridination of ten different benzhydryl imines. For aryl imines, 7,7’-di-t-butylVANOL gave 95-99% ee, and for alkyl imines, it gave 94-96% ee. For every imine, 7,7’-di-t-butylVANOL afforded a higher induction than VANOL or VAPOL. Higher cis/trans selectivities were observed for o-substituted aryl imines with 7,7’-di-t-butylVANOL. 7,7’-di-t-butylVANOL is also compatible with other N-substituents, such as MEDAM and BUDAM. Moreover, it improves the asymmetric induction with alkyl mines in the trans-aziridination reaction. 110 CHAPTER FOUR SYSTEMATIC EXPLORATION OF SINGLE-POINT AND DOUBLE-POINT CHANGES TO VANOL BOROX CATALYST: STRUCTURE-ACTIVITY RELATIONSHIP STUDY ON VANOL DERIVATIVES 4.1 Introduction Our group developed the first highly enantioselective cis-aziridination reaction of imine and 26a,26b diazo compound. Originally the catalyst was thought to be a Lewis acids. Later on, Dr. Hu determined that this transformation actually is a Brønsted acid catalyzed reaction through extensive NMR and crystallographic 26i,26l studies. The crystal structure of the chemzyme-substrate complex revealed the unique boroxinate topology, self-assembled from 26l VAPOL, B(OPh)3, H2O and the MEDAM imine of benzaldehyde (Scheme 4.1). There is an H bonding between the hydrogen of the protonated imine and one of the oxygens of the boroxinate ring (N-O distance is 2.84 Å). In addition, there are several non-covalent catalyst-substrate contacts. There is a π−π stacking interaction between the phenyl group of the protonated imine and the central ring of the phenanthrene of the catalyst (3.50 Å). Four CH-π interactions could be identified. One of the methyl groups of the MEDAM imine is over the central ring of one of the phenanthrenes of the catalyst (3.59 Å). The other methyl group on the same phenyl group is over one of the phenoxy groups of the boroxinate core (3.67 Å). One of the ortho-H’s of the other phenyl group of the imine is 3.60 Å away from the one of the phenyl groups (C3 phenyl) on the backside of VAPOL. The carbon of the methyl group next to this ortho-hydrogen is 4.42 Å away from the same phenyl ring (C3 phenyl). 111 112 Zhenjie Lu from our group synthesized some VANOL derivatives with variation in the substituents on the C3 aryl group and was able to get a crystal structure of the BOROX catalyst 64 from the VANOL derivative and the MEDAM imine of benzaldehyde (Scheme 4.2). The binding of the catalyst and substrate was not the same as in the previous one (Scheme 4.1). The protonated imine is H-bonded to the boroxinate core in a different way and is H-bonded to O-1 not O-2. The H bonding distance is 3.31 Å. The π−π stacking is now between the phenyl group of the iminium cation and the 3,5-dimethyl-4-methoxyphenyl substituent (C3 aryl) of the ligand (3.91 Å). There are at least six CH-π interactions. The phenyl group of the iminium cation is rotated about 90° and has a CH-π interaction with the naphthalene ring of the ligand (3.40 Å). The other naphthalene ring is involved in CH-π interactions with an ortho-hydrogen (3.80 Å) and a methyl group (3.68 Å) of one of the 3,5-dimethyl-4-metoxyphenyl groups of the MEDAM imine. A hydrogen in the 7-position of one of the naphthalene rings of the ligand is over the other 3,5-dimethyl-4-methoxyphenyl groups of the MEDAM imine (3.72 Å). The methyl group on the same 3,5-dimethyl-4-methoxyphenyl group of the MEDAM imine is over one of the phenyl groups of the boroxinate core (3.78 Å). There is a CH-π interaction between the same 3,5-dimethyl-4-methoxyphenyl group of the MEDAM imine and the methyl group of the 3,5-dimethyl-4-methoxyphenyl group (C3 aryl) of the ligand (4.06 Å). The biggest difference in this crystal structure is that the methine hydrogen of the imine is pointing away from the catalyst and projecting into free space, while in the previous structure, the methine hydrogen is pointing towards the catalyst and is engaged in a CH-O interaction with the boroxinate core (3.28 Å). 113 114 The hydrogen binding holds the catalyst and substrate together while the π−π and CH-π interactions organize the two parts and direct the path of the incoming diazo compound. Current but universally accepted thinking on CH-π interactions derives from experimental and computational studies and it is believed that an electron-withdrawing group on the edge ring will 97,98 increase the interaction between face and edge rings (Scheme 4.3). Electron-donating groups on the face ring will also enhance the interaction, while electron-withdrawing groups on the face ring will have opposite effect. 115 4.2 Background 4.2.1 Effect of the N-substituent on the imine In order to understand the details of the aziridination reaction, our group has carried out a continuous study, examining the contribution of each component in turn. Before the crystal structures discussed above were obtained and solved, Dr. Zhang and Dr. Lu investigated the interactions between the N-substituent and catalyst by changing the 26h conformation, electronics and sterics of the N-substituent (Scheme 4.4). The relative rate was determined in competition experiments in which 1.0 equiv of imine 9d and 1.0 equiv of a competitor imine were reacted with 0.2 equiv of EDA in the presence of 5 mol % of VAPOL BOROX catalyst at 25 °C for 24 h. The N-alkyl and benzyl imines give lower induction than the benzhydryl imine, indicating the importance of the interactions of the two phenyl groups and the catalyst. The reactions with the imines 1d, 1f, and 1g reveal that the orientation of the two phenyl groups is important. The increased reactivity and enantioselectivity of BUDAM imine 212o and the MEDAM imine 212p may be related to the CH-π interactions of methyl and t-butyl groups with the catalyst observed in the crystal structures of the MEDAM imines. Introduction of electron-withdrawing groups (Br or F) leads to slightly decreased induction, while that of electron-donating groups (Me or OMe) has opposite effect. The 3,5-bis(trifluoromethyl) analogue gives a much slower reaction rate and a much lower induction (37% ee). Those observations may be suggestive of the importance of the CH-π interaction between the phenyl group of the imine and the C3 phenyl of the ligand observed in the second crystal structure (Scheme 4.2). 116 117 4.2.2 Effect of diazo compounds Dr. Lu was the first to look at variation of the alcohol group in the ester group of the diazo acetate. The steric and electronic changes in the diazo acetates only affects the asymmetric 64 inductions in the range of 1-4% ee and give comparable yields (Table 4.1). The most sterically hindered (89% t-butyl diazo acetate gives lowest enantioselectivity ee). The electron-withdrawing phenyl diazo acetate leads to lower induction (91% ee) as well. b entry series of 214 1 Me a 90 Et b 84 93 3 i-Pr c 86 92 4 t-Bu d 95 89 5 Ph e 88 c 91 2 a R 91 % yield AZ % ee AZ Unless otherwise specified, all reactions was carried out at 0.5 M in imine in CCl4 with 10 mol% catalyst loading. The catalyst were prepared from 1 equiv VAPOL, 3 equiv B(OPh)3 at 80 b ºC in toluene for 1 h, followed by the high vacuum (0.5 mm Hg) at 80 ºC for 0.5 h. Isolated yield after silica gel chromatography. c Determined from chiral HPLC on a Chiralcel OD-H column. 118 26j The reaction of imines and the 3° diazoacetamide 216 give cis-aziridines (Scheme 4.5). The nature of the N-substituent on the imine influences the yield and induction. The yields vary from 14-66% and the inductions vary from 88-97%. 27 When switching to 2° diazoacetamide, the reaction gives trans-aziridines. Dr.Vetticatt performed a computational study on those observations. It is suggested that for cis-aziridine 119 formation, the protonated imine is H bonding to O-1 of the boroxinate core and the diazoactate or 3° acetamide H bonds to O-2; while for trans-aziridine formation, the protonated imine is H bonded to O-3 of the boroxinate core and the 2° acetamide is H bonded to O-1 and O-2. 4.2.3 Effect of phenols Our catalyst could also be prepared by self-assembly from the ligand, BH3•SMe2, a phenol, H2O and the imine. As discussed above, a CH-π interaction between the phenoxy group of the boroxinate ring and the phenyl rings of the benzhydryl group of the imine is observed in both the crystal structures (Scheme 4.1 and 4.2). Therefore, an investigation of the electronic and steric effects of this phenoxy group on asymmetric inductions in the aziridination reactions and thus on the interactions between the catalysts and the phenyl imine 9d was carried out by Dr. Lu and Dr. 64,86 Osminski. Phenol with para-electron-withdrawing group (OMe) gives lower enantioselectivity, while phenol with para-electron-donating group (NO2) gives comparable enantioselectivity to phenol itself (Scheme 4.6). A diminished CH-π interaction between the phenoxy ring of the boroxinate (face) and the phenyl ring of the benzhydryl group (edge) would be consistent with the low induction observed for EWG on the phenol. Steric hindrance in the ortho position has a small negative effect on the asymmetric induction. Increased steric bulk on the para-position of the phenol has almost no effect on the asymmetric induction, and this is not surprising as this position is quite far away from the sites of interaction in the catalyst-imine complex. Aliphatic alcohols can also be incoporated into the boroxinate ti give an effective 120 catalyst for the aziridination reaction, indicating that a CH-π interaction between the phenoxy ring of the boroxinate (face) and the phenyl ring of the benzhydryl group (edge) is not necessary for BOROX catalyst to function. Cyclohexanol turns out to be the optimal alcohol. The cyclohexyl imine 9i was catalysts prepared from the same set of phenols and alcohols and similar trends were observed (Scheme 4.7). Interestingly, cyclohexanol turns out to be the optimal alcohol for this imine as well. 121 a Unless otherwise specified, all reactions were run in toluene in 0.5 M of imine with 1.1 equiv EDA 30 and 10 mol% catalyst loading. The catalyst was prepared by heating 1 equiv ligand, 3 equiv BH3•SMe2, 2 equiv phenol or alcohol, and 1 equiv H2O in toluene at 100 ºC for 1 h and then exposure to high vacuum (0.5 mm Hg) for 0.5 h at 100 ºC. 122 a Unless otherwise specified, all reactions were run in toluene in 0.5 M of imine with 1.1 equiv EDA 30 and 10 mol% catalyst loading. The catalyst was prepared by heating 1 equiv ligand, 3 equiv BH3•SMe2, 2 equiv phenol or alcohol, and 1 equiv H2O in toluene at 100 ºC for 1 h and then exposure to high vacuum (0.5 mm Hg) for 0.5 h at 100 ºC. 123 4.2.4 Effect of C3 aryl group The first crystal structure (Scheme 4.1) reveals a possible CH-π interaction between the C3 phenyl group of the VAPOL ligand and the ortho hydrogen of the MEDAM group of the imine (4.42 Å). While in the second crystal structure (Scheme 4.2), there is a π−π stacking interaction between the phenyl group of the iminium cation and the 3,5-dimethyl-4-methoxyphenyl substituent of the C3 aryl group of the ligand (3.91 Å). Dr. Lu started an investigation on the dependence of various substituents in the C3 aryl group on VANOL with the asymmetric 64 inductions in the aziridination reaction. Her investigation focused on changing both the electronic and steric properties of the C3 phenyl group on VANOL with the hope that changes in the asymmetric induction might shed some light on the catalyst-substrate interactions. 124 The monomer 222 could be synthesized either via the benzannulation pathway (I) or the ketene insertion pathway (II) (Scheme 4.8). The thermal coupling of the monomer 222 in the presence of air gives the racemic ligand 223, which can be converted into (S)-223 via a Cu(II)-(–)-sparteine complex mediated deracemization procedure. 125 b entry mol% cat imine Ar ligand 1 10 9d C6H5 VANOL 87 93 2 10 9d 4-BrC6H4 223g 92 91 3 10 9d 4-PhC6H4 223h 92 89 4 10 9d 3,5-Me2C6H3 223c 91 94 5 10 9d 3,5-Me2-4-MeOC6H2 223e 84 96 6 10 9d 4-EtOC6H4 223o 81 94 7 5 9a C6H5 VANOL 86 89 8 5 9a 4-BrC6H4 223g 86 89 9 5 9a 3,5-Me2C6H3 223c 85 88 10 5 9g C6H5 VANOL 61 87 11 5 9g 4-BrC6H4 223g 68 85 12 5 9g 3,5-Me2C6H3 223c 54 92 13 5 9g 3,5-Me2-4-MeOC6H2 223e 62 96 14 5 9g 4-EtOC6H4 223o 58 88 126 % yield % ee c Table 4.2 (cont’d) a Unless otherwise specified, all reactions were carried out at 0.5 M in imine in toluene at 25 ºC for 24 h with 1.1 equiv EDA 13. The catalyst was generated from 1 equiv ligand, 4 equiv B(OPh)3, and 1 equiv H2O at 85 °C for 1 h, then 0.5 mm Hg vacuum was applied at 85 ºC for b c 0.5 h. Isolated yield after silica gel chromatography. Determined from HPLC on a Chiralcel OD-H column. Five chiral VANOL derivatives were prepared by Dr. Lu and examined for an evaluation of the interactions of C3 phenyl group (Table 4.2). The phenyl imine 9d was used as the standard imine in the aziridination reactions. To span a broader range of catalyst-substrate interactions, the para-nitrophenyl imine 9a and the para-methoxylphenyl imine 9g were also examined with some ligands. There was a small but measurable variation in the asymmetric inductions (89-96% ee) and the lowest enantioselectivities were observed with imine 9d (Table 4.2, entry 2 and entry 3) for the ligands with the most electron withdrawing groups on C3 phenyl group, which might be due to the weakened CH-π interaction in the complex I (Scheme 4.1) or π−π interaction in the complex II (Scheme 4.2). Ligands 223c and 223e enhance the enantioselectivity to a significant degree giving the highest asymmetric inductions for both imines 9d and 9g. This may be the result of enhanced CH-π interactions. Dr. Lu obtained the 4,4’-di-nitro-VANOL 169 from Dr. Hu and it gave racemic aziridine 31d but in comparable yield (73%). 127 4.3 Results and discussion 4.3.1 Effect of substitution on the naphthalene core In Chapter 3, an intensive study that evaluated various groups in the 7,7’-positions of VANOL in BOROX catalyst for the aziridination reaction was compiled. Given the strength of the effect that substituents in this position had, it would be of interest to evaluate the effects that substituents in all the positions of the naphthalene ring have on the aziridination reaction (Scheme 4.9). The reactions of 2-, 3- and 4-bromo phenylacetic acids with phenylacetylene were carried out under the optimal conditions for the CAEC cascade (Scheme 4.10). 4-bromo phenylacetic acid gives 7-bromo-3-phenyl-1-naphthol 175d in 67% yield and 2-bromo phenylacetic acid yields 5-bromo monomer 224d in 80% yield while 3-bromo phenylacetic acid affords the two regioisomers, 6-bromo-3-phenyl-1-naphthol 225d (47%) and 8-bromo monomer 226d (19%). 128 The thermal coupling of the those monomers 175d, 224d and 225d in the presence of air, followed by a Cu(II)-(–)-sparteine complex mediated deracemization procedure, generated the optically pure dibromo ligands with ≥ 99% ee (Scheme 4.11). The above three dibromo ligands were each converted to two sets of diaryl ligands via Suzuki coupling with 4-tert-butylphenylboronic acid and 4-(trifluoromethyl)phenylboronic acid, 129 respectively (Scheme 4.12). These set of substituents were chosen since the 4-tert-butylphenyl was among the best and 4-trifluoromethylphenyl was one the worst substituents for the aziridination reaction (Chapter 2). Access to the 4,4’-disubstituted VANOL derivatives was achieved by direct bromination of optically pure VANOL with bromine which gave 4,4’-dibromo VANOL in a quite high yield (98%) (Scheme 87 4.13). Suzuki coupling of 4,4’-dibromo VANOL 229d with 4-tert-butylphenylboronic acid gave the 4,4’-diaryl VANOL 229q in 59% yield. Since the azidination reaction with 229q gave racemic products, 4-trifluoromethylphenyl was not 130 introduced. The Stille coupling with tributylstannylethylene gave an unseparable mixture of compounds that was not further characterized. Gang Hu prepared the 8,8’-dimethyl and 8,8’-phenyl VANOL via the benzannulation pathway 13d (Scheme 4.14). Benzannulation reactions of the Fischer carbene complexes 230 with phenylacetylene, followed by deprotection gave the desired monomer 232. Resolution or deracemization of the oxidative coupling intermediates from the monomer afforded the optically pure ligands 233. 131 Aman Desai also synthesized 8,8’-phenyl VANOL 232ah by another route (Scheme 4.15). The major difference is that the monomer was prepared via a phenoxy-directed palladium-mediated 13e C–H activation/coupling protocol from the simple VANOL monomer. 132 In addition to introducing different groups in various positions of the naphthalene rings of VANOL, It was also of interest to examine H8-VANOL 234 given the proposed important π-π stacking interaction in Complex I (Scheme 4.1). After trials with various reduction conditions, H8-VANOL was successfully prepared via the hydrogenation catalyzed by Adams’ catalyst 88 (Scheme 4.16). 133 With the naphthalene skeleton modified VANOL derivatives in hand, phenyl and cyclohexyl imines were treated with boroxinate catalysts derived from these new ligands (Table 4.3). entry Ligand position of R 1 R % yield 1 VANOL 2 232ah 8,8’ 3 232h 4 1 31d R =Ph b % ee 31i R =Cy c % yield b % ee 84 92 77 81 Ph 62 8 26 15 8,8’ Me 83 80 72 77 174d 7,7’ Br 89 89 78 85 5 174q 7,7’ 4-t-BuC6H4 85 97 83 93 6 174p 7,7’ 4-CF3C6H4 92 84 93 78 7 228d 6,6’ Br 83 90 76 79 8 228q 6,6’ 4-t-BuC6H4 82 89 77 82 9 228p 6,6’ 4-CF3C6H4 92 87 86 78 10 227d 5,5’ Br 87 92 80 83 134 c Table 4.3 (cont’d) 11 5,5’ 4-t-BuC6H4 87 84 79 74 12 227p 5,5’ 4-CF3C6H4 92 78 84 69 13 229d 4,4’ Br 86 45 81 45 14 a 227q 229q 4,4’ 4-t-BuC6H4 75 3 68 1 unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 1.2 equiv EDA at 25 °C for 24 h and went to 100% completion with 5 mol% catalyst. The catalyst was prepared as indicated in Table 4.2. b yield of isolated cis-aziridine by c chromatography on silica gel. determined by HPLC on a Chiralcel OD-H column. The 8,8’-positions are apparently be too close to the boroxinate core. Introducing methyl groups in the 8,8’-positions gave lower asymmetric induction than VANOL (Table 4.3, entry 3). The even bigger phenyl group led to much lower induction and the reaction was much slower (Table 135 4.3, entry 2). As the substituents are moved from the 7-, to the 6-, to the 5-position, the groups are moving away from the boroxinate core. Generally, for each position, 4-t-BuC6H4 is better than Br, followed by 4-CF3C6H4 in terms of asymmetric induction. For each substituent, 7-position is superior to the 6-position, followed by the 5-position with respect to average asymmetric induction. However, each substituent behaves differently. The 4,4’-dibromo VANOL gave phenyl aziridine with 45% ee and cyclohexyl aziridine with 45% ee (Table 4.3, entry 13). Introducing the even bigger para-tert-butylphenyl group into the 4-position gave the phenyl aziridine 31d with 3% ee and cyclohexyl aziridine 31i with 1% ee (Table 4.3, entry 14). Those observed detrimental effects in the 4,4’-positions might be resulted from the change in the dihedral angle. To our surprise, H8-VANOL afforded the phenyl aziridine 31d with 82% ee and the cyclohexyl aziridine 31i with 90% ee (Scheme 4.17). The diminished asymmetric induction for the phenyl aziridine might be due to the loss of the π-π stacking interaction. However, neither of the crystal structures in Schemes 4.1 & 4.2. could rationalize all the above observations. The interactions in the solid state might not be the same as those in the solution state or more likely in the transition states with ethyl diazo acetate. And also different imines might adopt different interactions in their individual transition states. 4.3.2 Effect of C3-aryl substituents After illustrating the effect of perturbations in the substituents at various positions of the naphthalene skeleton on the aziridination reaction, the next set of ligands to be examined involve 136 varying the electronic and steric properties of the C3 phenyl group and looking for a relationship with the asymmetric induction of the aziridination reaction as well as to identify a superior ligand (Scheme 4.18). Several aryl alkynes were synthesized via two routes (Scheme 4.19). The first route involves the 89 Corey-Fuchs reaction. dibromoalkene. Treatment of the aldehyde with CBr4 and PPh3 leads to a Treatment with n-BuLi generates a bromoalkyne intermediate via dehydrohalogenation, which undergoes metal-halogen exchange and yields the terminal alkyne upon acidic work-up. The second route takes advantage of the Sonogashira coupling 90-93 reaction. The palladium and copper catalyzed coupling reactions of aryl iodides with trimethylsilylacetylene, followed by cleavage of the TMS group under basic conditions, gave the desired aryl acetylenes in good isolated yields. 137 The CAEC cascade reactions with various aryl acetylenes with 4-bromo phenylacetic acid gave different C3 aryl 7-bromo-1-naphthols as desired monomeric intermediates (Scheme 4.20). The reaction with 1,3-dimethyl-2-ethynyl-benzene gave complicated mixture and no desired product 1 was observed from H NMR of the crude mixture. 138 Those monomers were then applied to the oxidative coupling reaction conditions. All of the monomers except the 3,4,5-(OMe)3C6H2 substituted one gave dimmers that could be brought to purity. Gratefully, all the racemates underwent deracemization smoothly, affording the optically pure dibomo ligands with > 99% ee. 139 a a Entry % yield (±)-237 1 Ph 82 70 4-n-BuC6H4 62 80 >99 3 3,5-Me2C6H3 65 75 >99 4 4-MeOC6H4 69 >99 5 3,5-Me2-4-MeOC6H2 40 74 >99 6 4-FC6H4 70 87 >99 7 3,4,5-(OMe)3C6H2 nd - b >99 2 a Ar - 42 c % yield (S)-237 isolated yield by chromatography on silica gel. nd = not determined. b % ee (S)-237 determined by HPLC. c phenol coupling at 175 °C Since a 4-t-BuC6H4 in 7,7’-ositions of VANOL was the second best substituent other than t-Bu in terms of asymmetric induction of the aziridination reactions (Chapter 3), this group was installed in the 7,7’-positions of all the C3 aryl VANOL derivatives indicated in Table 4.4 was Suzuki coupling. The reactions of two substrates, 4-FC6H4 or 4-MeOC6H4 substituted ligands, 140 gave insoluble material and the yields were not determined. The other four ligands yielded the desired diaryl ligands successfully (Table 4.5). Entry % yield 238 1 Ph 4-n-BuC6H4 50 3 3,5-Me2C6H3 48 4 4-MeOC6H4 nd 5 3,5-Me2-4-MeOC6H2 26 6 4-FC6H4 a 41 2 a Ar nd isolated yield by chromatography on silica gel. nd = not determined. Phenyl and anthracenyl group could also be introduced via a protection/Suzuki coupling/deprotection sequence (Table 4.6). 141 entry Ar R % yield 1 240ah 4-n-BuC6H4 Ph 240x 4-n-BuC6H4 9-anthracenyl a 74 2 a compound 53 isolated yield by chromatography on silica gel. The CAEC cascade reaction was also used to generate VANOL monomers that only are modified in the C3 aryl group. The reaction of phenylacetyl chloride and various alkynes generated different C3-aryl-1-naphthols (Table 4.7). Aryl acetylenes as well as heteroaryl acetylenes, survived the reaction conditions. entry compond R 1 222c 3,5-Me2C6H3 142 % yield 66 a Table 4.7 (cont’d) 2 4-MeOC6H4 41 3 222e 3,5-Me2-4-MeOC6H2 56 4 222f 4-FC6H4 53 5 222g 4-BrC6H4 45 6 222s 2-C4H3S 37 7 a 222d 222t 3-C4H3S 57 isolated yield by chromatography on silica gel. To our delight, the oxidative coupling/deracemization sequence was applicable with all the monomers 222 obtained, even the C3 heteroaryl ones (Table 4.8). All the ligands were prepared with > 99% ee. entry compound R % yield (±)-223 1 223c 76 3,5-Me2C6H3 143 a % yield (S)-223 32 a % ee (S)-223 >99 b Table 4.8 (cont’d) 2 4-MeOC6H4 62 17 >99 3 223e 3,5-Me2-4-MeOC6H2 53 47 >99 4 223f 4-FC6H4 79 64 >99 5 223g 4-BrC6H4 59 74 >99 6 223s 2-C4H3S 45 7 a 223d 223t 3-C4H3S 59 isolated yield by chromatography on silica gel. b c 73 >99 c 40 >99 d d c determined by HPLC. phenol coupling at d 165 °C. (R)-enantiomer obtained upon deracemization with (+)-sparteine. The para-bromo substituted C3 phenyl VANOL derivatives 223e was then used to prepare an additional C3 aryl VANOL derivative 223f with a para-phenyl group via Suzuki coupling (Scheme 4.21). All of the C3 aryl modified VANOL ligands were then evaluated in the aziridination reactions of the phenyl and cyclohexyl imines. 144 The first subset examined was the 7,7’-dibromo ligands (Table 4.9, entries 1 to 6). Introduction of either an electron-withdrawing or an electron-donating substituent on the C3 phenyl group increases the asymmetric induction of the phenyl aziridine 31d, which does not support the CH-π interaction in complex I (Scheme 4.1) nor the π−π interaction in complex II (Scheme4.2). However, electron-withdrawing and electron-donating substituent have little effect on the asymmetric induction of the cyclohexyl aziridine 31i. entry ligand Ar R 1 1 31d R =Ph % yield 31i R =Cy % b ee c % yield % b ee c 1 237a Ph Br 89 89 78 85 2 237b 4-n-BuC6H4 Br 87 93 78 85 3 237c 3,5-Me2C6H3 Br 82 97 63 86 4 237d 4-MeOC6H4 Br 82 95 75 85 5 237e 3,5-Me2-4-MeOC6H2 Br 81 98 74 87 145 Table 4.9 (cont’d) 6 4-FC6H4 Br 81 94 77 84 7 238a Ph 4-t-BuC6H4 85 97 83 93 8 238b 4-n-BuC6H4 4-t-BuC6H4 87 97 80 90 9 238c 3,5-Me2C6H3 4-t-BuC6H4 87 98 83 93 10 238e 3,5-Me2-4-MeOC6H2 4-t-BuC6H4 86 96 83 92 11 240ah 4-n-BuC6H4 Ph 82 95 84 91 12 240x 4-n-BuC6H4 9-anthracenyl 57 90 25 d 64 13 223c Ph H 84 92 77 81 14 223d 3,5-Me2C6H3 H 87 95 84 88 15 223e 4-MeOC6H4 H 81 95 80 80 16 223f 3,5-Me2-4-MeOC6H2 H 85 96 79 87 17 223g 4-FC6H4 H 82 94 84 78 18 223s 4-BrC6H4 H 82 94 80 82 19 223t 4-PhC6H4 H 82 95 82 82 20 223c 2-C4H3S H 92 89 83 77 21 a 237f 223d 3-C4H3S H 91 89 83 79 unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 1.2 equiv EDA at 25 °C for 24 h and went to 100% completion with 5 mol% catalyst. b The catalyst was prepared as indicated in Table 4.2. yield of isolated cis-aziridine by 146 Table 4.9 (cont’d) chromatography on silica gel. c determined by HPLC on a Chiralcel OD-H column. d the reaction time was 48 h. The second subset evaluated was the 7,7’-diaryl ligands (Table 4.9, entries 7 to 12). Installation of either an electron-withdrawing or an electron-donating substituent on the C3 phenyl group has little effect on the asymmetric induction in the aziridination reactions of either the phenyl or the cyclohexyl imines. With the same C3 aryl, 4-t-BuC6H4 in the 7,7’-positions is better than phenyl, followed by 9-anthracenyl in terms of asymmetric induction (Table 4.9, entries 8,11 & 12). The third subset evaluated was the C3-aryl VANOL derivatives with no substituent in the 7,7’-positions (Table 4.9, entries 13 to 21). As for the phenyl imine, incorporation of either electron-withdrawing or electron-donating substituent on the C3 phenyl group increases the asymmetric induction. A 2- or 3-thienyl substituent leads to lower asymmetric induction, indicating that five-member aryl groups are worse than six-member aryl groups (Table 4.9, entries 20 & 21). Similar trends were observed in the aziridination reactions of the cyclohexyl imine. 4.3.3 C1-symmetric VANOL derivatives C1-symmetric BINOLs have also provened to be efficient chiral ligands in a variety of reactions and these are summarized in several reviews. 11a,94 A recent example that is not included in the reviews is the palladium catalyzed [3+2] cycloaddition of trimethylenemethane (TMM) and 95 aldehydes reported by Trost and coworkers. C1-symmetric BINOL outperformed those 147 A novel phophoramidite 244 derived from derived from C2-symmetric BINOLs. Methylenetetrahydrofurans 243 could be obtained in good yields and enantiopurities. One major utility of C1-symmetric BINOLs is their use in preparing immobilized ligands that can be 11a,94 recycled easily for multiple uses. The difficulties in the symthesis of C1-symmetric BINOLs hamper the study of their potential as useful chiral auxiliaries. 148 One synthetic route is the direct modification of optically pure BINOL (Scheme 4.23). Directed 95 ortho lithiation and subsequent electrophile quench yields 3-substituted BINOLs. aromatic substitution at the 6-position leads to various 6-substituted BINOLs. 96 Electrophilic However, one major problem associated with these approaches is the generation of mixtures of both mono- and bis-substituted BINOLs along with unreacted starting material, which requires costly chromatographic separation that is often quite difficult. Another attractive route is the Fe(salen) complex catalyzed asymmetric oxidative cross coupling of 2-naphthols with good to excellent enantioselectivities (Scheme 4.24). However, the substrate 149 scope is narrow and the resulting C1-symmetric BINOLs typically will need enhancement of their enantiopurities. Dr. Ding showed that mono lithiation and subsequent electrophilic quench led to 8-methyl and 8-bromo VANOLs. 73 However, there are no methods that will allow 7-mono substituted VANOL to be accessed from direct modification of VANOL. Retrosynthetic analysis discloses two possible routes to mono-substituted VANOL derivatives at the 7-position (Scheme 4.25). One route involves Suzuki cross coupling and the other one is via oxidative cross coupling of two different naphthols. In order to pursue the first route, bromine needs to be installed at the 2-poisition of 3-phenyl-1-naphthol 175. Various bromination conditions were tested and none of them gave required results (Scheme 4.26). Bromination with Br2 and t-BuNH2 gave a mixture based on the 1 H NMR of the crude reaction mixture. Bromination with Br2 in CCl4 also afforded a mixture 1 from the H NMR analysis of the crude reaction mixture. Bromination with NBS in acetonitrile 150 1 gave a clean reaction based on the H NMR of the crude reaction mixture. The intermediate phenol was not stable for chromatography on silica gel. Therefore it was protected and then 1 purified by column chromatography on on silica gel. H NMR analysis revealed that bromine was introduced at the para- not ortho- position. So far there is no ideal ortho-bromination procedure for 3-phenyl-1-naphthol 175. As for the second route involved a crossed phenol coupling of two different naphthols, Dr. Ding described some preliminary efforts. Exposure of a 2.8:1 mixture of 175 to 222g to the oxidative coupling conditions led to complete consumption of the starting materials (Scheme 4.27). However, only a single spot was observed on the TLC plate which, however, was a mixture of at least three compounds. Attempts to separate this reaction mixture using crystallization, column chromatography on silica gel and preparative TLC all failed. 151 After an extensive study, we found that one of the monomers should bear a MeO group in order to get separation of the products from the oxidative cross-coupling of two different naphthols. With this trick unveiled, several VANOL monomers were examined in the coupling and subsequent deracemization process (Table 4.10). Six C1-symmetric VANOL derivatives were obtained with >99% ee. 152 Table 4.10 (cont’d) entry series 1 R 2 R Ar 1 Ar 2 % yield (±)-260 a % yield (S)-260 a % ee (S)-260 1 H H Ph 4-MeOC6H4 52 18 >99 2 260b H H Ph 3,5-Me2-4-MeOC6H2 50 29 >99 3 260c Br H Ph 3,5-Me2-4-MeOC6H2 23 59 >99 4 260d I Br Ph 3,5-Me2-4-MeOC6H2 24 41 >99 5 260e t-Bu H Ph 3,5-Me2-4-MeOC6H2 13 63 >99 6 a 260a 260o Br Br Ph 3,5-Me2-4-MeOC6H2 51 a isolated yield by chromatography on silica gel. b determined by HPLC. 98 c c >99 (R)-260o obtained upon deracemization with (+)-sparteine. Other unsuccessful coupling reactions are showen in Scheme 4.28. Low yields or inseparable mixture were obtained from the cross coupling reactions. 153 The bromo substituted C1-symmetric VANOL derivatives could be further functionalized via the Suzuki coupling reactions with 4-tert-butylphenylboronic acid (Scheme 4.29). 154 With the establishment of the library of C1-symmetric VANOL derivatives, the phenyl and cyclohexyl imines were treated with BOROX catalysts prepared from those ligands (Table 4.11). With the same C3 aryl substituent at the 3’-position, 4-t-BuC6H4, Br and I substituents at the 7-position showed little effect in the aziridination reactions (Table 4.11, entries 3 to 5). Two 4-t-BuC6H4 substituents showed no beneficial effect compared to one 4-t-BuC6H4 substituent (Table 4.11, entry 8 vs 5). Two bromo groups gave lower induction than one bromo group (Table 4.11, entry 7 vs 3). 155 entry ligand R 1 2 R Ar 1 Ar 2 R=Ph % R=Cy % b c % % b c yield ee yield ee 1 260a H H Ph pMeOC6H2 83 88 85 78 2 260b H H Ph 3,5-Me2-4- 84 94 85 79 89 97 85 88 87 97 89 87 90 97 91 89 81 98 84 90 MeOC6H2 3 260c Br H Ph 3,5-Me2-4MeOC6H2 4 260d I H Ph 3,5-Me2-4MeOC6H2 5 260f 4-tBuC6H4 H Ph 3,5-Me2-4MeOC6H2 6 260e tBu H Ph 3,5-Me2-4MeOC6H2 156 Table 4.11 (cont’d) 7 260o Br Br Ph 3,5-Me2-4- 96 93 80 75 97 94 90 87 MeOC6H2 8 260p 4-tBuC6H4 4-tBuC6H4 Ph 3,5-Me2-4MeOC6H2 a unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 1.2 equiv EDA at 25 °C for 24 h and went to 100% completion with 5 mol% catalyst. The catalyst was prepared indicated in Table 4.2. b yield of isolated cis-aziridine by c chromatography on silica gel. determined by HPLC on a Chiralcel OD-H column. The comparison of C1- and C2-symmetric VANOL ligands is summarized in Table 4.12. Though none of the new ligands conld surpass 7,7’-di-t-butylVANOL in asymmetric induction, they provide complicated yet valuable mechanistic information in the aziridination reactions. It seems that both 7-substituents and C3-aryl groups influence the transition states. 157 Table 4.12 (cont’d) entry Ligand 1 R 2 R Ar 1 Ar 2 R=Ph % R=Cy % b c % % b c yield ee yield ee 1 VANOL H H Ph Ph 84 92 77 81 2 260b H H Ph Ar 84 94 85 79 3 223e H H Ar Ar 85 96 79 87 4 260c Br H Ph Ar 89 97 85 88 5 260o Br Br Ph Ar 96 93 80 75 6 237a Br Br Ph Ph 89 89 78 85 7 260f 4-t-Bu- H Ph Ar 90 97 91 89 4-t-Bu- 4-t-Bu- Ph Ar 97 94 90 87 C6H4 C6H4 4-t-Bu- 4-t-Bu- Ph Ph 85 97 83 93 C6H4 C6H4 C6H4 8 9 260p 238a 10 t-Bu H Ph Ar 81 98 84 90 11 a 260e 174m t-Bu t-Bu Ph Ph 82 98 88 94 unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 1.2 equiv EDA at 25 °C for 24 h and went to 100% completion with 5 mol% catalyst. 158 Table 4.12 (cont’d) The catalyst was prepared as indicated in Table 4.2. Ar = 3,5-Me2-4-OMeC6H2. isolated cis-aziridine by chromatography on silica gel. OD-H column. 159 c b yield of determined by HPLC on a Chiralcel 4.4 Future plan One potential use of C1-symmetric VANOL ligand is to prepare a polymer-supported VANOL derivative. The proposed synthetic route is outlined in Scheme 4.30. Suzuki coupling of the C1-symmetric VANOL ligand with arylboronic acid, followed by hydrolysis, should give the COOH-functionalized VANOL derivaritive 267. Then subsequent amide formation should afford the desired polymer-supported VANOL derivative 268. 160 161 4.5 Conclusion Three sets of VANOL ligands: 1) naphthalene skeleton modified; 2) C3-aryl group modified; 3) C1-symmetric VANOL derivatives were successfully synthesized and evaluated in the aziridination reaction. Several trends were found: 1) Introducing big aryl groups in the 8,8’- or 4,4’-positions lead to dramatic decreased asymmetric inductions; 2) The substituents in the 5,5’or 6,6’-positions have less effect on the asymmetric induction; 3) C3-aryl groups influences the asymmetric induction to some extent; 4) 7-substituents and C3-aryl groups together effect the asymmetric induction in a complicated manner. The present study not only demonstrates practical routes to those VANOL derivatives but also provides insightful information to guide further computation study on the transition states in the aziridination reaction. From a combination of the outcomes with these ligands in the aziridination reaction and crystal structures of the two catalyst-substrate complexes that have been previously obtained (Scheme 4.1 & 4.20, it could be concluded that The interactions in the solid state might not reflect those in the solution state or in the transition states of the reactions of both aryl or alkyl imines. The C1-symmetric ligands described in this work promise to provide access to solid supported VANOL ligands. 162 CHAPTER FIVE STUDY OF VAPOL DERIVATIVES AND OTHER ORGANOCATALYSTS The previous chapters deal with completed major projects. In this chapter, some small projects or unfinished projects will be discussed briefly. 5.1 Synthesis of VAPOL derivatives and their applications in asymmetric catalysis 5.1.1 Background Previously Dr. Heller from our group reported the synthesis of 6,6’-disubstituted VAPOL ligands 15 (Scheme 5.1). One of the key steps is the benzannulation reaction of Fischer carbene complex 269 and phenylacetylene, leading to the formation of dihydrophenanthene 270 in 75% yield. Dehydrogenation of gave phenanthrene intermediate 271, of which the triphenylsilyl group could be converted into the bromide by treatment with bromine. This was followed by simultaneous demethylation and acetate reduction with AlCl3 and ethanethiol. The oxidative coupling step follows the procedure developed for the synthesis of VAPOL. Heating the neat melted monomer 271 in air afforded racemic 6,6’-dibromo-VAPOL 272 in 95% yield. The racemate was deracemized with (–)-sparteine and copper (II) complex, providing optically pure (>99% ee) (S)-6,6’-dibromo-VAPOL 272. From the 6,6’-dibromo-VAPOL (S)-272, other derivatives could be accessed divergently. The nickel-catalyzed Kumada coupling of 6,6’-dibromo-VAPOL with methyl magnesium bromide yielded 6,6’-dimethyl VAPOL 275. The 6,6’-diaryl VAPOL ligands 273 and 274 could be prepared via the Suzuki coupling reactions of 6,6’-dibromo VAPOL with different aryl boronic acids. Those VAPOL derivatives were evaluated in the Diels-Alder 163 reactions of both methyl acrylate and methacrolein. However, none of these ligands were found to exceed VAPOL in terms of asymmetric induction. Later on, Dr. Rampalakos from our group synthesized 7,7’-dimethyl VAPOL in a different 19 fashion (Scheme 5.2). The first step involves a formal Diels-Alder reaction between toluene and furoic acid, furnishing 6-methylnaphthoic acid 276. The acyl chloride generated from acid 276 reacted with (i-Pr)2NH to afford diisopropyl-6-methyl naphthamide 277 in 74% yield over 164 two steps. Treatment of the 6-methyl naphthamide 277 with s-BuLi, MgBr2 and a-bromomethyl styrene gave the o-allylation product 278 in 75% yield. Upon treatment of the o-allyl naphthamide 278 with MeLi at –78 °C, the cyclization went smoothly to give the monomer 279 in 80% yield. The subsequent dimerization and deracemization led to (S)-7,7’-dimethyl VAPOL 280. This ligand was examined in the iminoaldol reaction between imines and silyl ketene 19 acetals. 165 5.1.2 Synthesis of novel VAPOL derivatives The shortcomings of the above two routes are the narrow substrate scope, the low yields and the numbers of steps, compared to the recent developed cycloaddition/electrocyclic 13g,73 ring-opening/electrocyclic ring closure/tautomerization (CAEC) cascade route. Therefore, the CAEC cascade was employed in the following study. The desired alkyne was synthesized via a Sonogashira coupling/deprotection sequence (Scheme 5.3). The overall yield was high (90%). 6-Bromo-2-naphthaleneacetic acid 286 was synthesized in a facile, clean and cheap route 99 adapted from the published multikilogram scale synthesis (Scheme 5.4). Subjection of the commercially available ester 281 to DABAL-H gave the alcohol 282 in 95% yield. Chlorination 166 of the alcohol 282 was accomplished with SOCl2 in the presence of ZnCl2 as a catalyst. The one-carbon homologation of the chloride 283 with NaCN afforded the desired nitrile 284 in 98% yield. The following hydrolysis provided the acid 286 in quantitative yield. The above four steps involve no column chromatography separation. entry Ar % yield 1 3,5-Me2C6H3 56 2 3,5-Me2-4-MeOC6H2 35 3 3,5-tBu2-4-MeOC6H2 43 The CAEC cascade reactions of 2-naphthaleneacetic acid with various aryl alkynes proceeded smoothly, giving the targeted 2-aryl-4-phenanthrols in decent yields (Table 5.1). The CAEC cascade reactions of 6-bromo-2-naphthaleneacetic acid with a variety of aryl alkynes also progressed well as expected in moderate yields (Table 5.2). 167 entry compound Ar % yield 1 288a C6H5 45 2 288b 4-n-BuC6H4 53 3 288c 3,5-Me2C6H3 46 4 288x 3,5-tBu2-4-MeOC6H2 25 Entry Ar series % yield (±)-289 a % yield (S)-289 a % ee (S)-289 1 3,5-Me2C6H3 289c 80 90 >99 2 3,5-Me2-4-MeOC6H2 289d 60 95 >99 3 3,5-tBu2-4-MeOC6H2 289x 82 94 97 168 b The 2-aryl-4-phenanthrols obtained from the CAEC cascade reactions were then subjected to the oxidative thermal coupling conditions (Table 5.3). The reactions proceeded successfully. Deracemization of those racemates progressed smoothly and gave optically pure VAPOL ligands in high yields. The oxidative couplings of the 2-aryl-7-bromo-4-phenanthrols led to mixtures with very low solubilities in common solvents. The purification and low solubilities made deracemization difficult to pursue. To make utility of the 2-aryl-7-bromo-4-phenanthrols, the MOM protected 7-bromo-4-phenanthrol 290 was treated with t-BuLi and t-BuPh2SiCl, and the silyl group was installed successfully (Scheme 5.5). The deprotection with Amberlyst 15 led to 7-silyl-4-phenanthrol 291. The thermal coupling and deracemization progressed successfully. 169 5.1.3 VAPOL derivatives in asymmetric catalysis The four new VAPOL ligands were evaluated in the aziridination reactions with phenyl and cyclohexyl imines, respectively (Table 5.4). If the C3 aryl group is 3,5-Me2C6H3 or 3,5-Me2-4-MeOC6H2, higher asymmetric inductions were observed, though the increases were low (2-4%). However, if the C3 aryl group is 3,5-tBu2-4-MeOC6H2, slightly lower asymmetric inductions were obtained. The increased sterics (SiPh2t-Bu) in the 7,7’-positions in VAPOL appear to have a limited effect on the enantioselectivities. entry ligand Ar R 1 1 R =Ph % yield R =Cy % b ee c % yield % b ee c 1 VAPOL Ph H 76 93 78 82 2 289c 3,5-Me2C6H3 H 77 95 78 86 3 289e 3,5-Me2-4-MeOC6H2 H 76 95 76 86 4 289x 3,5-tBu2-4-MeOC6H2 H 85 89 75 81 5 292 4-n-BuC6H4 SiPh2t-Bu 80 95 77 84 170 Table 5.4 (cont’d) a unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 1.2 equiv EDA at 25 °C for 24 h and went to 100% completion with 5 mol% catalyst. The catalyst was prepared from 1 equiv ligand, 4 equiv B(OPh)3 and 1 equiv H2O at 80 °C in toluene for 1 h, followed by removal of volatiles under vacuum (0.5 mm Hg) at 80 °C for 0.5 h. yield of isolated cis-aziridine by chromatography on silica gel. c b determined by HPLC on a Chiralcel OD-H column. Another important reaction mediated by VAPOL ligands is the enantioselective Ugi-type 25 reaction. This project was initiated by Li Huang and taken over by Wenjun Zhao. An examination of the new VAPOL ligands revealed that VAPOL derivative 289x is much better than VAPOL in terms of asymmetric induction (Table 5.5). b entry 1 VAPOL 87 289x 91 c 40 2 a ligand 72 % yield % ee Unless otherwise specified, the catalyst was prepared by heating a mixture of 1 equiv of the ligand, 3 equiv BH3•SMe2, 2 equiv 2,4,6-trimethylphenol, 3 equiv H2O in toluene at 100 °C for 171 Table 5.5 (cont’d) b 1 h. The volatiles were then removed under vacuum (0.1 mm Hg) at 100 °C for 1 h. yield of c isolated trans-aziridine by chromatography on silica gel. determined by HPLC. 172 5.2 The CAEC cascade: scope and limitations In the previous chapters, we have employed the CAEC cascade in the synthesis of many new ligands. It would be instructive to even further explore the substate scope of this cascade, leading to valuable polyaromatic compounds. Those results are summarized as below For a given phenylacetic acid, various alkynes could be successfully employed (Table 5.6). There is no general trend in the relationship of the aryl group and the yield. Heterocycles, such as 2- or 3-thienyl group, are also applicable. More interestingly, but-3-yn-1-ylbenzene gave 3-phenethyl-1-naphthol, making the synthesis of 3-alkyl-1-naphthols feasible (Table 5.6, entry 12). 1 entry compound R R % yield 1 175a C6H5 H 70% 2 222c 3,5-Me2C6H3 H 66% 3 222e 3,5-Me2-4-MeOC6H2 H 56% 4 222d 4-MeOC6H4 H 41% 5 222h 4-EtOC6H4 H 61% 6 222i 4-PhC6H4 H 61% 7 222f 4-FC6H4 H 53% 173 Table 5.6 (cont’d) 8 222g 4-BrC6H4 H 45% 9 222j 3,5-(CF3)2C6H3 H 51% 10 222s 2-C4H3S H 37% 11 222t 3-C4H3S H 57% 12 333 PhCH2CH2 H 36% 13 236a C6H5 Br 67% 14 236b 4-n-BuC6H4 Br 68% 15 236c 3,5-Me2C6H3 Br 61% 16 236f 4-FC6H4 Br 37% 17 236p 3,4,5-(MeO)3C6H2 Br 47% 18 236d 4-MeOC6H4 Br 30% 19 236q 2,6-Me2C6H3 Br nd 20 236e 3,5-Me2-4-MeOC6H2 Br 50% 21 175g C6H5 OMe 50% 22 334b 4-n-BuC6H4 OMe 43% 23 334c 3,5-Me2C6H3 OMe 52% 174 For a given alkyne, such as phenylacetylene, different types of phenylacetic acids are applicable in the CAEC cascade, with some exceptions (Table 5.7). The reactions of p-CF3, p-NO2, or 175 p-NMe2 phenylacetic acid led to inseparable mixtures. So did that of 2-thiopheneacetic acid. Interestingly, 2-phenanthreneacetic acid could afford 2-phenylchrysen-4-ol 294, demonstrating that the CAEC cascade is a good way of making conjugated polycyclic compounds. entry Ar R % yield 1 3,5-Me2C6H3 H 56 2 3,5-Me2-4-MeOC6H2 H 35 3 3,5-tBu2-4-MeOC6H2 H 43 4 C6H5 Br 45 5 4-n-BuC6H4 Br 53 6 3,5-Me2C6H3 Br 46 7 3,5-tBu2-4-MeOC6H2 Br 25 2-Naphthaleneacetic acid and 6-bromo-2-naphthaleneacetic acid were treated with various alkynes as well (Table 5.8). And all the reactions proceeded as expected. The synthesis of 2-phenanthreneacetic acid is outlined in Scheme 5.6. The Friedal-Crafts acylation of commercially available 9,10-dihydrophenanthrene 295 gave the acyl intermediate 74,100 296 in 84% yield. Dehydrogenation led to 1-(phenanthren-2-yl)ethanone 297 in 70% 176 15,101 yield. The subsequent Willgerodt-Kindler reaction afforded 2-phenanthreneacetic acid 298 77,102 in 86% yield. The monomer from the CAEC cascade could be functionalized in a variety of ways (Scheme 5.7). Nitration, bromination and iodination proceeded smoothly and afforded 1-substituted 4-methoxy-2-phenylnaphthalene in good yields. 72,73,103 177 5.3 Reduction of 2-quinoline The reduction reaction of 2-quinolines is a useful method to generate 1,2,3,4-tetrahydroquinolines, a common structural motifs in numerous alkaloid natural products. There are a number of successful systems for the asymmetric reduction of quinolines using 104 organometallic catalysts. Later on, BINOL derived phosphoric acids were employed in the asymmetric transfer hydrogenation of quinolines with the Hantzsch ester as the hydrogen 105 source. Dr. Desai in our group initiated a collaborative project with Prof. Odom. He worked on the development of a catalytic asymmetric transfer hydrogenation of 2-quinolines, which were provided by the Odom group, into the corresponding 1,2,3,4-tetrahydroquinolines. The investigation involved the optimization of the solvents, the phenols, the Hantzsch esters, and 106 additional additives. As a continuation of this project, I carried out a ligand screen on this transformation. The results of various ligands tested are summarized in Scheme 5.8. All the ligands gave complete conversion with variable amount of asymmetric induction in a range of 9-78% ee, and VAPOL turned out to be the best ligand of all those examined. 178 179 5.4 Synthesis of a novel DMAP-squaramide catalyst and its applications in catalysis This work is a continuation of Dr. Rampalakos’ research. In 2008, Dr. Rampalakos from our group reported that a bifunctional DMAP-thiourea derived from BINAM could promote a highly 107 enantioselective Michael addition of nitroalkanes to nitroalkenes. Though the reaction gives high asymmetric induction, the diastereoselectivity is not good. In order to achieve high diastereoselectivity, the existing ligand should further optimized. Thus, the 180 thiourea motif was replaced with the squaramide motif and the synthesis of new catalyst 311 is outlined in Scheme 5.9. 2-Chloro DMAP 305 could be obtained through the nucleophilic aromatic substitution of 2,4-dichloropyridine 304. Buchwald amination of BINAM and 2-chloro DMAP 305 gave the desired monosubstituted product 310 in 51% yield. The reaction of 310 and mono substituted squaramide 308 afforded the desired disubstituted squaramide 311 in 92% 108 yield. The original bifunctional DMAP-thiourea 313 was synthesized as well. b c entry 1 313 80 84:16 311 79 88:12 d 95 2 a catalyst 97 % yield syn:anti % ee unless otherwise specified, all reactions were run at 0.2 M in nitroalkene 314 with 30 equiv of 315 and 2 mol% of catalyst. c b combined isolated yields of syn and anti isomers after 1 chromatography on silica gel. determined by H NMR spectrum of the crude reaction mixture. d determined by HPLC. The two catalysts were examined in the reaction of 314 and 315 with the same reaction conditions indicated in the original report and both gave similar results (Table 5.9). 181 5.5 One-pot imine formation-AZ reaction Based on the results and observations accumulated in our studies on the aziridination reaction, it was clear that the quality of the imine was crucial for obtaining good yields and excellent enantioselectivities. These imines tend to decompose via hydrolysis in the presence of a catalytic amount of acid, which can lead to significantly diminished asymmetric inductions. Although the quality of the purified imines can remain high for several months if stored in a well-sealed desiccator, there are some imines that cannot be purified by either crystallization or distillation, especially primary alkyl substituted imines, which are more prone to decomposition. It was envisioned that a one-pot imine formation-AZ reaction starting directly from amines and aldehydes might be possible. The major concerns for this one-pot protocol are the possible adverse effects on the yield and asymmetric induction that may be due to the presence of an excess of the amine, the aldehyde or the presence of the dehydrating reagent required in the imine formation step. The advantages of such a one-pot procedure would include: (a) simplification of the overall process and (b) prevention of the possible decomposition of imines during the purification step in the synthesis of these imines. Previous results from Zhenjie’s thesis showed that an excess amount of the amine in the reaction would likely have a major detrimental effect due to the strong coordination of the amine nitrogen 64 to the catalyst, which leads to a very low conversion (< 5%). An excess of the aldehyde would slightly diminish the yield but would not affect the enantioselectivity. We also screened different dehydrating reagents (molecular sieves and MgSO4) and found that the use of activated 4Å MS 182 afforded better enantioselectivity than that of MgSO4, which might be due to the stronger Lewis acid character of MgSO4 compared to 4Å MS. Based on these findings, a one-pot imine generation-aziridination procedure was developed. entry procedure c d 2 II 3 II 4 II 5 a I II mole% g VAPOL 1 mol% B(OPh)3 a 10 40 1 100 71 96 b 10 40 1 100 70 94 b 5 15 1 67 42 95 b 5 15 0.5 39 31 94 b 5 15 0.2 100 63 e MS 93 % conv % yield % ee reactions were run by using procedure I described in the experimental part. The catalyst was prepared as indicated in Table 5.4. After adding 1.2 equiv. EDA, the reaction mixtures were stirred at room temperature for 40 h. b reactions were run by using procedure II described in the experimental part. The solution of (S)-VAPOL and B(OPh)3 in 2 mL distilled toluene was transferred via syringe to the round bottom flask containing imine generated in situ. After adding 183 Table 5.10 (cont’d) 1.2 equiv. EDA, the mixtures were stirred at room temperature for 40 h. NMR spectrum of the crude reaction mixture. d c 1 determined by H isolated yield of cis-aziridine after e chromatography on silica gel. determined by HPLC on a CHIRALCEL OD-H column. Inspired by Gang’s one-pot procedure (procedure III), in which the solution of imine, VAPOL/ VANOL ligand (5 mol %) and triphenyl borate (15 mol %) could react with EDA in an open vessel, a new simplified one-pot procedure was proposed and tested. The new procedure (procedure II in the experimental part) worked well for the following reaction (Table 5.10, entry 2), in which the toluene solution of VAPOL/VANOL ligand and triphenyl borate was transferred into the vessel where the imine generation step was completed in 2 h. It gave comparable result as Zhenjie’s one-pot imine generation-aziridination procedure (Table 5.10, entry 2 vs entry 1). Encouraged by procedure II, efforts have been made to optimize it. Reducing the catalyst loading from 10 mol% to 5 mol% resulted in lower conversion and lower yield albeit the same enantioselectivity (Table 5.10, entry 3). The assumption that 4Å MS attributed to the lower yield led us to reduce the amount of 4Å MS. It was found that 0.2 g seems to be the best amount and the last entry in table 1 is the optimal condition by far (Table 5.10, entry 5). However, Gang’s procedure, in which 5 mol% of VAPOL, 15 mol% of B(OPh)3, and the imine were mixed in toluene and stirred for 10 min opened to air before the addition of EDA (procedure III), turned out to be not that generally applicable from some results by other group members. Therefore, we decided to revisit Gang’s procedure (Table 5.11). 184 entry R b c d % yield % ee % yield % ee (ref 26j) % conv (ref 26j) 1 100 80 90 82 94 2 NO2 81 76 87 79 79 3 Br 56 43 88 78 90 4 a H OMe 43 34 86 51 86 Unless otherwise specified, all the reactions were run in toluene containing 0.5 M imine, 5 mol% (S)-VAPOL, 15 mol% B(OPh)3 at room temperature for 24 h with 1.2 equiv of EDA opened to air. b 1 c determined by H NMR spectrum of the crude reaction mixture. isolated yield of cis-aziridine after chromatography on silica gel. d determined by HPLC on a CHIRALCEL OD-H column. From the results in Table 5.11, some conclusion could be made: 1) only the imine from benzaldehyde works well with Gang’s procedure and 2) the ee will be low if the conversion is low. At this point, the improvement on Gang’s procedure became a priority. We assumed that the moisture in the air might affect the catalyst and carried out experiments in Table 5.12. Therefore, 185 procedure IV, a variation of procedure III, in which the AZ reaction was performed under argon, was investigated. entry R mol% mol% VAPOL b c % yield % ee 1 H 5 15 94 83 89 2 NO2 5 15 44 nd nd 3 NO2 5 20 48 nd nd 4 a d B(OPh)3 % conv NO2 10 40 87 nd nd Unless otherwise specified, all the reactions were run in toluene containing 0.5 M imine, 5 mol% (S)-VAPOL, 15 mol% B(OPh)3 at room temperature for 24 h with 1.2 equiv of EDA b 1 under Ar. nd = not determined. determined by H NMR spectrum of the crude reaction mixture. c isolated yield of cis-aziridine after chromatography on silica gel. d determined by HPLC on a CHIRALCEL OD-H column. However, the results in Table 5.12 showed that the attempted improvement on Gang’s procedure was not successful even by increasing the catalyst loading up to 10 mol % (Table 5.12, entry 4). 186 Therefore, we resumed the investigation of Zhenjie’s one-pot procedure. Several trials on further optimization in Table 5.13 revealed that the first entry was the optimal condition. entry b c mol% g VAPOL B(OPh)3 10 40 1 100 66 93 2 10 40 0.25 98 63 92 3 5 20 0.25 97 58 d MS 1 a mol% 91 % conv % yield % ee Unless otherwise specified, all the reactions were run by using procedure I described in the experimental part. The catalyst was prepared as indicated in Table 5.4. After adding 1.2 equiv. EDA, the mixtures were stirred at room temperature for 40 h. b 1 determined by H NMR c spectrum of the crude reaction mixture. isolated yield of cis-aziridine after chromatography on d silica gel. determined by HPLC on a CHIRALCEL OD-H column. The optimal conditions were then applied to different aldehydes with benzhydryl amine. From the results in Table 5.14, this one-pot protocol gave better yields and enantioselectivities compared with the published results. This improvement may be attributed to the existence of 4Å MS that might slow down the reactions. Both electron rich and electron poor aromatic aldehydes 187 gave excellent yields and enantioselectivities. However, sterically hindered aldehydes, such as 2-methyl-benzaldehyde, would not go to complete conversion in 40 h. 1-Naphthaldehyde would not undergo condensation with benzaldehyde in 4 h even in the presence of 2 g 4Å MS. entry R b c d % yield % ee % yield % ee (ref 26j ) % conv (ref 26j) 1 100 66 93 63 94 2 4-BrC6H4 100 61 94 55 90 3 4-NO2C6H4 e 96 64 89 63 79 4 4-NO2C6H4 f 93 60 89 63 79 5 4-MeC6H4 100 64 95 63 92 6 a C6H5 4-MeOC6H4 100 55 91 43 86 g Unless otherwise specified, all the reactions were run by using procedure A described in the experimental part. The catalysts were prepared as indicated in Table 5.4. After adding 1.2 equiv. EDA, the mixtures were stirred at room temperature for 40 h. b 1 determined by H NMR c spectrum of the crude reaction mixture. isolated yield of cis-aziridine after chromatography on d e silica gel. determined by HPLC on a CHIRALCEL OD-H column. used as purchased without f g purification. used with purification. 1.5 g MS and 2 equiv EDA were used. 188 CHAPTER SIX EXPERIMENTAL PART General information Material: Dichloromethane, acetonitrile and triethylamine were distilled from calcium hydride under nitrogen. Toluene, THF, benzene and diethyl ether were distilled from sodium under nitrogen. Hexanes and ethyl acetate were ACS grade and used as purchased. Other reagents were used as purchased from Aldrich or other commercial sources. Commercially available benzhydrylamine and propynals were distilled prior to use. Both VAPOL and VANOL ligands are commercially available from Aldrich as well as Strem Chemicals, Inc. If desired, they could be purified using column chromatography on regular silica gel using an eluent mixture of 2:1 dichloromethane:hexanes. Phenol was sublimed and stored under Argon in a dry desiccator. 27a Diazoacetamides 31, 36, 26j amine), 9a-j 26g bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (MEDAM 26h bis-(3,5-di-tert-butyl-4-methoxyphenyl)methanamine (BUDAM amine), imines were prepared according to the published procedures. Instrumentation: The silica gel for column chromatography was purchased from Sorbent Technologies with the following specifications: standard grade, 60 Å porosity, 230 X 400 mesh 2 particle size, 500 – 600 m /g surface area and 0.4 g/mL bulk density. Melting points were determined on a Thomas Hoover capillary melting point apparatus and were uncorrected. IR 1 spectra were taken on a Galaxy series FTIR-3000 spectrometer. H NMR and 13 C NMR were recorded on a Varian Inova-300 MHz, Varian UnityPlus-500 MHz or Varian Inova-600 MHz 189 instrument in CDCl3 unless otherwise noted. CDCl3 was used as the internal standard for both 1 H NMR (δ = 7.24) and 13 C NMR (δ = 77.0). Low-resolution mass spectra and elemental analysis were performed in the Department of Chemistry at Michigan State University. HR-MS was performed in the Department of Biochemistry at Michigan State University. Analytical thin-layer chromatography (TLC) was performed on silica gel plates with F-254 indicator. Visualization was by short wave (254 nm) and long wave (365 nm) ultraviolet light, or by staining with phosphomolybdic acid in ethanol. Column chromatography was performed with silica gel 60 (230 – 450 mesh). HPLC 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. 6.1 Experimental for chapter two 6.1.1 Preparation of propynols General procedure for the preparation of propynols – illustrated for the synthesis of 3-(4-bromophenyl)prop-2-yn-1-ol 132e (Procedure A) 63a To a 250 mL flame dried flask filled with argon was added 1-bromo-4-iodobenzene (11.32 g, 40.0 mmol), Pd(PPh3)2Cl2 (421 mg, 0.60 mmol), CuI (114 mg, 0.60 mmol) and dry THF (40 190 mL). After the addition of Et3N (16.2 g, 22.3 mL, 160 mmol), the reaction mixture was stirred at room temperature for 5 minutes and then prop-2-yn-1-ol (2.60 mL, 44.0 mmol) was added. After stirring at the room temperature over night under an argon balloon, hexanes were added to the mixture. After removal of the solvent, the crude mixture was purified by column chromatography on silica gel (50 mm x 200 mm, CH2Cl2/hexanes 1:1 to 1:0, then ethyl acetate/hexanes 1:3) to afford 132e as an off-white solid (6.90 g, 32.7 mmol, 82%). mp 80-81 °C 63a (lit. 1 mp 68-69 °C); Rf = 0.17 (CH2Cl2). Spectral data for 132e: H NMR (CDCl3, 500 MHz) δ 1.67 (t, 1H, OH, J = 6.0 Hz), 4.46 (d, 2H, J = 6.0 Hz), 7.25-7.29 (m, 2H), 7.41-7.45 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 51.60, 84.66, 88.29, 121.45, 122.79, 131.59, 133.10; IR (thin -1 + 81 film) 3223br s, 1483s, 1393s, 1013s cm ; mass spectrum, m/z (% rel intensity) 212 M ( Br, + 79 84), 210 M ( Br, 88), 131 (100), 102 (100), 77 (100), 74 (100). 3-(4-Nitrophenyl)prop-2-yn-1-ol 132g: The reaction of 1-iodo-4-nitrobenzene (14.94 g, 60.0 mmol) and prop-2-yn-1-ol (3.90 mL, 66.0 mmol) was performed according to the general procedure (Procedure A). Purification of the crude mixture by column chromatography on silica gel (50 mm x 200 mm, CH2Cl2/hexanes 1:1 to 1:0, then ethyl acetate/hexanes 1:3) gave 132g as 63a a yellow solid (9.91 g, 56.0 mmol, 93%). mp 95-96 °C (lit. Spectral data for 132g: 1 mp 95-96 °C); Rf = 0.13 (CH2Cl2). H NMR (CDCl3, 500 MHz) δ 1.89 (t, 1H, OH, J = 6.5 Hz), 4.52 (d, 2H, J = 6.5 Hz), 7.53-7.57 (m, 2H), 8.14-8.17 (m, 2H); 191 13 C NMR (CDCl3, 125 MHz) δ 51.48, 83.78, -1 92.48, 123.56, 129.41, 132.38, 147.20; IR (thin film) 3318br s, 1595s, 1516s, 1348s, 1024s cm ; + mass spectrum, m/z (% rel intensity) 177 M (12), 160 (22), 130 (74), 102 (62), 77 (100). 3-(4-Methoxyphenyl)prop-2-yn-1-ol 132d: The reaction of 1-iodo-4-methoxybenzene (9.36 g, 40.0 mmol) and prop-2-yn-1-ol (2.60 mL, 44.0 mmol) was performed according to the general procedure (Procedure A). Purification of the crude mixture by column chromatography on silica gel (50 mm x 200 mm, CH2Cl2/hexanes 1:1 to 1:0, then ethyl acetate/hexanes 1:3) gave 63d 132d as an off-white solid (3.80 g, 23.5 mmol, 59%). mp 65-66 °C (lit. = 0.12 (1:3 EtOAc / hexane). Spectral data for 132d: 1 mp 62.5-64.5 °C); Rf H NMR (CDCl3, 500 MHz) δ 1.67 (t, 1H, OH, J = 6.0 Hz), 4.46 (d, 2H, J = 6.0 Hz), 6.80-6.84 (m, 2H), 7.34-7.37 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 51.70, 55.26, 85.64, 85.82, 113.92, 114.57, 133.16, 159.72; IR (thin film) -1 3250 br s, 1507s, 1252s, 1028s cm ; mass spectrum, m/z (% rel intensity) 162 M+ (100), 145 (37), 131 (32), 119 (26), 91 (27), 77 (15). Methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate 132f: The reaction of methyl 4-iodobenzoate (20.96 g, 80.0 mmol) and prop-2-yn-1-ol (5.20 mL, 88.0 mmol) was performed according to the general procedure (Procedure A). Purification of the crude mixture by column chromatography 192 on silica gel (50 mm x 200 mm, CH2Cl2/hexanes 1:1 to 1:0, then ethyl acetate/hexanes 1:3) gave 132f as a white solid (13.26 g, 69.8 mmol, 87%). mp 82-83 °C; Rf = 0.18 (1:2 EtOAc/hexanes). 1 Spectral data for 132f: H NMR (CDCl3, 500 MHz) δ 1.93 (t, 1H, OH, J = 6.0 Hz), 3.89 (s, 3H), 4.50 (s, 2H, J = 6.0 Hz), 7.44-7.47 (m, 2H), 7.94-7.97 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 51.55, 52.26, 84.87, 90.18, 127.22, 129.46, 129.74, 131.56, 166.51; IR (thin film) 3320br s, -1 + 1725s, 1431s, 1281s, 1117s, 1032s cm ; mass spectrum, m/z (% rel intensity) 190 M (41), 159 (33), 131 (100), 103 (33), 77 (30). Anal calcd for C11H10O3: C, 69.46; H, 5.30. Found: C, 69.10; H, 5.73. 63e 3-(naphthalen-1-yl)prop-2-yn-1-ol 132j: The reaction of 1-iodonaphthalene (20.32 g, 80.0 mmol) and prop-2-yn-1-ol (5.20 mL, 88.0 mmol) was performed according to the general procedure (Procedure A). Purification of the crude mixture by column chromatography on silica gel (50 mm x 300 mm, CH2Cl2/hexanes 1:1 to 1:0) gave 132j as an off-white solid (8.04 g, 44.2 1 mmol, 55%). mp 46-48 °C; Rf = 0.20 (CH2Cl2). Spectral data for 132j: H NMR (CDCl3, 500 MHz) δ 1.83 (t, 1H, OH, J = 6.0 Hz), 4.64 (d, 2H, J = 6.0 Hz), 7.38-7.42 (m, 1H), 7.48-7.52 (m,1H), 7.54-7.58 (m, 1H), 7.65-7.67 (m, 1H), 7.83 (t, 2H, J = 8.0 Hz), 8.31 (d, 1H, J = 8.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 51.88, 83.79, 92.02, 120.12, 125.14, 126.02, 126.43, 126.80, 193 128.26, 128.98, 130.62, 133.09, 133.23; IR (thin film) 3331br s, 3059s, 2226w, 1586s, 1509s, -1 1397s cm . 6.1.2 Preparation of propynals General procedure for the preparation of propynal – illustrated for the synthesis of phenyl-2-propynal 131c 62a Procedure B: n-Butyllithium (2.5 M in hexanes, 20.0 mL, 50.0 mmol) was added dropwise to a solution of phenylacetylene (5.49 mL, 50.0 mmol) in dry Et2O (40 mL) at –40 °C under nitrogen. After 30 min, dry DMF (5.81 mL, 75.0 mmol) was added, and then the mixture was allowed to warm up to room temperature, and stirring was continued for 30 min. The mixture was poured into ice water and acidified slightly with concentrated hydrochloric acid. The mixture was then neutralized with sodium hydrogen carbonate until a pH between 6 and 7 was reached. The organic layer was separated and the aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by vacuum distillation (65 °C at 0.5 mmHg) to afford 131c as a colorless oil (3.37 g, 25.2 mmol, 50%). 62b,62c Procedure C: n-Butyllithium (2.5 M in hexanes, 24.0 mL, 60.0 mmol) was added dropwise to a solution of phenylacetylene (6.12 g, 60.0 mmol) in dry THF (150 mL) at –40 °C under nitrogen. After 30 min, dry DMF (9.28 mL, 120.0 mmol) was added, and then the mixture 194 was allowed to warm up to room temperature, and stirring was continued for 30 min. The reaction mixture was then poured into a vigourously stirred biphasic solution prepared from a 10% aqueous solution of KH2PO4 (325 mL) and Et2O (300 mL) at 0 °C. Layers were separated and the organic layer was washed with water (2 x 200 mL). The combined aqueous layers were then extracted with Et2O (200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2/hexanes 1:1) and then vacuum distillation (65 °C at 0.5 mmHg) to afford phenyl-2-propynal 131c as a colorless oil (6.62 g, 50.9 mmol, 85%). Rf = 0.21 (1:1 1 CH2Cl2/hexanes). Spectral data for 41c: H NMR (CDCl3, 500 MHz) δ 7.37-7.41 (m, 2H), 7.45-7.50 (m, 1H), 7.57-7.61 (m, 2H), 9.41 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 88.41, 95.11, 119.42, 128.72, 131.28, 133.27, 176.76; IR (thin film) 3061w, 2857m, 2242m, 2189s, 1661s, -1 + 1445m, 1389m, 1262m cm ; mass spectrum, m/z (% rel intensity) 130 M (100), 103 (81), 75 (32). 62c 3-(m-tolyl)propiolaldehyde 131h: The reaction of 3-ethynyltoluene (2.32 g, 20.0 mmol) with n-Butyllithium (2.5 M in hexanes, 8 mL, 20.0 mmol) and dry DMF (2.32 mL, 30.0 mmol) was performed according to the general procedure (Procedure B). The residue was purified by column chromatography on silica gel (35 mm x 300 mm, CH2Cl2/hexanes 1:2) to afford 131h as a light yellow oil (2.17 g, 15.0 mmol, 75%). Rf = 0.26 (1:1 CH2Cl2/hexanes). Spectral data for 195 1 131h: H NMR (CDCl3, 500 MHz) δ 2.38 (s, 3H), 7.25-7.30 (m, 2H), 7.37-7.41 (m, 2H), 9.40 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 21.15, 88.24, 95.56, 119.22, 128.61, 130.43, 132.24, -1 133.74, 138.60, 176.80; IR (thin film) 2857m, 2188s, 1658s, 1559m, 1456m cm . 62e 3-(o-tolyl)propiolaldehyde 131i: The reaction of 2-ethynyltoluene (1.16 g, 10.0 mmol) with n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) and dry DMF (1.16 mL, 15.0 mmol) was performed according to the general procedure (Procedure B). The residue was purified by column chromatography on silica gel (30 mm x 280 mm, CH2Cl2/hexanes 1:3) to afford 131i as a light yellow oil (0.99 g, 6.9 mmol, 69%). Rf = 0.30 (1:1 CH2Cl2/hexanes). Spectral data for 1 131i: H NMR (CDCl3, 500 MHz) δ 2.49 (s, 3H), 7.18-7.22 (m, 1H), 7.24-7.27 (m, 1H), 7.36 (td, 1H, J = 7.5, 1.5 Hz), 7.55 (dd, 1H, J = 7.5, 1.0 Hz), 9.45 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 20.58, 92.22, 94.24, 119.24, 125.96, 129.91, 131.32, 133.81, 142.61, 176.73; IR (thin film) -1 2857m, 2234m, 2186s, 1661s, 1456m, 1387m, 1256m cm . 62 hept-2-ynal 131k: The reaction of 1-hexyne (2.46 g, 30.0 mmol) with n-Butyllithium (1.6 M in hexanes, 18.75 mL, 30.0 mmol) and dry DMF (3.50 mL, 45.2 mmol) was performed according to the general procedure (Procedure B). The residue was purified by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2/hexanes 1:1) and then by vacuum 196 distillation (52 °C at 0.5 mm Hg with a slow bleed of air through a needle) to afford 131k as a colorless oil (1.85 g, 16.8 mmol, 56%). Rf = 0.39 (1:1 CH2Cl2/hexanes). Spectral data for 131k: 1 H NMR (CDCl3, 500 MHz) δ 0.89 (t, 3H, J = 7.0 Hz), 1.37-1.45 (m, 2H), 1.51-1.58 (m, 2H), 2.38 (td, 2H, J = 7.0, 1.0 Hz), 9.14 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 13.39, 18.76, 21.87, -1 29.49, 81.63, 99.29, 177.22; IR (thin film) 2963s, 2238s, 1686s cm ; mass spectrum, m/z (% rel + intensity) 110 M (3), 109 (48), 95 (94), 81 (79), 68 (84), 41 (100). 62d 3-cyclohexylpropiolaldehyde 131l: The reaction of cyclohexylacetylene (3.24 g, 30.0 mmol) with n-butyllithium (2.5 M in hexanes, 12.0 mL, 30.0 mmol) and dry DMF (3.50 mL, 45.2 mmol) was performed according to the general procedure (Procedure B). The residue was purified by vacuum distillation (86 °C at 0.5 mm Hg with a slow bleed of air through a needle) to afford 131l as a colorless oil (3.03 g, 22.2 mmol, 74%). Rf = 0.32 (1:1 CH2Cl2/hexanes). 1 Spectral data for 131l: H NMR (CDCl3, 500 MHz) δ 1.30-1.37 (m, 3H), 1.46-1.54 (m, 3H), 1.66-1.73 (m, 2H), 1.81-1.85 (m, 2H), 2.54-2.60 (m, 1H), 9.18 (d, 1H, J = 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 24.58, 25.52, 29.25, 31.40, 81.60, 102.77, 177.39; IR (thin film) 2934s, -1 + 2857s, 2234m, 2201s, 1669s cm ; mass spectrum, m/z (% rel intensity) 136 M (4), 135 (29), 107 (59), 91 (37), 79 (100). 197 62f 4,4-dimethylpent-2-ynal 131m: The reaction of 3,3-dimethylbutyne (4.41 g, 53.8 mmol) with n-butyllithium (1.5 M in hexanes, 35.9 mL, 53.8 mmol) and dry DMF (3.50 mL, 45.2 mmol) was performed according to the general procedure (Procedure C). The residue was purified by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2/hexanes 1:2) and then by distillation (bp 132 ºC at 760 mmHg) to afford 131m as a colorless oil (2.98 g, 27.1 mmol, 50%). 1 Rf = 0.30 (1:1 CH2Cl2/hexanes). Spectral data for 131m: H NMR (CDCl3, 500 MHz) δ 1.28 (s, 9H), 9.17 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 27.92, 29.88, 80.22, 106.32, 177.44; IR (thin -1 film) 2975s, 2220s, 1686s cm . 62f 3-(triisopropylsilyl)propiolaldehyde 131a: n-Butyllithium (2.5 M in hexanes, 10.7 mL, 50.0 mmol) was added dropwise to a solution of (triisopropylsilyl)acetylene (4.87 mL, 26.7 mmol) in dry THF (35 mL) at 0 °C under nitrogen. After stirring 2 h at room temperature, dry DMF (5.81 mL, 75.0 mmol) was added to the mixture at 0 ºC, and then the mixture was allowed to warm up to room temperature, and stirring was continued for 12 h. The mixture was poured into ice cold HCl solution (aq. 10%, 30 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (35 mm x 300 mm, EtOAc/hexanes 1:10) to afford 131a as a light yellow oil (4.40 g, 21.0 mmol, 78%). Rf = 0.15 (1:10 EtOAc/hexanes). Spectral data for 131a: 198 1 H NMR (CDCl3, 500 MHz) δ 1.07-1.14 (m, 21H), 9.19 (s, 1H); 13 C NMR (CDCl3, 125 MHz) -1 δ 10.92, 18.41, 100.81, 104.45, 176.61; IR (thin film) 2947s, 2869s, 2151m, 1671s cm . General procedure for the MnO2 oxidation reaction in the preparation of propynals – illustrated for the preparation of (4-Bromophenyl)-propynal 131e (Procedure D) Preparation of γ-MnO2: 109 To a solution of MnSO4· H2O (30.2 g, 0.178 mol) in H2O (574 mL) at 60 °C was added, with stirring, a solution of KMnO4 (21.0 g, 0.133 mol) in H2O (400 mL), and the suspension was stirred at 60 °C for 1 h, filtered, and the precipitate washed with water until free of sulfate ions. The precipitate was dried to constant weight at 60 °C; yield 32.2 g (dark-brown, amorphous powder). γ-MnO2 (4.17 g, 47.9 mmol) was added to a solution of 3-(4-bromophenyl)-prop-2-yn-1-ol 132e (2.02 g, 9.58 mmol) in dry CH2Cl2 (20 mL). The resulting mixture was stirred at room temperature over night and then filtered through a pad of silica gel with CH2Cl2 as eluent. After removal of the solvent 131e was obtained as an off-white 63a solid (1.33 g, 6.36 mmol, 66%). mp 104-106 °C (lit. mp 54-55 °C); Rf = 0.20 (1:1 1 CH2Cl2/hexanes). Spectral data for 131e: H NMR (CDCl3, 500 MHz) δ 7.43-7.46 (m, 2H), 7.52-7.56 (m, 2H), 9.39 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 89.03, 93.57, 118.30, 126.22, -1 132.17, 134.49, 176.52; IR (thin film) 2193s, 1653s, 1584s, 1476s, 1393s, 1263s cm ; mass 199 + 81 + 79 spectrum, m/z (% rel intensity) 210 M ( Br, 39), 208 M ( Br, 46), 182 (47), 180 (55), 101 (94), 74 (100). 3-(4-methoxyphenyl)propiolaldehyde 131d: The reaction of 3-(4-methoxyphenyl)prop-2-yn-1-ol 132d (2.43 g, 15.0 mmol) with γ-MnO2 (6.52 g, 75.0 mmol) was performed according to the general procedure (Procedure D). Ynal 131d was obtained as an 63d off-white solid (1.60 g, 10.0 mmol, 67%). mp 47-48 °C (lit. mp 47-48.5 °C); Rf = 0.14 (1:1 1 CH2Cl2/hexanes). Spectral data for 131d: H NMR (CDCl3, 500 MHz) δ 3.83 (s, 3H), 6.88-6.90 (m, 2H), 7.53-7.55 (m, 2H), 9.37 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 55.44, 88.72, 96.54, 111.13, 114.48, 135.42, 162.12, 176.71; IR (thin film) 2180s, 1643s, 1599s, 1510s, 1451s, 1389s, -1 + 1256s cm ; mass spectrum, m/z (% rel intensity) 160 M (100), 132 (39), 117 (31), 89 (35). methyl 4-(3-oxoprop-1-yn-1-yl)benzoate 131f: The reaction of methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate 132f (3.80 g, 20.0 mmol) with γ-MnO2 (8.69 g, 100.0 mmol) was performed according to the general procedure (Procedure D). Ynal 131f was obtained as a white solid (2.53 g, 13.4 mmol, 67%). mp 85-86 °C; Rf = 0.39 (CH2Cl2). Spectral 1 data for 131f: H NMR (CDCl3, 500 MHz) δ 3.92 (s, 3H), 7.63-7.65 (m, 2H), 8.03-8.06 (m, 2H), 9.42 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 52.48, 89.63, 93.02, 123.80, 129.70, 132.18, 200 -1 133.00, 165.93, 176.45; IR (thin film) 2188s, 1717s, 1645s, 1433s, 1277s cm ; mass spectrum, + m/z (% rel intensity) 188 M (77), 157 (100), 129 (50), 101 (46), 75 (28). Anal calcd for C11H8O3: C, 70.21; H, 4.29. Found: C, 70.34; H, 4.48. 3-(4-nitrophenyl)propiolaldehyde 131g: The reaction of 3-(4-nitrophenyl)-prop-2-yn-1-ol 132g (1.77 g, 10.0 mmol) with γ-MnO2 (4.35 g, 50.0 mmol) was performed according to the general procedure (Procedure D). Ynal 131g was obtained as a yellow solid (1.22 g, 7.0 mmol, 63a 70%). mp 120-122 °C (lit. mp 122-123 °C); Rf = 0.14 (1:1 CH2Cl2/hexanes). Spectral data 1 for 131g: H NMR (CDCl3, 500 MHz) δ 7.73-7.77 (m, 2H), 8.24-8.28 (m, 2H), 9.44 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 90.59, 90.76, 123.85, 125.97, 133.87, 148.80, 176.10; IR (thin film) -1 + 2197s, 1657s, 1593, 1516s, 1345s, 1290s cm ; mass spectrum, m/z (% rel intensity) 175 M (100), 147 (20), 128 (29), 101 (63), 89 (25), 75 (55). 3-(naphthalen-1-yl)propiolaldehyde 63e 131j: The reaction of 3-(naphthalen-1-yl)prop-2-yn-1-ol 132j (3.64 g, 20.0 mmol) with γ-MnO2 (8.69 g, 100.0 mmol) was performed according to the general procedure (Procedure D). The crude mixture was purified by column chromatography on silica gel (50 mm x 200 mm, CH2Cl2/hexanes 1:1) to 201 afford 131j as an orange oil (2.60 g, 14.4 mmol, 72%). Rf = 0.25 (1:1 CH2Cl2/hexanes). Spectral 1 data for 131j: H NMR (CDCl3, 500 MHz) δ 7.46-7.50 (m, 1H), 7.54-7.59 (m, 1H), 7.61-7.65 (m, 1H), 7.86-7.90 (m, 2H), 7.98 (d, 1H, J = 8.0 Hz), 8.32 (dd, 1H, J = 8.5, 0.5 Hz), 9.56 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 93.09, 93.44, 116.93, 125.17, 125.62, 127.06, 127.86, 128.59, 132.13, 133.01, 133.58, 133.73, 176.62; IR (thin film) 3059m, 2857m, 2203s, 2184s, 1653s, -1 1508, 1397s, 1283s cm . 6.1.3 Preparation of alkynyl imines General procedure for the preparation of the aldimines – illustrated for the synthesis of 1,1-bis(3,5-di-tert-butyl-4-methoxyphenyl)-N-(3-phenylprop-2-yn-1-ylidene)methanamine 136c (Procedure E) 27a,26h,26j To a flame dried 100 mL round bottom flask filled with argon was added MgSO4 (4.0 g, 33.3 mmol) and dried DCM (40 mL). This was followed by the addition of bis-(3,5-di-tert-butyl-4-methoxyphenyl)methanamine (4.77 g, 10.2 mmol). minutes, phenyl-2-propynal 131c (1.33 g, 10.2 mmol) was added. After stirring for 5 The reaction mixture was stirred for 24 h at room temperature. Thereafter, the reaction mixture was filtered through a pad of Celite, concentrated and placed under high vacuum (0.5 mm Hg) for 5 minutes to afford the crude imine as a white solid. Crystallization (1:30 EtOAc/hexanes) afforded 136c as an off-white 202 solid (4.79 g, 8.27 mmol, 83%) and as a mixture of trans and cis isomers. Cis:trans = 0.63:1 1 1 (from H NMR). Spectral data for 136c: H NMR (CDCl3, 500 MHz): cis isomer: δ 1.37 (s, 36H), 3.65 (s, 6H), 6.17 (s, 1H), 7.20 (s, 4H), 7.30-7.41 (m, 3H), 7.51-7.55 (m, 2H), 7.87 (d, 1H, J = 1.0 Hz); trans isomer: δ 1.38 (s, 36H), 3.65 (s, 6H), 5.40 (s, 1H), 7.11 (s, 4H), 7.30-7.41 (m, 3H), 7.51-7.55 (m, 2H), 7.92 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 32.08, 35.79, 35.80, 64.15, 64.19, 72.67, 79.17, 82.72, 87.00, 91.98, 97.20, 121.41, 121.73, 126.22, 128.39, 128.55, 129.43, 129.74, 132.15, 132.29, 136.17, 136.87, 141.58, 143.19, 143.31, 144.50, 158.42, 158.58; IR (thin -1 + film) 2961s, 2870s, 2207m, 1412s, 1221s cm ; mass spectrum, m/z (% rel intensity) 580 M +1 (10), 451 (23), 183 (10), 114 (37), 57 (100). Anal calcd for C40H53NO2: C, 82.85; H, 9.21; N, 2.42. Found: C, 82.70; H, 9.51; N, 2.35. 1,1-Bis(3,5-di-tert-butyl-4-methoxyphenyl)-N-(3-(triisopropylsilyl)prop-2-yn-1-ylidene)methana mine19a: The reaction of 131a (2.31 g, 11.0 mmol) with bis-(3,5-di-tert-butyl-4-methoxyphenyl)methanamine (5.14 g, 11.0 mmol) was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:30 EtOAc/hexanes) afforded 136a as a white solid (6.14 g, 9.30 mmol, 85%) and as a mixture of 1 1 trans and cis isomers. Cis:trans = 2.68:1 (from H NMR). Spectral data for 136a: H NMR (CDCl3, 500 MHz): cis isomer: δ 1.08-1.13 (m, 21H), 1.37 (s, 18H), 3.65 (s, 6H), 6.24 (s, 1H), 7.18 (s, 4H), 7.64 (s, 1H); trans isomer: δ 1.07-1.12 (m, 21H), 1.36 (s, 18H), 3.65 (s, 6H), 5.33 (s, 203 1H), 7.06 (s, 4H), 7.73 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 11.13, 11.15, 18.53, 18.65, 32.05, 35.76, 35.79, 64.12, 64.18, 73.19, 78.78, 95.76, 98.93, 100.70, 103.87, 126.09, 126.27, 136.10, 136.64, 140.95, 143.23, 143.25, 144.61, 158.46, 158.55; IR (thin film): 2961s, 2869s, 1593s, -1 + 1414s, 1221s cm ; mass spectrum m/z (% rel intensity): 660 M (<1), 451 (9), 183 (10), 155 (100), 108 (30). Anal calcd for C43H69NO2Si: C, 78.24; H, 10.54; N, 2.12. Found: C, 78.62; H, 10.97; N, 2.15. (E)-1,1-Bis(3,5-di-tert-butyl-4-methoxyphenyl)-N-(3-(trimethylsilyl)prop-2-yn-1-ylidene)methana mine 136b: The reaction of 131b (2.07 g, 16.5 mmol) with bis-(3,5-di-tert-butyl-4-methoxyphenyl)methanamine (7.01 g, 15.0 mmol) was performed according to the general procedure for imine formation (Procedure E). The crude product was a mixture of cis:trans imines in a ratio of 1.5 : 1, and was purified by crystallization (1: 30 EtOAc/hexanes) to afford 136b as a white solid as a mixture of cis:trans isomers in a ratio of 19 : 1 (6.46 g, 11.2 mmol, 75%); mp 142-143 ºC. The major isomer was assigned as cis based on NOE studies. Irradiation of the methine proton in the minor isomer (d = 7.66 ppm) gave an enhancement in the imine proton at d = 5.32, but irradiation of the methine proton in the major isomer (d = 7.62) gave no enhancement at the imine proton at d = 6.15. The cis isomer (19:1) was observed to isomerize to a mixture of cis and trans isomers slowly in solution over a few 204 1 hours. Spectral data for cis-136b: H NMR (CDCl3, 500 MHz) δ 0.26 (s, 9H), 1.37 (s, 36H), 3.65 1 (s, 6H), 6.15 (s, 1H), 7.15 (s, 4H), 7.62 (d, 1H, J = 1.5 Hz); trans-136b: H NMR (CDCl3, 500 MHz) δ 0.20 (s, 9H), 1.36 (s, 36H), 3.64 (s, 6H), 5.32 (s, 1H), 7.06 (s, 4H), 7.66 (s, 1H). The following data were collected on the 19:1 mixture of cis:trans isomers: 13 C (CDCl3, 125 MHz) δ –0.42, 32.06, 35.75, 64.15, 72.55, 76.57, 97.12, 126.22, 136.62, 141.25, 143.16, 158.44; IR (thin -1 + film) 2961s, 1412s, 1221s, 849s cm ; mass spectrum, m/z (% rel intensity) 575 M (10), 451 (100), 421 (9), 379 (7), 218 (15), 197 (11), 182 (30), 168 (11), 128 (10), 110 (10), 83 (19), 73 + (64), 57 (97), 41 (45). HRMS (EI+) m/z calcd for C37H57NO2Si (M ) 575.4159, meas 575.4136. 1,1-Bis(3,5-di-tert-butyl-4-methoxyphenyl)-N-(3-(4-methoxyphenyl)prop-2-yn-1-ylidene)methana mine 136d: The reaction of 131d (1.60 g, 10.0 mmol) with bis-(3,5-di-tert-butyl-4-methoxyphenyl)methanamine (4.67 g, 10.0 mmol) was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:30 EtOAc/hexanes) afforded 136d as a white solid (3.97 g, 6.52 mmol, 65%) and as a mixture of 1 1 trans and cis isomers. Cis:trans = 1.30:1 (from H NMR). Spectral data for 136d: H NMR (CDCl3, 300 MHz): cis isomer: δ 1.37 (s, 36H), 3.65 (s, 6H), 3.83 (s, 3H), 6.16 (s, 1H), 6.87-6.91 (m, 2H), 7.20 (s, 4H), 7.45-7.47 (m, 2H), 7.84 (d, 1H, J = 2.5 Hz); trans isomer: δ 1.37 (s, 36H), 3.65 (s, 6H), 3.80 (s, 3H), 5.38 (s, 1H), 6.83-6.87 (m, 2H), 7.10 (s, 4H), 7.47-7.50 (m, 205 2H), 7.90 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 32.08, 35.78, 35.79, 55.30, 55.36, 64.15, 64.18, 72.46, 79.09, 82.16, 86.26, 92.49, 97.75, 113.38, 113.71, 114.10, 114.26, 126.24, 133.87, 133.96, 136.28, 136.98, 141.84, 143.13, 143.25, 144.65, 158.38, 158.54, 160.57, 160.82; IR (thin -1 film) 2961s, 2870s, 2188s, 1597s, 1510s, 1412s, 1254s, 1223s cm ; HRMS (ESI+) m/z calcd for + C41H56NO3 (M+H ) 610.4260, meas 610.4269. N-(3-(4-Bromophenyl)prop-2-yn-1-ylidene)-1,1-bis(3,5-di-tert-butyl-4-methoxyphenyl)methanam ine 136e: The reaction of 131e (2.09 g, 10.0 mmol) with bis-(3,5-di-tert-butyl-4-methoxyphenyl)methanamine (4.67 g, 10.0 mmol) was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:30 EtOAc/hexanes) afforded 136e as a white solid (4.76 g, 7.23 mmol, 72%) and as a mixture of 1 1 trans and cis isomers. Cis:trans = 0.56:1 (from H NMR). Spectral data for 136e: H NMR (CDCl3, 500 MHz): cis isomer: δ 1.36 (s, 36H), 3.65 (s, 6H), 6.13 (s, 1H), 7.18 (s, 4H), 7.36-7.38 (m, 2H), 7.50-7.53 (m, 2H), 7.85 (d, 1H, J = 1.5 Hz); trans isomer: δ 1.37 (s, 36H), 3.65 (s, 6H), 5.40 (s, 1H), 7.10 (s, 4H), 7.38-7.40 (m, 2H), 7.45-7.48 (m, 2H), 7.89 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 32.08, 35.80, 35.81, 64.16, 64.20, 72.81, 79.24, 83.59, 87.95, 90.66, 95.90, 120.30, 120.66, 123.98, 124.35, 126.17, 126.19, 131.75, 131.94, 133.46, 133.63, 136.05, 136.73, 141.28, 143.25, 143.36, 144.23, 158.47, 158.62; IR (thin film) 2961s, 2209m, 1607s, 206 -1 + 81 + 1485s, 1412s, 1221s cm ; mass spectrum, m/z (% rel intensity) 660 M +1 ( Br, 16), 658 M +1 79 ( Br, 16), 452 (35), 451 (100). Anal calcd for C40H52BrNO2: C, 72.93; H, 7.96; N, 2.13. Found: C, 72.80; H, 8.20; N, 2.05. Methyl 4-(3-((bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)imino)prop-1-yn-1-yl)benzoate 136f: The reaction of 131f (1.88 g, 10.0 mmol) with bis-(3,5-di-tert-butyl-4-methoxyphenyl)methanamine (4.67 g, 10.0 mmol) was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:30 EtOAc/hexanes) afforded 136f as a white solid (5.10 g, 8.00 mmol, 80%) and as a mixture of 1 1 trans and cis isomers. Cis:trans = 0.64:1 (from H NMR). Spectral data for 136f: H NMR (CDCl3, 500 MHz): cis isomer: δ 1.36 (s, 36H), 3.65 (s, 6H), 3.93 (s, 3H), 6.15 (s, 1H), 7.19 (s, 4H), 7.57-7.59 (m, 2H), 7.89 (d, 1H, J = 1.5 Hz), 8.03-8.05 (m, 2H); trans isomer: δ 1.37 (s, 36H), 3.65 (s, 6H), 3.91 (s, 3H), 5.14 (s, 1H), 7.11 (s, 4H), 7.58-7.60 (m, 2H), 7.92 (s, 1H), 7.98-8.01 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 32.07, 35.79, 35.80, 52.27, 52.35, 64.16, 64.19, 72.94, 79.30, 84.77, 89.26, 90.60, 95.85, 125.87, 126.16, 126.17, 126.28, 129.50, 129.65, 130.61, 130.94, 132.02, 132.16, 136.01, 136.68, 141.12, 143.28, 143.38, 144.10, 158.49, 158.63, -1 166.18, 166.28; IR (thin film) 2961s, 2870s, 2209m, 1728s, 1609s, 1412s, 1277s, 1223s cm ; 207 + mass spectrum, m/z (% rel intensity) 638 M +1 (23), 550 (9), 452 (35), 451 (100). Anal calcd for C42H55NO4: C, 79.08; H, 8.69; N, 2.20. Found: C, 78.71; H, 8.68; N, 2.20. 1,1-Bis(3,5-di-tert-butyl-4-methoxyphenyl)-N-(3-(4-nitrophenyl)prop-2-yn-1-ylidene)methanami ne 136g: The reaction of 131g (1.75 g, 10.0 mmol) with bis-(3,5-di-tert-butyl-4-methoxyphenyl)methanamine (4.67 g, 10.0 mmol) was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:25 EtOAc/hexanes) afforded 136g as a white solid (5.70 g, 9.13 mmol, 91%) and as a mixture of 1 1 trans and cis isomers. Cis:trans = 0.77:1 (from H NMR). Spectral data for 136g: H NMR (CDCl3, 500 MHz): cis isomer: δ 1.36 (s, 36H), 3.65 (s, 6H), 6.11 (s, 1H), 7.17 (s, 4H), 7.65-7.67 (m, 2H), 7.91 (d, 1H, J = 1.0 Hz), 8.23-8.26 (m, 2H); trans isomer: δ 1.37 (s, 36H), 3.65 (s, 6H), 5.43 (s, 1H), 7.10 (s, 4H), 7.67-7.69 (m, 2H), 7.92 (s, 1H), 8.18-8.21 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 32.06, 35.82, 64.18, 64.20, 73.24, 79.41, 86.33, 88.93, 91.03, 94.16, 123.62, 123.79, 126.09, 126.15, 128.00, 128.47, 132.87, 133.01, 135.82, 136.49, 140.59, 143.38, 143.48, 143.71, 147.80, 148.01, 158.58, 158.71; IR (thin film) 2963s, 2870s, 2209w, 1597s, -1 + 1524s, 1414s, 1346s, 1223s cm ; HRMS (ESI+) m/z calcd for C40H53N2O4 (M+H ) 625.4005, meas 625.3979. 208 N-(3-Cyclohexylprop-2-yn-1-ylidene)-1,1-bis(3,5-di-tert-butyl-4-methoxyphenyl)methanamine 136l: The reaction of 131l (1.42 g, 10.0 mmol) with bis-(3,5-di-tert-butyl-4-methoxyphenyl)methanamine (4.67 g, 10.0 mmol) was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:40 EtOAc/hexanes) afforded 136l as a white solid (4.89 g, 8.36 mmol, 84%) and as a mixture of 1 1 trans and cis isomers. Cis:trans = 3.47:1 (from H NMR). Spectral data for 136l: H NMR (CDCl3, 500 MHz): cis isomer: δ 1.28-1.37 (m, 3H), 1.36 (s, 36H), 1.49-1.55 (m, 3H), 1.72-1.77 (m, 2H), 1.80-1.86 (m, 2H), 2.61-2.67 (m, 1H), 3.65 (s, 6H), 6.11 (s, 1H), 7.15 (s, 4H), 7.61 (s, 1H); trans isomer: δ 1.28-1.37 (m, 3H), 1.37 (s, 36H), 1.49-1.55 (m, 3H), 1.72-1.77 (m, 2H), 1.80-1.86 (m, 2H), 2.48-2.54 (m, 1H), 3.64 (s, 6H), 5.29 (s, 1H), 7.07 (s, 4H), 7.70 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 24.55, 24.86, 25.72, 25.77, 29.50, 29.63, 32.02, 32.07, 35.75, 35.77, 64.14, 64.17, 72.13, 75.21, 78.82, 78.98, 98.40, 103.44, 126.20, 136.37, 136.93, 141.99, 143.08, 143.16, 144.96, 158.34, 158.46; IR (thin film) 2959s, 2863s, 2207m,1609s, 1449s, 1412s, 1221s -1 + cm ; mass spectrum, m/z (% rel intensity) 586 M +1 (46), 452 (40), 451 (100). Anal calcd for C40H59NO2: C, 82.00; H, 10.15; N, 2.39. Found: C, 81.68; H, 10.52; N, 2.33. 209 1,1-Bis(3,5-di-tert-butyl-4-methoxyphenyl)-N-(hept-2-yn-1-ylidene)methanamine The reaction of 131k (1.28 g, 11.6 136k: mmol) with bis-(3,5-di-tert-butyl-4-methoxyphenyl)methanamine (5.43 g, 11.6 mmol) was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:40 EtOAc/hexanes) afforded 136k as a white solid (3.81 g, 6.82 mmol, 59%) and as a mixture of 1 1 trans and cis isomers. Cis:trans = 10.6:1 (from H NMR). Spectral data for 136k: H NMR (CDCl3, 500 MHz): cis isomer: δ 0.94 (t, 3H, J = 7.0 Hz), 1.37 (s, 36H), 1.45-1.51 (m, 2H), 1.55-1.62 (m, 2H), 2.43 (td, 2H, J = 7.0, 1.0 Hz), 3.65 (s, 6H), 6.09 (s, 1H), 7.15 (s, 4H), 7.60 (d, 1H, J = 1.0 Hz); trans isomer: δ 0.89 (t, 3H, J = 7 Hz), 1.35 (s, 36H), 1.41-1.47 (m, 2H), 1.53-1.60 (m, 2H), 2.35 (t, 2H, J = 7.0 Hz), 3.64 (s, 6H), 5.29 (s, 1H), 7.07 (s, 4H), 7.68 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 13.52, 13.55, 19.78, 21.98, 22.01, 30.10, 30.27, 32.07, 35.76, 64.14, 64.17, 72.16, 75.24, 78.98, 94.56, 99.80, 126.16, 126.19, 136.40, 136.92, 141.93, 143.07, 143.16, 144.76, 158.34, 158.46; IR (thin film) 2961s, 2870s, 2207w,1559m,1456s,1412s, 1221s -1 + cm ; mass spectrum, m/z (% rel intensity) 560 M +1 (32), 466 (9), 452 (70), 451 (100). Anal calcd for C38H57NO2: C, 81.52; H, 10.26; N, 2.50. Found: C, 81.55; H, 10.52; N, 2.52. 210 1,1-Diphenyl-N-(3-phenylprop-2-yn-1-ylidene)methanamine 134c: The reaction of 131c (1.30 g, 10.0 mmol) with benzhydrylamine (1.83 g, 10.0 mmol) was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:30 EtOAc/hexanes) afforded 134c as an off-white solid (2.72 g, 9.22 mmol, 92%) and as a mixture of trans and cis 1 1 isomers. Cis:trans = 0.22:1 (from H NMR). Spectral data for 134c: H NMR (CDCl3, 500 MHz): cis isomer: δ 6.28 (s, 1H), 7.21-7.26 (m, 2H), 7.29-7.42 (m, 11H), 7.50-7.54 (m, 2H), 7.90 (d, 1H, J = 1.5 Hz); trans isomer: δ 5.54 (s, 1H), 7.21-7.26 (m, 2H), 7.29-7.42 (m, 11H), 7.50-7.54 (m, 2H), 7.88 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 72.64, 78.83, 82.26, 86.66, 92.61, 97.83, 121.13, 121.46, 127.07, 127.24, 127.71, 128.40, 128.46, 128.53, 128.58, 129.54, 129.89, 132.16, 132.25, 142.61, 142.65, 143.30, 145.45; IR (thin film) 3061s, 3027s, 2209s, -1 1609s, 1491s, 1453s, 1364m cm . Anal calcd for C22H17N: C, 89.46; H, 5.80; N, 4.74. Meas: C, 89.21; H, 5.98; N, 4.72. 1,1-Bis(4-methoxy-3,5-dimethylphenyl)-N-(3-(triisopropylsilyl)prop-2-yn-1-ylidene)methanamin e 135a: The reaction of 131a 211 (420 mg, 2.00 mmol) with bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) was performed according to the general procedure for imine formation (Procedure E). The crude product was obtained as a yellow liquid and was used without purification. Imine 135a was produced as a 1 1 mixture of trans and cis isomers. Cis:trans = 2.36 :1 (from H NMR). Spectral data for 135a: H NMR (CDCl3, 500 MHz): cis isomer: δ 1.10-1.14 (m, 21H), 2.24 (s, 12H), 3.68 (s, 6H), 6.09 (s, 1H), 7.00 (d, 4H, J = 0.5 Hz), 7.65 (d, 1H, J = 1.5 Hz); trans isomer: δ 1.07-1.10 (m, 21H), 2.25 (s, 12H), 3.68 (s, 6H), 5.24 (s, 1H), 6.93 (s, 4H), 7.64 (d, 1H, J = 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 11.09, 11.15, 16.14, 16.16, 18.53, 18.56, 59.58, 59.59, 72.00, 78.25, 96.45, 98.74, 101.84, 103.57, 127.82, 127.92, 130.70, 130.77, 137.98, 138.60, 141.92, 144.92, 155.90, 156.00; -1 IR (thin film) 2944s, 2867s, 1609s, 1483s, 1221s, 1144s,1017s cm ; HRMS (ESI+) m/z calcd + for C31H46NO2Si (M+H ) 492.3298, meas 492.3305. 1,1-Bis(4-methoxy-3,5-dimethylphenyl)-N-(3-(trimethylsilyl)prop-2-yn-1-ylidene)methanamine 135b: The reaction of 131b (252 mg, 2.00 bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) mmol) with was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:60 EtOAc/hexanes) afforded 135b as a white solid (658 mg, 1.62 mmol, 81%) and as a mixture of 1 1 trans and cis isomers. Cis:trans = 0.34:1 (from H NMR). Spectral data for 135b: H NMR (CDCl3, 500 MHz): cis isomer: δ 0.26 (s, 9H), 2.25 (s, 12H), 3.68 (s, 6H), 5.99 (s, 1H), 6.99 (s, 212 4H), 7.60 (d, 1H, J = 1.0 Hz); trans isomer: δ 0.21 (s, 9H), 2.24 (s, 12H), 3.68 (s, 6H), 5.22 (s, 1H), 6.92 (s, 4H), 7.58 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ –0.53, –0.52, 16.13, 16.18, 59.58, 71.66, 78.27, 96.86, 99.04, 101.49, 104.92, 127.83, 127.86, 130.66, 130.76, 137.90, 138.65, -1 141.98, 144.70, 155.88, 156.00; IR (thin film) 2953s, 1609s, 1483s, 1221s, 1144s, 1015s cm ; + HRMS (ESI+) m/z calcd for C25H34NO2Si (M+H ) 408.2359, meas 408.2372. 1,1-Bis(4-methoxy-3,5-dimethylphenyl)-N-(3-phenylprop-2-yn-1-ylidene)methanamine 135c: The reaction of 131c (1.30 g, 10.0 mmol) with bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (2.99 mg, 10.0 mmol) was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:30 EtOAc/hexanes) afforded 135c as an off-white solid (2.72 g, 1 9.22 mmol, 92%) and as a mixture of trans and cis isomers. Cis:trans = 0.48:1 (from H NMR). 1 Spectral data for 135c: H NMR (CDCl3, 500 MHz): cis isomer: δ 2.24 (s, 12H), 3.68 (s, 6H), 6.05 (s, 1H), 7.02 (s, 4H), 7.30-7.42 (m, 3H), 7.50-7.53 (m, 2H), 7.82 (s, 1H); trans isomer: δ 2.24 (s, 12H), 3.68 (s, 6H), 5.29 (s, 1H), 6.96 (s, 4H), 7.30-7.42 (m, 3H), 7.50-7.53 (m, 2H), 7.85 (d, 1H, J = 1.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 16.16, 16.19, 59.59, 59.60, 71.93, 78.38, 82.32, 86.78, 92.41, 97.71, 121.26, 121.54, 127.83, 127.86, 128.38, 128.56, 129.48, 129.82, 130.72, 130.81, 132.13, 132.22, 138.08, 138.68, 142.01, 144.84, 155.89, 156.01; IR (thin film) -1 2944s, 2209s, 1609s, 1485s, 1221s, 1144s,1015s cm . Anal calcd for C28H29NO2: C, 81.72; H, 7.10; N, 3.40. Found: C, 81.82; H, 7.02; N, 3.36. 213 1,1-Bis(4-methoxy-3,5-dimethylphenyl)-N-(3-(4-methoxyphenyl)prop-2-yn-1-ylidene)methanami ne 135d: The reaction of 131d (320 mg, 2.00 bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) mmol) with was performed according to the general procedure for imine formation (Procedure E). The crude product was obtained as a yellow foamy solid and was used without purification. Imine 135d was produced as 1 a mixture of trans and cis isomers. Cis:trans = 0.67:1 (from H NMR). Spectral data for 135d: 1 H NMR (CDCl3, 500 MHz): cis isomer: δ 2.25 (s, 12H), 3.68 (s, 6H), 3.83 (s, 3H), 6.06 (s, 1H), 6.90 (d, 2H, J = 9.0 Hz), 7.03 (s, 4H), 7.46 (d, 2H, J = 9.0 Hz), 7.84 (d, 1H, J = 1.5 Hz); trans isomer: δ 2.25 (s, 12H), 3.68 (s, 6H), 3.80 (s, 3H), 5.29 (s, 1H), 6.84 (d, 2H, J = 9.0 Hz), 6.97 (s, 4H), 7.47 (d, 2H, J = 9.0 Hz), 7.81 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.14, 16.17, 55.26, 55.33, 59.57, 71.73, 78.29, 81.79, 86.04, 92.94, 98.31, 113.20, 113.50, 114.06, 114.24, 127.83, 127.87, 130.66, 130.75, 133.85, 133.89, 138.20, 138.79, 142.25, 144.98, 155.84, 155.96, -1 160.56, 160.84; IR (thin film) 2938s, 2201s, 1599s, 1510s, 1483s, 1221s, 1144s,1015s cm ; + HRMS (ESI+) m/z calcd for C29H32NO3 (M+H ) 442.2382, meas 442.2380. 214 N-(3-(4-Bromophenyl)prop-2-yn-1-ylidene)-1,1-bis(4-methoxy-3,5-dimethylphenyl)methanamine 135e: The reaction of 131e (418 mg, 2.00 mmol) with bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) was performed according to the general procedure for imine formation (Procedure E). The crude product was obtained as a yellow foamy solid and was used without purification. Imine 135e was produced as 1 a mixture of trans and cis isomers. Cis:trans = 0.51:1 (from H NMR). Spectral data for 135e: 1 H NMR (CDCl3, 500 MHz): cis isomer: δ 2.24 (s, 12H), 3.68 (s, 6H), 6.01 (s, 1H), 7.01 (s, 4H), 7.36 (d, 2H, J = 8.0 Hz), 7.52 (d, 2H, J = 8.0 Hz), 7.83 (s, 1H); trans isomer: δ 2.24 (s, 12H), 3.68 (s, 6H), 5.30 (s, 1H), 6.95 (s, 4H), 7.37 (d, 2H, J = 8.0 Hz), 7.46 (d, 2H, J = 8.0 Hz), 7.79 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.17, 16.21, 59.61, 72.09, 78.44, 83.17, 87.72, 91.07, 96.44, 120.16, 120.49, 124.04, 124.43, 127.81, 127.82, 130.77, 130.87, 131.75, 131.93, 133.46, 133.57, 137.96, 138.56, 141.71, 144.59, 155.94, 156.05; IR (thin film) 2942s, 2209s, 1609s, -1 79 1486s, 1221s, 1144s,1010s cm ; HRMS (ESI+) m/z calcd for C28H29NO2 Br (M+H+) 490.1382, meas 490.1365. Methyl The 4-(3-((bis(4-methoxy-3,5-dimethylphenyl)methyl)imino)prop-1-yn-1-yl)benzoate reaction of 131f (376 mg, 2.00 bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) mmol) 135f: with was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:60 215 EtOAc/hexanes) afforded 135f as an off-white solid (910 mg, 1.94 mmol, 97%) and as a mixture 1 1 of trans and cis isomers. Cis:trans = 0.52:1 (from H NMR). Spectral data for 135f: H NMR (CDCl3, 500 MHz): cis isomer: δ 2.25 (s, 12H), 3.68 (s, 6H), 3.93 (s, 3H), 6.04 (s, 1H), 7.02 (s, 4H), 7.55-7.58 (m, 2H), 7.87 (d, 1H, J = 1.0 Hz), 8.03-8.06 (m, 2H); trans isomer: δ 2.25 (s, 12H), 3.68 (s, 6H), 3.90 (s, 3H), 5.32 (s, 1H), 6.96 (s, 4H), 7.56-7.59 (m, 2H), 7.82 (s, 1H), 7.98-8.01 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 16.14, 16.18, 52.26, 52.35, 59.58, 72.19, 78.45, 84.32, 89.02, 90.95, 96.34, 125.71, 126.09, 127.79, 127.81, 129.47, 129.62, 130.61, 130.77, 130.86, 130.95, 132.00, 132.08, 137.89, 138.49, 141.54, 144.45, 155.95, 156.06, 166.13, -1 166.23; IR (thin film) 2951s, 2211s, 1727s, 1609s, 1484s, 1221s, 1142s,1019s cm ; HRMS + (ESI+) m/z calcd for C30H32NO4 (M+H ) 470.2331, meas 470.2352. 1,1-Bis(4-methoxy-3,5-dimethylphenyl)-N-(3-(4-nitrophenyl)prop-2-yn-1-ylidene)methanamine 135g: The reaction of 131g (350 mg, 2.00 bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) mmol) with was performed according to the general procedure for imine formation (Procedure E). The crude product was obtained as a yellow foamy solid and was used without purification. Imine 135g was produced as 1 a mixture of trans and cis isomers. Cis:trans = 0.35:1 (from H NMR). Spectral data for 135g: 1 H NMR (CDCl3, 500 MHz): cis isomer: δ 2.25 (s, 12H), 3.68 (s, 6H), 6.00 (s, 1H), 6.99 (s, 4H), 7.65 (d, 2H, J = 9.0 Hz), 7.89 (d, 1H, J = 1.0 Hz), 8.25 (d, 2H, J = 9.0 Hz); trans isomer: δ 2.25 216 (s, 12H), 3.68 (s, 6H), 5.33 (s, 1H), 6.95 (s, 4H), 7.66 (d, 2H, J = 9.0 Hz), 7.82 (s, 1H), 8.20 (d, 2H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 16.14, 16.18, 59.57, 72.47, 78.52, 85.82, 89.23, 90.75, 94.61, 123.58, 123.73, 127.73, 127.75, 127.80, 128.24, 130.83, 130.92, 132.84, 132.92, 137.68, 138.29, 140.98, 144.06, 147.72, 147.94, 156.01, 156.10; IR (thin film) 2940s, 2211m, -1 1595s, 1522s, 1484s, 1345s, 1221s, 1142s,1015s cm ; HRMS (ESI+) m/z calcd for + C28H29N2O4 (M+H ) 457.2127, meas 457.2147. 1,1-Bis(4-methoxy-3,5-dimethylphenyl)-N-(3-(m-tolyl)prop-2-yn-1-ylidene)methanamine The reaction of 131h (288 mg, 2.00 bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) mmol) 135h: with was performed according to the general procedure for imine formation (Procedure E). The crude product was obtained as a yellow semi-solid and was used without purification. Imine 135h was produced as 1 a mixture of trans and cis isomers. Cis:trans = 0.59:1 (from H NMR). Spectral data for 135h: 1 H NMR (CDCl3, 500 MHz): cis isomer: δ 2.25 (s, 12H), 2.37 (s, 3H), 3.69 (s, 6H), 6.07 (s, 1H), 7.04 (s, 4H), 7.16-7.29 (m, 2H), 7.32-7.35 (m, 2H), 7.85 (d, 1H, J = 1.0 Hz); trans isomer: δ 2.25 (s, 12H), 2.32 (s, 3H), 3.69 (s, 6H), 5.30 (s, 1H), 6.98 (s, 4H), 7.16-7.29 (m, 2H), 7.32-7.35 (m, 2H), 7.82 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.15, 16.19, 21.15, 21.19, 59.59, 71.88, 78.37, 82.07, 86.51, 92.58, 98.02, 121.07, 121.34, 127.83, 127.88, 128.27, 128.45, 129.24, 217 129.33, 130.41, 130.69, 130.73, 130.79, 132.62, 132.74, 138.10, 138.13, 138.34, 138.72, 142.11, -1 144.87, 155.88, 156.00; IR (thin film) 2942s, 2205s, 1609s, 1484s, 1219s, 1142s,1015s cm ; + HRMS (ESI+) m/z calcd for C29H32NO2 (M+H ) 426.2433, meas 426.2420. 1,1-Bis(4-methoxy-3,5-dimethylphenyl)-N-(3-(o-tolyl)prop-2-yn-1-ylidene)methanamine 135i: The with reaction of 131i (288 mg, 2.00 bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) mmol) was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:60 EtOAc/hexanes) afforded 135i as a white solid (750 mg, 1.76 mmol, 88%) and as a mixture of 1 1 trans and cis isomers. Cis:trans = 0.88:1 (from H NMR). Spectral data for 135i: H NMR (CDCl3, 500 MHz): cis isomer: δ 2.25 (s, 12H), 2.49 (s, 3H), 3.68 (s, 6H), 6.11 (s, 1H), 7.03 (s, 4H), 7.18-7.21 (m, 2H), 7.31 (t, 1H, J = 7.5 Hz), 7.49 (t, 1H, J = 7.5 Hz), 7.90 (s, 1H); trans isomer: δ 2.26 (s, 12H), 2.46 (s, 3H), 3.69 (s, 6H), 5.31 (s, 1H), 6.98 (s, 4H), 7.14 (t, 1H, J = 7.5 Hz), 7.24-7.27 (m, 2H), 7.49 (t, 1H, J = 7.5 Hz), 7.88 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.17, 16.19, 20.69, 20.81, 59.59, 59.60, 72.05, 78.39, 86.07, 90.49, 91.54, 96.70, 121.13, 121.35, 125.60, 125.80, 127.82, 127.86, 129.46, 129.52, 129.72, 129.89, 130.73, 130.81, 132.67, 132.68, 138.14, 138.66, 140.92, 141.05, 142.02, 144.94, 155.90, 156.01; IR (thin film) 2940s, 2197s, 218 -1 + 1607s, 1484s, 1221s, 1144s, 1015s cm ; HRMS (ESI+) m/z calcd for C29H32NO2 (M+H ) 426.2433, meas 426.2438. 1,1-Bis(4-methoxy-3,5-dimethylphenyl)-N-(3-(naphthalen-1-yl)prop-2-yn-1-ylidene)methanamin e 135j: The reaction of 131j (360 mg, 2.00 bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) mmol) with was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:60 EtOAc/hexanes) afforded 135j as an off-white solid (798 mg, 1.73 mmol, 87%) and as a mixture 1 1 of trans and cis isomers. Cis:trans = 0.36 :1 (from H NMR). Spectral data for 135j: H NMR (CDCl3, 500 MHz): cis isomer: δ 2.27 (s, 12H), 3.70 (s, 6H), 6.24 (s, 1H), 7.10 (s, 4H), 7.47 (t, 1H, J = 8.0 Hz), 7.49-7.59 (m, 2H), 7.76-7.80 (m, 1H), 7.88 (d, 1H, J = 8.0 Hz), 7.92 (d, 1H, J = 8.0 Hz), 8.03 (d, 1H, J = 1.0 Hz), 8.26 (d, 1H, J = 8.0 Hz); trans isomer: δ 2.28 (s, 12H), 3.70 (s, 6H), 5.38 (s, 1H), 7.02 (s, 4H), 7.43 (t, 1H, J = 8.0 Hz), 7.49-7.59 (m, 2H), 7.76-7.80 (m, 1H), 7.85 (d, 1H, J = 8.0 Hz), 7.87 (d, 1H, J = 8.0 Hz), 7.99 (s, 1H), 8.37 (d, 1H, J = 8.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 16.18, 16.21, 59.58, 59.59, 72.27, 78.41, 86.90, 90.70, 91.49, 95.94, 118.87, 119.18, 125.13, 125.18, 125.81, 126.08, 126.60, 126.75, 127.08, 127.31, 127.85, 127.91, 128.30, 128.48, 130.06, 130.44, 130.78, 130.84, 131.70, 131.75, 133.02, 133.09, 133.13, 133.27, 138.07, 138.71, 142.03, 144.89, 155.95, 156.05; IR (thin film) 2944s, 2201s, 1605s, 1485s, 219 -1 + 1221s, 1144s,1017s cm ; HRMS (ESI+) m/z calcd for C32H32NO2 (M+H ) 462.2433, meas 462.2441. N-(Hept-2-yn-1-ylidene)-1,1-bis(4-methoxy-3,5-dimethylphenyl)methanamine 135k: The reaction of 131k (220 mg, 2.00 mmol) with bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) was performed according to the general procedure for imine formation (Procedure E). The crude product was obtained as an orange liquid was used without purification. 1 Imine 135k was produced as a mixture of trans and cis isomers. Cis:trans = 0.76:1 (from H 1 NMR). Spectral data for 135k: H NMR (CDCl3, 500 MHz): cis isomer: δ 0.94 (t, 3H, J = 7.5 Hz), 1.37-1.48 (m, 4H), 2.23 (s, 12H), 2.41 (td, 2H, J = 7.0, 1.5 Hz), 3.67 (s, 6H), 5.96 (s, 1H), 6.97 (s, 4H), 7.57-7.59 (m, 1H); trans isomer: δ 0.89 (t, 3H, J = 7.5 Hz), 1.49-1.60 (m, 4H), 2.22 (s, 12H), 2.34 (td, 2H, J = 7.0, 1.5 Hz), 3.67 (s, 6H), 5.18 (s, 1H), 6.93 (s, 4H), 7.57-7.59 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 13.50, 13.52, 16.13, 16.17, 19.05, 19.07, 21.94, 21.98, 30.05, 30.14, 59.57, 71.37, 74.93, 78.18, 78.77, 95.01, 100.55, 127.74, 127.82, 130.60, 130.70, 138.35, 138.81, 142.23, 145.06, 155.81, 155.91; IR (thin film) 2934s, 2865s, 2220s, 1611s, 1484s, 1221s, -1 + 1144s,1017s cm ; HRMS (ESI+) m/z calcd for C26H34NO2 (M+H ) 392.2590, meas 392.2608. 220 N-(3-Cyclohexylprop-2-yn-1-ylidene)-1,1-bis(4-methoxy-3,5-dimethylphenyl)methanamine 135l: The reaction of 131l (272 mg, 2.00 mmol) bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) with was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:60 EtOAc/hexanes) afforded 135l as an off-white solid (755 mg, 1.81 mmol, 91%) and as a mixture 1 1 of trans and cis isomers. Cis:trans = 0.92:1 (from H NMR). Spectral data for 135l: H NMR (CDCl3, 500 MHz): cis isomer: δ 1.28-1.84 (m, 10H), 2.60-2.65 (m, 1H), 2.25 (s, 12H), 3.68 (s, 6H), 5.97 (s, 1H), 6.99 (s, 4H), 7.62 (s, 1H); trans isomer: δ 1.28-1.84 (m, 10H), 2.49-2.54 (m, 1H), 2.24 (s, 12H), 3.67 (s, 6H), 5.20 (s, 1H), 6.94 (s, 4H), 7.62 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.12, 16.16, 24.53, 24.83, 25.66, 25.70, 29.49, 29.61, 31.94, 59.56, 71.26, 74.91, 78.18, 78.63, 98.86, 104.26, 127.77, 127.83, 130.58, 130.67, 138.29, 138.86, 142.61, 145.24, 155.77, -1 155.88; IR (thin film) 2932s, 2216s, 1611s, 1483s, 1221s, 1144s,1017s cm ; HRMS (ESI+) m/z + calcd for C28H36NO2 (M+H ) 418.2746, meas 418.2762. 221 N-(4,4-Dimethylpent-2-yn-1-ylidene)-1,1-bis(4-methoxy-3,5-dimethylphenyl)methanamine 135m: The reaction of 131m (220 mg, 2.00 bis-(3,5-dimethyl-4-methoxyphenyl)methanamine (598 mg, 2.00 mmol) mmol) with was performed according to the general procedure for imine formation (Procedure E). Crystallization (1:60 EtOAc/hexanes) afforded 135m as a white solid (678 mg, 1.73 mmol, 87%) and as a mixture of 1 1 trans and cis isomers. Cis:trans = 0.86:1 (from H NMR). Spectral data for 135m: H NMR (CDCl3, 500 MHz): cis isomer: δ 1.30 (s, 9H), 2.24 (s, 12H), 3.68 (s, 6H), 5.93 (s, 1H), 6.99 (s, 4H), 7.59 (d, 1H, J = 1.0 Hz); trans isomer: δ 1.26 (s, 9H), 2.23 (s, 12H), 3.67 (s, 6H), 5.20 (s, 1H), 6.93 (s, 4H), 7.61 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.14, 16.18, 27.93, 28.18, 30.41, 30.43, 59.58, 71.14, 73.56, 77.39, 78.18, 102.76, 108.12, 127.85, 127.87, 130.60, 130.69, 138.22, 138.91, 142.67, 145.35, 155.79, 155.91; IR (thin film) 2971s, 2865s, 2211s, 1610s, -1 + 1484s, 1221s, 1144s,1015s cm ; HRMS (ESI+) m/z calcd for C26H34NO2 (M+H ) 392.2590, meas 392.2599. 27a 6.1.4 Preparation of diazoacetamide 148 A 100 mL round bottom flask fitted with a magnetic stir bar was flame dried and cooled under Argon. The p-toluenesulfonylhydrazone of glyoxylic acid chloride (3.60 g, 13.8 mmol) was added to this flask followed by the addition of dry CH2Cl2 (30 mL). The flask was then 222 fitted with a rubber septum and an Argon balloon and cooled to 0 °C in an ice-bath. The reaction mixture was stirred at 0 °C for 15 min. Aniline (1.40 mL, 15.2 mmol) and DBU (4.20 mL, 28.1 mmol) were then added sequentially to the reaction flask at 0 °C via plastic syringes. The reaction mixture was stirred at 0 °C for 2 h, and then warmed up to room temperature. It was then added to NH4Cl (sat. aq. 30 mL), and the layers separated. The aqueous layer was extracted with CH2Cl2 (30 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4 and filtered. Purification of the major product by silica gel chromatography (30 mm × 270 mm, 1:50 MeOH/CH2Cl2) afforded the impure product 148 as a yellow solid. The impure product was then washed with ether (15 mL x 3) until a single spot was observed on TLC, which afforded pure 148 as a bright yellow solid (1.17 g, 7.27 mmol, 52% yield). Rf = 0.18 (1:50 1 MeOH/CH2Cl2). Spectral data for 31: H NMR (DMSO-d6, 500 MHz) δ 5.48 (s, 1H), 6.97-7.01 (m, 1H), 7.24-7.28 (m, 2H), 7.50-7.52 (m, 2H), 9.69 (s, 1H); 13 C NMR (DMSO-d6, 125 MHz) δ 47.97, 118.57, 122.64, 128.72, 139.50, 163.50. 6.1.5 Catalytic asymmetric aziridination of alkynyl imines with ethyl diazoacetate General procedure for catalytic asymmetric aziridination of alkynyl imines with ethyl diazoacetate – illustrated for the synthesis of 1-benzhydryl-3-(phenylethynyl)aziridine-2-carboxylate 137c (Procedure F) 223 (2R,3R)-Ethyl 26h A 25 mL pear-shaped single necked Schlenk flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it) and cooled to room temperature under N2 and charged with (S)-VAPOL (54 mg, 0.10 mmol) and triphenyl borate (116 mg, 0.40 mmol). The mixture was dissolved in 2 mL distilled toluene. After the addition of H2O (1.8 µL, 0.10 mmol), the Teflon valve was closed and the flask was heated at 80 °C for 1 h. Toluene was carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon valve. After removal of the volatiles, the Teflon valve was completely opened and the flask was heated to 80 °C under high vacuum (0.5 mm Hg) for 30 min. After cooling down to room temperature, 134c (295 mg, 1.00 mmol) and dry toluene (2 mL) were added to the Schlenk flask containing the catalyst. The mixture was stirred at room temperature for 5 minutes and then ethyl diazoacetate (124 µL, 1.2 mmol) was added via syringe and the Teflon valve was closed and the reaction mixture was stirred at room temperature for 24 h. The mixture was then diluted with 5 mL of hexanes and transferred to a 25 mL round bottom flask. 224 The reaction flask was rinsed twice with 5 mL of dichloromethane and the rinse was added to the round bottom flask. Rotary evaporation of the solvent followed by exposure to high vacuum (0.5 mm Hg) for 30 minutes gave the crude aziridine as a yellow amorphous solid. The conversion was determined 1 from the H NMR spectrum of the crude reaction mixture by integration of the aziridine ring methine protons relative to either the imine methine proton or the H on the imine carbon. The 1 cis/trans ratio was determined on the crude reaction mixture by H NMR integration of the ring methine protons for each aziridine. The cis (J = 6-8 Hz) and the trans (J = 1-3 Hz) coupling constants were used to differentiate the two isomers. The presence of 142c in the crude reaction mixture was assigned on the basis of the following absorptions: 1H NMR (CDCl3, 500 MHz) δ 2.73 (d, 1H, J = 6.5 Hz), 3.03 (d, 1H, J = 6.5 Hz). These data are consistent with the corresponding product 144g isolated and characterized from the reaction of imine 136g. The yield of 142c was determined to be 2% by integration against the aziridine 137c in the 1H NMR spectrum of the crude reaction mixture and based on the isolated yield of 137c. The trans isomer of 137c could not be detected. The major product was purified by column chromatography on silica gel (40 mm x 400 mm, EtOAc/hexanes 1:15) to afford 137c as a white solid (80 mg, 0.21 mmol, 21%). The optical purity of 137c was determined to be 17% ee by HPLC (Chiralcel OD-H column, 222 nm, 98:2 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: Rt = 6.54 min for (2S,3S)-137c (minor) and Rt = 13.25 min for (2R,3R)-137c (major). mp 153-154 °C; Rf = 0.13 1 (1:9 EtOAc/hexanes). Spectral data for 137c: H NMR (CDCl3, 500 MHz) δ 1.24 (t, 3H, J = 7.0 Hz), 2.61 (d, 1H, J = 6.5 Hz), 2.75 (d, 1H, J = 6.5 Hz), 3.82 (s, 1H), 4.18-4.28 (m, 2H), 7.20-7.33 225 (m, 9H), 7.38-7.41 (m, 2H), 7.45-7.50 (m, 4H); 13 C NMR (CDCl3, 125 MHz) δ 14.36, 34.81, 45.03, 61.24, 77.34, 82.54, 84.10, 122.59, 127.46, 127.50, 127.54, 128.13, 128.35, 128.51, 128.54, 132.00, 141.66, 167.44 2 (2 sp C not located); IR (thin film) 2923m, 1738s, 1491s, -1 + 1455s, 1373s, 1190s cm ; mass spectrum: m/z (% rel intensity) 381 M (2), 308 (3), 214 (77), 186 (35), 167 (100), 152 (56), 114 (52); Anal calcd for C26H23NO2: C, 81.86; H, 6.08; N, 3.67. 20 Found: C, 81.86; H, 6.11; N, 3.47. [α] D –5.2 (c = 1.0, CH2Cl2) on 17% ee (2R,3R)-137c from (S)-VAPOL. (2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(phenylethynyl)aziridine-2-carbox ylate 138c: The reaction of 135c (411 mg, 1.00 mmol) and ethyl diazoacetate (124 µL, 1.2 mmol) 1 was performed according to the general procedure (Procedure F). An analysis of the H NMR spectrum of the crude reaction mixture revealed that the reaction went to 22% completion and there was <1% formation of the pyrrazole aziridine 143c. be detected. The trans isomer of 138c could not The product was purified by column chromatography on slica gel (40 mm x 450 226 mm, EtOAc/hexanes 1:8) to afford 138c as an off-white solid (70 mg, 0.14 mmol, 14%). The optical purity of 138c was determined to be 49% ee by HPLC (Chiralcel OD-H column, 225 nm, 99:1 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: Rt = 8.37 min for (2R,3R)-138c (major) and Rt = 10.59 min for (2S,3S)-138c (minor); mp 50-55 °C; Rf = 0.20 (1:5 1 EtOAc/Hexane). Spectral data for 138c: H NMR (CDCl3, 500 MHz) δ 1.25 (t, 3H, J = 7.5 Hz), 2.22 (s, 6H), 2.24 (s, 6H), 2.54 (d, 1H, J = 6.5 Hz), 2.67 (d, 1H, J = 6.5 Hz), 3.55 (s, 1H), 3.67 (s, 6H), 4.18-4.29 (m, 2H), 7.08 (s, 2H), 7.11 (s, 2H), 7.24-7.27 (m, 3H), 7.37-7.40 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.42, 16.17, 16.20, 34.87, 45.22, 59.58, 59.60, 61.21, 76.83, 82.48, 84.28, 122.65, 127.72, 127.77, 128.13, 128.32, 130.69, 130.72, 131.96, 136.99, 137.01, 156.17, 2 167.61 (1 sp C not located); IR (thin film) 2926s, 1734s, 1559s, 1456s, 1221s, 1184s, 1011s -1 + cm ; mass spectrum: m/z (% rel intensity) 497 M (1), 424 (2), 283 (100), 268 (8), 209 (3), 142 (4), 114 (15); Anal calcd for C32H35NO4: C, 77.24; H, 7.09; N, 2.81. Found: C, 76.85; H, 7.43; 20 N, 2.65. [α] D –6.2 (c = 1.0, CH2Cl2) on 49% ee (2R,3R)-138c from (S)-VAPOL. 227 (2R,3R)-Ethyl 1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-((4-(methoxycarbonyl)-phenyl)ethynyl)aziridine-2-carboxylate 139c (Table 2.5, entry 9): The reaction of 136c (579 mg, 1.00 mmol) and ethyl diazoacetate (124 µL, 1.2 mmol) was performed according to the general procedure (Procedure F) except that the solvent was ether and the temperature was –20 °C. The presence of 144c in the crude reaction mixture was assigned on the basis of the 1 following absorptions: H NMR (CDCl3, 500 MHz) δ 2.76 (d, 1H, J = 6.0 Hz), 2.99 (d, 1H, J = 6.0 Hz) and the presence of a compound with Rf = 0.15 (1:4 EtOAc/hexanes) in TLC. These data are consistent with the corresponding product 144g isolated and characterized from the reaction of imine 136g. The yield of 27c was determined to be 18% by integration against the aziridine 1 139c in the H NMR spectrum of the crude reaction mixture and based on the isolated yield of 139c. The trans isomer of 139c could not be detected. The major product was purified by column chromatography on silica gel (35 mm x 400 mm, Et2O/hexanes 1:20) to afford 139c as a white foamy solid (443 mg, 0.66 mmol, 66%). The optical purity of 139c was determined to be 97% ee 228 by HPLC (Pirkle covalent (R,R) Whelk-O1 column, 225 nm, 98:2 Hexane/2-PrOH, flow rate: 1.0 mL/min). Retention time: Rt = 7.29 min for (2S,3S)-139c (minor) and Rt = 13.47 min for (2R,3R)-139c (major). mp 62-64 °C; Rf = 0.20 (1:10 Et2O/hexanes). The outcomes of this reaction under a number of different conditions are given in Table 2.5 in the text. Spectral data 1 for 139c: H NMR (CDCl3, 500 MHz) δ 1.25 (t, 3H, J = 7.0 Hz), 1.37 (s, 36H), 2.62 (d, 1H, J = 6.5 Hz), 2.83 (d, 1H, J = 6.5 Hz), 3.64 (s, 6H), 3.81 (s, 1H), 4.17-4.28 (m, 2H), 7.24-7.28 (m, 7H), 7.36-7.38 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.44, 32.10, 32.11, 35.61, 35.79, 35.81, 44.97, 61.20, 64.07, 64.08, 76.40, 82.55, 84.61, 122.79, 125.81, 125.83, 128.13, 128.25, 131.88, 135.44, 135.80, 143.08, 143.21, 158.55, 158.61, 168.00; IR (thin film) 2961s, 1734s, 1456s, -1 + 1414s, 1221s, 1013s cm ; mass spectrum: m/z (% rel intensity) 665 M (0.47), 592 (5), 451 (100), 379 (12), 305 (2), 142 (19), 114 (45). Anal calcd for C44H59NO4: C, 79.36; H, 8.93; N, 20 2.10. Found: C, 79.02; H, 9.10; N, 1.95. [α] D –10.4 (c = 1.0, CH2Cl2) on 97% ee (2R,3R)-139c from (S)-VAPOL. The aziridination of 136c with 0.9 equiv of ethyl diazo acetate (Table 2.5, entry 12): The reaction of 136c (579 mg, 1.00 mmol) and ethyl diazoacetate (contains 11 wt% CH2Cl2, 105 µL, 0.9 mmol) was performed according to the general procedure (Procedure F) except that the solvent was ether and the temperature was –20 °C. The yields of 139c (32%) and 139c (6%) 1 were determined from the H NMR spectrum of the crude reaction mixture by integration against an internal standard (Ph3CH). The aziridination of 136c with 4.0 equiv of ethyl diazo acetate (Table 2.5, entry 13): The reaction of 136c (579 mg, 1.00 mmol) and ethyl diazoacetate (contains 11 wt% CH2Cl2, 466 229 µL, 4.0 mmol) was performed according to the general procedure (Procedure F) except that the solvent was ether and the temperature was –20 °C. The yields of 139c (58%) and 139c (3%) 1 were determined from the H NMR spectrum of the crude reaction mixture by integration against an internal standard (Ph3CH). A third compound was observed in this reaction with the 1 following absorptions: H NMR (CDCl3, 500 MHz) δ 2.60 (d, 1H, J = 6.5 Hz), 2.95 (d, 1H, J = 6.5 Hz). This compound is tentatively assigned as the regioisomer of 144c resulting from a regioisomeric [3+2] cycloaddition and is formed in 18% yield. (2R,3R)-Ethyl 1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-((4-methoxyphenyl)-ethynyl)-aziridine-2-carboxylate 139d: The reaction of 136d (609 mg, 1.00 mmol) and ethyl diazoacetate (124 µL, 1.2 mmol) was performed according to the general procedure (Procedure F) except that the solvent was ether and the temperature was –20 °C. The presence of 144d in the 1 crude reaction mixture was assigned on the basis of the following absorptions: H NMR (CDCl3, 500 MHz) δ 2.76 (d, 1H, J = 6.0 Hz), 2.99 (d, 1H, J = 6.0 Hz) and the presence of a compound 230 with Rf = 0.15 (1:4 EtOAc/hexanes) in TLC. These data are consistent with the corresponding product 144g isolated and characteristed from the reaction of imine 136g. The yield of 144d was 1 determined to be 27% by integration against the aziridine 139d in the H NMR spectrum of the crude reaction mixture and based on the isolated yield of 139d. The trans-isomer of 139d was not detected. The major product was purified by column chromatography on silica gel (40 mm x 450 mm, Et2O/hexanes 1:10) to afford 139d as a white foamy solid (315 mg, 0.45 mmol, 45%). The optical purity of 139d was determined to be 96% ee by HPLC (Pirkle covalent (R,R) Whelk-O1 column, 225 nm, 98:2 Hexane/2-PrOH, flow rate: 1.0 mL/min). Retention time: Rt = 9.85 min for (2S,3S)-139d (minor) and Rt = 23.03 min for (2R,3R)-139d (major). mp 58-61 °C; 1 Rf = 0.18 (1:5 Et2O/hexanes). Spectral data for 139d: H NMR (CDCl3, 500 MHz) δ 1.25 (t, 3H, J = 7.0 Hz), 1.37 (s, 36H), 2.61 (d, 1H, J = 6.5 Hz), 2.84 (d, 1H, J = 6.5 Hz), 3.64 (s, 3H), 3.64 (s, 3H), 3.78 (s, 3H), 3.80 (s, 1H), 4.17-4.28 (m, 2H), 6.77-6.79 (m, 2H), 7.23 (s, 2H), 7.25 (s, 2H), 7.29-7.32 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.45, 32.08, 35.76, 35.79, 35.87, 44.89, 55.21, 61.18, 64.06, 64.08, 76.34, 82.52, 83.03, 113.76, 114.86, 125.83, 125.85, 133.30, 135.38, 3 135.81, 143.00, 143.17, 158.51, 158.58, 159.54, 168.11 (1 sp C not located); IR (thin film) -1 + 2961s, 1734s, 1559s, 1456s cm ; mass spectrum, m/z (% rel intensity) 695 M (0.63), 451 (68), 408 (9), 233 (12), 132 (60), 57 (100); Anal calcd for C45H61NO5: C, 77.66; H, 8.83; N, 2.01. 20 Found: C, 77.91; H, 8.90; N, 1.85. [α] D –9.4 (c = 1.0, CH2Cl2) on 96% ee (2R,3R)-139d from (S)-VAPOL. 231 (2R,3R)-Ethyl 1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-((4-bromophenyl)-ethynyl)-aziridine-2-carboxylate 139e: The reaction of 136e (658 mg, 1.00 mmol) and ethyl diazoacetate (124 µL, 1.2 mmol) was performed according to the general procedure (Procedure F) except that the solvent was ether and the temperature was –20 °C. The presence of 144e in the 1 crude reaction mixture was assigned on the basis of the following absorptions: H NMR (CDCl3, 500 MHz) δ 2.76 (d, 1H, J = 6.0 Hz), 2.92 (d, 1H, J = 6.0 Hz) and the presence of a compound with Rf = 0.15 (1:4 EtOAc/hexanes) in TLC. These data are consistent with the corresponding product 144g isolated and characterized from the reaction of imine 136g. The yield of 144e was 1 determined to be 24% by integration against the aziridine 139e in the H NMR spectrum of the crude reaction mixture and based on the isolated yield of 139e. The trans-isomer of 139e was not detected. The major product was purified by column chromatography on silica gel (35 mm x 400 mm, Et2O/hexanes 1:20) to afford 139e as a white foamy solid (404 mg, 0.54 mmol, 54%). The optical purity of 139e was determined to be 97% ee by HPLC (Pirkle covalent (R,R) Whelk-O1 232 column, 225 nm, 98:2 Hexane/2-PrOH, flow rate: 1.0 mL/min). Retention time: Rt = 5.60 min for (2S,3S)-139e (minor) and Rt = 7.97 min for (2R,3R)-139e (major). mp 68-72 °C; Rf = 0.20 1 (1:10 Et2O/hexanes). Spectral data for 139e: H NMR (CDCl3, 500 MHz) δ 1.25 (t, 3H, J = 7.5 Hz), 1.37 (s, 36H), 2.64 (d, 1H, J = 6.5 Hz), 2.81 (d, 1H, J = 6.5 Hz) 3.64 (s, 3H), 3.64 (s, 3H) 3.81 (s, 1H), 4.17-4.28 (m, 2H), 7.22-7.24 (m, 6H), 7.37-7.40 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.43, 32.07, 35.46, 35.77, 35.79, 44.92, 61.24, 64.08, 76.34, 81.48, 85.85, 121.68, 122.56, 125.75, 125.77, 131.45, 133.28, 135.30, 135.67, 143.08, 143.22, 158.56, 158.62, 167.86 3 -1 (2 sp C not located); IR (thin film) 2961s, 1734s, 1559s, 1456s, 1414s, 1221s, 1011s cm ; mass + spectrum, m/z (% rel intensity) 745 M (0.60, 81 + Br), 743 M (0.42, 79 Br), 465 (2), 451 (100), 379 (6), 247 (6). Anal calcd for C44H58BrNO4: C, 70.95; H, 7.85; N, 1.88. Found: C, 70.80; H, 20 7.96; N, 1.91. [α] D –11.4 (c = 1.0, CH2Cl2) on 97% ee (2R,3R)-139e from (S)-VAPOL. (2R,3R)-Ethyl-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-((4-(methoxycarbonyl)-phenyl )-ethynyl)aziridine-2-carboxylate 139f: The reaction of 136f (637 mg, 1.00 mmol) and ethyl 233 diazoacetate (124 µL, 1.2 mmol) was performed according to the general procedure (Procedure F) except that the solvent was ether and the temperature was –20 °C. The presence of 144f in the 1 crude reaction mixture was assigned on the basis of the following absorptions: H NMR (CDCl3, 500 MHz) δ 2.77 (d, 1H, J = 6.0 Hz), 2.93 (d, 1H, J = 6.0 Hz) and the presence of a compound with Rf = 0.15 (1:4 EtOAc/hexanes) in TLC. These data are consistent with the corresponding product 144g isolated and characterized from the reaction of imine 136g. The yield of 144f was 1 determined to be 19% by integration against the aziridine 139f in the H NMR spectrum of the crude reaction mixture and based on the isolated yield of 139f. The trans-isomer of 139f was not detected. The major product was purified by column chromatography on silica gel (40 mm x 450 mm, Et2O/hexanes 1:12) to afford 139f as a white foamy solid (410 mg, 0.57 mmol, 57%). The optical purity of 139f was determined to be 94% ee by HPLC (Pirkle covalent (R,R) Whelk-O1 column, 225 nm, 98:2 Hexane/2-PrOH, flow rate: 1.0 mL/min). Retention time: Rt = 13.47 min for (2S,3S)-139f (minor) and Rt = 26.15 min for (2R,3R)-139f (major). mp 59-62 °C; Rf = 0.16 1 (1:5 Et2O/hexanes). Spectral data for 139f: H NMR (CDCl3, 500 MHz) δ 1.25 (t, 3H, J = 7.0 Hz), 1.37 (s, 36H), 2.66 (d, 1H, J = 6.5 Hz), 2.82 (d, 1H, J = 6.5 Hz), 3.64 (s, 3H), 3.64 (s, 3H), 3.82 (s, 1H), 3.89 (s, 3H), 4.17-4.28 (m, 2H), 7.24 (s, 4H), 7.42-7.44 (m, 2H), 7.92-7.94 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.42, 32.09, 32.10, 35.29, 35.79, 35.81, 45.06, 52.17, 61.26, 64.08, 76.43, 81.80, 87.90, 125.75, 125.76, 127.47, 129.36, 129.64, 131.79, 135.38, 135.69, 3 143.16, 143.28, 158.60, 158.65, 166.50, 167.80 (1 sp C not located); IR (thin film) 2961s, -1 + 1728s, 1559s, 1456s, 1277s, 1223s cm ; mass spectrum, m/z (% rel intensity) 723 M (0.17), 234 598 (0.15), 451 (23), 379 (6), 128 (11), 44 (100). Anal calcd for C46H61NO6: C, 76.31; H, 8.49; 20 N, 1.93. Found: C, 76.43; H, 8.45; N, 1.79. [α] D –12.7 (c = 1.0, CH2Cl2) on 94% ee (2R,3R)-139f from (S)-VAPOL. (2R,3R)-Ethyl-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-((4-nitrophenyl)-ethynyl)-aziridine-2-carboxylate 139g: The reaction of 136g (624 mg, 1.00 mmol) and ethyl diazoacetate (124 µL, 1.2 mmol) was performed according to the general procedure (Procedure F) except that the solvent was ether and the temperature was –20 °C. The yield of 144g was 1 determined to be 22% by integration against the aziridine 139g in the H NMR spectrum of the crude reaction mixture and based on the isolated yield of 139g. not detected. The trans-isomer of 139g was The major product was purified by column chromatography on silica gel (40 mm x 450 mm, Et2O/hexanes 1:12) to afford 139g as an off-white foamy solid (252 mg, 0.35 mmol, 35%); mp 73-76 °C; Rf = 0.22 (1:5 Et2O/hexanes). The column was flushed with ethyl acetate, the residue was loaded onto a silica gel column (40 mm x 450 mm) and elution with a 1:5 235 mixture of ethyl acetate and hexanes gave a few fractions of pure 144g as a yellow foamy solid (15 mg); mp 91-95 °C; Rf = 0.15 (1:4 EtOAc/hexanes). The optical purity of 139g was determined to be 88% ee by HPLC (Pirkle covalent (R,R) Whelk-O1 column, 225 nm, 96:4 Hexane/2-PrOH, flow rate: 1.0 mL/min). Retention time: Rt = 7.06 min for (2S,3S)-139g (minor) 1 and Rt = 8.50 min for (2R,3R)-139g (major). Spectral data for 139g: H NMR (CDCl3, 500 MHz) δ 1.25 (t, 3H, J = 7.0 Hz), 1.37 (s, 36H), 2.70 (d, 1H, J = 6.5 Hz), 2.83 (d, 1H, J = 6.5 Hz), 3.64 (s, 3H), 3.65 (s, 3H) 3.83 (s, 1H), 4.18-4.28 (m, 2H), 7.23 (s, 2H), 7.24 (s, 2H), 7.50-7.53 (m, 2H), 8.12-8.15 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.42, 32.08, 32.10, 35.02, 35.79, 35.82, 45.13, 61.33, 64.09, 76.43, 80.69, 90.46, 123.50, 125.68, 125.72, 129.64, 132.60, 135.24, 135.56, 143.21, 143.33, 147.16, 158.65, 158.70, 167.58 3 (1 sp C not located); IR (thin film) 2961s, -1 1734s, 1595s, 1522s, 1414s,1345, 1223s, 1013s cm ; mass spectrum, m/z (% rel intensity) 710 + M (0.20), 637 (1), 551 (1), 494 (1), 452 (28), 450 (100), 379 (9), 246 (21), 146 (15). Anal calcd 20 for C44H58N2O6: C, 74.33; H, 8.22; N, 3.94. Found: C, 74.34; H, 8.43; N, 4.27. [α] D –16.2 (c 1 = 1.0, CH2Cl2) on 88% ee (2R,3R)-139g from (S)-VAPOL. Spectral data for 144g: H NMR (CDCl3, 500 MHz) δ 1.21 (t, 3H, J = 7.5 Hz), 1.26 (t, 3H, J = 7.5 Hz), 1.28 (s, 18H), 1.36 (s, 18H), 2.81 (d, 1H, J = 6.0 Hz), 2.88 (d, 1H, J = 6.0 Hz), 3.61 (s, 3H), 3.65 (s, 3H), 3.88 (s, 1H), 4.11-4.20 (m, 2H), 4.24-4.30 (m, 2H), 7.10-7.13 (m, 2H), 7.15 (s, 2H), 7.23 (s, 2H), 8.10-8.13 (m, 2H), 11.48 (br, 1H); 13 C NMR (CDCl3, 125 MHz) δ 14.05, 14.13, 31.96, 32.02, 35.74, 35.81, 39.13, 46.83, 61.00, 62.12, 64.10, 64.18, 76.71, 122.64, 123.09, 125.08, 125.38, 131.19, 135.16, 2 135.46, 137.98, 138.35, 143.56, 143.84, 147.03, 158.70, 158.76, 161.92, 169.16 (1 sp C not 236 -1 located); IR (thin film) 2961s, 1734s, 1522s, 1414s, 1345s, 1202s, 1115s cm ; HRMS (ESI+) + 20 m/z calcd for C48H65N4O8 (M+H ) 825.4805, meas 825.4790. [α] D –2.5 (c = 1.0, CH2Cl2). 6.1.6 Catalytic asymmetric aziridination of alkynyl imines with diazoacetamides General procedure for catalytic asymmetric aziridination with alkynyl imine with diazoacetamides – illustrated for the synthesis of (2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-phenyl-3-(phenylethynyl)aziridine-2carboxamide 152c (Procedure G, Table 2.7, entry 16) 27a A 25 mL pear-shaped single necked Schlenk flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it) and cooled to room temperature under N2 and charged with (S)-VANOL (11 mg, 0.025 mmol), phenol (4.7 mg, 0.050 mmol), dry toluene (1.0 mL), BH3•SMe2 (2 M solution in toluene, 37.5 µL, 0.075 mmol) and water (1.35 µL, 0.075 mmol). The Teflon valve was closed and the flask was heated at 100 °C for 1 hour. The toluene was then carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon valve. After the solvent was removed, the Teflon valve was completely opened and the flask was heated to 100 °C under high vacuum for 30 min. The flask was then removed from the oil bath and allowed to cool to room temperature under N2. The 237 residue was then completely dissolved in 1.25 mL of dry toluene (10 mmol% catalyst) or 2.5 mL of dry toluene (5 mol% catalyst) to afford the stock solution of the catalyst. A 10 mL round-bottom single-neck (14/20) flask fitted with a magnetic stir bar was flame dried under high vacuum and cooled to room temperature under N2. To the flask was then added imine 135c (82 mg, 0.20 mmol, 1 equiv). The flask was then fitted with a rubber septum and a N2 balloon. To this flask was added 1.00 mL of the catalyst stock solution (5 mol% catalyst) via a plastic syringe fitted with a metallic needle. This catalyst-imine complex was cooled to –40 °C with the aid of an immersion cooler for 15-20 min. Diazoacetamide 148 (45 mg, 0.28 mmol, 1.4 equiv) was then added to the reaction flask, and the reaction stirred at –40 °C for 4 h. To the reaction mixture was added cold saturated aq. NaHCO3 (8 mL). The mixture was transferred to a 50 mL separatory funnel. The reaction flask was rinsed with EtOAc (8 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (8 mL x 2) and the organic layers were then combined. This solution was dried over MgSO4, filtered through a pad of Celite, rinsed with EtOAc, subjected to rotary evaporation until dry and finally exposed to high vacuum (0.5 mm Hg) to afford the crude product as a foamy yellow solid. The conversion was determined from the 1H NMR spectrum of the crude reaction mixture by integration of the aziridine ring methine protons relative to either the imine methine proton or the H on the imine 1 carbon. The cis/trans ratio was determined on the crude reaction mixture by H NMR integration of the ring methine protons for each aziridine. The cis (J = 6-8 Hz) and the trans (J = 1-3 Hz) coupling constants were used to differentiate the two isomers. This reaction was examined under the variety of conditions and the results are presented in Table 2.7 of the text. 238 1 The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 50:1. The major product was purified by column chromatography on silica gel (30 mm x 400 mm, EtOAc/hexanes 1:7 to 1:5 to 1:4) to afford 152c as an off-white foamy solid (99 mg, 0.182 mmol, 91%). The optical purity of 152c was determined to be 97% ee by HPLC (Chiralpak AD column, 222 nm, 90:10 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 15.87 min for (2R,3R)-152c (minor) and Rt = 27.87 min for (2S,3S)-152c (major); mp 74-77 °C; Rf = 0.29 (1:2 1 EtOAc/hexanes); Spectra data for 152c: H NMR (CDCl3, 500 MHz) δ 2.24 (s, 6H), 2.29 (s, 6H), 2.69 (d, 1H, J = 6.5 Hz), 2.74 (d, 1H, J = 6.5 Hz), 3.67 (s, 3H), 3.71 (s, 3H), 3.76 (s, 1H), 6.98 (s, 2H), 7.07-7.11 (m, 1H), 7.12 (s, 2H), 7.15-7.19 (m, 4H), 7.22-7.26 (m, 1H), 7.27-7.31 (m, 2H), 7.49-7.51 (m, 2H), 8.45 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.28, 16.31, 35.72, 46.44, 59.59, 59.65, 75.50, 83.14, 83.97, 120.13, 122.14, 124.42, 127.43, 127.83, 128.18, 128.49, 128.95, 130.88, 131.16, 131.85, 136.52, 136.77, 137.04, 156.19, 156.54, 165.57; IR (thin film) -1 3355br m, 2926s, 1686s, 1528s, 1445s, 1223s, 1013s cm ; HRMS (ESI+) m/z calcd for + 20 C36H37N2O3 (M+H ) 545.2804, meas 545.2815. [α] D +30.2 (c = 1.0, CH2Cl2) on 94% ee (2S,3S)-152c from (S)-VANOL. (2S,3S)-1-Benzhydryl-N-phenyl-3-(phenylethynyl)aziridine-2-carboxamide 151c: The reaction of 134c (59 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 0.28 mmol) was 239 performed according to the general procedure except that the temperature was 0 °C and the time was 24 h (Procedure G). The 1H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 25:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:7 to 1:5) to afford 151c as an off-white foamy solid (66 mg, 0.154 mmol, 77%). The optical purity of 151c was determined to be 89% ee by HPLC (Chiralpak AD column, 222 nm, 98:2 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: Rt = 55.12 min for (2R,3R)-151c (minor) and Rt = 71.77 min for (2S,3S)-151c (major); mp 50-55 °C; Rf = 0.17 (1:4 1 EtOAc/hexanes). Spectral data for 151c: H NMR (CDCl3, 500 MHz) δ 2.79 (d, 1H, J = 7.0 Hz), 2.83 (d, 1H, J = 7.0 Hz), 3.99 (s, 1H), 7.08-7.12 (m, 1H), 7.15-7.18 (m, 4H), 7.22-7.34 (m, 7H), 7.35-7.40 (m, 4H), 7.50-7.53 (m, 4H), 8.45 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 35.87, 46.35, 76.28, 83.29, 83.67, 119.98, 121.98, 124.42, 127.14, 127.48, 127.55, 128.04, 128.15, 128.53, 128.64, 128.90, 128.95, 131.89, 137.00, 141.17, 141.31, 165.29; IR (thin film) 3355br m, 2926s, -1 + 1684s, 1528s, 1445s cm ; HRMS (ESI+) m/z calcd for C30H25N2O (M+H ) 429.1967, meas 20 429.1978. [α] D +44.6 (c = 1.0, CH2Cl2) on 89% ee (2S,3S)-151c from (S)-VANOL. (2S,3S)-1-(Bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-phenyl-3-(phenylethynyl)aziridine-2 -carboxamide 35c: The reaction of 136c (116 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 0.28 mmol) was performed according to the general procedure (Procedure G) except that the 240 1 temperature was 0 °C and the time was 24 h. The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 2:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:18) to afford 153c as an off-white foamy solid (49 mg, 0.068 mmol, 34%). The optical purity of 153c was determined to be 71% ee by HPLC (Pirkle covalent (R,R) Whelk-O1 column, 222 nm, 95:5 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: Rt = 13.65 min for (2S,3S)-153c (major) and Rt = 25.65 min for (2R,3R)-153c 1 (minor); mp 59-65 °C; Rf = 0.27 (1:5 EtOAc/hexanes). Spectral data for 153c: H NMR (CDCl3, 500 MHz) δ 1.36 (s, 18H), 1.41 (s, 18H), 2.76 (d, 1H, J = 7.0 Hz), 2.87 (d, 1H, J = 7.0 Hz), 3.65 (s, 3H), 3.68 (s, 3H), 3.93 (s, 1H), 7.08 (t, 1H, J = 7.7 Hz), 7.15 (s, 2H), 7.16 (d, 2H, J = 7.5 Hz), 7.21-7.24 (m, 3H), 7.28 (t, 2H, J = 7.5 Hz), 7.32 (s, 2H), 7.50 (d, 2H, J = 8.0 Hz), 8.51 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 32.05, 32.11, 35.75, 35.86, 36.04, 46.54, 64.12, 64.15, 75.72, 83.19, 84.16, 120.02, 122.10, 124.39, 125.43, 125.55, 128.15, 128.45, 128.93, 131.79, 135.36, 135.43, 137.03, 143.37, 143.67, 158.58, 158.83, 165.81; IR (thin film) 3357br m, 2961s, 1700s, -1 + 1528s, 1445s, 1223s, 1013s cm ; HRMS (ESI+) m/z calcd for C48H61N2O3 (M+H ) 713.4682, 20 meas 713.4664. [α] D +14.3 (c = 1.0, CH2Cl2) on 71% ee (2S,3S)-153c from (S)-VANOL. (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-phenyl-3-((triisopropylsilyl)ethynyl)-azi ridine-2-carboxamide 152a: The reaction of 135a (98 mg, 0.20 mmol) and diazoacetamide 148 241 (45 mg, 0.28 mmol) was performed according to the general procedure (Procedure G) except that 1 the temperature was –20 °C. The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 50:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:7) to afford 152a as a white foamy solid (107 mg, 0.171 mmol, 86%). The optical purity of 152a was determined to be 98% ee by HPLC (Chiralpak AD column, 222 nm, 98:2 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: Rt = 10.82 min for (2R,3R)-152a (minor) and Rt = 28.42 min for (2S,3S)-152a (major). A repeat of the reaction gave an 87% yield of 152a with 98% ee; mp 54-59 °C; Rf = 0.20 (1:4 EtOAc/hexanes). Spectral data 1 for 152a: H NMR (CDCl3, 500 MHz) δ 0.83-0.93 (m, 21H), 2.22 (s, 6H), 2.27 (s, 6H), 2.56 (d, 1H, J = 6.5 Hz), 2.60 (d, 1H, J = 6.5 Hz), 3.66 (s, 3H), 3.70 (s, 1H), 3.71 (s, 3H), 6.95 (s, 2H), 7.03-7.07 (m, 1H), 7.10 (s, 2H), 7.25-7.29 (m, 2H), 7.48-7.51 (m, 2H), 8.43 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 10.94, 16.24, 18.39, 18.42, 35.95, 46.12, 59.57, 59.64, 75.26, 84.84, 101.61, 119.34, 124.05, 127.24, 127.85, 128.74, 130.81, 131.17, 136.57, 136.88, 137.24, 156.10, 156.54, -1 165.15; IR (thin film) 3351br m, 2944s, 2867s, 1694s, 1530s, 1445s, 1223s, 1017s cm ; HRMS + 20 (ESI+) m/z calcd for C39H53N2O3Si (M+H ) 625.3825, meas 625.3799. [α] D +24.8 (c = 1.0, CH2Cl2) on 98% ee (2S,3S)-152a from (S)-VANOL. 242 (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-phenyl-3-((trimethylsilyl)ethynyl)-azirid ine-2-carboxamide 152b: The reaction of 135b (81 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 0.28 mmol) was performed according to the general procedure (Procedure G) except that the 1 temperature was –20 °C. The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 5:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:7) to afford 152b as a white foamy solid (86 mg, 0.159 mmol, 80%). The optical purity of 152b was determined to be 83% ee by HPLC (Chiralpak AD column, 222 nm, 99:1 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 12.95 min for (2R,3R)-152b (minor) and Rt = 15.15 min for (2S,3S)-152b (major). A repeat of the reaction gave an 80% yield of 152b with 86% ee; mp 123-127 °C; Rf = 0.20 (1:4 EtOAc/hexanes). 1 Spectral data for 152b: H NMR (CDCl3, 500 MHz) δ -0.02 (s, 9H), 2.23 (s, 6H), 2.28 (s, 6H), 2.50 (d, 1H, J = 6.5 Hz), 2.59 (d, 1H, J = 6.5 Hz), 3.67 (s, 3H), 3.71 (s, 3H), 3.72 (s, 1H), 6.94 (s, 2H), 7.07 (s, 2H), 7.07-7.11 (m, 1H), 7.28-7.32 (m, 2H), 7.48-7.51 (m, 2H), 8.35 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ -0.47, 16.25, 45.45, 45.99, 59.58, 59.65, 75.14, 88.67, 99.99, 119.96, 124.34, 127.42, 127.88, 128.86, 130.78, 131.11, 136.40, 136.68, 136.98, 156.11, 156.51, 165.40 3 -1 (1 sp C not located); IR (thin film) 3357br m, 2957s, 1686s, 1530s, 1445s, 1223s, 1013s cm ; + 20 HRMS (ESI+) m/z calcd for C33H41N2O3Si (M+H ) 541.2886, meas 541.2899. [α] D +4.2 (c = 1.0, CH2Cl2) on 83% ee (2S,3S)-152b from (S)-VANOL. 243 (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((4-methoxyphenyl)ethynyl)-N-phenylazi ridine-2-carboxamide 152d: The reaction of 135d (88 mg, 0.20 mmol) and diazoacetamide 148 1 (45 mg, 0.28 mmol) was performed according to the general procedure (Procedure G). The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of >100:1. The major product was purified by column chromatography on silica gel (30 mm x 300 mm, EtOAc/hexanes 1:4 to 1:3) to afford 152d as an off-white foamy solid (103 mg, 0.179 mmol, 90%). The optical purity of 152d was determined to be 99% ee by HPLC (Chiralpak AD column, 222 nm, 85:15 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 9.25 min for (2R,3R)-152d (minor) and Rt = 23.24 min for (2S,3S)-152d (major). A repeat of the reaction gave an 89% yield of 152d 1 with 99% ee; mp 76-79 °C; Rf = 0.42 (1:1 EtOAc/hexanes). Spectral data for 152d: H NMR (CDCl3, 500 MHz) δ 2.24 (s, 6H), 2.29 (s, 6H), 2.67 (d, 1H, J = 6.5 Hz), 2.73 (d, 1H, J = 6.5 Hz), 3.67 (s, 3H), 3.71 (s, 3H), 3.74 (s, 3H), 3.75 (s, 1H), 6.68-6.72 (m, 2H), 6.98 (s, 2H), 7.07-7.14 (s, 3H), 7.12 (s, 2H), 7.27-7.31 (m, 2H), 7.49-7.52 (m, 2H), 8.45 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.28, 16.31, 35.90, 46.40, 55.22, 5958, 59.65, 75.49, 82.54, 83.12, 113.81, 114.21, 120.14, 124.38, 127.45, 127.84, 128.93, 130.83, 131.12, 133.31, 136.58, 136.82, 137.08, 156.16, 156.50, 159.72, 165.71; IR (thin film) 3351br m, 2932s, 1686s, 1528s, 1510s, 1445s, 1250s, 244 -1 + 1223s, 1015s cm ; HRMS (ESI+) m/z calcd for C37H39N2O4 (M+H ) 575.2910, meas 20 575.2896. [α] D +32.9 (c = 1.0, CH2Cl2) on 99% ee (2S,3S)-152d from (S)-VANOL. (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((4-bromophenyl)ethynyl)-N-phenylaziri dine-2-carboxamide 152e: The reaction of 135e (98 mg, 0.20 mmol) and diazoacetamide 148 (45 1 mg, 0.28 mmol) was performed according to the general procedure (Procedure G). The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of >100:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:7 to 1:5 to 1:4) to afford 152e as an off-white foamy solid (116 mg, 0.186 mmol, 93%). The optical purity of 152e was determined to be 98% ee by HPLC (Chiralpak AD column, 222 nm, 90:10 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: Rt = 6.65 min for (2R,3R)-152e (minor) and Rt = 23.21 min for (2S,3S)-152e (major). A repeat of the reaction gave a 92% yield of 152e 1 with 99% ee; mp 74-78 °C; Rf = 0.32 (1:2 EtOAc/hexanes). Spectral data for 152e: H NMR (CDCl3, 500 MHz) δ 2.24 (s, 6H), 2.28 (s, 6H), 2.71 (d, 1H, J = 7.0 Hz), 2.72 (d, 1H, J = 7.0 Hz), 3.67 (s, 3H), 3.71 (s, 3H), 3.76 (s, 1H), 6.98 (s, 2H), 7.00-7.03 (m, 2H), 7.08-7.12 (m, 1H), 7.10 (s, 2H), 7.28-7.32 (m, 4H), 7.48-7.51 (m, 2H), 8.43 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.29, 16.32, 35.55, 46.45, 59.59, 59.65, 75.47, 81.99, 85.24, 119.97, 121.04, 122.84, 124.50, 127.40, 127.79, 129.00, 130.91, 131.20, 131.47, 133.24, 136.42, 136.66, 136.98, 156.22, 156.56, 245 -1 165.41; IR (thin film) 3353br m, 2928s, 1684s, 1528s, 1445s, 1223s,1011s cm ; HRMS (ESI+) 79 + 20 m/z calcd for C36H36N2O3 Br (M+H ) 623.1909, meas 623.1881. [α] D +31.0 (c = 1.0, CH2Cl2) on 98% ee (2S,3S)-152e from (S)-VANOL. Methyl 4-(((2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(phenylcarbamoyl)-aziridin-2-yl)ethynyl)benzoate 152f: The reaction of 135f (94 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 0.28 mmol) was performed according to the general procedure 1 (Procedure G). The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 23:1. The major product was purified by column chromatography on silica gel (30 mm x 300 mm, EtOAc/hexanes 1:4) to afford 152f as a light yellow foamy solid (108 mg, 0.179 mmol, 90%). The optical purity of 152f was determined to be 96% ee by HPLC (Chiralpak AD column, 222 nm, 80:20 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 7.58 min for (2R,3R)-152f (minor) and Rt = 35.70 min for (2S,3S)-152f (major). A repeat of the reaction gave an 89% yield of 152f with 95% ee; mp 71-74 °C; Rf = 0.23 (1:2 EtOAc/hexanes). Spectral data 1 for 152f: H NMR (CDCl3, 500 MHz) δ 2.24 (s, 6H), 2.28 (s, 6H), 2.73 (d, 1H, J = 6.5 Hz), 2.76 (d, 1H, J = 6.5 Hz), 3.67 (s, 3H), 3.71 (s, 3H) 3.77 (s, 1H), 3.87 (s, 3H), 6.98 (s, 2H), 7.08-7.12 (m, 1H), 7.11 (s, 2H), 7.20-7.23 (m, 2H), 7.28-7.32 (m, 2H), 7.49-7.52 (m, 2H), 7.82-7.86 (m, 2H), 8.44 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.28, 16.31, 35.46, 46.55, 52.20, 59.58, 246 59.64, 75.49, 82.25, 87.09, 119.98, 124.56, 126.75, 127.38, 127.78, 129.01, 129.33, 129.77, 130.93, 131.21, 131.74, 136.37, 136.63, 136.93, 156.24, 156.58, 165.32, 166.35; IR (thin film) -1 3353br m, 2951s, 1725s, 1530s, 1445s, 1277s, 1223s, 1019s cm ; HRMS (ESI+) m/z calcd for + 20 C38H39N2O5 (M+H ) 603.2859, meas 603.2845. [α] D +34.9 (c = 1.0, CH2Cl2) on 96% ee (2S,3S)-152f from (S)-VANOL. (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((4-nitrophenyl)ethynyl)-N-phenylaziridi ne-2-carboxamide 152g: The reaction of 135g (91 mg, 0.20 mmol) and diazoacetamide 148 (45 1 mg, 0.28 mmol) was performed according to the general procedure (Procedure G). The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 25:1. The major product was purified by column chromatography on silica gel (30 mm x 300 mm, EtOAc/hexanes 1:4 to 1:3) to afford 152g as a light yellow foamy solid (107 mg, 0.182 mmol, 91%). The optical purity of 152g was determined to be 95% ee by HPLC (Chiralpak AD column, 222 nm, 80:20 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 8.77 min for (2R,3R)-152g (minor) and Rt = 47.72 min for (2S,3S)-152g (major). A repeat of the reaction gave an 89% yield of 152g 1 with 96% ee; mp 80-83 °C; Rf = 0.20 (1:2 EtOAc/hexanes). Spectral data for 152g: H NMR (CDCl3, 500 MHz) δ 2.45 (s, 6H), 2.29 (s, 6H), 2.77 (s, 2H), 3.68 (s, 3H), 3.71 (s, 3H), 3.78 (s, 1H), 6.99 (s, 2H), 7.10 (s, 2H), 7.10-7.14 (m, 1H), 7.25-7.29 (m, 2H), 7.29-7.33 (m, 2H), 247 7.50-7.53 (m, 2H), 8.01-8.05 (m, 2H), 8.43 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.30, 16.33, 35.21, 46.67, 59.59, 59.66, 75.50, 81.03, 89.57, 119.79, 123.45, 124.66, 127.35, 127.74, 128.90, 129.10, 131.00, 131.31, 132.57, 136.24, 136.48, 136.90, 147.19, 156.31, 156.65, 165.07; IR (thin -1 film) 3351br m, 2930s, 1696s, 1595s, 1522s, 1445s, 1345s, 1223s, 1013s cm ; HRMS (ESI+) + 20 m/z calcd for C36H36N3O5 (M+H ) 590.2655, meas 590.2652. [α] D +38.4 (c = 1.0, CH2Cl2) on 95% ee (2S,3S)-152g from (S)-VANOL. (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-phenyl-3-(m-tolylethynyl)aziridine-2-ca rboxamide 152h: The reaction of 135h (85 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 1 0.28 mmol) was performed according to the general procedure (Procedure G). The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 33:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:6) to afford 152h as a white foamy solid (99 mg, 0.177 mmol, 89%). The optical purity of 152h was determined to be 96% ee by HPLC (Chiralpak AD column, 222 nm, 85:15 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 9.35 min for (2R,3R)-152h (minor) and Rt = 16.21 min for (2S,3S)-152h (major). A repeat of the reaction gave a 90% yield of 152h with 96% ee; mp 1 68-72 °C; Rf = 0.30 (1:2 EtOAc/hexanes). Spectral data for 152h: H NMR (CDCl3, 500 MHz) δ 2.16 (s, 3H), 2.24 (s, 6H), 2.29 (s, 6H), 2.69 (d, 1H, J = 6.5 Hz), 2.73 (d, 1H, J = 6.5 Hz), 3.68 248 (s, 3H), 3.71 (s, 3H), 3.76 (s, 1H), 6.93 (s, 1H), 6.98 (s, 2H), 7.00-7.08 (m, 3H), 7.08 -7.12 (m, 1H), 7.12 (s, 2H), 7.28-7.32 (m, 2H), 7.51-7.54 (m, 2H), 8.46 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.29, 16.31, 21.01, 35.74, 46.44, 59.58, 59.64, 75.47, 83.27, 83.63, 120.09, 121.91, 124.39, 127.43, 127.82, 128.04, 128.77, 128.93, 129.36, 130.86, 131.14, 132.59, 136.52, 136.77, 137.09, 137.86, 156.17, 156.51, 165.62; IR (thin film) 3355br m, 2928s, 1686s, 1528s, 1445s, -1 + 1223s, 1013s cm ; HRMS (ESI+) m/z calcd for C37H39N2O3 (M+H ) 559.2961, meas 20 559.2941. [α] D +35.2 (c = 1.0, CH2Cl2) on 96% ee (2S,3S)-152h from (S)-VANOL. (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-phenyl-3-(o-tolylethynyl)aziridine-2-car boxamide 152i: The reaction of 135i (85 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 0.28 1 mmol) was performed according to the general procedure (Procedure G). The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 33:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:6) to afford 152i as a white foamy solid (106 mg, 0.190 mmol, 95%). The optical purity of 152i was determined to be 95% ee by HPLC (Chiralpak AD column, 222 nm, 85:15 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 10.84 min for (2R,3R)-152i (minor) and Rt = 21.46 min for (2S,3S)-152i (major). A repeat of the reaction gave a 90% yield of 152i with 96% ee; mp 68-73 1 °C; Rf = 0.29 (1:2 EtOAc/hexanes). Spectral data for 34i: H NMR (CDCl3, 500 MHz) δ 2.20 (s, 249 3H), 2.24 (s, 6H), 2.29 (s, 6H), 2.71 (d, 1H, J = 6.5 Hz), 2.80 (d, 1H, J = 6.5 Hz), 3.67 (s, 3H), 3.71 (s, 3H), 3.77 (s, 1H), 6.99 (s, 2H), 6.99-7.03 (m, 1H), 7.05-7.09 (m, 2H), 7.13-7.17 (m, 1H), 7.14 (s, 2H), 7.20 (dd, 1H, J = 8.0, 1.5 Hz), 7.25-7.29 (m, 2H), 7.47-7.50 (m, 2H), 8.48 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.28, 16.31, 20.44, 36.00, 46.52, 59.59, 59.65, 75.51, 81.98, 87.71, 119.83, 121.93, 124.31, 125.40, 127.35, 127.83, 128.50, 128.90, 129.28, 130.87, 131.18, 132.32, 136.59, 136.84, 137.11, 140.53, 156.16, 156.54, 165.47; IR (thin film) 3353br m, 2967s, -1 + 1696s, 1530s, 1445s, 1223s, 1013s cm ; HRMS (ESI+) m/z calcd for C37H39N2O3 (M+H ) 20 559.2961, meas 559.2949. [α] D +30.1 (c = 1.0, CH2Cl2) on 95% ee (2S, 3S)-152i from (S)-VANOL. (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(naphthalen-1-ylethynyl)-N-phenylazirid ine-2-carboxamide 152j: The reaction of 135j (92 mg, 0.20 mmol) and diazoacetamide 148 (45 1 mg, 0.28 mmol) was performed according to the general procedure (Procedure G). The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 25:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:4) to afford 152j as an off-white foamy solid (113 mg, 0.190 mmol, 95%). The optical purity of 152j was determined to be 97% ee by HPLC (Chiralpak AD column, 222 nm, 85:15 Hexane/2-PrOH, 250 flow rate: 0.7 mL/min). Retention time: Rt = 9.03 min for (2R,3R)-152j (minor) and Rt = 26.87 min for (2S,3S)-152j (major). A repeat of the reaction gave a 94% yield of 152j with 99% ee; mp 1 83-88 °C; Rf = 0.24 (1:2 EtOAc/hexanes). Spectral data for 152j: H NMR (CDCl3, 500 MHz) δ 2.26 (s, 6H), 2.30 (s, 6H), 2.80 (d, 1H, J = 6.5 Hz), 2.91 (d, 1H, J = 6.5 Hz), 3.68 (s, 3H), 3.72 (s, 3H), 3.83 (s, 1H), 7.03 (s, 2H), 7.06-7.11 (m, 1H), 7.11 -7.14 (m, 1H), 7.19 (s, 2H), 7.26-7.32 (m, 3H), 7.37-7.41 (m, 1H), 7.48 (dd, 1H, J = 7.5, 1.5 Hz), 7.53-7.56 (m, 2H), 7.76 (d, 2H, J = 8.5 Hz), 8.07 (dd, 1H, J = 8.5, 1.0 Hz), 8.59 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.29, 16.33, 36.07, 46.68, 59.59, 59.66, 75.58, 81.30, 88.70, 119.77, 119.96, 124.36, 125.00, 125.91, 126.35, 126.71, 127.39, 127.84, 128.08, 128.97, 129.01, 130.93, 131.07, 131.22, 132.92, 133.18, 136.58, 136.84, 137.16, 156.21, 156.57, 165.51; IR (thin film) 3349br m, 2930s, 1684s, 1528s, -1 + 1445s, 1223s, 1013s cm ; HRMS (ESI+) m/z calcd for C40H39N2O3 (M+H ) 595.2961, meas 20 595.2944. [α] D +46.8 (c = 1.0, CH2Cl2) on 97% ee (2S,3S)-152j from (S)-VANOL. (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(hex-1-yn-1-yl)-N-phenylaziridine-2-car boxamide 152k: The reaction of 135k (78 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 0.28 mmol) was performed according to the general procedure (Procedure G) except that the 1 temperature was –20 °C. The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 25:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:6) to afford 152k as a white foamy solid (86 mg, 0.164 mmol, 82%). 251 The optical purity of 152k was determined to be 97% ee by HPLC (Chiralpak AD column, 222 nm, 80:20 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 10.05 min for (2S,3S)-152k (major) and Rt = 40.11 min for (2R,3R)-152k (minor). A repeat of the reaction gave an 81% yield of 152k with 98% ee; mp 125-127 °C; Rf = 0.32 (1:2 EtOAc/hexanes). 1 Spectral data for 152k: H NMR (CDCl3, 500 MHz) δ 0.73 (t, 3H, J = 7.5 Hz), 1.22-1.30 (m, 4H), 2.07 (t, 2H, J = 6.5 Hz), 2.22 (s, 6H), 2.28 (s, 6H), 2.51 (dt, 1H, J = 6.5, 1.5 Hz), 2.53 (d, 1H, J = 6.5 Hz), 3.66 (s, 4H), 3.71 (s, 3H), 6.95 (s, 2H), 7.06-7.10 (m, 1H), 7.08 (s, 2H), 7.28-7.32 (m, 2H), 7.48-7.51 (m, 2H), 8.39 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 13.42, 16.25, 16.26, 18.29, 21.67, 30.41, 35.70, 45.89, 59.57, 59.63, 74.64, 75.38, 84.01, 119.80, 124.19, 127.39, 127.84, 128.88, 130.73, 131.06, 136.68, 136.91, 137.22, 156.08, 156.44, 165.80; IR (thin -1 film) 3353br m, 2930s, 2865m, 1686s, 1530s, 1445s, 1223s, 1017s cm ; HRMS (ESI+) m/z + 20 calcd for C34H41N2O3 (M+H ) 525.3117, meas 525.3092. [α] D –0.7 (c = 1.0, CH2Cl2) on 97% ee (2S,3S)-152k from (S)-VANOL. (2S,3S)-1-Bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(cyclohexylethynyl)-N-phenylaziridine-2carboxamide 152l: The reaction of 135l (83 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 0.28 mmol) was performed according to the general procedure (Procedure G) except that the 1 temperature was –20 °C. The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 25:1. The major product was purified by column chromatography on silica gel (30 mm x 252 350 mm, EtOAc/hexanes 1:6 to 1:5) to afford 152l as a white foamy solid (92 mg, 0.167 mmol, 84%). The optical purity of 152l was determined to be 97% ee by HPLC (Chiralpak AD column, 222 nm, 80:20 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 9.82 min for (2S,3S)-152l (major) and Rt = 34.88 min for (2R,3R)-152l (minor). The same reaction at –40 °C for 4 h gave a 78% yield of 152l with 99% ee and >100:1 cis/trans selectivity after 81% 1 conversion; mp 140-145 °C; Rf = 0.18 (1:4 EtOAc/hexanes). Spectral data for 152l: H NMR (CDCl3, 500 MHz) δ 1.16-1.56 (m, 11H), 2.22 (s, 6H), 2.28 (s, 6H), 2.51 (dd, 1H, J = 6.5, 1.5 Hz), 2.54 (d, 1H, J = 6.5 Hz), 3.66 (s, 3H), 3.68 (s, 1H), 3.71 (s, 3H), 6.94 (s, 2H), 7.05-7.09 (m, 3H), 7.27-7.31 (m, 2H), 7.49-7.52 (m, 2H), 8.40 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.25, 16.27, 24.25, 25.76, 28.58, 32.15, 32.19, 35.75, 45.85, 59.58, 59.65, 74.81, 75.23, 87.98, 119.68, 124.14, 127.40, 127.89, 128.84, 130.71, 131.06, 136.70, 136.92, 137.22, 156.05, 156.45, 165.82 3 -1 (1 sp C not located); IR (thin film) 3353br m, 2930s, 1686s, 1528s, 1445s, 1223s, 1013s cm ; + 20 HRMS (ESI+) m/z calcd for C36H43N2O3 (M+H ) 551.3274, meas 551.3279. [α] D +3.0 (c = 1.0, CH2Cl2) on 97% ee (2S,3S)-152l from (S)-VANOL. (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(3,3-dimethylbut-1-yn-1-yl)-N-phenylazi ridine-2-carboxamide 152m: The reaction of 135m (78 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 0.28 mmol) was performed according to the general procedure (Procedure G) except that 253 1 the temperature was –20 °C and the time was 24 h. The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 4:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:6) to afford 152m as a white foamy solid (81 mg, 0.154 mmol, 77%). The optical purity of 152m was determined to be 91% ee by HPLC (Chiralpak AD column, 222 nm, 90:10 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 10.94 min for (2S,3S)-152m (major) and Rt = 30.61 min for (2R,3R)-152m (minor). A repeat of the reaction gave a 78% yield of 152m with 91% ee; mp 66-71 °C; Rf = 0.30 (1:2 1 EtOAc/hexanes). Spectral data for 152m: H NMR (CDCl3, 500 MHz) δ 1.03 (s, 9H), 2.22 (s, 6H), 2.28 (s, 6H), 2.47 (d, 1H, J = 6.5 Hz), 2.54 (d, 1H, J = 6.5 Hz), 3.67 (s, 3H), 3.70 (s, 1H), 3.71 (s, 3H), 6.94 (s, 2H), 7.05-7.09 (m, 1H), 7.08 (s, 2H), 7.28-7.32 (m, 2H), 7.50-7.53 (m, 2H), 8.38 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.25, 16.26, 27.26, 30.69, 35.60, 45.69, 59.57, 59.66, 73.21, 75.01, 92.23, 119.67, 124.15, 127.43, 127.96, 128.86, 130.68, 131.05, 136.67, 136.88, 137.14, 156.01, 156.46, 165.84; IR (thin film) 3353br m, 2967s, 1696s, 1530s, 1445s, -1 + 1223s, 1015s cm ; HRMS (ESI+) m/z calcd for C34H41N2O3 (M+H ) 525.3117, meas 20 525.3098. [α] D –6.4 (c = 1.0, CH2Cl2) on 91% ee (2S,3S)-152m from (S)-VANOL. (2S,3S)-1-(Bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-butyl-3-(phenylethynyl)aziridine-2-carb 27a oxamide 155c: The reaction of 135c (82 mg, 0.20 mmol) and diazoacetamide 154 254 (40 mg, 1 0.28 mmol) was performed according to the general procedure (Procedure G). The H NMR spectrum of the crude reaction mixture gave cis/trans ratio of 33:1. The major product was purified by column chromatography on silica gel (30 mm x 350 mm, EtOAc/hexanes 1:3) to afford 155c as an off-white foamy solid (88 mg, 0.168 mmol, 84%). The optical purity of 155c was determined to be 94% ee by HPLC (Chiralpak AD column, 222 nm, 85:15 Hexane/2-PrOH, flow rate: 0.7 mL/min). Retention time: Rt = 8.19 min for (2R,3R)-155c (minor) and Rt = 13.53 min for (2S,3S)-155c (major). mp 50-55 °C; Rf = 0.32 (1:1 EtOAc/hexanes). Spectral data for 1 155c: H NMR (CDCl3, 500 MHz) δ 0.78 (t, 3H, J = 6.5 Hz), 1.19-1.28 (m, 2H), 1.35-1.48 (m, 2H), 2.22 (s, 6H), 2.27 (s, 6H), 2.55 (d, 1H, J = 6.5 Hz), 2.63 (d, 1H, J = 6.5 Hz), 3.15-3.23 (m, 1H), 3.24-3.31 (m, 1H), 3.66 (s, 1H), 3.68 (s, 3H), 3.70 (s, 3H), 6.68 (t, 1H, J = 6.0 Hz), 6.92 (s, 2H), 7.09 (s, 2H), 7.25-7.32 (m, 3H), 7.35-7.38 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.67, 16.20, 16.29, 19.94, 31.95, 35.42, 38.65, 46.10, 59.57, 59.63, 75.68, 82.65, 84.47, 122.48, 127.42, 127.82, 128.26, 128.47, 130.74, 130.93, 131.84, 136.78, 136.96, 156.09, 156.41, 167.13; IR (thin -1 film) 3401br m, 2930s, 1676s, 1530s, 1489s, 1223s, 1013s cm ; HRMS (ESI+) m/z calcd for + 20 C34H41N2O3 (M+H ) 525.3117, meas 525.3102. [α] D +59.5 (c = 1.0, CH2Cl2) on 94% ee (2S,3S)-155c from (S)-VANOL. 6.1.7 Detemination of the absolute configurations of cis-aziridines from diazoacetamides 255 Conversion of the cis-amide aziridine 152c to the cis-ester aziridine 138c 27a,26o (2S,3S)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(phenylethynyl)aziridine-2-carbox ylate 138c: To a 25 mL flame dried round bottom flask charged with N2 were added the cis-aziridine (2S,3S)-152c (56 mg, 0.103 mmol, 94% ee), dry CH3CN (4.5 mL), and dry CH2Cl2 (0.5 mL). The flask was then fitted with a rubber septum and a N2 balloon. This was followed by the addition of DMAP (26 mg, 0.213 mmol) and di-tert-butyl dicarbonate (68 mg, 0.312 mmol). The reaction mixture was then stirred at room temperature for 12 h. The reaction mixture was then subjected to rotary evaporation to afford a yellow oil, which was loaded onto a silica gel chromatography column (20 mm × 200 mm, 1:5 EtOAc/hexanes) to afford the intermediate product as a white foamy solid. Rf = 0.16 (1:4 EtOAc/hexanes). This intermediate was added to a 25 mL round bottom flask fitted with a magnetic stir bar and then EtOH (2 mL) was added. The flask was fitted with a rubber septum and a N2 balloon and the solution was cooled to 0 °C in an ice bath, and then NaOEt (21 wt% solution of NaOEt in EtOH, 77 µL, 0.206 mmol) was added. This reaction mixture was stirred at 0 °C for 1 h. The reaction was then quenched by the addition of NH4Cl (sat. aq. 1mL) and the reaction mixture was concentrated by rotary evaporation. This was followed by the addition of water (1 mL) and the mixture was extracted with CH2Cl2 (5 mL x 3). The organic layers were combined, dried over Na2SO4, filtered through a pad of Celite and 256 the solvents removed. Purification of the major product by silica gel chromatography (20 mm × 200 mm, 1:12 EtOAc/hexanes) afforded the cis-ester aziridine 138c (40 mg, 0.080 mmol, 80%). The optical purity of 138c was determined to be 94% ee by HPLC (Chiralcel OD-H column, 225 nm, 99:1 Hexane/2-PrOH, flow rate: 1 mL/min). Retention time: Rt = 8.37 min for 20 (2R,3R)-21c (major) and Rt = 10.59 min for (2S,3S)-138c (minor). [α] D +59.5 (c = 1.0, CH2Cl2) on 94% ee (2S,3S)-138c. Conversion of the aziridine 138c to the aziridine 156 by alkyne reduction (2S,3S)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenethylaziridine-2-carboxylate 156: A flame dried 10 mL round bottom flask was charged with (2S,3S)-138c (25 mg, 0.050 mmol), Pearlman’s catalyst (20% Pd(OH)2 on carbon, moisture ca 60%, 9 mg, 0.005 mmol) and EtOAc (1 mL) under N2. The flask was equipped with a 3-way valve connected with vacuum and a H2 balloon. The valve to vacuum was opened for a few seconds and switched to the H2 balloon. This process was repeated 3 additional times. The suspension was stirred under a H2 balloon for 24 h. Then the mixture was filtered through a Celite pad on a sintered glass funnel and washed well with EtOAc. The filtrate was concentrated by rotary evaporation. Purification of the major product by silica gel chromatography (20 mm × 300 mm, 1:15 EtOAc/hexanes) afforded the cis-aziridine 156 as a colorless oil (16 mg, 0.032 mmol, 64%). Rf = 0.27 (1:4 1 EtOAc/hexanes). Spectral data for 156: H NMR (CDCl3, 500 MHz) δ 1.23 (t, 3H, J = 7.0 Hz), 1.80-1.92 (m, 2H), 1.95 (q, 1H, J = 7.0 Hz), 2.19 (d, 1H, J = 7.0 Hz) 2.22 (s, 6H), 2.25 (s, 6H), 2.28-2.33 (m, 1H), 2.45-2.52 (m, 1H), 3.39 (s, 1H), 3.66 (s, 3H), 3.67 (s, 3H), 4.11-4.20 (m, 2H), 257 6.89 (d, 2H, J = 7.5 Hz), 7.06 (s, 2H), 7.08 (s, 2H), 7.10-7.13 (m, 1H), 7.16-7.20 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.32, 16.15, 16.18, 29.60, 33.26, 43.36, 46.15, 59.58, 59.64, 60.76, 77.26, 125.72, 127.27, 128.07, 128.17, 128.39, 130.54, 130.62, 137.77, 138.30, 141.37, 155.80, 20 26m 156.22, 169.57. [α] D = –58.9 (c = 1.0, EtOAc) on 94% ee material; lit. 20 [α] D –62.3 (c = 1.0, EtOAc) on 96 % ee material. A 25 mL pear-shaped single necked Schlenk flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it) and cooled to room temperature under N2 and charged with (S)-VAPOL (54 mg, 0.10 mmol) and triphenyl borate (116 mg, 0.40 mmol). The mixture was dissolved in 2 mL distilled toluene. After the addition of H2O (1.8 µL, 0.10 mmol), the Teflon valve was closed and the flask was heated at 80 °C for 1 h. Toluene was carefully removed by exposing to high vacuum (0.1 mm Hg) by slightly cracking the Teflon valve. After removal of the volatile, the Teflon valve was completely opened and the flask was heated to 80 °C under high vacuum (0.5 mm Hg) for 30 min. To the Schlenk flask containing the catalyst were added benzhydryl phenyl imine (27.1 mg, 0.10 mmol) and dry ether (2 mL). The reaction mixture was stirred at room temperature for 5 minutes. At the same time, to 258 a flame dried 25 mL round bottom flask was added aziridine 139c (266 mg, 0.4 mmol) under N2. The VAPOL-BOROX catalyst solution (0.8 mL) in the Schlenk flask was then transferred to the flask. The resulting mixture was stirred at room temperature for 5 min and then ethyl diazoacetate (50 µL, 0.48 mmol) was added via syring. The reaction mixture was stirred at room temperature for 24 h. The mixture was then diluted with hexanes (5 mL). Rotary evaporation of the solvent followed by exposure to high vacuum (0.5 mm Hg) for 30 minutes gave the crude 1 mixture as a yellow amorphous solid. The H NMR of the crude mixture didn’t show any [3+2] cycloaddtion product 144c. 259 6.2 Experimental for chapter three 6.2.1 Preparation of boronic acids General procedure for the preparation of boronic acids – illustrated for the synthesis of (3,5-di-tert-butyl-4-methoxyphenyl)boronic acid 198s (Procedure H) To a flame-dried 250 mL round bottom 80 flask was added 5-bromo-1,3-di-tert-butyl-2-methoxybenzene 197s (5.98 g, 20.0 mmol) and anhydrous THF (100 mL). The mixture was cooled to –78 °C and n-BuLi (2.5 M in hexanes, 8.4 mL, 21.0 mmol) was added dropwise. The resulting mixture was stirred at –78 °C for 1 h and then B(OMe)3 (5.60 mL, 50.2 mmol) was added all at once. The mixture was warmed up to room temperature and stirred overnight. H2O (80 mL) was added to the mixture. The mixture was acidified with 10% HCl to pH 3-5. The organic layer was separated and the aqueous layer was extracted with ether (80 mL x 2). The combined organic layer was washed with brine (25 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Petroleum ether (50 mL) was added to the residue. After filtration through filter paper, the product was obtained as a white solid (1.66 g, 6.29 mmol, 1 31% yield). Spectral data for 198s: H NMR (CDCl3, 500 MHz) δ 1.50 (s, 18H), 3.74 (s, 3H), 8.15 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 32.00, 35.73, 64.37, 134.14, 143.30, 163.80 (1 sp C not located). 260 2 81 anthracene-9-boronic acid 198x: The reaction of 9-bromoanthracene 197x (5.14 g, 20.0 mmol) with n-BuLi (2.5 M in hexanes, 8.4 mL, 21.0 mmol) and B(OMe)3 (5.60 mL, 50.2 mmol) was performed according to the general procedure (Procedure A). Purification of the crude product by column chromatography on silica gel (50 mm x 200 mm, CH2Cl2/hexanes 1:1, then acetone/hexanes 1:3) gave 198x as a yellow solid (2.34 g, 10.5 mmol, 53%). Spectral data for 1 198x: H NMR (DMSO-d6, 500 MHz) δ 7.46-7.52 (m, 4H), 7.98-8.01 (m, 2H), 8.04-8.07 (m, 2H), 8.51 (s, 1H), 8.77 (br s, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 124.89, 125.05, 125.84, 2 128.35, 128.99, 130.73, 132.70 (1 sp C not located). 6.2.2 Preparation of 4-substituted-phenylacetic acids 74 4-iodophenylacetic acid 191e: To a 500 mL round bottom flask was added 4-aminophenylacetic acid 190 (15.1 g, 100 mol), H2O (150 mL) and H2SO4 (20 mL). To the resulting mixture was added a solution of NaNO2 (8.28 g, 120 mmol) in H2O (30 mL). The mixture was stirred at 0 °C for 30 min prior to the addition of a cooled solution of KI (33.2 g, 261 200 mmol) in H2O (120 mL). The reaction was stirred at 0 °C for 2.5 h. The mixture was extracted with EtOAc (150 mL x 4). The combined organic layer was 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 1:1, then acetone/hexanes 1:3) 74 gave 191e as a yellow solid (15.9 g, 60.7 mmol, 61%). mp 137-138 °C (lit. mp 138-140 °C); 1 Rf = 0.20 (1:3 acetone:hexanes). Spectral data for 191e: H NMR (CDCl3, 500 MHz) δ 3.57 (s, 2H), 6.99-7.03 (m, 2H), 7.62-7.66 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 40.46, 92.96, 131.34, -1 132.76, 137.75, 177.17; IR (thin film) 1698s, 1487s, 1406s cm . 75 4-t-butylacetophenone 193: 74 compound: The following procedure was adapted from one for a related To a flame-dried 500 mL round bottom flask was added AlCl3 (147 g, 1.1 mol) and CS2 (200 mL). To the stirred mixture was added a solution of t-butylbenzene (155 mL, 1.0 mol), acetyl chloride (71.1 mL, 1.0 mol) in CS2 (100 mL) at 0 °C. After stirring at 0 °C for 2 h, the mixture was refluxed overnight. The mixture was cooled to room temperature and poured into a mixture of ice (600 g) and H2SO4 (40 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Vacuum distillation (94 °C at 1 mm Hg) gave 193 as a clear colorless oil (160 g, 0.91 mol, 91%). Spectral 1 data for 193: H NMR (CDCl3, 500 MHz) δ 1.32 (s, 9H), 2.57 (s, 3H), 7.44-7.48 (m, 2H), 262 7.86-7.90 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 26.52, 31.06, 35.07, 125.48, 128.26, 134.60, 156.80, 197.84; IR (thin film) 2965s, 1684s, 1406s, 1360s, 1271s, 1113s cm 76 4-tert-butyl-phenylacetic acid 191m: -1 . The following procedure was adapted from one for a related compound:7 To a 1 L round bottom flask was added 4-tert-butylacetophenone 193 (26.4 g, 150 mmol), morpholine (45 mL, 0.5 mol), sulfur (9.6 g, 0.3 mol) and p-toluene sulfonic acid monohydrate (0.4 g, 2 mmol). The mixture was stirred at 125 ºC for 10 h. After cooling down to room temperature, alcoholic KOH (3M, 250 mL) was added and the mixture was stirred at 110 ºC overnight. After cooling down to room temperature, H2O (200 mL) was added to the mixture. The mixture was acidified with 6N HCl to pH 2. CH2Cl2 (300 mL) was added to the mixture and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (100 mL x 2). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm column, CH2Cl2/hexanes 1:3, then CH2Cl2, and then acetone/hexanes 1:3 as eluent) gave 191m as an off-white solid (25.2 g, 132 mmol, 88%). mp 77-79 °C; Rf = 0.20 (CH2Cl2). Spectral 1 data for 191m: H NMR (CDCl3, 500 MHz) δ 1.30 (s, 9H), 3.61 (s, 2H), 7.19-7.22 (m, 2H), 7.33-7.36 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 31.31, 34.47, 40.50, 125.59, 129.01, 130.19, -1 150.24, 177.88; IR (thin film) 2957s, 1715s, 1520s, 1458s, 1402s cm . 263 6.2.3 Preparation of 7-substituted-3-phenyl-1-naphthols General procedure for the preparation of 7-substituted-3-phenyl-1-naphthols – illustrated for the synthesis of 7-bromo-3-phenyl-1-naphthol 175d (Procedure I) 13g,73 A single-neck 500 mL round bottom flask equipped with a condenser was charged with 4-bromo-phenylacetic acid 191d (19.35 g, 90 mmol), and SOCl2 (24 mL, 329 mmol). 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 phenylacetylene (13.2 mL, 120 mmol) and (i-PrCO)2O (30 mL, 181 mmol) 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. 60 °C, oil bath temperature) and a solution of KOH (30 g, 536 mmol) in H2O (120 mL) was then added slowly. This two-phase mixture was stirred at 100 °C overnight. The mixture was cooled to room temperature and ethyl acetate (200 mL) was added and the mixture stirred for 10 min before the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (100 mL × 3) and the combined organic layer was washed with brine (100 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography 264 on silica gel (50 mm × 250 mm, CH2Cl2:hexanes 1:3 to 1:2 to 1:1 to 1:0) gave 175d as an off-white solid (17.94 g, 60.0 mmol, 67%). mp 94-95 °C; Rf = 0.33 (CH2Cl2). Spectral data for 1 175d: H NMR (CDCl3, 500 MHz) δ 5.24 (s, 1H), 7.07 (d, 1H, J = 1.5 Hz), 7.35-7.39 (m, 1H), 7.43-7.47 (m, 2H), 7.56 (dd, 1H, J = 8.5, 1.5 Hz), 7.59 (s, 1H), 7.62-7.65 (m, 2H), 7.70 (d, 1H, J = 9.0 Hz), 8.35 (d, 1H, J = 1.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 109.28, 118.62, 119.30, 124.27, 124.65, 127.24, 127.69, 128.90, 129.59, 130.31, 133.36, 139.41, 140.49, 150.84; IR (thin -1 film) 3526br m, 3058w, 1590s, 1495s,1408s, 1248m cm ; mass spectrum, m/z (% rel intensity) + 300 M (90, 81 + Br), 298 M (100, 79 Br), 269 (3), 218 (8), 191 (58, 81 Br), 189 (68, 79 Br), 150 (18). Anal calcd for C16H11BrO: C, 64.24; H, 3.71. Found: C, 64.61; H, 3.65. 7-fluoro-3-phenylnaphthalen-1-ol 175b: The reaction of 4-fluoro-phenylacetic acid 191b (3.66 g, 23.8 mmol), SOCl2 (6.35 mL, 87 mmol), phenylacetylene (3.49 mL, 31.8 mmol) and (i-PrCO)2O (7.93 mL, 47.9 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:2 to 1:1 to 1:0) gave 175b as an off-white solid (3.66 g, 15.4 mmol, 1 65%). mp 82-84 °C; Rf = 0.28 (CH2Cl2). Spectral data for 175b: H NMR (CDCl3, 500 MHz) δ 5.21 (s, 1H), 7.09 (s, 1H), 7.27 (td, 1H, J = 8.5, 2.5 Hz), 7.34-7.38 (m, 1H), 7.43-7.47 (m, 2H), 7.62-7.66 (m, 3H), 7.78 (dd, 1H, J = 10.0, 2.5 Hz), 7.83 (dd, 1H, J = 9.0, 5.5 Hz); 265 13 C NMR 2 2 4 (CDCl3, 125 MHz) δ 105.59 ( J CF = 22.6 Hz), 109.11, 117.25 ( J CF = 25.3 Hz), 118.61 ( J CF 3 2 3 = 1.4 Hz), 124.25 ( J CF = 8.9 Hz), 127.35 ( J CF = 36.9 Hz), 128.86, 130.35 ( J CF = 8.9 Hz), 4 1 131.92, 138.13 ( J CF = 2.8 Hz), 140.60, 151.19, 151.23, 160.42 ( J CF = 244.5 Hz); 19 F NMR -1 (CDCl3, 283 Hz) δ –112.77; IR (thin film) 3528br s, 3063m, 1501s, 1414s, 1244s cm ; mass + spectrum, m/z (% rel intensity) 238 M (100), 209 (73), 183 (29), 157 (6). Anal calcd for C16H11OF: C, 80.66; H, 4.65. Found: C, 80.65; H, 4.60. 7-chloro-3-phenylnaphthalen-1-ol 175c: The reaction of 4-chloro-phenylacetic acid 191c (10.10 g, 59.2 mmol), SOCl2 (15.8 mL, 217 mmol), phenylacetylene (8.8 mL, 80 mmol) and (i-PrCO)2O (19.7 mL, 119 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:1 to 1:0) gave 175c as a white solid (10.73 g, 42.1 mmol, 71%). mp 1 94.5-95.5 °C; Rf = 0.33 (CH2Cl2). Spectral data for 175c: H NMR (CDCl3, 500 MHz) δ 5.27 (s, 1H), 7.07 (d, 1H, J = 1.0 Hz), 7.35-7.39 (m, 1H), 7.42-7.48 (m, 3H), 7.60 (s, 1H), 7.62-7.65 (m, 2H), 7.76 (dd, 1H, J = 8.0, 0.5 Hz), 8.17 (d, 1H, J = 1.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 109.26, 118.54, 120.96, 124.18, 127.23, 127.65, 127.82, 128.89, 129.52, 131.15, 133.15, 139.20, -1 140.47, 150.92; IR (thin film) 3308br s, 1593s, 1497s, 1410s, 1275s cm ; HRMS (ESI–) m/z 35 + calcd for C16H10 ClO (M-H ) 253.0420, meas 253.0423. 266 7-iodo-3-phenylnaphthalen-1-ol 175e: The reaction of 4-iodo-phenylacetic acid 191e (15.72 g, 60.0 mmol), SOCl2 (16 mL, 219 mmol), phenylacetylene (8.8 mL, 80 mmol) and (i-PrCO)2O (20 mL, 120 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:1 to 1:0) gave 175e as a yellow solid (10.76 g, 31.0 mmol, 52%). mp 1 95-97 °C; Rf = 0.31 (CH2Cl2). Spectral data for 175e: H NMR (CDCl3, 500 MHz) δ 5.23 (s, 1H), 7.06 (d, 1H, J = 1.5 Hz), 7.35-7.39 (m, 1H), 7.43-7.47 (m, 2H), 7.56 (d, 1H, J = 8.5 Hz), 7.60 (s, 1H), 7.62-7.65 (m, 2H), 7.73 (dd, 1H, J = 8.5, 1.5 Hz), 8.56-8.58 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 90.62, 109.14, 118.63, 125.09, 127.24, 127.71, 128.89, 129.49, 130.86, 133.61, 135.47, 139.62, 140.48, 150.62; IR (thin film) 3526br s, 3056m, 1581s, 1493s, 1406s, -1 + 1248s cm ; mass spectrum, m/z (% rel intensity) 346 M (76), 218 (7), 189 (71), 173 (44), 165 (24), 109 (15), 94 (100). Anal calcd for C16H11IO: C, 55.51; H, 3.20. Found: C, 55.52; H, 3.02. 7-methoxy-3-phenylnaphthalen-1-ol 175g: The reaction of 4-methoxy-phenylacetic acid 191g (12.46 g, 75.0 mmol), SOCl2 (20 mL, 274 mmol), phenylacetylene (11 mL, 100 mmol) and 267 (i-PrCO)2O (25 mL, 150 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:2 to 1:1 to 1:0) gave 175g as a yellow solid (9.35 g, 37.4 mmol, 50%). mp 1 81-82 °C; Rf = 0.16 (CH2Cl2). Spectral data for 175g: H NMR (CDCl3, 500 MHz) δ 3.95 (s, 3H), 5.24 (s, 1H), 7.06 (d, 1H, J = 1.5 Hz), 7.18 (dd, 1H, J = 9.0, 2.5 Hz), 7.31-7.36 (m, 1H), 7.41-7.46 (m, 3H), 7.59 (s, 1H), 7.62-7.65 (m, 2H), 7.75 (d, 1H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 55.42, 99.85, 108.84, 118.65, 119.75, 124.45, 127.11, 127.16, 128.79, 129.62, 130.45, 136.46, 140.94, 150.74, 157.50; IR (thin film) 3397br s, 2940m, 1597s, 1501s, 1401s, -1 + 1257s, 1213s cm ; mass spectrum, m/z (% rel intensity) 250 M (100), 235 (34), 207 (71), 178 (41), 176 (11), 152 (10), 125 (18). Anal calcd for C17H14O2: C, 81.58; H, 5.64. Found: C, 81.37; H, 5.59. 7-methyl-3-phenylnaphthalen-1-ol 175h: The reaction of 4-methyl-phenylacetic acid 191h (11.25 g, 75 mmol), SOCl2 (20 mL, 274 mmol), phenylacetylene (11 mL, 100 mmol) and (i-PrCO)2O (25 mL, 150 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:2 to 1:1 to 1:0) gave 175h as a yellow solid (9.88 g, 42.2 mmol, 56%). 1 mp 91-92 °C; Rf = 0.30 (CH2Cl2). Spectral data for 175h: H NMR (CDCl3, 500 MHz) δ 2.54 (s, 3H), 5.23 (s,1H), 7.05 (d, 1H, J = 1.5 Hz), 7.33-7.37 (m, 2H), 7.42-7.47 (m, 2H), 7.60 (s, 1H), 268 7.64-7.67 (m, 2H), 7.75 (d, 1H, J = 8.5 Hz), 7.92 (d, 1H, J = 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 21.91, 108.46, 118.61, 120.31, 123.61, 127.22, 127.29, 127.94, 128.79, 129.14, 133.23, 135.15, 137.90, 141.00, 151.18; IR (thin film) 3335br s, 3054m, 2919w, 1572s, 1501s, 1410s, -1 + 1258s cm ; mass spectrum, m/z (% rel intensity) 234 M (30), 191 (17), 165 (5). Anal calcd for C17H14O: C, 87.15; H, 6.02. Found: C, 87.00; H, 6.05. 7-isopropyl-3-phenylnaphthalen-1-ol 175k: The reaction of 4-isopropyl-phenylacetic acid 191k (14.79 g, 83.1 mmol), SOCl2 (22.1 mL, 303 mmol), phenylacetylene (12.2 mL, 111 mmol) and (i-PrCO)2O (27.6 mL, 167 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:1 to 1:0) gave 175k as an off-white solid (13.19 g, 50.3 1 mmol, 61%). mp 100-101 °C; Rf = 0.42 (CH2Cl2). Spectral data for 175k: H NMR (CDCl3, 500 MHz) δ 1.36 (d, 6H, J = 7.0 Hz), 3.07-3.14 (m, 1H), 5.32 (s, 1H), 7.05 (d, 1H, J = 1.5 Hz), 7.33-7.38 (m, 1H), 7.42-7.47 (m, 3H), 7.62 (s, 1H), 7.64-7.67 (m, 2H), 7.80 (d, 1H, J = 8.5 Hz), 7.97 (d, 1H, J = 0.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 23.96, 34.47, 108.40, 117.59, 118.57, 123.57, 126.74, 127.22, 127.28, 128.08, 128.78, 133.61, 137.99, 141.00, 146.09, 151.41; IR (thin -1 film) 3225br s, 2955s, 1496s, 1398s, 1254s cm ; HRMS (ESI+) m/z calculated for C19H19O + (M+H ) 263.1436, found 263.1431. 269 7-(tert-butyl)-3-phenylnaphthalen-1-ol 175m: The reaction of 4-tert-butyl-phenylacetic acid 191m (13.44 g, 70.0 mmol), SOCl2 (18.7 mL, 256 mmol), phenylacetylene (10.3 mL, 94 mmol) and (i-PrCO)2O (23.4 mL, 141 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:1 to 1:0) gave 175m as an off-white solid (9.78 g, 35.4 1 mmol, 51%). mp 135-137 °C; Rf = 0.40 (CH2Cl2). Spectral data for 175m: H NMR (CDCl3, 500 MHz) δ 1.43 (s, 9H), 5.25 (s, 1H), 7.06 (d, 1H, J = 2.0 Hz), 7.32-7.37 (m, 1H), 7.42-7.47 (m, 2H), 7.59-7.62 (m, 2H), 7.64-7.67 (m, 2H), 7.80 (d, 1H, J = 8.5 Hz), 8.08-8.10 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 31.31, 35.10, 108.41, 116.25, 118.40, 123.31, 125.80, 127.24, 127.29, 127.81, 128.78, 133.22, 138.19, 141.06, 148.30, 151.66; IR (thin film) 3505br s, 2961s, -1 + 1601s, 1559s, 1458s, 1408s, 1273s cm ; mass spectrum, m/z (% rel intensity) 276 M (54), 261 (96), 233 (15), 202 (24), 189 (15), 165 (9), 130 (13), 116 (100). Anal calcd for C20H20O: C, 86.92; H, 7.29. Found: C, 86.92; H, 7.04. 270 3,7-diphenylnaphthalen-1-ol 175ag: The reaction of 4-phenyl-phenylacetic acid 191ag (15.92 g, 75 mmol), SOCl2 (20 mL, 274 mmol), phenylacetylene (11 mL, 100 mmol) and (i-PrCO)2O (25 mL, 150 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:2 to 1:1 to 1:0) gave 175ag as a yellow solid (14.42 g, 48.7 mmol, 1 65%). mp 202-207 °C; Rf = 0.38 (CH2Cl2). Spectral data for 175ag: H NMR (CDCl3, 500 MHz) δ 5.30 (s, 1H), 7.10 (d, 1H, J = 1.5 Hz), 7.35-7.39 (m, 2H), 7.45-7.50 (m, 4H), 7.66-7.70 (m, 3H), 7.74-7.80 (m, 3H), 7.92 (d, 1H, J = 8.5 Hz), 8.38 (d, 1H, J = 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 108.76, 118.55, 119.49, 123.81, 126.56, 127.26, 127.35, 127.41, 127.50, 128.58, 128.85, 2 134.13, 138.06, 138.96, 140.85, 141.15, 151.98 (1 sp C not located); IR (thin film) 3473br s, -1 + 1557s, 1507s, 1456s cm ; mass spectrum, m/z (% rel intensity) 296 M (100), 295 (10), 267 (11), 265 (10), 252 (8), 189 (11), 165 (6), 148 (21), 119 (7). Anal calcd for C22H16O: C, 89.16; H, 5.44. Found: C, 89.09; H, 5.42. 7-bromo-1-methoxy-3-phenylnaphthalene 195d: To a flame-dried 250 mL round bottom flask was added 7-bromo-3-phenylnaphthalen-1-ol 175d (4.49 g, 15.0 mmol) and dry THF (75 mL) under N2. The resulting solution was cooled to 0 °C and NaH (1.2 g, 60% in mineral oil, 30 mmol) was added. The resulting mixture was stirred at 0 °C for 15 minutes. MeI (3.8 mL, 61 mmol) was then added to the mixture at 0 °C. The mixture was warmed up to room temperature 271 and stirred for an additional 24 h. NH4Cl (sat. aq. 20 mL) was added to the mixture and the organic solvent was removed by rotary evaporation. The residue was extracted with CH2Cl2 (20 mL × 3). The combined organic layer was washed with Na2S2O3 (sat. aq. 20 mL × 2) and brine (20 mL) and then dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 300 mm, CH2Cl2:hexanes 1:8) gave 195d as a white solid (4.25 g, 13.5 mmol, 90%). mp 99-100 °C; Rf = 1 0.30 (1:4 CH2Cl2/hexanes). Spectral data for 195d: H NMR (CDCl3, 500 MHz) δ 4.05 (s, 3H), 7.06 (d, 1H, J = 7.5 Hz), 7.38 (t, 1H, J = 7.5 Hz), 7.45-7.49 (m, 2H), 7.54-7.57 (m, 2H), 7.67-7.70 (m, 3H), 8.41 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 55.69, 104.77, 118.14, 119.27, 124.60, 125.89, 127.38, 127.61, 128.86, 129.42, 130.20, 133.04, 139.52, 141.27, -1 154.97; IR (thin film) 1588s, 1491s, 1372s, 1229s, 1119s cm ; mass spectrum, m/z (% rel + intensity) 314 M (66, 81 + Br), 312 M (70, 79 Br), 271 (34, 81 Br), 269 (39, 79 Br), 218 (35), 202 (29), 189 (80), 157 (33). Anal calcd for C17H13BrO: C, 65.19; H, 4.18. Found: C, 65.15; H, 3.95. 7-(tert-butyldiphenylsilyl)-3-phenylnaphthalen-1-ol 175n: The following procedure was adapted from one for a related compound: 15 To a 250 mL flame-dried round bottom flask was added 7-bromo-1-methoxy-3-phenylnaphthalene 195d (2.75 g, 8.80 mmol) and dry THF (10 mL) 272 under N2. The resulting solution was cooled to –78 °C and t-BuLi (1.7 M in pentane, 10.6 mL, 18.0 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 1 h. TBDPSCl (2.5 mL, 9.8 mmol) was then added to the mixture at –78 °C. The mixture was warmed up to room temperature and stirred for an additional 24 h. NaHCO3 (sat. aq. 6 mL) was added to the mixture. The reaction mixture was partitioned between ethyl acetate (100 mL) and NaHCO3 (sat. aq. 100 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. The product was partially purified by column chromatography on silica gel (30 mm x 300 mm, CH2Cl2:hexanes 1:5). The partially purified product was dissolved in CH2Cl2 (70 mL) and BBr3 (1 M in CH2Cl2, 26.4 mL, 26.4 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature overnight under an argon balloon. The mixture was cooled to 0 °C and H2O (140 mL) was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (30 mL × 3). The combined organic layer was washed with brine (50 mL) and 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 1:1) gave 175n as a yellow foamy solid in 63% yield over two steps (2.53 g, 5.52 mmol). mp 72-74 °C; Rf = 0.21 (2:1 CH2Cl2/hexanes). Spectral data 1 for 175n: H NMR (CDCl3, 500 MHz) δ 1.23 (s, 9H), 5.17 (s, 1H), 7.08 (d, 1H, J = 1.5 Hz), 7.33-7.37 (m, 5H), 7.39-7.43 (m, 2H), 7.43-7.47 (m, 2H), 7.61-7.64 (m, 5H), 7.64-7.68 (m, 3H), 7.81 (d, 1H, J = 8.0 Hz), 8.44 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 18.88, 28.90, 108.63, 118.54, 122.81, 126.70, 127.33, 127.54, 127.72, 128.83, 129.24, 130.61, 131.89, 133.56, 134.79, 273 135.15, 136.60, 139.82, 140.88, 151.85; IR (thin film) 3384br s, 2930s, 1588s, 1428s, 1404s, -1 + 1260s, 1105s cm ; HRMS (ESI-) m/z calcd for C32H29OSi (M-H ) 457.1988, meas 457.1994. 7-iodo-1-(methoxymethoxy)-3-phenylnaphthalene 196e: To a flame-dried 250 mL round bottom flask was added 7-iodo-3-phenylnaphthalen-1-ol 175e (4.57 g, 13.2 mmol) and dry THF (50 mL) under N2. The resulting solution was cooled to 0 °C and NaH (580 mg, 60% in mineral oil, 14.5 mmol) was added. The resulting mixture was stirred at 0 °C for 1 h. MOMCl (1.11 mL, 14.6 mmol) was then added to the mixture at 0 °C. The mixture was warmed up to room temperature and stirred for additional 24 h. NH4Cl (sat. aq. 10 mL) was added to the mixture and the organic solvent was removed by rotary evaporation. The two phase residue was extracted with CH2Cl2 (15 mL × 3). The combined organic layer was washed with brine (10 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:3) gave 196e as a white solid (4.22 g, 10.8 mmol, 82%). mp 100-101 °C; Rf = 0.19 (1:3 1 CH2Cl2/hexanes). Spectral data for 196e: H NMR (CDCl3, 500 MHz) δ 3.56 (s, 3H), 5.43 (s, 2H), 7.35-7.39 (m, 2H), 7.44-7.48 (m, 2H), 7.56 (d, 1H, J = 8.5 Hz), 7.61 (s, 1H), 7.66-7.69 (m, 2H), 7.73 (dd, 1H, J = 8.5, 2.0 Hz), 8.64 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 56.40, 90.85, 94.87, 108.44, 119.13, 126.51, 127.39, 127.64, 128.84, 129.45, 131.06, 133.32, 274 135.28, 139.71, 140.86, 152.25; IR (thin film) 3056w, 2955m, 1578s, 1485s, 1366s, 1233m, -1 + 1154s cm ; HRMS (ESI+) m/z calcd for C18H16IO2 (M+H ) 391.0195, meas 391.0207. 3-phenyl-7-(trifluoromethyl)naphthalen-1-ol 175f: The following procedure was adapted 79 from one for a related compound: To a flame-dried 25 mL Schlenk flask were added 7-iodo-1-(methoxymethoxy)-3-phenylnaphthalene 196e (858 mg, 2.20 mmol) and trifluoromethyl(1,10-phenanthroline)copper (1.05 g, 3.34 mmol) under N2. The Schlenk flask was evacuated and backfilled with N2 three times. Dry DMF (9 mL) was added to the mixture under N2. The Schlenk flask was sealed and the mixture was stirred at 50 °C for 24 h. The mixture was cooled to room temperature, diluted with Et2O and filtered through a pad of Celite. The Celite was washed with Et2O. The combined filtrate was washed with HCl (aq. 1 M, 10 mL), NaHCO3 (sat. aq. 10 mL), brine (10 mL), dried over MgSO4, filtered through Celite and 1 concentrated to dryness. The H NMR spectrum of the crude mixture indicated incomplete conversion. The mixture was exposed to the above trifluoromethylation procedure with another portion of trifluoromethyl(1,10-phenanthroline)copper (344 mg, 1.10 mmol) and dry DMF (3 mL). The workup was repeated as mentioned above. The product was purified by column chromatography on silica gel (30 mm x 200 mm, Et2O:hexanes 1:10). The purified product was 275 obtained as a white solid and was dissolved in a mixture of THF and MeOH (44 mL, 1:1) and Amberlyst 15 (0.55 g) was added. The mixture was stirred at 65 ºC for 15 h under N2 in a balloon. After cooling down to room temperature, the mixture was filtered through filter paper and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 2:1) gave 175f as a white solid in 97% yield over 1 two steps (617 mg, 2.14 mmol). mp 108-109 °C; Rf = 0.35 (CH2Cl2). Spectral data for 175f: H NMR (CDCl3, 500 MHz) δ 5.49 (s, 1H), 7.12 (d, 1H, J = 1.5 Hz), 7.38-7.42 (m, 1H), 7.45-7.50 (m, 2H), 7.64-7.67 (m, 4H), 7.92 (d, 1H, J = 8.5 Hz), 8.52 9d, 1H, J = 1.0 Hz); 3 13 C NMR 3 (CDCl3, 125 MHz) δ 109.43, 118.50, 120.04 (q, J CF = 4.5 Hz), 122.46, 122. 52 (q, J CF = 3.3 1 2 Hz), 124.33 (q, J CF = 271.0 Hz), 126.95 (q, J CF = 32.0 Hz), 127.34, 127.97, 128.87, 128.95, 136.08, 140.26, 141.31, 152.40; 19 F NMR (CDCl3, 283 Hz) δ –62.28; IR (thin film) 3517br s, -1 + 1482s, 1412s, 1323s, 1235s cm ; HRMS (ESI–) m/z calcd for C17H10OF3 (M-H ) 287.0684, meas 287.0678. 7-chloro-1-methoxy-3-phenylnaphthalene 195c: To a flame-dried 250 mL round bottom flask was added 7-chloro-3-phenylnaphthalen-1-ol 175c (1.27 g, 5.00 mmol) and dry THF (20 mL) under N2. The resulting solution was cooled to 0 °C and NaH (220 mg, 60% in mineral oil, 5.5 mmol) was added. The resulting mixture was stirred at 0 °C for 15 minutes. MeI (1.25 mL, 20 mmol) was then added to the mixture at 0 °C. The mixture was warmed up to room 276 temperature and stirred for an additional 24 h. NH4Cl (sat. aq. 5 mL) was added to the mixture and the organic solvent was removed by rotary evaporation. The residue was extracted with CH2Cl2 (5 mL × 3). The combined organic layer was washed with Na2S2O3 (sat. aq. 5 mL × 2) and brine (5 mL) and then dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:10) gave 195c as a white solid (1.23 g, 4.58 mmol, 92%). mp °C; Rf = 0.21 1 (1:8 CH2Cl2/hexanes). Spectral data for 195c: H NMR (CDCl3, 500 MHz) δ 4.05 (s, 3H), 7.06 (d, 1H, J = 1.5 Hz), 7.36-7.41 (m, 1H), 7.43 (dd, 1H, J = 8.5, 2.0 Hz), 7.45-7.50 (m, 2H), 7.57 (s, 1H), 7.67-7.70 (m, 2H), 7.75 (d, 1H, J = 8.5 Hz), 8.23 (d, 1H, J = 2.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 55.65, 104.70, 118.05, 121.28, 125.41, 127.36, 127.57, 127.68, 128.85, 129.32, 131.09, 132.80, 139.31, 141.23, 155.01; IR (thin film) 3058w, 2936w, 1591s, 1495s, -1 35 + 1234s,1123s cm ; HRMS (EI+) m/z calcd for C17H13 ClO (M ) 268.0655, meas 268.0656. 1-methoxy-7-nitro-3-phenylnaphthalene 195ai: The following procedure was adapted from 5 one for a related compound: To a flame-dried 25 mL Schlenk flask were added 7-chloro-1-methoxy-3-phenylnaphthalene 195c (268 mg, 1.00 mmol), Pd2dba3 (9.2 mg, 0.0100mol), t-BuBrettPhos (11.6 mg, 0.024 mmol) and NaNO2 (138 mg, 2.00 mmol) under N2. The Schlenk flask was evacuated and 277 backfilled with N2 three times. Tris[2-(2-methoxyethoxy)ethyl]amine (16 mL, 0.050 mmol) and t-BuOH (2 mL) were added to the mixture under N2. The Schlenk flask was sealed and the mixture was stirred at 130 °C for 24 h. The mixture was cooled to room temperature, diluted with CH2Cl2 (10 mL). The organic layer was washed with H2O (10 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:2) gave 195ai as a yellow solid (254 mg, 0.91 mmol, 91%). mp 148-150 1 °C; Rf = 0.27 (1:1 CH2Cl2/hexanes). Spectral data for 195ai: H NMR (CDCl3, 500 MHz) δ 4.09 (s, 3H), 7.13 (d, 1H, J = 1.5 Hz), 7.41-7.45 (m, 1H), 7.48-7.52 (m, 2H), 7.64 (s, 1H), 7.68-7.71 (m, 2H), Hz); 13 7.88 (d, 1H, J = 9.0 Hz), 8.22 (dd, 1H, J = 9.0, 2.5 Hz), 9.18 (d, 1H, J = 2.5 C NMR (CDCl3, 125 MHz) δ 55.84, 105.43, 117.90, 119.74, 120.32, 123.45, 127.48, 128.31, 129.01, 129.05, 137.07, 140.52, 143.51, 144.82, 157.22; IR (thin film) 1559s, 1458s, -1 + 1335s, 1130s cm ; HRMS (ESI+) m/z calcd for C17H14NO3 (M+H ) 280.0974, found 280.0963. 7-chloro-1-(methoxymethoxy)-3-phenylnaphthalene 196c: To a flame-dried 250 mL round bottom flask was added 7-chloro-3-phenylnaphthalen-1-ol 175c (2.54 g, 10.0 mmol) and dry THF (40 mL) under N2. The resulting solution was cooled to 0 °C and NaH (440 mg, 60% in mineral oil, 11.0 mmol) was added. The resulting mixture was stirred at 0 °C for 1 h. MOMCl (0.84 mL, 11.1 mmol) was then added to the mixture at 0 °C. The mixture was warmed up to 278 room temperature and stirred for additional 24 h. NH4Cl (sat. aq. 10 mL) was added to the mixture and the organic solvent was removed by rotary evaporation. The two phase residue was extracted with CH2Cl2 (15 mL × 3). The combined organic layer was washed with brine (10 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:3) gave 196c as a white solid (2.71 g, 9.1 mmol, 91%). mp 77-79 °C; Rf = 0.24 (1:3 CH2Cl2/hexanes). 1 Spectral data for 196c: H NMR (CDCl3, 500 MHz) δ 3.56 (s, 3H), 5.44 (s, 2H), 7.35-7.40 (m, 2H), 7.42-7.49 (m, 3H), 7.65 (s, 1H), 7.66-7.69 (m, 2H), 7.77 (d, 1H, J = 8.5 Hz), 8.24 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 56.38, 94.86, 108.61, 119.08, 121.17, 125.69, 127.39, 127.59, 127.63, 128.84, 129.47, 131.27, 132.89, 139.34, 140.89, 152.55; IR (thin film) 3058w, -1 35 2955m, 1591s, 1493s, 1372s, 1235m, 1154s cm ; HRMS (ESI+) m/z calcd for C18H16 ClO2 + (M+H ) 299.0839, meas 299.0843. 1-(methoxymethoxy)-7-nitro-3-phenylnaphthalene 196ai: The following procedure was 5 adapted from one for a related compound: To a flame-dried 25 mL Schlenk flask were added 7-chloro-1-(methoxymethoxy)-3-phenylnaphthalene 196c (299 mg, 1.00 mmol), Pd2dba3 (9.2 mg, 0.0100mol), t-BuBrettPhos (11.6 mg, 0.024 mmol) and NaNO2 (138 mg, 2.00 mmol) under 279 N2 . The Schlenk flask was evacuated and backfilled with N2 three times. Tris[2-(2-methoxyethoxy)ethyl]amine (16 mL, 0.050 mmol) and t-BuOH (2 mL) were added to the mixture under N2. The Schlenk flask was sealed and the mixture was stirred at 130 °C for 24 h. The mixture was cooled to room temperature, diluted with CH2Cl2 (10 mL). The organic layer was washed with H2O (10 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 2:3) gave 196ai as a yellow solid (278 mg, 0.90 mmol, 90%). mp 127-129 1 °C; Rf = 0.20 (1:1 CH2Cl2/hexanes). Spectral data for 196ai: H NMR (CDCl3, 500 MHz) δ 3.58 (s, 3H), 5.49 (s, 2H), 7.39-7.44 (m, 1H), 7.47-7.51 (m, 3H), 7.68-7.73 (m, 3H), 7.92 (d, 1H, J = 9.0 Hz), 8.24 (dd, 1H, J = 9.0, 2.5 Hz), 9.21 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 56.60, 94.91, 109.19, 118.89, 119.68, 120.25, 123.72, 127.53, 128.33, 129.01, 129.26, 137.08, 140.23, 143.51, 145.00, 154.87; IR (thin film) 2961m, 1605s, 1493s, 1337s, 1238m, -1 + 1157s cm ; HRMS (EI+) m/z calcd for C18H15NO4 (M ) 309.1001, found 309.1010. 7-nitro-3-phenylnaphthalen-1-ol 175ai: 1-(methoxymethoxy)-7-nitro-3-phenyl-naphthalene 196ai (1.24 g, 4.00 mmol) was dissolved in a mixture of THF and MeOH (80 mL, 1:1) and Amberlyst 15 (1.00 g) was added. The mixture was stirred at 65 ºC for 15 h under N2 in a balloon. After cooling down to room temperature, the mixture was filtered through filter paper 280 and concentrated to dryness. CH2Cl2 (10 mL) and hexanes (50 mL) was added to the crude product. Filtration of the crude product through filter paper gave 175ai as a orange solid (954 mg, 1 3.60 mmol, 90%). mp 186-189 °C; Rf = 0.20 (CH2Cl2). Spectral data for 175ai: H NMR (DMSO-d6, 500 MHz) δ 7.31 (d, 1H, J = 1.5 Hz), 7.41-7.46 (m, 1H), 7.50-7.54 (m, 2H), 7.73-7.76 (m, 2H), 7.81 (s, 1h), 8.09 (d, 1H, J = 9.0 Hz), 8.19 (dd, 1H, J = 9.0, 2.5 Hz), 8.99 (d, 1H, J = 2.5 Hz); 13 C NMR (DMSO-d6, 125 MHz) δ 108.92, 116.18, 119.13, 119.67, 122.21, 127.05, 128.34, 129.11, 129.78, 137.06, 139.49, 142.88, 143.94, 155.66; HRMS (EI+) m/z calcd + for C16H11NO3 (M ) 265.0739, found 265.0732. 6.2.4 Preparation of 7,7’-disubstituted VANOL ligands General procedure for the preparation of 7,7’-disubstituted VANOL ligands – illustrated for the synthesis of 7,7’-di-bromo VANOL 174d (Procedure J) 13g,73 Oxidative phenol-coupling: To a 500 mL flame-dried three neck round bottom flask equipped with a cooling condenser was added 7-bromo-3-phenylnaphthalen-1-ol 175d (14.12 g, 47.2 mmol) and mineral oil (55 mL). Airflow was introduced from one side neck via a needle located one inch above the mixture. The airflow rate is about one bubble per second. The mixture 281 was stirred at 165 °C for 24 h. After cooling down to room temperature, CH2Cl2 (50 mL) and hexanes (100 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) and then filtered through filter paper. The yellow powder was washed with chilled CH2Cl2/hexanes and dried under vacuum to afford a yellow solid (11.41 g). Purification of the product remaining in the mother liquor by column chromatography on silica gel (35 mm x 250 mm, CH2Cl2:hexanes 1:2) gave racemic 174d as a white solid (0.46 g). The total yield is 84% (11.87 g, 19.9 mmol). 13c De-racemization: The original procedure involves sonification to presumably facilitate reaction. However, it was later found that the deracemization of VAPOL gives the same result 17 whether or not sonification is employed. The following procedure follows the original report: To a 500 mL round bottom flask was added (–)-sparteine (8.20 g, 35.0 mmol), CuCl (1.68 g, 17.0 mmol) and MeOH (270 mL) under an atmosphere of air. sonicated in a water bath for 60 minutes with exposure to air. The reaction mixture was The flask was then sealed with a septum and purged with argon, which was introduced by a needle under the surface for 60 minutes. At the same time, to a 2 L flame-dried round bottom flask was added racemic 174d (5.96 g, 10.0 mmol) and CH2Cl2 (1080 mL). The resulting solution was purged with argon for 60 minutes under the surface. The green Cu(II)-sparteine solution was then transferred via cannula to the solution of racemic 174d under argon and then the combined mixture was sonicated for 15 minutes and then allowed to stir at room temperature overnight with an argon balloon attached to the flask which was covered with aluminum foil. The reaction was quenched by slow addition of 282 NaHCO3 (sat. aq.125 mL), H2O (400 mL) and most of the organic solvent was removed under reduced pressure. The residue was then extracted with CH2Cl2 (300 mL × 3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2:hexanes 1:2) gave the product (S)-174d as an off-white foamy solid (4.97 g, 83.3 mmol, 83%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 26.47 min for (R)-174d (minor) and Rt = 30.62 min for (S)-174d (major). mp 1 136-138 °C; Rf = 0.27 (1:1 CH2Cl2/hexanes). Spectral data for 174d: H NMR (CDCl3, 500 MHz) δ 5.75 (s, 2H), 6.58-6.61 (m, 4H), 6.94-6.98 (m, 4H), 7.06-7.10 (m, 2H), 7.27 (s, 2H), 7.62-7.63 (m, 4H), 8.49-8.50 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 113.55, 119.90, 121.93, 123.96, 125.30, 126.95, 127.57, 128.76, 129.37, 131.06, 133.03, 139.64, 141.07, 149.49; IR (thin -1 + film) 3501br m, 1561s, 1487s, 1373s, 1265s cm ; mass spectrum, m/z (% rel intensity) 598 M (2, 81 81 + Br Br), 596 M (5, 81 79 + Br Br), 594 M (2, 79 79 Br Br), 299 (5, 81 Br), 297 (5, 79 Br), 209 (10), 193 (12). Anal calcd for C32H20Br2O2: C, 64.45; H, 3.38. Found: C, 64.52; H, 3.33. 20 [α] D = –190.3 (c 1.0, CH2Cl2) on >99% ee (S)-174d (HPLC). 283 7,7’-di-fluoro VANOL 174b: The synthesis of racemic 174b was performed according to the general procedure (Procedure J) with 7-fluoro-3-phenylnaphthalen-1-ol 175b (3.81 g, 16.0 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:3 to 2:3) gave racemic 174b as a yellow solid (3.44 g, 7.26 mmol, 91% yield). After de-racemization of racemic 174b (2.46 g, 5.19 mmol) with CuCl (873 mg, 8.82 mmol) and (–)-sparteine (4.26 g, 18.2 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:2) to afford (S)-174b as an off-white foamy solid (1.11 g, 2.34 mmol, 45%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 19.71 min for (R)-174b (minor) and Rt = 22.75 min for (S)-174b (major). 1 mp 190-192 °C; Rf = 0.26 (1:1 CH2Cl2/hexanes). Spectral data for 174b: H NMR (CDCl3, 500 MHz) δ 5.75 (s, 2H), 6.61 (dd, 4H, J = 8.5, 1.5 Hz), 6.96 (t, 4H, J = 7.5 Hz), 7.07 (t, 2H, J = 7.5 Hz), 7.30-7.35 (m, 4H), 7.76 (dd, 2H, J = 9.0, 5.5 Hz), 7.93 (dd, 2H, J = 10.0, 2.5 Hz); 2 13 C NMR 2 (CDCl3, 125 MHz) δ 106.70 ( J CF = 22.4 Hz), 113.50, 117.96 ( J CF = 25.6 Hz), 121.90, 3 3 4 123.65 ( J CF = 9.1 Hz), 126.78, 127.52, 128.83, 130.17 ( J CF = 8.8 Hz), 131.62, 139.81 ( J CF 284 1 = 2.4 Hz), 149.78, 149.82, 160.71 ( J CF = 244.9 Hz); 19 F NMR (CDCl3, 283 Hz) δ -111.93; IR -1 (thin film) 3519br s, 3059w, 1597s, 1497s, 1385s, 1267s, 1156s cm ; mass spectrum, m/z (% rel + intensity) 474 M (100), 397 (8), 338 (15), 307 (7), 249 (26), 237 (93), 209 (64). Anal calcd for 20 C32H20O2F2: C, 81.00; H, 4.25. Found: C, 80.93; H, 4.18. [α] D = –226.2 (c 1.0, CH2Cl2) on >99% ee (S)-174b (HPLC). 7,7’-di-chloro VANOL 174c: The synthesis of racemic 174c was performed according to the general procedure (Procedure J) with 7-chloro-3-phenylnaphthalen-1-ol 175c (1.27 g, 5.0 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:2) gave racemic 174c as a white solid (919 mg, 1.81 mmol, 73% yield). After de-racemization of racemic 174c (406 mg, 0.80 mmol) with CuCl (135 mg, 1.36 mmol) and (–)-sparteine (655 mg, 2.80 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 1:2) to afford (S)-174c as a white foamy solid (336 mg, 0.66 mmol, 83%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 23.87 min for (R)-174c (minor) and Rt = 27.98 min for (S)-174c (major). mp 214-215 285 1 °C; Rf = 0.27 (1:1 CH2Cl2/hexanes). Spectral data for 174c: H NMR (CDCl3, 500 MHz) δ 5.77 (s, 2H), 6.58-6.61 (m, 4H), 6.94-6.99 (m, 4H), 7.06-7.10 (m, 2H), 7.27 (s, 2H), 7.49 (dd, 2H, J = 8.0, 2.0 Hz), 7.70 (d, 2H, J = 8.0 Hz), 8.31-8.32 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 113.54, 121.85, 122.00, 123.50, 126.91, 127.55, 128.56, 128.76, 129.30, 131.74, 132.81, 139.62, 140.87, -1 149.55; IR (thin film) 3507br s, 3058m, 1590s, 1489s, 1377s, 1265s cm ; HRMS (ESI+) m/z 35 + 20 calcd for C32H21 Cl2O2 (M+H ) 507.0919, meas 507.0907. [α] D = –206.0 (c 1.0, CH2Cl2) on >99% ee (S)-174c (HPLC). 7,7’-di-iodo VANOL 174e: The synthesis of racemic 174e was performed according to the general procedure (Procedure J) with 7-iodo-3-phenylnaphthalen-1-ol 175e (1.43 g, 4.13 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, EtOAc/hexanes 1:10) gave racemic 174e as a yellow solid (1.22 g, 1.77 mmol, 86%). After de-racemization of racemic 174e (5.06 g, 7.33 mmol) with CuCl (1.23 g, 12.4 mmol) and (–)-sparteine (6.01 g, 25.9 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 250 m, CH2Cl2/hexanes 1:2) to afford (S)-6e as a yellow solid (3.82 g, 5.54 mmol, 76%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 286 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 29.63 min for (R)-174e (minor) and Rt = 33.56 min for (S)-174e (major). mp 292-294 °C; Rf = 0.36 (1:1 1 CH2Cl2/hexanes). Spectral data for 174e: H NMR (CDCl3, 500 MHz) δ 5.73 (s, 2H), 6.57-6.60 (m, 4H), 6.94-6.98 (m, 4H), 7.06-7.10 (m, 2H), 7.24 (d, 2H, J = 4.0 Hz), 7.49 (d, 2H, J = 9.0 Hz), 7.79 (dd, 2H, J = 8.5, 2.0 Hz), 8.72-8.73 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 91.28, 113.36, 121.96, 124.35, 126.95, 127.57, 128.74, 129.24, 131.86, 133.28, 136.23, 139.62, 141.28, 149.26; -1 IR (thin film) 3463br s, 3056m, 1559s, 1485s,1373s, 1265s cm ; mass spectrum, m/z (% rel + intensity) 690 M (91), 599 (2), 564 (6), 486 (6), 389 (24), 345 (100), 300 (40), 194 (93). Anal 20 calcd for C32H20I2O2: C, 55.68; H, 2.92. Found: C, 55.53; H, 2.78. [α] D = –111.6 (c 1.0, CH2Cl2) on >99% ee (S)-174e (HPLC). 7,7’-di-trifluoromethyl VANOL 174f: The synthesis of racemic 174f was performed according to the general procedure (Procedure J) with 3-phenyl-7-(trifluoromethyl)naphthalen-1-ol 175f (576 mg, 2.00 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:3) gave racemic 174f as an off-white solid (292 mg, 0.51 mmol, 51%). After de-racemization of racemic 174f (208 mg, 0.36 mmol) with CuCl (61 mg, 0.62 mmol) and (+)-sparteine (297 mg, 1.27 mmol), the crude product 287 was purified by column chromatography on silica gel (30 mm × 250 m, CH2Cl2/hexanes 1:2) to afford (R)-174f as an off-white solid (165 mg, 0.29 mmol, 79%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 15.50 min for (R)-174f (major) and Rt = 17.18 min for (S)-174f (minor). mp 215-218 °C; Rf = 0.38 (1:1 1 CH2Cl2/hexanes). Spectral data for 174f: H NMR (CDCl3, 500 MHz) δ 5.90 (s, 2H), 6.59-6.62 (m, 4H), 6.97-7.01 9m, 4H), 7.09-7.13 (m, 2H), 7.36 (s, 2H), 7.73 (dd, 2H, J = 8.5, 1.5 Hz), 7.87 (d, 2H, J = 8.5 Hz), 8.68 (d, 2H, J = 1.0 Hz); 3 13 C NMR (CDCl3, 125 MHz) δ 113.64, 121.06 (q, 3 1 J CF = 4.5 Hz), 121.84, 121.95, 123.36 (q, J CF = 3.1 Hz), 124.38 (q, J CF = 270.9 Hz), 2 127.21, 127.64 (q, J CF = 32.6 Hz), 127.66, 128.73, 128.75, 135.75, 139.33, 142.98, 151.06; 19 F NMR (CDCl3, 283 Hz) δ –62.81; IR (thin film) 3524br s, 1572s, 1466s, 1377s, 1319s, 1296s, -1 + 1123s cm ; HRMS (ESI–) m/z calcd for C34H19O2F6 (M-H ) 573.1289, meas 573.1272. 20 [α] D = +187.7 (c 1.0, CH2Cl2) on >99% ee (R)-174f (HPLC). 7,7’-di-methyl VANOL 174h: The synthesis of racemic 174h was performed according to the general procedure (Procedure J) with 7-methyl-3-phenylnaphthalen-1-ol 175h (3.77 g, 16.1 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, 288 CH2Cl2/hexanes 1:2) gave racemic 174h as a yellow solid (2.02 g, 4.33 mmol, 54%). After de-racemization of racemic 174h (932 mg, 2.00 mmol) with CuCl (337 mg, 3.40 mmol) and (–)-sparteine (1.64 g, 7.00 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:2) to afford (S)-174h as an off-white solid (509 mg, 1.09 mmol, 55%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 16.70 min for (R)-174h (minor) and Rt = 18.60 min for (S)-174h (major). 1 mp 132-134 °C; Rf = 0.26 (1:1 CH2Cl2/hexanes). Spectral data for 174h: H NMR (CDCl3, 500 MHz) δ 2.58 (s, 6H), 5.77 (s, 2H), 6.63 (dd, 4H, J = 8.5, 1.5 Hz), 6.94 (t, 4H, J = 8.0 Hz), 7.02-7.06 (m, 2H), 7.27 (s, 2H), 7.39 (dd, 2H, J = 8.0, 1.5 Hz), 7.68 (d, 2H, J = 8.0 Hz), 8.11 (d, 2H, J = 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 21.94, 112.82, 121.68, 121.80, 122.97, 126.46, 127.40, 127.58, 128.88, 129.71, 132.86, 135.51, 139.70, 140.32, 149.80; IR (thin film) 3509br s, -1 3054m, 2920m, 1599s, 1497s, 1387s, 1294s, 1265s cm ; mass spectrum, m/z (% rel intensity) + 466 M (86), 389 (8), 302 (9), 233 (100), 194 (65). Anal calcd for C34H26O2: C, 87.52; H, 5.62. 20 Found: C, 87.47; H, 5.74. [α] D = –292.4 (c 1.0, CH2Cl2) on >99% ee (S)-174h (HPLC). 289 7,7’-di-isopropyl VANOL 174k: The synthesis of racemic 174k was performed according to the general procedure (Procedure J) with 7-isopropyl-3-phenylnaphthalen-1-ol 175k (1.31 g, 5.00 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:3) gave racemic 174k as a white solid (1.08 g, 2.07 mmol, 82%). After de-racemization of racemic 174k (418 mg, 0.80 mmol) with CuCl (135 mg, 1.36 mmol) and (+)-sparteine (655 mg, 2.80 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 1:3) to afford (R)-174k as a white foamy solid (300 mg, 0.57 mmol, 72%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 99:1 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 12.60 min for (R)-174k (major) and Rt = 13.87 min for (S)-174k (minor). 1 mp 123-129 °C; Rf = 0.20 (1:2 CH2Cl2/hexanes). Spectral data for 6k: H NMR (CDCl3, 500 MHz) δ 1.40 (d, 12H, J = 7.0 Hz), 3.12-3.19 (m, 2H), 5.81 (s, 2H), 6.61-6.64 (m, 4H), 6.93-6.98 (m, 4H), 7.03-7.08 (m, 2H), 7.29 (s, 2H), 7.48 (dd, 2H, J = 8.5, 1.5 Hz), 7.73 (d, 2H, J = 8.5 Hz), 8.15-8.17 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 23.95, 24.02, 35.52, 112.76, 119.06, 121.81, 122.96, 126.41, 127.28, 127.42, 127.73, 128.89, 133.25, 139.85, 140.38, 146.38, 150.05; IR (thin -1 film) 3513br s, 3054m, 2959s, 1561s, 1497s, 1387s, 1265m, 1173s cm ; HRMS (ESI+) m/z 20 calcd for C38H35O2 (M+H+) 523.2637, meas 523.2645. [α] D = +207.6 (c 1.0, CH2Cl2) on >99% ee (R)-174k (HPLC). 290 7,7’-di-t-butyl VANOL 174m: The synthesis of racemic 174m was performed according to the general procedure (Procedure J) with 7-(tert-butyl)-3-phenylnaphthalen-1-ol 175m (201 mg, 0.73 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:2) gave racemic 174m as an off-white solid (145 mg, 0.26 mmol, 72%). After de-racemization of racemic 174m (525 mg, 0.95 mmol) with CuCl (160 mg, 1.62 mmol) and (–)-sparteine (782 mg, 3.34 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 250 m, CH2Cl2/hexanes 1:2) to afford (S)-174m as an off-white foamy solid (404 mg, 0.73 mmol, 77%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 99:1 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 8.67 min for (R)-174m (minor) and Rt = 10.19 min for (S)-174m (major). 1 mp 154-156 °C; Rf = 0.26 (1:2 CH2Cl2/hexanes). Spectral data for 174m: H NMR (CDCl3, 500 MHz) δ 1.48 (s, 18H), 5.81 (s, 2H), 6.61 (dd, 4H, J = 8.0, 1.0 Hz), 6.95 (t, 4H, J = 8.0 Hz), 7.03-7.07 (m, 2H), 7.28 (s, 2H), 7.66 (dd, 2H, J = 8.5, 2.0 Hz), 7.73 (d, 2H, J = 8.5 Hz), 8.29-8.30 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 31.33, 35.19, 112.72, 117.71, 121.63, 122.65, 2 126.39, 127.43, 127.45, 128.90, 132.83, 140.01, 140.40, 148.58, 150.24 (1 sp C not located); IR 291 -1 (thin film) 3519br s, 3058w, 2961s, 1597s, 1497s, 1385s, 1265s cm ; mass spectrum, m/z (% rel + intensity) 550 M (47), 535 (13), 275 (29), 260 (89), 232 (29). Anal calcd for C40H38O2: C, 20 87.23; H, 6.95. Found: C, 86.90; H, 7.16. [α] D = –215.2 (c 1.0, CH2Cl2) on >99% ee (S)-174m (HPLC). The synthesis of racemic 174n was performed according to the general procedure (Procedure J) with 7-(tert-butyldiphenylsilyl)-3-phenylnaphthalen-1-ol 175n (2.49 g, 5.43 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 2:5) gave racemic 174n as an off-white solid (2.07 mg, 2.26 mmol, 84%). After de-racemization of racemic 174n (2.05 g, 2.23 mmol) with CuCl (376 mg, 3.80 mmol) and (–)-sparteine (1.84 g, 7.86 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 250 m, CH2Cl2/hexanes 1:2) to afford (S)-174n as an off-white foamy solid (1.64 g, 1.79 mmol, 80%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 8.74 min for (R)-174n (minor) and Rt = 9.99 min for (S)-174n (major). mp 152-155 1 °C; Rf = 0.27 (1:2 CH2Cl2/hexanes). Spectral data for 174n: H NMR (CDCl3, 500 MHz) δ 1.26 (s, 18H), 5.79 (s, 2H), 6.58 (dd, 4H, J = 8.0, 1.0 Hz), 6.96 (t, 4H, J = 7.5 Hz), 7.07 (t, 2H, J = 7.5 292 Hz), 7.27 (s, 2H), 7.35-7.44 (m, 12H), 7.63-7.67 (m, 8H), 7.67-7.73 (m, 4H), 8.64 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 18.94, 28.94, 112.80, 121.76, 122.19, 126.45, 126.58, 127.47, 127.73, 127.74, 128.90, 129.28, 131.97, 132.33, 134.17, 134.72, 134.74, 136.64, 140.22, 2 141.52 ,150.50 (3 sp C not located); IR (thin film) 3519br s, 2963s, 1553s, 1427s, 1381s, 1267s, -1 + 1105s cm ; HRMS (ESI-) m/z calcd for C64H57O2Si2 (M-H ) 913.3897, meas 913.3873. 20 [α] D = –81.1 (c 1.0, CH2Cl2) on >99% ee (S)-174n (HPLC). To a flame-dried 250 mL round bottom flask was added NaH (672 mg, 60% in mineral oil, 16.8 mmol) and THF (30 mL). The resulting mixture was cooled to 0 °C and a solution of (S)-174d (4.17 g, 7.00 mmol) in THF (15 mL) was added. The mixture was stirred at 0 °C for 1 h and then allowed to warm up to room temperature for 15 minutes. The mixture was re-cooled to 0 °C and MeI (2.5 mL, 40 mmol) was added. The mixture was warmed up to room temperature and stirred for additional 24 h. NH4Cl (sat. aq. 15 mL) was added to the mixture and the organic solvent was removed by rotary evaporation. The residue was extracted with CH2Cl2 (20 mL × 3). The combined organic layer was washed with Na2S2O3 (sat. aq. 15 mL × 2), brine (20 mL), and dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude 293 product by column chromatography on silica gel (30 mm x 300 mm, CH2Cl2:hexanes 1:3) gave (S)-199d as an off-white solid (3.58 g, 5.74 mmol, 82%). mp 235-236 °C; Rf = 0.24 (1:2 1 CH2Cl2/hexanes). Spectral data for 199d: H NMR (CDCl3, 500 MHz) δ 3.67 (s, 6H), 6.75-6.77 (m, 4H), 6.93-6.97 (m, 4H), 7.05-7.09 (m, 2H), 7.50 (s, 2H), 7.58 (dd, 2H, J = 8.5, 2.0 Hz), 7.71 (d, 2H, J = 9.0 Hz), 8.33 (d, 2H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 61.20, 120.24, 125.06, 125.25, 126.25, 126.51, 127.58, 128.18, 128.94, 129.88, 130.03, 132.98, 140.38, 140.65, -1 153.42; IR (thin film) 1559s, 1480s, 1352s, 1105s cm ; HRMS (ESI+) m/z calcd for 79 + 20 C34H24O2 Br2Na (M+Na ) 645.0041, meas 645.0068. [α] D = –44.8 (c 1.0, CH2Cl2). To a flame-dried 250 mL round bottom flask were added NaH (352 mg, 60% in mineral oil, 8.8 mmol) and THF (18 mL). The resulting mixture was cooled to 0 °C and a solution of (S)-174d (2.38 g, 4.00 mmol) in THF (6 mL) was added. The mixture was stirred at 0 °C for 1 h and then allowed to warm up to room temperature for 15 minutes. The mixture was re-cooled to 0 °C and MOMCl (0.67 mL, 8.8 mmol) was added. The mixture was warmed up to room temperature and stirred for an additional 24 h. NH4Cl (sat. aq. 6 mL) was added to the mixture and the organic solvent was removed on a rotary evaporator. The residue was extracted with 294 CH2Cl2 (10 mL × 3). The combined organic layer was washed with brine (10 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:2 to 3:4 to 1:1) gave (S)-200d as an off-white solid (2.24 g, 3.27 mmol, 82%). mp 96-98 °C; Rf = 0.22 (1:1 1 CH2Cl2/hexanes). Spectral data for 200d: H NMR (CDCl3, 500 MHz) δ 2.76 (s, 6H), 5.04-5.09 (m, 4H), 6.71 (dd, 4H, J = 8.5, 1.0 Hz), 6.89-6.93 (m, 4H), 7.03-7.08 (m, 2H), 7.47 (s, 2H), 7.57 (dd, 2H, J = 8.5, 2.0 Hz), 7.69 (d, 2H, J = 9.0 Hz), 8.32-8.34 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 56.48, 99.50, 120.43, 125.17, 125.48, 126.29, 127.51, 127.53, 128.16, 129.03, 129.86, 130.02, 132.84, 140.42, 141.13, 151.52; IR (thin film) 3056m, 2930s, 1572s, 1482s, 1352s, -1 79 + 1159s cm ; HRMS (ESI+) m/z calcd for C36H28O2Na Br2 (M+Na ) 705.0252, meas 705.0273. 20 [α] D = –118.2 (c 1.0, CH2Cl2). To a flame-dried 250 mL round bottom flask were added NaH (352 mg, 60% in mineral oil, 8.8 mmol) and THF (18 mL). The resulting mixture was cooled to 0 °C and a solution of (S)-174e (2.76 g, 4.00 mmol) in THF (6 mL) was added. The mixture was stirred at 0 °C for 1 h and then allowed to warm up to room temperature for 15 minutes. The mixture was re-cooled to 0 °C and MOMCl (0.67 mL, 8.8 mmol) was added. The mixture was warmed up to room 295 temperature and stirred for additional 24 h. NH4Cl (sat. aq. 6 mL) was added to the mixture and the organic solvent was removed. The residue was extracted with CH2Cl2 (10 mL × 3). The combined organic layer was washed with brine (10 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 280 mm, CH2Cl2:hexanes 1:1) gave (S)-200e as an off-white solid in 90% isolated yield (2.81 g, 3.61 mmol). mp 110-114 °C; Rf = 0.24 (1:1 CH2Cl2/hexanes). Spectral 1 data for 200e: H NMR (CDCl3, 500 MHz) δ 2.76 (s, 6H), 5.04-5.08 (m, 4H), 6.70 (dd, 4H, J = 8.5, 1.5 Hz), 6.90 (t, 4H, J = 7.5 Hz), 7.03-7.07 (m, 2H), 7.45 (s, 2H), 7.54 (d, 2H, J = 9.0 Hz), 7.74 (dd, 2H, J = 8.5, 1.5 Hz), 8.57 (d, 2H, J = 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 56.50, 91.94, 99.52, 125.50, 126.29, 127.32, 127.51, 128.57, 129.02, 129.70, 131.84, 133.07, 135.15, -1 140.41, 141.32, 151.30; IR (thin film) 2953s, 1570s, 1480s, 1350s, 1159s cm ; HRMS (ESI+) + 20 m/z calcd for C36H29O4I2 (M+H ) 779.0155, meas 779.0159. [α] D = –74.7 (c 1.0, CH2Cl2). Suzuki coupling – illustrated for the synthesis of (S)-174q 296 15 Procedure K: Benzene, ethanol and Na2CO3 (aq. 2 M) were purged (>10 min) with inert gas (Ar or N2) prior to use. To a 25 mL round bottom flask was added (S)-174d (60 mg, 0.10 mmol), tetrakis(triphosphine)palladium (12 mg, 0.010 mmol), benzene (1 mL) and Na2CO3 (aq. 2 M, 0.5 mL) under argon. To the stirred mixture was added 4-tert-butylphenylboronic acid (71 mg, 0.40 mmol) and ethanol (0.5 mL). The mixture was stirred at 90 ºC for 14 h with an argon balloon attached to the condenser. After cooling down to room temperature, the mixture was partitioned between EtOAc (10 mL) and brine (5 mL). The organic layer was separated, dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (20 mm x 250 mm, CH2Cl2:hexanes 1:2) gave (S)-174q as a white solid (29 mg, 0.041 mmol, 41%). 15 Procedure L: Toluene, ethanol and Na2CO3 (aq. 2 M) were purged (>10 min) with inert gas (Ar or N2) prior to use. To a 100 mL round bottom flask was added (S)-199d (780 mg, 1.25 mmol), tetrakis(triphosphine)palladium (144 mg, 0.125 mmol), toluene (15 mL) and Na2CO3 (aq. 2 M, 7.5 mL). To the stirred mixture was added 4-tert-butylphenylboronic acid (890 mg, 5.0 mmol) and ethanol (7.5 mL). The mixture was stirred at 90 ºC for 14 h with an 297 argon balloon attached. After cooling down to room temperature, the mixture was partitioned between EtOAc (40 mL) and brine (20 mL). The organic layer was separated, dried over MgSO4 and passed through a pad of silica gel (eluted with EtOAc). The crude product was concentrated to dryness. The residue was dissolved in CH2Cl2 (20 mL) and cooled to 0 ºC, and then BBr3 (1 M in CH2Cl2, 7.5 mL, 7.5 mmol) was added dropwise to the mixture at 0 ºC. The mixture was stirred at room temperature overnight with an argon balloon attached to the flask. The mixture was then cooled to 0 ºC and H2O (40 mL) was added dropwise. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (10 mL × 3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:2) gave (S)-174q as a white solid in 89% yield over two steps (785 mg, 1.12 mmol). mp >300 °C; Rf = 1 0.21 (1:2 CH2Cl2/hexanes). Spectral data for 174q: H NMR (CDCl3, 500 MHz) δ 1.39 (s, 18H), 5.89 (s, 2H), 6.67 (dd, 4H, J = 8.5, 1.5 Hz), 6.96-7.00 (m, 4H), 7.06-7.10 (m, 2H), 7.34 (d, 2H, J = 1.0 Hz), 7.51-7.55 (m, 4H), 7.73-7.76 (m, 4H), 7.84 (d, 4H, J = 1.5 Hz), 8.56 (d, 2H, J = 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 31.39, 34.60, 113.11, 120.45, 121.80, 123.24, 125.86, 126.64, 127.09, 127.11, 127.50, 128.21, 128.90, 133.66, 138.11, 138.31, 140.25, 140.58, 150.55, -1 150.61; IR (thin film) 3517br s, 2961s, 1559s, 1456s, 1387s, 1267s cm ; HRMS (ESI–) m/z + 20 calcd for C52H45O2 (M-H ) 701.3420, meas 701.3448. [α] D = +29.2 (c 1.0, CH2Cl2). 298 The reaction of (S)-174d (179 mg, 0.30 mmol), tetrakis(triphosphine)palladium (35 mg, 0.030 mmol), benzene (3 mL), Na2CO3 (aq. 2 M, 1.5 mL), p-tolylboronic acid (162 mg, 1.20 mmol) and ethanol (1.5 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 3:4) gave (S)-174o as a white solid (64 mg, 0.104 mmol, 35%). mp > 260°C; Rf = 0.29 (1:1 1 CH2Cl2/hexanes). Spectral data for 174o: H NMR (CDCl3, 500 MHz) δ 2.42 (s, 6H), 5.88 (s, 2H), 6.64-6.67 (m, 4H), 6.95-6.99 (m, 4H), 7.05-7.10 (m, 2H), 7.30-7.32 (m, 4H), 7.34 (d, 2H, J = 0.5 Hz), 7.69-7.71 (m, 4H), 7.83-7.84 (m, 4H), 8.54-8.55 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 21.41, 113.29, 120.57, 122.03, 123.43, 126.87, 127.33, 127.51, 127.74, 128.47, 129.13, 129.88, 133.86, 137.53, 138.33, 138.58, 140.42, 140.79, 150.80; IR (thin film) 3503br s, 2922m, -1 + 1595s, 1493s, 1388s, 1275m cm ; HRMS (ESI–) m/z calcd for C46H33O2 (M-H ) 617.2481, 20 meas 617.2493. [α] D = +7.8 (c 1.0, CH2Cl2). 299 The reaction of (S)-174d (179 mg, 0.30 mmol), tetrakis(triphosphine)palladium (35 mg, 0.030 mmol), benzene (3 mL), Na2CO3 (aq. 2 M, 1.5 mL), 4-(trifluoromethyl)phenylboronic acid (228 mg, 1.20 mmol) and ethanol (1.5 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 2:5) gave (S)-174p as a white solid (67 mg, 0.092 mmol, 31%). mp > 260 °C; 1 Rf = 0.39 (1:1 CH2Cl2/hexanes). Spectral data for 174p: H NMR (CDCl3, 500 MHz) δ 5.91 (s, 2H), 6.64-6.67 (m, 4H), 6.96-7.00 (m, 4H), 7.07-7.11 (m, 2H), 7.35 (s, 2H), 7.74 (d, 4H, J = 8.0 Hz), 7.82 (dd, 2H. J = 8.0, 1.5 Hz), 7.86-7.90 (m, 6H), 8.57-8.59 (m, 2H); 13 C NMR (CDCl3, 1 3 125 MHz) δ 113.25, 121.33, 121.86, 123.04, 124.31 (q, J CF = 270.4 Hz), 125.84 (q, J CF = 2 3.8 Hz), 126.84, 127.56, 127.67, 128.62, 128.83, 129.48 (q, J CF = 32.6 Hz), 134.09, 136.90, 2 139.88, 141.26, 144.46, 150.68 (1 sp C not located); 19 F NMR (CDCl3, 283 Hz) δ –62.34; IR -1 (thin film) 3517br s, 3058m, 1560s, 1497s, 1387s, 1325s, 1281s cm ; HRMS (ESI-) m/z calcd + 20 for C46H27O2F6 (M-H ) 725.1915, meas 725.1930. [α] D = –11.8 (c 1.0, CH2Cl2). 300 The reaction of (S)-174d (119 mg, 0.20 mmol), tetrakis(triphosphine)palladium (23 mg, 0.020 mmol), benzene (2 mL), Na2CO3 (aq. 2 M, 1 mL), 3,5-dimethylphenylboronic acid (120 mg, 0.80 mmol) and ethanol (1 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:2) gave (S)-174r as an off-white solid (67 mg, 0.092 mmol, 31%). 301 The reaction of (S)-199d (119 mg, 0.20 mmol), tetrakis(triphosphine)palladium (29 mg, 0.025 mmol), toluene (3 mL), Na2CO3 (aq. 2 M, 1.5 mL), 3,5-dimethylphenylboronic acid (120 mg, 0.80 mmol) and ethanol (1.5 mL) was performed according to Procedure L. Purification of the crude product by column chromatography on silica gel (20 mm x 300 mm, CH2Cl2:hexanes 1:2) gave (S)-174r as an off-white solid in 65% yield over two steps (105 mg, 0.163 mmol). mp 1 159-162 °C; Rf = 0.36 (1:1 CH2Cl2/hexanes). Spectral data for 174r: H NMR (CDCl3, 500 MHz) δ 2.43 (s, 12H), 5.88 (s, 2H), 6.67 (dd, 4H, J = 8.0, 1.0 Hz), 6.96-7.00 (m, 4H), 7.04 (s, 2H), 7.06-7.10 (m, 2H), 7.35 (d, 2H, J = 0.5 Hz), 7.41 (s, 4H), 7.83 (d, 4H, J = 1.5 Hz), 8.53 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 21.46, 113.07, 120.59, 121.83, 123.17, 125.38, 126.65, 127.33, 127.50, 128.15, 128.90, 129.14, 133.73, 138.42, 138.74, 140.21, 140.59, 141.01, 150.60; -1 IR (thin film) 3515br s, 3027m, 2919s, 1595s, 1456s, 1387s, 1265s cm ; HRMS (ESI–) m/z + 20 calcd for C48H37O2 (M-H ) 645.2794, meas 645.2762. [α] D = –7.2 (c 1.0, CH2Cl2). 302 The reaction of (S)-174d (119 mg, 0.20 mmol), tetrakis(triphosphine)palladium (23 mg, 0.020 mmol), benzene (2 mL), Na2CO3 (aq. 2 M, 1 mL), (3,5-di-tert-butyl-4-methoxyphenyl)boronic acid (120 mg, 0.80 mmol) and ethanol (1 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (20 mm x 250 mm, CH2Cl2:hexanes 1:2) gave (S)-174s as an off-white solid (105 mg, 0.12 mmol, 60%). 12 The following procedure was adapted from one for a related compound: To a 25 mL round bottom flask filled with argon were added (S)-200d (171 mg, 0.25 mmol), tetrakis(triphosphine)palladium (29 mg, 0.025 mmol) and DME (1.7 mL). To the stirred mixture was added (3,5-di-tert-butyl-4-methoxyphenyl)boronic acid (230 mg, 0.87 mmol) and Na2CO3 (aq. 2 M, 0.7 mL). The mixture was stirred at 90 ºC for 14 h with an argon balloon attached to the condenser. After cooling down to room temperature, the mixture was passed through a pad of Celite and washed with CH2Cl2. After removal of the solvents, the residue was dissolved in 303 CH2Cl2 (20 mL) and washed with NH4Cl (sat. aq. 5 mL) and brine (5 mL). The organic layer was separated, dried over MgSO4, filtered through Celite and concentrated to dryness. The product was purified by column chromatography on silica gel (20 mm x 200 mm, CH2Cl2:hexanes 1:1). The purified product was dissolved in a mixture of THF and MeOH (10 mL, 1:1) and Amberlyst 15 (0.125g) was added. The mixture was stirred at 65 ºC for 15 h with an argon balloon attached to the condenser. After cooling down to room temperature, the mixture was filtered through filter paper and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:2) gave the pure product as an off-white solid in 86% yield over two steps (189 mg, 0.216 mmol,). mp 176-179 1 °C; Rf = 0.29 (1:2 CH2Cl2/hexane). Spectral data for 174s: H NMR (CDCl3, 500 MHz) δ 1.52 (s, 36H), 3.76 (s, 6H), 5.90 (s, 2H), 6.66 (dd, 4H, J = 8.5, 1.0 Hz), 6.95-6.99 (m, 4H), 7.05-7.09 (m, 2H), 7.35 (s, 2H), 7.64 (s, 4H), 7.80 (dd, 2H, J = 8.5, 2.0 Hz), 7.84 (d, 2H, J = 8.5 Hz), 8.47-8.49 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 32.20, 36.00, 64.35, 113.10, 120.33, 121.82, 123.19, 125.83, 126.60, 127.43, 127.49, 128.13, 128.91, 133.49, 135.34, 139.22, 140.25, 140.41, -1 144.11, 150.49, 159.45; IR (thin film) 3521br s, 2959s, 1559s, 1456s, 1387s cm ; mass spectrum, m/z (% rel intensity) 875 M+1 (8), 437 (10). Anal calcd for C62H66O4: C, 85.09; H, 20 7.60. Found: C, 84.95; H, 7.91. [α] D = +22.1 (c 1.0, CH2Cl2). 304 The reaction of (S)-174d (179 mg, 0.30 mmol), tetrakis(triphosphine)palladium (35 mg, 0.030 mmol), benzene (3 mL), Na2CO3 (aq. 2 M, 1.5 mL), 3,5-bis(trifluoromethyl)phenylboronic acid (228 mg, 1.20 mmol) and ethanol (1.5 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:4) gave (S)-174t as a yellow solid (85 mg, 0.099 mmol, 33%). 305 The reaction of (S)-199d (312 mg, 0.50 mmol), tetrakis(triphosphine)palladium (58 mg, 0.050 mmol), toluene (6 mL), Na2CO3 (aq. 2 M, 3 mL), 3,5-bis(trifluoromethyl)phenylboronic acid (516 mg, 2.00 mmol) and ethanol (3 mL) was performed according to Procedure L. Purification of the crude product by column chromatography on silica gel (25 mm x 250 mm, CH2Cl2:hexanes 1:2) gave (S)-174t as a yellow solid (362 mg, 0.099 mmol, 84%). mp 155-159 1 °C; Rf = 0.27 (1:2 CH2Cl2/hexanes). Spectral data for 174t: H NMR (CDCl3, 500 MHz) δ 5.94 (s, 2H), 6.63-6.66 (m, 4H), 6.96-7.00 (m, 4H), 7.07-7.11 (m, 2H), 7.36 (s, 2H), 7.81 (dd, 2H, J = 8.5, 2.0 Hz), 7.89 (s, 2H), 7.91 (d, 2H. J = 8.5 Hz), 8.19 (s, 4H), 8.56-8.57 (m, 2H); 13 C NMR 1 (CDCl3, 125 MHz) δ 113.46, 121.03 (m), 121.62, 121.91, 123.01, 123.41 (q, J CF = 271.0 Hz), 3 2 126.49, 126.99, 127.45 (q, J CF = 3.3 Hz), 127.60, 128.80, 129.03, 132.25 (q, J CF = 32.5 Hz), 134.30, 135.36, 139.67, 141.70, 143.11, 150.71; 19 F NMR (CDCl3, 283 Hz) δ –62.76; IR (thin -1 film) 3528br s, 3059m, 1563s, 1472s, 1372s, 1277s cm ; HRMS (ESI–) m/z calcd for + 20 C48H25O2F12 (M-H ) 861.1663, meas 861.1635. [α] D = –27.3 (c 1.0, CH2Cl2). 306 The reaction of (S)-174d (238 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2 M, 2 mL), 2,6-dimethylphenylboronic acid (240 mg, 1.60 mmol) and ethanol (2 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (25 mm x 250 mm, CH2Cl2:hexanes 1:2) gave (S)-174u as an off-white solid (148 mg, 0.229 mmol, 57%). mp >260 °C; Rf = 0.37 (1:1 1 CH2Cl2/hexanes). Spectral data for 174u: H NMR (CDCl3, 500 MHz) δ 2.11 (s, 6H), 2.15 (s, 6H), 5.86 (s, 2H), 6.67-6.70 (m, 4H), 6.98-7.02 (m, 4H), 7.08-7.13 (m, 2H), 7.15-7.23 (m, 6H), 7.36-7.38 (m, 4H), 7.84 (d, 2H, J = 8.5 Hz), 8.12-8.14 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 21.04, 21.08, 112.99, 121.86, 122.59, 123.02, 126.61, 127.22, 127.39, 127.42, 127.47, 127.83, 128.93, 129.31, 133.40, 136.21, 136.26, 138.60, 140.33, 140.59, 141.70, 150.53; IR (thin film) -1 3519br s, 3056s, 2923s, 1559s, 1474s, 1383s, 1265s cm ; HRMS (ESI-) m/z calcd for + 20 C48H37O2 (M-H ) 645.2794, meas 645.2820. [α] D = –186.9 (c 1.0, CH2Cl2). 307 The reaction of (S)-174d (238 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2 M, 2 mL), naphthalene-1-boronic acid (275 mg, 1.60 mmol) and ethanol (2 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:2) gave (S)-174v as a white solid (132 mg, 0.191 mmol, 48%). mp >260 °C; Rf = 0.35 (1:1 1 CH2Cl2/hexanes). Spectral data for 6v: H NMR (CDCl3, 500 MHz) δ 5.91 (s, 2H), 6.70-6.74 (m, 4H), 7.02-7.06 (m, 4H), 7.11-7.15 (m, 2H), 7.42 (s, 2H), 7.45-7.54 (m, 4H), 7.56-7.62 (m, 4H), 7.73 (dd, 2H, J = 8.5, 2.0 Hz), 7.88-7.96 (m, 6H), 8.01-8.04 (m, 2H), 8.48-8.40 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 113.18, 121.92, 122.99, 123.70, 125.48, 125.87, 126.07, 126.22, 126.71, 127.47, 127.58, 127.90, 128.39, 128.97, 130.16, 131.74, 133.74, 133.89, 138.30, 140.14, 2 140.25, 140.91, 150.60 (1 sp C not located); IR (thin film) 3511br s, 3056s, 1559s, 1381s, -1 + 20 1265s cm ; HRMS (ESI+) m/z calcd for C52H35O2 (M+H ) 691.2637, meas 691.2615. [α] D = –153.1 (c 1.0, CH2Cl2). 308 The reaction of (S)-174d (238 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2 M, 2 mL), naphthalene-2-boronic acid (275 mg, 1.60 mmol) and ethanol (2 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:1) gave (S)-174w as a white solid (108 mg, 0.157 mmol, 39%). mp >260 °C; Rf = 0.29 (1:1 1 CH2Cl2/hexanes). Spectral data for 174w: H NMR (DMSO-d6, 500 MHz) δ 6.77-6.79 (m, 4H), 7.01 (t, 4H, J = 7.5 Hz), 7.05-7.09 (m, 2H), 7.22 (s, 2H), 7.52-7.59 (m, 4H), 7.94-8.02 (m, 6H), 8.05-8.10 (m, 6H), 8.41 (s, 2H), 8.76 (s, 2H), 9.28 (s, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 117.98, 119.44, 120.34, 124.12, 125.22, 125.25, 126.07, 126.19, 126.44, 126.96, 127.50, 128.20, 2 128.56, 128.71, 132.21, 132.91, 133.45, 135.94, 137.69, 141.23, 141.47, 151.92 (2 sp C not -1 located); IR (thin film) 3511br s, 3056s, 1559s, 1497s, 1389s, 1213m cm ; HRMS (ESI–) m/z + 20 calcd for C52H33O2 (M-H ) 689.2481, meas 689.2501. [α] D = –153.1 (c 1.0, THF). 309 Benzene, ethanol and Na2CO3 (aq. 2 M) were purged (>10 min) with inert gas (Ar or N2) prior to use. To a 100 mL round bottom flask was added (S)-200d (171 mg, 0.25 mmol), tetrakis(triphosphine)palladium (29 mg, 0.025 mmol), benzene (5 mL) and Na2CO3 (aq. 2 M, 2 mL). To the stirred mixture was added anthracene-9-boronic acid (222 mg, 1.00 mmol) and ethanol (2 mL). The mixture was stirred at 90 ºC for 14 h with an argon balloon attached to the condenser. After cooling down to room temperature, the mixture was partitioned between EtOAc (20 mL) and brine (10 mL). The organic layer was separated, dried over MgSO4, filtered through Celite and concentrated to dryness. The product was purified by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:2). The purified product was dissolved in a mixture of THF and MeOH (10 mL, 1:1) and Amberlyst 15 (0.125g) was added. The mixture was stirred at 65 ºC for 15 h with an argon balloon attached to the condenser. After cooling down to room temperature, the mixture was filtered through filter paper and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, 310 CH2Cl2:hexanes 2:1) gave (S)-174x as a brownish pink solid in 95% yield over two steps (188 1 mg, 0.238 mmol). mp >260 °C; Rf = 0.29 (1:1 CH2Cl2/hexanes). Spectral data for 174x: H NMR (THF-d8, 500 MHz) δ 8.71-8.74 (m, 4H), 8.89-8.93 (m, 4H), 8.95-8.99 (m, 2H), 9.12-9.16 (m, 2H), 9.20 (s, 2H), 9.24-9.31 (m, 4H), 9.32-9.36 (m, 2H), 9.39 (dd, 2H, J = 8.5, 2.0 Hz), 9.54 (dd, 2H, J = 8.5, 1.0 Hz), 9.66 (dd, 2H, J = 8.5, 1.0 Hz), 9.82 (d, 2H, J = 8.0 Hz), 9.95 (t, 4H, J = 8.5 Hz), 10.29 (d, 2H, J = 9.0 Hz), 10.31 (d, 2H, J = 1.0 Hz), 10.44 (s, 2H); 13 C NMR (THF-d8, 125 MHz) δ 116.72, 121.21, 125.26, 125.78, 125.90, 125.95, 126.16, 126.24, 127.06, 127.42, 127.50, 127.75, 127.94, 128.44, 129.22, 129.30, 130.13, 130.71, 131.46, 131.47, 132.58, 132.60, + 134.78, 136.03, 138.25, 142.58, 143.18, 153.36; HRMS (ESI–) m/z calcd for C60H37O2 (M-H ) 20 789.2794, meas 789.2814. [α] D = –368.5 (c 1.0, THF). The reaction of (R)-174d (238 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2 M, 2 mL), thiophene-3-boronic acid (205 mg, 1.60 mmol) and ethanol (2 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:1) gave 311 (S)-174aa as an off-white solid (160 mg, 0.266 mmol, 66%). mp >260 °C; Rf = 0.27 (1:1 1 CH2Cl2/hexanes). Spectral data for 174aa: H NMR (DMSO-d6, 500 MHz) δ 6.72-6.75 (m, 4H), 6.98 (t, 4H, J = 7.5 Hz), 7.05 (t, 2H, J = 7.5 Hz), 7.70-7.74 (m, 4H), 7.84 (d, 2H, J = 8.5 Hz), 7.88 (dd, 2H, J = 8.5, 1.5 Hz), 8.00 (dd, 2H, J = 2.5, 1.5 Hz), 8.60 (s, 2H), 9.16 (s, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 117.92, 118.96, 119.44, 120.93, 123.96, 124.81, 126.13, 126.18, 126.92, 127.24, 128.35, 128.67, 131.30, 132.67, 141.08, 141.25, 141.77, 151.68; HRMS (ESI–) + 20 m/z calcd for C40H25O2S2 (M-H ) 601.1296, meas 601.1289. [α] D = +101.4 (c 1.0, THF). The reaction of (R)-174d (238 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2 M, 2 mL), furan-3-boronic acid (180 mg, 1.61 mmol) and ethanol (2 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:1) gave (S)-174ab as an off-white solid (110 mg, 0.193 mmol, 48%). mp 259-261 °C; Rf = 0.20 (1:1 1 CH2Cl2/hexanes). Spectral data for 174ab: H NMR (CDCl3, 500 MHz) δ 5.87 (s, 2H), 6.62-6.65 (m, 4H), 6.90 (dd, 2H, J = 2.0, 1.0 Hz), 6.94-6.98 (m, 4H), 7.04-7.09 (m, 2H), 7.29 (s, 2H), 7.53 (t, 2H, J = 1.5 Hz), 7.69 (dd, 2H, J = 8.5, 2.0 Hz), 7.77 (d, 2H, J = 8.5 Hz), 7.90 (t, 2H, 312 J = 1.5 Hz), 8.42-8.43 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 108.95, 113.19, 118.96, 121.89, 123.17, 126.04, 126.56, 126.66, 127.48, 128.31, 128.85, 129.77, 133.64, 139.05, 140.06, 140.42, -1 143.90, 150.29; IR (thin film) 3503br w, 1559s, 1507s, 1387s, 1163s cm ; HRMS (ESI–) m/z + 20 calcd for C40H25O4 (M-H ) 569.1753, meas 569.1766. [α] D = +105.1 (c 1.0, CH2Cl2). Stille coupling – illustrated for the synthesis of (S)-174ac (Procedure M) 82 7,7’-di-vinyl VANOL 174ac: To a flame-dried 25 mL Schlenk flask were added (S)-174d (119mg, 0.20 mmol) and tetrakis(triphosphine)palladium (23 mg, 0.020 mmol). The Schlenk flask was evacuated and backfill with N2 three times. Tributylstannylethylene (234 mL, 0.80 mmol) and dry benzene (5 mL) were added to the mixture under N2. The Schlenk flask was sealed and mixture was stirred at 95 °C overnight. The mixture was cooled to room temperature, diluted with CH2Cl2 and filtered through a pad of Celite (eluted with CH2Cl2). Purification of the crude product by column chromatography on silica gel (20 mm x 250 mm, CH2Cl2:hexanes 1:2) gave (S)-174ac as a white foamy solid (63 mg, 0.129 mmol, 64%). mp 113-119 °C; Rf = 1 0.28 (1:1 CH2Cl2/hexanes). Spectral data for 174ac: H NMR (CDCl3, 500 MHz) δ 5.37 (d, 2H, J =11.5 Hz), 5.84 (s, 2H), 5.93 (d, 2H, J = 17.5 Hz), 6.61-6.63 (m, 4H), 6.92-6.98 (m, 6H), 313 7.04-7.08 (m, 2H), 7.27 (s, 2H), 7.69-7.74 (m, 4H), 8.26 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 113.09, 114.38, 121.24, 121.87, 122.93, 124.85, 126.66, 127.46, 128.01, 128.82, 134.24, 134.95, -1 136.95, 140.05, 140.70, 150.48; IR (thin film) 3511br s, 3058s, 1559s, 1497s, 1381s, 1246s cm ; + 20 HRMS (ESI–) m/z calcd for C36H25O2 (M-H ) 489.1855, meas 489.1845. [α] D = –205.2 (c 1.0, CH2Cl2). The reaction of (R)-174d (238 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), 2-(tributylstannyl)thiophene (508 mL, 1.60 mmol) and benzene (10 mL) was performed according to Procedure M. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 2:3) gave (R)-174y as an off-white solid (170 mg, 0.282 mmol, 71%). mp > 260 °C; Rf = 0.20 (1:1 CH2Cl2/hexanes). 1 Spectral data for 174y: H NMR (THF-d8, 500 MHz) δ 8.57 (d, 4H, J = 7.0 Hz), 8.79 (t, 4H, J = 8.0 Hz), 8.86 (t, 2H, J = 8.0 Hz), 8.97-8.99 (m, 2H), 9.01 (s, 2H), 9.26 (d, 2H, J = 5.0 Hz), 9.41 (d, 2H, J = 4.0 Hz), 9.60 (d, 2H, J = 8.5 Hz), 9.66 (dd, 2H, J = 3.5, 1.5 Hz), 10.21 (s, 2H), 10.50 (s, 2H); 13 C NMR (THF-d8, 125 MHz) δ 116.69, 120.03, 121.16, 124.09, 125.44, 125.57, 125.60, 126.98, 127.84, 128.88, 129.02, 129.99, 131.85, 134.72, 142.26, 142.79, 145.79, 153.21; 314 -1 IR (thin film) 3505br s, 1559s, 1456s, 1387s cm ; HRMS (ESI+) m/z calcd for C40H27O2S2 + 20 (M+H ) 603.1452, meas 603.1440. [α] D = +30.6 (c 1.0, THF). The reaction of (R)-174d (238 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), 2-(tributylstannyl)furan (504 mL, 1.60 mmol) and benzene (10 mL) was performed according to Procedure M. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 2:3) gave (R)-174z as an off-white solid (199 mg, 1 0.349 mmol, 87%). mp 185-191 °C; Rf = 0.20 (1:1 CH2Cl2/hexanes). Spectral data for 174z: H NMR (CDCl3, 500 MHz) δ 5.89 (s, 2H), 6.53 (dd, 2H, J = 8.5, 2.0 Hz), 6.64-6.67 (m, 4H), 6.83 (d, 2H, J = 3.0 Hz), 6.94-6.98 (m, 4H), 7.05-7.09 (m, 2H), 7.28 (s, 2H), 7.54 (d, 2H, J = 2.0 Hz), 7.77 (d, 2H, J = 8.5 Hz), 7.86 (dd, 2H, J = 8.5, 2.0 Hz), 8.63-8.64 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 105.83, 111.87, 113.31, 117.17, 121.90, 123.05, 123.90, 126.69, 127.47, 128.16, 128.21, 128.83, 133.73, 140.05, 140.66, 142.46, 150.57, 154.08; IR (thin film) 3509br s, 1559s, -1 + 1387s, 1223s cm ; HRMS (ESI+) m/z calcd for C40H27O4 (M+H ) 571.1909, meas 571.1899. 20 [α] D = –1.5 (c 1.0, CH2Cl2). 315 7,7’-di-n-butyl VANOL 174j: The following procedure was adapted from one for a related 14 compound: To a 25 mL round bottom flask was added (R)-174z (193 mg, 0.32 mmol), MeOH (10 mL), THF (10 mL) and Raney-Ni (50% slurry in H2O, 10 mL). A H2 balloon was attached to the flask and the mixture was stirred at room temperature for 24 h. The resulting mixture was filtered through a pad of Celite (eluted with CH2Cl2). After removal of the solvent, the residue was partitioned between CH2Cl2 (10 mL) and NaHCO3 (sat. aq. 10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL x 2). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2:hexanes 1:3) gave the product (R)-174j as an off-white foamy solid (115 mg, 0.21 mmol, 65%). mp 68-72 °C; Rf = 1 0.26 (1:2 CH2Cl2/hexanes). Spectral data for 174j: H NMR (CDCl3, 500 MHz) δ 0.96 (t, 6H, J = 7.5 Hz), 1.41-1.49 (m, 4H), 1.71-1.78 (m, 4H), 2.84 (t, 4H, J = 7.5 Hz), 5.81 (s, 2H), 6.61-6.64 (m, 4H), 6.93-6.97 (m, 4H), 7.03-7.07 (m, 2H), 7.28 (s, 2H), 7.42 (dd, 2H, J = 8.5, 2.0 Hz), 7.70 (d, 2H, J = 8.5 Hz), 8.12 (d, 2H, J = 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 14.01, 22.53, 33.67, 36.09, 112.78, 121.14, 121.81, 122.98, 126.43, 127.40, 127.60, 128.89, 129.05, 133.07, 139.77, 316 -1 140.38, 140.54,149.93; IR (thin film) 3515br s, 2928s, 1559s, 1456s, 1387s, 1167s cm ; HRMS + 20 (ESI–) m/z calcd for C40H37O2 (M-H ) 549.2794, meas 549.2813. [α] D = +196.3 (c 1.0, CH2Cl2). Kumada coupling – illustrated for the synthesis of 7,7’-di-ethyl VANOL 174i (Procedure N) 15 To a flame-dried 25 mL round bottom flask was added (S)-199d (156 mg, 0.25 mmol), NidppeCl2 (22 mg, 0.042 mmol) and dry THF (5 mL). To the resulting mixture was added EtMgBr (3 M in ether, 0.28 mL, 0.84 mmol) dropwise at 0 °C. The mixture was stirred at 60 °C for 24 h. After cooling to room temperature, NH4Cl (sat. aq. 1 mL) was added to the mixture. After removal of the organic solvent, the residue was partitioned between CH2Cl2 (6 mL) and H2O (3 mL). The organic layer was separated, dried over MgSO4 filtered through Celite and concentrated to dryness. The residue was purified by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:3). The purified product was dissolved in CH2Cl2 (4 mL) and cooled to 0 ºC, and then BBr3 (1 M in CH2Cl2, 1.5 mL, 1.5 mmol) was added dropwise to the mixture at 0 ºC. The mixture was stirred at room temperature overnight with an argon balloon 317 attached to the flask. The mixture was then cooled to 0 ºC and H2O (8 mL) was added dropwise. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (10 mL × 3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 2:5) gave (S)-174i as an off-white foamy solid in 74% yield over two steps 1 (91 mg, 0.184 mmol). mp 61-66 °C; Rf = 0.21 (1:2 CH2Cl2/hexanes). Spectral data for 174i: H NMR (CDCl3, 500 MHz) δ 1.39 (t, 6H, J = 7.5 Hz), 2.89 (q, 4H, J = 7.5 Hz), 5.82 (s, 2H), 6.62-6.65 (m, 4H), 6.94-6.97 (m, 4H), 7.03-7.08 (m, 2H), 7.29 (s, 2H), 7.44 (dd, 2H, J = 8.5, 2.0 Hz), 7.71 (d, 2H, J = 8.5 Hz), 8.13-8.15 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 15.59, 29.31, 112.81, 120.46, 121.82, 123.02, 126.44, 127.40, 127.70, 128.66, 128.89, 133.09, 139.80, 140.36, -1 141.83, 149.96; IR (thin film) 3513br m, 2928s, 1559s 1456s, 1387s, 1167s cm ; HRMS (ESI+) + 20 m/z calcd for C36H31O2 (M+H ) 495.2324, meas 495.2334. [α] D = –228.7 (c 1.0, CH2Cl2). 7,7’-di-cyclohexyl VANOL 174l: The reaction of (S)-199d (156 mg, 0.25 mmol), NidppeCl2 (22 mg, 0.042 mmol) and CyMgCl (2 M in ether, 0.42 mL, 0.84 mmol) was performed according to Procedure N. Purification of the crude product by column chromatography on silica gel (30 318 mm x 200 mm, CH2Cl2:hexanes 1:4) gave (S)-174l as an off-white foamy solid over in 71% yield two steps (107 mg, 0.178 mmol). mp 131-137 °C; Rf = 0.33 (1:2 CH2Cl2/hexanes). 1 Spectral data for 174l: H NMR (CDCl3, 500 MHz) δ 1.30-1.38 (m, 2H), 1.42-1.52 (m, 4H), 1.56-1.65 (m, 4H), 1.78-1.82 (m, 2H), 1.89-1.94 (m, 4H), 2.01-2.05 (m, 4H), 2.71-2.78 (m, 2H), 6.60-6.64 (m, 4H), 6.93-6.97 (m, 4H), 7.03-7.07 (m, 2H), 7.28 (s, 2H), 7.46 (dd, 2H, J = 8.5, 2.0 Hz), 7.71 (d, 2H, J = 8.5 Hz), 8.15 (d, 2H, J = 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 26.21, 26.96, 34.43, 34.48, 44.95, 112.69, 119.46, 121.78, 122.98, 126.40, 127.41, 127.61, 127.73, 128.88, 133.25, 139.81, 140.39, 145.62, 150.06; IR (thin film) 3513br m, 2924s, 1559s, 1497s, -1 + 1387s, 1265s, 1165s cm ; HRMS (ESI–) m/z calcd for C44H41O2 (M-H ) 601.3107, meas 20 601.3093. [α] D = –156.7 (c 1.0, CH2Cl2). Ullman coupling15 7,7’-di-methoxyl VANOL 174g: To a flame-dried 25 mL round bottom flask was added (S)-200e (1.32 g, 1.70 mmol), NaOMe (551 mg, 10.2 mmol), CuCl (50 mg, 0.51 mmol), MeOH (5 mL) and dry DMF (5 mL). The mixture was stirred at 80 °C for 2 h. After cooling down to room temperature, the mixture was poured into ice water (50 mL). The mixture was extracted 319 with EtOAc (30 mL x 3). The combined organic layer was washed with H2O (50 mL x 4) and brine (50 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. The product was purified by column chromatography on silica gel (20 mm x 200 mm, EtOAc:hexanes 1:2). The purified product was dissolved in a mixture of THF and MeOH (68 mL, 1:1) and Amberlyst 15 (0.85g) was added. The mixture was stirred at 65 ºC for 15 h with an argon balloon attached to the condenser. After cooling down to room temperature, the mixture was filtered through filter paper and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (20 mm x 200 mm, CH2Cl2) gave (S)-174g as an off-white solid in 60% yield over two steps (505 mg, 1.01 mmol). mp 178-180 °C; Rf = 0.26 (CH2Cl2). 1 Spectral data for 174g: H NMR (CDCl3, 500 MHz) δ 3.99 (s, 6H), 5.75 (s, 2H), 6.62 (dd, 4H, J = 8.5, 1.5 Hz), 6.95 (t, 4H, J = 7.5 Hz), 7.05 (t, 2H, J = 7.5 Hz), 7.72 (dd, 2H, J = 9.0, 3.0 Hz), 7.26 (s, 2H), 7.60 (d, 2H, J = 3.0 Hz), 7.68 (d, 2H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 55.48, 100.88, 113.38, 120.36, 121.82, 123.80, 126.40, 127.42, 128.88, 129.33, 130.08, 138.22, 140.30, 149.26, 157.76; IR (thin film) 3507br w, 2936w, 1597s, 1497s, 1392s, 1206s, 1163s -1 + 20 cm ; HRMS (ESI–) m/z calcd for C34H25O4 (M-H ) 497.1753, meas 497.1751. [α] D = –206.6 (c 1.0, CH2Cl2). Sonogashira coupling – illustrated for the synthesis of (S)-6ae (Procedure O) 320 63c To a flame-dried 25 mL round bottom flask was added (S)-174e (345 mg, 0.50 mmol), bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.02 mmol), CuI (4 mg, 0.02 mmol) and THF (2mL) under N2. Triethylamine (0.56 mL, 4 mmol) was then added to the mixture. The reaction mixture was stirred at room temperature for 5 minutes and then ethynyltrimethylsilane (0.16 mL, 1.1 mmol) was added. After stirring at room temperature for 24 h, the mixture was treated with hexanes (2 mL) and concentrated. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:2) gave (S)-174ae as an off-white solid (262 mg, 0.416 mmol, 83%). mp 267-269 °C; Rf = 0.45 (1:1 CH2Cl2/hexane). 1 Spectral data for 174ae: H NMR (CDCl3, 500 MHz) δ 0.29 (s, 18H), 5.79 (s, 2H), 6.62 (dd, 4H, J = 8.5, 1.5 Hz), 6.93-6.97 (m, 4H), 7.04-7.09 (m, 2H), 7.27 (s, 2H), 7.57 (dd, 2H, J = 8.5, 1.5 Hz), 7.68 (d, 2H, J = 8.5 Hz), 8.47-8.49 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 0.01, 95.07, 105.43, 113.26, 120.35, 121.88, 122.46, 126.91, 127.08, 127.52, 127.66, 128.78, 130.28, 133.97, 139.79, 141.57, 150.18; IR (thin film) 3521s, 3059m, 2959s, 2155s, 1559s, 1497m, 1387s, 1250s, -1 + 858s cm ; mass spectrum, m/z (% rel intensity) 630 M (30), 315 (15), 300 (69), 239 (3). Anal 321 20 calcd for C42H38O2Si2: C, 79.95; H, 6.07. Found: C, 79.88; H, 6.22. [α] D = –43.8 (c 1.0, CH2Cl2). The reaction of (S)-174e (138 mg, 0.20 mmol), bis(triphenylphosphine)palladium(II) dichloride (5.6 mg, 0.0080 mmol), CuI (1.6 mg, 0.0080 mmol), triethylamine (0.23 mL, 1.6 mmol) and 3,3-dimethyl-1-butyne (54 mL, 0.44 mmol) was performed according to Procedure O. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:3) gave (S)-174af as an off-white solid (106 mg, 0.177 mmol, 89%). mp 1 175-182 °C; Rf = 0.41 (1:1 CH2Cl2/hexanes). Spectral data for 174af: H NMR (CDCl3, 500 MHz) δ 1.37 (s, 18H), 5.79 (s, 2H), 6.60-6.63 (m, 4H), 6.92-6.96 (m, 4H), 7.04-7.08 (m, 2H), 7.25 (s, 2H), 7.52 (dd, 2H, J = 8.5, 1.5 Hz), 7.66 (d, 2H, J = 8.5 Hz), 8.38-8.39 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 28.08, 31.08, 79.43, 99.39, 113.05, 121.31, 121.81, 122.55, 125.98, 126.76, 127.45, 127.53, 128.78, 130.47, 133.46, 139.89, 140.93, 149.97; IR (thin film) 3521br s, -1 + 2987s, 1559s, 1456s, 1387s, 1279s cm ; HRMS (ESI+) m/z calcd for C44H39O2 (M+H ) 20 599.2950, meas 599.2925. [α] D = –76.1 (c 1.0, CH2Cl2). 322 To a flame-dried 25 mL round bottom flask was added (S)-174ae (126 mg, 0.20 mmol) and dry THF (8 mL) under N2. To the solution was slowly added TBAF (1 M in THF, 0.8 mL, 0.8 mmol). After stirring at room temperature for 1 h, the reaction was quenched by the addition of brine (2 mL) and ether (8 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (8 mL x 2). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:1) gave (S)-174ad as an off-white solid (78 mg, 0.160 mmol, 89%). mp >260 °C; Rf = 0.17 (1:1 CH2Cl2/hexanes). 1 Spectral data for 174ad: H NMR (CDCl3, 500 MHz) δ 3.17 (s, 2H), 5.83 (s, 2H), 6.58-6.61 (m, 4H), 6.94-6.98 (m, 4H), 7.06-7.10 (m, 2H), 7.27 (s, 2H), 7.59 (dd, 2H, J = 8.5, 1.5 Hz), 7.70 (d, 2H, J = 8.5 Hz), 8.53-8.54 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 77.80, 84.01, 113.23, 119.22, 121.86, 122.38, 126.91, 127.41, 127.52, 127.79, 128.75, 130.27, 134.07, 139.66, 141.73, -1 150.11 IR (thin film) 3505br s, 3293s, 1559s, 1497s, 1385s, 1265s cm ; HRMS (ESI+) m/z + 20 calcd for C36H23O2 (M+H ) 487.1698, meas 487.1682. [α] D = –173.7 (c 1.0, CH2Cl2). 323 6.2.5 Catalytic asymmetric aziridination of benzhydryl imines with ethyl diazoacetate mediated by a catalyst prepared from 7,7’-di-t-butylVANOL 174m General procedure illustrated for the synthesis 1-benzhydryl-3-phenylaziridine-2-carboxylate (Procedure P) of (2R,3R)-ethyl 26g A 25 mL pear-shaped single necked Schlenk flask which had its 14/20 joint replaced by a threaded high vacuum Teflon valve was flame dried (with a stir bar in it) and cooled to room temperature under N2 and charged with (S)-t-Bu2VANOL 174m (13.8 mg, 0.025 mmol) and triphenyl borate (29 mg, 0.10 mmol). The mixture was dissolved in dry toluene (1 mL). After the addition of H2O (0.45 mL, 0.025 mmol), the Teflon valve was closed and the flask was heated at 80 °C for 1 h. Toluene was carefully removed by exposing to high vacuum (0.1 mmHg) by slightly cracking the Teflon valve. After removal of the solvent, the Teflon valve was completely opened and the flask was heated to 80 °C under high vacuum for 30 min. To the Schlenk flask containing the catalyst were added imine 31d (136 mg, 0.50 mmol) and dry toluene (1 mL). The reaction mixture was stirred at room temperature for 5 minutes and then ethyl diazoacetate (62 µL, 0.6 mmol) was added via syringe. The Teflon valve was closed and the reaction mixture was stirred at room temperature for 24 h. The mixture was then diluted with hexanes (5 mL) and transferred to a 25 mL round bottom flask. Rotary evaporation of the solvent followed by 324 exposure to high vacuum (0.5 mm Hg) for 30 minutes gave the crude mixture as an off-white 1 solid. The conversion was determined from the H NMR spectrum of the crude reaction mixture by integration of the aziridine ring methine protons relative to either the imine methine proton or 1 the H on the imine carbon. The cis/trans ratio was determined to be >100:1 from the H NMR spectrum of the crude reaction mixture by integration of the ring methine protons for each aziridine. The cis (J = 6-8 Hz) and the trans (J = 1-3 Hz) coupling constants were used to differentiate the two isomers. The yields of the acyclic enamine products were determined to be 1 <1% from the H NMR spectrum of the crude reaction mixture by integration of the N-H proton of the enamine relative to the aziridine ring methine protons with the aid of the isolated yield of the cis-aziridine. The crude product was purified by column chromatography on silica gel (35 mm x 400 mm, EtOAc:hexanes 1:19) to afford 31d as a white solid (146 mg, 0.41 mmol, 82%). The optical purity was determined to be 98% ee by HPLC (Chiralcel OD-H column, 222 nm, 90:10 hexane/iPrOH, flow rate: 0.7 mL/min). Retention time: Rt = 4.42 min for (2S,3S)-31d (minor) and Rt = 8.17 min for (2R,3R)-31d (major). The reaction was repeated and stopped after a reaction time of 4 h to give an 89% yield of 31d with 97.4% ee. mp 126-127 °C; Rf = 0.13 (1:9 1 EtOAc:hexanes). Spectral data for 31d: H NMR (CDCl3, 500 MHz) δ 0.96 (t, 3H, J = 7.0 Hz), 2.65 (d, 1H, J = 7.0 Hz), 3.19 (d, 1H, J = 7.0 Hz), 3.93 (s, 1H), 3.90-3.94 (m, 2H), 7.14-7.20 (m, 2H), 7.20-7.26 (m, 5H), 7.30-7.34 (m, 2H), 7.37-7.40 (m, 2H), 7.46-7.49 (m, 2H), 7.57-7.60 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.93, 46.38, 48.03, 60.55, 77.71, 127.19, 127.21, 127.31, 2 127.40, 127.54, 127.75, 127.78, 128.48, 135.03, 142.38, 142.52, 167.72 (1 sp C not located); IR 325 -1 (thin film) 3031w, 2982w, 1738s, 1456m, 1204s cm ; mass spectrum, m/z (% rel intensity) 357 + 20 M (0.05), 190 (46), 167 (100), 117 (61). [α] D = +36.2 (c 1.0, CH2Cl2) on 98% ee (2R,3R)-31d. 26g (2R,3R)-ethyl 1-benzhydryl-3-(4-nitrophenyl)aziridine-2-carboxylate 31a: The reaction of imine 9a (158 mg, 0.50 mmol) and ethyl diazoacetate (62 µL, 0.6 mmol) was performed according to the general procedure (Procedure P). Cis/trans >100:1 and the acyclic enamine 1 products were determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (25 mm x 300 mm, EtOAc/benzene 1:40) to afford 31a as an off-white solid (193 mg, 0.48 mmol, 96%). The optical purity was determined to be 98% ee by HPLC (Chiralcel OD-H column, 222 nm, 90:10 hexane/iPrOH, flow rate: 0.7 mL/min). Retention time: Rt = 8.01 min for (2S,3S)-31a (minor) and Rt = 9.86 min for (2R,3R)-31a (major). mp 134-135 °C; Rf = 0.30 (1:40 EtOAc/benzene). 1 Spectral data for 31a: H NMR (CDCl3, 500 MHz) δ 1.00 (t, 3H, J = 7.0 Hz), 2.78 (d, 1H, J = 7.0 Hz), 3.24 (d, 1H, J = 7.0 Hz), 3.93 (q, 2H, J = 7.0 Hz), 3.98 (s, 1H), 7.16-7.20 (m, 1H), 7.22-7.27 (m, 3H), 7.31-7.35 (m, 2H), 7.42-7.45 (m, 2H), 7.55-7.60 (m, 4H), 8.08-8.12 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.00, 46.91, 47.05, 60.94, 77.54, 123.05, 127.05, 127.36, 127.44, 127.68, 128.60, 128.65, 128.77, 141.82, 142.04, 142.50, 147.32, 166.95; IR (thin film) 326 -1 3029w, 2982w, 1744s, 1522s, 1348s, 1202s cm ; mass spectrum, m/z (% rel intensity) 402 M 20 (0.03), 167 (100), 165 (49), 152 (32), 89 (14). [α] D = –10.9 + (c 1.0, CH2Cl2) on 98% ee (2R,3R)-31a. 26g (2R,3R)-ethyl 1-benzhydryl-3-(4-bromophenyl)aziridine-2-carboxylate 31b: The reaction of imine 9b (175 mg, 0.50 mmol) and ethyl diazoacetate (62 µL, 0.6 mmol) was performed according to the general procedure (Procedure P). Cis/trans >100:1 and the acyclic enamine 1 products were determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (35 mm x 400 mm, EtOAc/hexanes 1:19) to afford 31b as a white solid (196 mg, 0.45 mmol, 90%). The optical purity was determined to be 98% ee by HPLC (Chiralcel OD-H column, 222 nm, 98:2 hexane/iPrOH, flow rate: 0.7 mL/min). Retention time: Rt = 5.22 min for (2S,3S)-31b (minor) and Rt = 12.73 min for (2R,3R)-31b (major). mp 151-152 °C; Rf = 0.44 (1:40 EtOAc/benzene). Spectral data for 31b: 1H NMR (CDCl3, 500 MHz) δ 1.01 (t, 3H, J = 7.0 Hz), 2.66 (d, 1H, J = 7.0 Hz), 3.12 (d, 1H, J = 7.0 Hz), 3.91-3.97 (m, 3H), 7.15-7.19 (m, 1H), 7.21-7.29 (m, 5H), 7.30-7.34 (m, 2H), 7.34-7.37 (m, 2H), 7.42-7.45 (m, 2H), 7.55-7.57 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.00, 46.47, 47.35, 60.71, 77.62, 121.35, 127.14, 127.29, 127.43, 127.50, 128.52, 128.53, 129.55, 130.90, 134.08, 142.15, 142.32, 167.42; IR (thin film) 2978w, 1734s, 1456m, 327 -1 + 1202s, 1065m cm ; mass spectrum, m/z (% rel intensity) 437 M (0.67, 79 Br), 270 (23, 81 Br), 268 (21, 79 Br), 167 (100, 81 Br), 165 (41, 79 81 + Br), 435 M (0.35, 20 Br). [α] D = +9.9 (c 1.0, CH2Cl2) on 98% ee (2R,3R)-31b. 26g (2R,3R)-ethyl 1-benzhydryl-3-(2-bromophenyl)aziridine-2-carboxylate 31c: The reaction of imine 9c (175 mg, 0.50 mmol) and ethyl diazoacetate (62 µL, 0.6 mmol) was performed according to the general procedure (Procedure P). Cis/trans = 8:1 and the acyclic enamine 1 products were determined to be 4% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (25 mm x 300 mm, EtOAc/benzene 1:400) to afford 31c as a white solid (171 mg, 0.39 mmol, 78%). The optical purity was determined to be 95% ee by HPLC (Chiralcel OD-H column, 222 nm, 99.5:0.5 hexane/iPrOH, flow rate: 0.7 mL/min). Retention time: Rt = 14.66 min for (2S,3S)-31c (minor) and Rt = 18.68 min for (2R,3R)-31c (major). mp 145-146 °C; Rf = 0.41 (1:40 EtOAc/benzene). 1 Spectral data for 31c: H NMR (CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.0 Hz), 2.78 (d, 1H, J = 7.0 Hz), 3.33 (d, 1H, J = 7.0 Hz), 3.93 (q, 2H, J = 7.0 Hz), 4.00(s, 1H), 7.05 (td, 1H, J = 7.5, 1.5 Hz), 7.17-7.29 (m, 5H), 7.30-7.34 (m, 2H), 7.40 (dd, 1H, J = 7.5, 1.5 Hz), 7.47-7.50 (m, 2H), 7.56 (d, 3H, J = 8.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.89, 45.91, 48.81, 60.61, 77.59, 123.27, 126.74, 127.03, 127.21, 127.60, 127.69, 128.52, 128.58, 128.80, 130.82, 131.59, 134.45, 328 -1 20 142.16, 142.39, 167.57; IR (thin film) 1738s, 1456s, 1200s cm ; [α] D = +21.8 (c 1.0, CH2Cl2) on 95% ee (2R,3R)-31c. (2R,3R)-ethyl 1-benzhydryl-3-(naphthalen-1-yl)aziridine-2-carboxylate 26g 31e: The reaction of imine 9e (161 mg, 0.50 mmol) and ethyl diazoacetate (62 µL, 0.6 mmol) was performed according to the general procedure (Procedure P). Cis/trans >100:1 and the acyclic 1 enamine products were determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (35 mm x 400 mm, EtOAc/hexanes 1:19) to afford 31e as a white solid (186 mg, 0.46 mmol, 91%). The optical purity was determined to be 99% ee by HPLC (Chiralcel OD-H column, 222 nm, 99:1 hexane/iPrOH, flow rate: 0.7 mL/min). Retention time: Rt = 9.32 min for (2R,3R)-31e (major) and Rt = 11.52 min for (2S,3S)-31e (minor). mp 152-154 °C; Rf = 0.13 (1:9 EtOAc/hexanes). 1 Spectral data for 31e: H NMR (CDCl3, 500 MHz) δ 0.62 (t, 3H, J = 7.0 Hz), 2.90 (d, 1H, J = 7.0 Hz), 3.68-3.76 (m, 3H), 4.07 (s, 1H), 7.17-7.21 (m, 1H), 7.23-7.30 (m, 3H), 7.32-7.38 (m, 3H), 7.40-7.44 (m, 1H), 7.44-7.48 (m, 1H), 7.52-7.55 (m, 2H), 7.61-7.64 (m, 2H), 7.66 (d, 1H, J = 7.0 Hz)7.68 (d, 1H, J = 8.0 Hz), 7.77-7.79 (m, 1H), 8.08 (d, 1H, J = 8.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.58, 46.06, 46.40, 60.38, 78.03, 122.97, 125.32, 125.41, 125.85, 126.56, 127.17, 127.19, 127.61, 127.62, 127.91, 128.52, 128.58, 130.53, 131.46, 133.08, 142.27, 142.51, 329 2 -1 20 167.79 (1 sp C not located); IR (thin film) 3032w, 2980w, 1738s, 1455m, 1192s cm ; [α] D = –16.1 (c 1.0, CH2Cl2) on 99% ee (2R,3R)-31e. 26g (2R,3R)-ethyl 1-benzhydryl-3-(o-tolyl)aziridine-2-carboxylate 31f: The reaction of imine 9f (143 mg, 0.50 mmol) and ethyl diazoacetate (62 µL, 0.6 mmol) was performed according to the general procedure (Procedure P). Cis/trans >100:1 and the acyclic enamine products were 1 determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (25 mm x 300 mm, EtOAc/benzene 1:200) to afford 31f as a white solid (171 mg, 0.46 mmol, 92%). The optical purity was determined to be 97% ee by HPLC (Chiralcel OD-H column, 222 nm, 99:1 hexane/iPrOH, flow rate: 1.0 mL/min). Retention time: Rt = 5.71 min for (2S,3S)-31f (minor) and Rt = 7.42 min for (2R,3R)-31f (major). mp 162-163 °C; Rf = 0.35 (1:40 EtOAc/benzene). 1 Spectral data for 31f: H NMR (CDCl3, 500 MHz) δ 0.88 (t, 3H, J = 7.0 Hz), 2.29 (s, 3H), 2.72 (d, 1H, J = 7.0 Hz), 3.20 (d, 1H, J = 7.0 Hz), 3.89 (q, 2H, J = 7.0 Hz), 3.94 (s, 1H), 7.00-7.03 (m, 1H), 7.06-7.12 (m, 2H), 7.16-7.20 (m, 1H), 7.21-7.29 (m, 3H), 7.30-7.34 (m, 2H), 7.49-7.54 (m, 3H), 7.58-7.61 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.82, 18.77, 45.61, 46.90, 60.43, 77.91, 125.33, 127.12, 127.13, 127.51, 127.72, 128.47, 128.49, 128.52, 129.08, 133.11, 135.99, 142.39, 330 2 -1 20 142.55, 167.91 (1 sp C not located); IR (thin film) 1740s, 1455s, 1196s cm . [α] D = +36.0 (c 1.0, CH2Cl2) on 97% ee (2R,3R)-31f. (2R,3R)-ethyl 1-benzhydryl-3-(4-methoxyphenyl)aziridine-2-carboxylate 26g 31g: The reaction of imine 9g (151 mg, 0.50 mmol) and ethyl diazoacetate (62 µL, 0.6 mmol) was performed according to the general procedure (Procedure P). Cis/trans >100:1 and the acyclic 1 enamine products were determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography. The silica gel for column chromatography was pre-conditioned by preparing a slurry in a 1:9 mixture of Et3N:CH2Cl2 which was loaded into a column (35 x 400 mm). The solvent was drained out and then the silica gel was dried by flushing with nitrogen for one hour to remove excess Et3N. The silica gel column was then saturated with a 1:1:8 mixture of CH2Cl2:ether:hexanes. The crude aziridine was loaded onto the column and then elution with the same solvent afforded 31g as a white solid (138 mg, 0.36 mmol, 71%). The optical purity was determined to be 98% ee by HPLC (Chiralcel OD-H column, 222 nm, 95:5 hexane/iPrOH, flow rate: 0.7 mL/min). Retention time: Rt = 6.65 min for (2S,3S)-16g (minor) and Rt = 13.51 min for (2R,3R)-31g (major). mp 134-135 °C; Rf = 1 0.21 (1:5 EtOAc/hexanes). Spectral data for 31g: H NMR (CDCl3, 500 MHz) δ 1.01 (t, 3H, J = 7.0 Hz), 2.61 (d, 1H, J = 7.0 Hz), 3.14 (d, 1H, J = 7.0 Hz), 3.74 (s, 3H), 3.90-3.97 (m, 2H), 3. 92 331 (s, 1H), 6.75-6.79 (m, 2H), 7.14-7.18 (m, 1H), 7.20-7.26 (m, 3H), 7.29-7.33 (m, 4H), 7.44-7.47 (m, 2H), 7.56-7.59 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.00, 46.32, 47.73, 55.16, 60.52, 77.72, 113.23, 127.12, 127.16, 127.22, 127.35, 127.52, 128.45, 128.88, 142.41, 142.57, 158.90, 2 167.86 (1 sp C not located); IR (thin film) 2932w, 1734s, 1518s, 1456s, 1240s, 1198s, 1032s -1 + cm ; mass spectrum, m/z (% rel intensity) 387 M (0.09), 222 (7), 221 (100), 167 (48), 166 (22), 20 147 (23), 146 (47), 91 (14). [α] D = +23.2 (c 1.0, CH2Cl2) on 98% ee (2R,3R)-31g. 26g (2R,3R)-ethyl 1-benzhydryl-3-propylaziridine-2-carboxylate 31h: The reaction of imine 9h (119 mg, 0.50 mmol) and ethyl diazoacetate (62 µL, 0.6 mmol) was performed according to the general procedure (Procedure P). Cis/trans >100:1 and the acyclic enamine products were 1 determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (25 mm x 300 mm, EtOAc/benzene 1:200) to afford 31h as a white solid (125 mg, 0.39 mmol, 77%). The optical purity was determined to be 94% ee by HPLC (Chiralcel OD-H column, 222 nm, 99:1 hexane/iPrOH, flow rate: 1.0 mL/min). Retention time: Rt = 3.30 min for (2S,3S)-31h (minor) and Rt = 6.32 min for (2R,3R)-31h (major). mp 102-103 °C; Rf = 0.26 (1:40 EtOAc/benzene). 1 Spectral data for 31h: H NMR (CDCl3, 500 MHz) δ 0.73 (t, 3H, J = 7.0 Hz), 1.00-1.08 (m, 1H), 1.10-1.18 (m, 1H), 1.23 (t, 3H, J = 7.0 Hz), 1.40-1.48 (m, 1H), 1.50-1.58 (m, 1H), 2.02 (dd, 1H, J = 6.5, 6.5 Hz), 2.27 (d, 1H, J = 6.5 Hz), 3.65 (s, 1H), 4.11-4.23 (m, 2H), 7.17-7.23 (m, 2H), 332 7.24-7.29 (m, 4H), 7.36-7.39 (m, 2H), 7.45-7.48 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.61, 14.26, 20.31, 29.90, 43.37, 46.68, 60.67, 77.96, 126.99, 127.15, 127.35, 127.86, 128.32, 128.34, -1 142.46, 142.82, 169.52; IR (thin film) 2959m, 1732s, 1456m, 1196s cm ; mass spectrum, m/z + (% rel intensity) 323 M (0.81), 294 (9), 206 (9), 167 (100), 156 (100), 152 (80), 128 (78). 20 [α] D = +102.2 (c 1.0, CH2Cl2) on 94% ee (2R,3R)-31h. 26g (2R,3R)-ethyl 1-benzhydryl-3-cyclohexylaziridine-2-carboxylate 31i: The reaction of imine 9i (139 mg, 0.50 mmol) and ethyl diazoacetate (62 µL, 0.6 mmol) was performed according to the general procedure (Procedure P). Cis/trans >100:1 and the acyclic enamine 1 products were determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (25 mm x 300 mm, EtOAc/benzene 1:200) to afford 31i as a white solid (160 mg, 0.44 mmol, 88%). The optical purity was determined to be 94% ee by HPLC (Chiralcel OD-H column, 222 nm, 99:1 hexane/iPrOH, flow rate: 1.0 mL/min). Retention time: Rt = 3.29 min for (2S,3S)-31i (minor) and Rt = 6.41 min for (2R,3R)-31i (major). mp 161-162 °C; Rf = 0.30 (1:40 EtOAc/benzene). 1 Spectral data for 31i: H NMR (CDCl3, 500 MHz) δ 0.45-0.54 (m, 1H), 0.90-1.33 (m, 6H), 1.24 (t, 3H, J = 7.0 Hz), 1.42-1.62 (m, 4H), 1.79 (dd, 1H, J = 7.0, 2.5 Hz), 2.25 (d, 1H, J = 7.0 Hz), 3.60 (s, 1H), 4.13-4.26 (m, 2H), 7.17-7.22 (m, 2H), 7.24-7.30 (m, 4H), 7.31-7.34 (m, 2H), 333 7.47-7.49 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.28, 25.36, 25.54, 26.14, 30.13, 30.73, 36.28, 43.41, 52.14, 60.67, 78.22, 126.89, 127.08, 127.49, 128.27, 128.31, 128.36, 142.36, -1 20 142.76, 169.64; IR (thin film) 2919s, 1732s, 1450m, 1190s cm . [α] D = +125.7 (c 1.0, CH2Cl2) on 94% ee (2R,3R)-31i. 26g (2R,3R)-ethyl 1-benzhydryl-3-(tert-butyl)aziridine-2-carboxylate 31j: The reaction of imine 9j (126 mg, 0.50 mmol) and ethyl diazoacetate (62 µL, 0.6 mmol) was performed according to the general procedure (Procedure P). Cis/trans >100:1 and the acyclic enamine 1 products were determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (25 mm x 300 mm, EtOAc/benzene 1:200) to afford 31j as a white solid (150 mg, 0.45 mmol, 89%). The optical purity was determined to be 96% ee by HPLC (Chiralcel OD-H column, 222 nm, 99:1 hexane/iPrOH, flow rate: 1.0 mL/min). Retention time: Rt = 3.56 min for (2S,3S)-31j (minor) and Rt = 9.31 min for (2R,3R)-31j (major). mp 148-149 °C; Rf = 0.41 (1:40 EtOAc/benzene). 1 Spectral data for 31j: H NMR (CDCl3, 500 MHz) δ 0.69 (s, 9H), 1.28 (t, 3H, J = 7.0 Hz), 1.75 (d, 1H, J = 7.0 Hz), 2.15 (d, 1H, J = 7.0 Hz), 3.58 (s, 1H), 4.04-4.12 (m, 1H), 4.19-4.26 (m, 1H), 7.17-7.21 (m, 2H), 7.24-7.31 (m, 4H), 7.37-7.40 (m, 2H), 7.64-7.67 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.09, 27.40, 31.60, 43.39, 56.09, 60.58, 79.24, 126.85, 127.27, 127.37, 128.19, 334 -1 128.21, 128.27, 142.63, 143.46, 169.73; IR (thin film) 2953m, 1738s, 1449m, 1194s cm . 20 [α] D = +133.2 (c 1.0, CH2Cl2) on 96% ee (2R,3R)-31j. (2R,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(4-bromophenyl)aziridine26j -2-carboxylate 202b: The reaction of imine 201b (93.2 mg, 0.20 mmol) and ethyl diazoacetate (25 µL, 0.24 mmol) was performed according to the general procedure (Procedure P). Cis/trans 1 >100:1 and the acyclic enamine products were determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (30 mm x 250 mm, EtOAc/benzene 1:40) to afford 202b as a white foamy solid (105 mg, 0.19 mmol, 95%). The optical purity was determined to be 99% ee by HPLC (Chiralcel OD-H column, 222 nm, 99:1 hexane/iPrOH, flow rate: 0.7 mL/min). Retention time: Rt = 7.62 min for (2R,3R)-202b (major) and Rt = 11.58 min for (2S,3S)-202b (minor). mp 1 147-148 °C; Rf = 0.21 (1:40 EtOAc/benzene). Spectral data for 202b: H NMR (CDCl3, 500 MHz) δ 1.03 (t, 3H, J = 7.5 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.57 (d, 1H, J = 6.5 Hz), 3.04 (d, 1H, J = 7.0 Hz), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H), 3.92-3.96 (m, 2H), 7.06 (s, 2H), 7.16 (s, 2H), 7.26 (dd, 2H, J = 6.5, 2.0 Hz), 7.35 (dd, 2H, J = 6.5, 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 14.07, 16.18, 16.23, 46.34, 47.54, 59.54, 59.59, 60.64, 76.95, 121.22, 127.35, 127.68, 129.61, 2 130.68, 130.82, 134.36, 137.57, 137.76, 156.01, 156.16, 167.70 (1 sp C not located); IR (thin 335 -1 20 film) 2934s, 1742s, 1487s, 1221s cm . [α] D = +17.7 (c 1.0, CH2Cl2) on 99% ee (2R,3R)-202b (HPLC). (2R,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-cyclohexylaziridine-2-carboxylate 26j 202i: The reaction of imine 201i (197 mg, 0.50 mmol) and ethyl diazoacetate (62 µL, 0.60 mmol) was performed according to the general procedure (Procedure P). Cis/trans >100:1 and 1 the acyclic enamine products were determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (25 mm x 300 mm, EtOAc/benzene 1:40) to afford 202b as a white foamy solid (220 mg, 0.46 mmol, 92%). The optical purity was determined to be 97% ee by HPLC (Chiralcel OD column, 222 nm, 99:1 hexane/iPrOH, flow rate: 0.7 mL/min). Retention time: Rt = 6.61 min for (2R,3R)-202i (major) and Rt = 8.16 min for (2S,3S)-202i (minor). mp 46-47 °C; Rf = 0.27 (1:40 1 EtOAc/benzene). Spectral data for 202i: H NMR (CDCl3, 600 MHz) δ 0.48-0.55 (m, 1H), 0.81-1.11 (m, 4H), 1.24 (t, 3H, J = 7.2 Hz), 1.21-1.28 (m, 2H), 1.41-1.60 (m, 4H), 1.71-1.73 (m, 1H), 2.16 (d, 1H, J = 7.2 Hz), 2.21 (s, 6H), 2.22 (s, 6H), 3.34 (s, 1H), 3.64 (s, 3H), 3.67 (s, 3H), 4.15-4.23 (m, 2H), 6.94 (s, 2H), 7.09 (s, 2H); 13 C NMR (CDCl3, 150 MHz) δ 14.34, 16.06, 16.16, 25.35, 25.53, 26.17, 30.10, 30.83, 36.35, 43.47, 52.25, 59.60, 59.65, 60.65, 77.51, 127.35, 128.54, 130.33, 130.46, 137.56, 138.11, 155.74, 156.26, 169.81; IR (thin film) 2928s, 1735s, 336 -1 + 1457s, 1222s, 1182s, 1017m cm ; mass spectrum, m/z (% rel intensity) 479 M (4), 450 (15), 20 396 (32), 283 (100), 268 (75), 195 (29), 141 (66). [α] D = +103.0 (c 1.0, CH2Cl2) on 97% ee (2R,3R)-202i (HPLC). (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-ethyl-N-phenylaziridine-2-carboxam 27a ide 204k: The reaction of 203k (101 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 0.28 mmol) was performed according to the general procedure except that the catalyst loading was 10 mol%, temperature was 0 °C and the time was 24 h (Procedure G). Cis/trans >100:1 and the 1 acyclic enamine products were determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (25 mm x 300 mm, EtOAc/benzene 1:80) to afford 204k as a white solid (83 mg, 0.130 mmol, 65%). The optical purity was determined to be 90% ee by HPLC (Regis Pirkle Covalent (R,R) Whelk O1 column, 222 nm, 98:2 hexane/iPrOH, flow rate: 1.0 mL/min). Retention time: Rt = 15.73 min for (2S,3R)-204k (minor) and Rt = 25.68 min for (2R,3S)-204k (major). mp 186-192 °C; Rf = 0.27 (1:40 EtOAc/benzene). Spectral data for 204k: 1H NMR (CDCl3, 500 MHz) δ 0.85 (t, 3H, J = 7.5 Hz), 1.32 (s, 18H),1.41 (s, 18H), 1.65-1.69 (m, 2H), 2.19 (d, 1H, J = 3.0 Hz), 2.36 (bs, 1H), 3.60 (s, 3H), 3.65 (s, 3H), 4.27 (s, 1H), 7.06 (t, 1H, J = 7.5 Hz), 7.25 (s, 1H), 7.29 (t, 2H, J = 8.0 Hz), 7.33 (s, 2H), 7.47 (d, 2H, J = 7.5 Hz), 8.56 (s, 1H); 337 13 C NMR (CDCl3, 125 MHz) δ 12.36, 19.82, 32.03, 32.13, 35.68, 35.76, 45.11, 49.05, 64.00, 64.18, 68.33, 119.16, 123.91, 125.20, 125.26, 128.93, 136.97, 137.12, 137.56, 143.24, 143.49, 158.33, 158.46, 168.85; IR (thin film) -1 3330w, 2963s, 1684m, 1603s 1526s, 1445s, 1414s,1221s cm ; mass spectrum, m/z (% rel + 20 intensity) 640 M (<1), 611 (3), 518 (6), 466 (23), 451 (100), 161 (41). [α] D = +52.9 (c 1.0, EtOAc) on 90% ee (2R,3S)-204k (HPLC). (2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-phenyl-3-propylaziridine-2-carboxa mide 204l: The reaction of 203l (104 mg, 0.20 mmol) and diazoacetamide 148 (45 mg, 0.28 mmol) was performed according to the general procedure except that the catalyst loading was 10 mol%, temperature was 0 °C and the time was 24 h (Procedure G). Cis/trans >100:1 and the 1 acyclic enamine products were determined to be <1% from the H NMR spectrum of the crude reaction mixture. The crude product was purified by column chromatography on silica gel (25 mm x 300 mm, EtOAc/benzene 1:80) to afford 204l as a white solid (90 mg, 0.138 mmol, 69%). The optical purity was determined to be 85% ee by HPLC (Regis Pirkle Covalent (R,R) Whelk O1 column, 222 nm, 98:2 hexane/iPrOH, flow rate: 1.0 mL/min). Retention time: Rt = 15.06 min for (2S,3R)-204l (minor) and Rt = 25.66 min for (2R,3S)-204l (major). mp 174-176 °C; Rf = 0.30 1 (1:40 EtOAc/benzene). Spectral data for 204l: H NMR (CDCl3, 600 MHz) δ 0.84 (t, 3H, J = 7.2 Hz), 1.14-1.63 (m, 4H), 1.32 (s, 18H), 1.41 (s, 18H), 2.19 (d, 1H, J = 3.0 Hz), 2.37 (dd, 1H, J = 338 3.0 Hz), 3.60 (s, 3H), 3.65 (s, 3H), 4.25 (s, 1H), 7.05 (t, 1H, J = 7.8 Hz), 7.25 (s, 2H), 7.28 (t, 2H, J = 7.8 Hz), 7.33 (s, 2H), 7.47 (d, 2H, J = 7.8 Hz), 8.55 (s, 1H); 13 C NMR (CDCl3, 150 MHz) δ 13.84, 21.29, 28.40, 32.05, 32.13, 35.69, 35.77, 45.36, 47.33, 64.00, 64.18, 68.44, 119.16, 123.90, 125.18, 125.26, 128.93, 136.99, 137.15, 137.59, 143.25, 143.51, 158.36, 158.47, 168.82; IR (thin -1 film) 3330w, 2961s, 1684m, 1603s, 1528s, 1445s, 1414s, 1223s cm ; HRMS (ESI+) m/z + 20 calculated for C43H63N2O2 (M+H ) 655.4839, found 655.4835. [α] D = +39.4 (c 1.0, CH2Cl2) on 85% ee (2R,3S)-204l (HPLC). 339 6.3 Experimental for chapter four 6.3.1 Preparation of alkynes General procedure for the preparation of alkynes – illustrated for the synthesis of 90 1-ethynyl-3,5-dimethylbenzene 235c (Procedure Q) 64 To a 1 L flame-dried flask filled was added 1-iodo-3,5-dimethylbenzene 331c (69.6 g, 300 mmol), Pd(PPh3)2Cl2 (3.16 g, 4.50 mol) and CuI (855 mg, 4.5 mmol), dry THF (450 mL) and Et3N (168 mL, 1.20 mol) under argon. The reaction mixture was stirred at room temperature for 5 minutes and then trimethylsilyl acetylene (47 mL, 333 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight. After removal of the solvent by rotary evaporation, the residue was treated with NaHCO3 (sat. aq. 800 mL) and Et2O (600 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (300 mL × 2). The combined organic layer was washed with H2O (300 mL × 2), dried over MgSO4, filtered through Celite and concentrated to dryness. 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. The oil was then taken up in MeOH (900 mL) and treated with K2CO3 (124 g, 900 mmol). The reaction mixture was stirred at room temperature overnight. To the resulting reaction mixture was added H2O (2.4 L) and this mixture was extracted with Et2O (500 mL × 3). The organic layer was dried 340 over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (50 mm × 200 mm, hexanes) gave 235c as a 1 yellow oil (34.2 g, 263 mmol, 88%). Rf = 0.21 (hexanes). Spectral data for 235c: H NMR (CDCl3, 500 MHz) δ 2.28 (s, 6H), 2.99 (s, 1H), 6.97(s, 1H), 7.11 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 21.04, 76.34, 83.99, 121.69, 129.78, 130.67, 137.87; IR (thin film) 3295s, 2921s, -1 + 2108m, 1601s, 1456s, 1264s cm ; mass spectrum, m/z (% rel intensity) 130 M (91), 115 (100), 102 (10), 89 (12). 1-ethynyl-4-methoxybenzene 235d: 91 The reaction of 1-iodo-4-methoxybenzene 331d (23.4 g, 100 mmol) and trimethylsilyl acetylene (15.5 mL, 110 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm × 150 mm, CH2Cl2:hexanes 1:5) gave 235d as a colorless solid (10.9 g, 1 82.6 mmol, 83%). Rf = 0.19 (1:5 CH2Cl2:hexanes). Spectral data for 235d: H NMR (CDCl3, 500 MHz) δ 2.97 (s, 1H), 3.80 (s, 3H), 6.82 (dd, 2H, J = 6.5, 2.0 Hz), 7.41 (dd, 2H, J = 6.5, 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 55.28, 75.73, 83.66, 113.93, 114.18, 133.59, 159.95; IR -1 (thin film) 3289s, 2961m, 2840m, 2107m, 1507s, 1458m, 1250s, 1170s cm ; mass spectrum, + m/z (% rel intensity) 132 M (100), 117 (65), 102 (11), 89 (86). 341 64 5-iodo-2-methoxy-1,3-dimethylbenzene 331e: To a 1 L flame-dried flask filled with argon was added 5-bromo-2-methoxy-1,3-dimethylbenzene 330e (21.5 g, 100 mmol) and dry Et2O (250 mL). The mixture was stirred until the bromide was dissolved at room temperature and then the flask was submerged into a –78 ºC bath, followed by slow addition of t-BuLi (118 mL, 200 mmol, 1.7 M in hexanes) and then the solution was stirred at –78 ºC for 1h. At the same time, to a flame-dried 250 mL flask iodine (27.9 g, 110 mmol) was dissolved in dry Et2O (150 mL). The iodine solution was then cooled to –78 ºC and transferred to the aryllithium solution via cannula under argon. The mixture was warmed up gradually to room temperature and stir for an additional 2 h. The reaction was quenched by pouring the reaction mixture slowly into a Na2S2O3 solution (aq. 5%, 200 mL) and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted with Et2O (100 mL × 3). the combined organic layer was washed with H2O (100 mL × 2) and NaCl (aq. sat.), dried over MgSO4 and filtered through Celite. Removal of the solvent by rotary evaporation afforded the crude product as a yellow oil 1 in 100% yield. The H NMR spectrum of the crude was clean, and it was used in the next step 1 without purification. Spectral data for 331e: H NMR (CDCl3, 500 MHz) δ 2.21 (s, 6H), 3.68 (s, 3H), 7.32 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 15.67, 59.69, 87.55, 133.47, 137.49, 157.01. 342 5-ethynyl-2-methoxy-1,3-dimethylbenzene 235e: 91 The reaction of 5-iodo-2-methoxy-1,3-dimethylbenzene 331e from the above and trimethylsilyl acetylene (15.5 mL, 110 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm × 150 mm, CH2Cl2:hexanes 1:5) gave 235e as a yellow oil (15.1 g, 94.4 mmol, 94%). Rf = 0.14 (1:5 CH2Cl2:hexanes). 1 Spectral data for 235e: H NMR (CDCl3, 300 MHz) δ 2.24 (s, 6H), 2.96 (s, 1H), 3.70 (s, 3H), 7.15 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 15.89, 59.70, 75.94, 83.63, 117.26, 131.11, 132.65, -1 157.66; IR (thin film) 3291s, 29446s, 2107m, 1482s, 1304s, 1227s, 1140s cm ; mass spectrum, + m/z (% rel intensity) 160 M (100), 145 (70), 128 (6), 115 (45). 92 1-bromo-4-ethynylbenzene 235g: The reaction of 1-bromo-4-iodobenzene 331g (28.3 g, 100 mmol) and trimethylsilyl acetylene (15.5 mL, 110 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm × 200 mm, hexanes) gave 235g as a white solid (15.9 g, 87.8 mmol, 88%). mp 63-65 °C (lit. 92 1 56-58 °C); Rf = 0.27 (hexanes). Spectral data for 235g: H NMR (CDCl3, 343 500 MHz) δ 3.10 (s, 3H), 7.33 (dd, 2H, J = 7.0, 2.0 Hz), 7.44 (dd, 2H, J = 7.0, 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 78.32, 82.55, 121.04, 123.13, 131.60, 133.54; IR (thin film) 3270s, -1 1586s, 1485s, 1397s cm . 93 2-ethynyl-1,3-dimethylbenzene 235q: The reaction of 1-bromo-4-iodobenzene 331q (13.9 g, 60 mmol) and trimethylsilyl acetylene (15.5 mL, 110 mmol) was performed according to the general procedure (Procedure Q). Vacuum distillation (85 °C at 0.5 mm Hg with a slow bleed of air through a needle) gave 235q as a colorless oil (4.68 g, 36 mmol, 60%). Rf = 0.31 (hexanes). 1 Spectral data for 235q: H NMR (CDCl3, 500 MHz) δ 2.45 (s, 6H), 3.50 (s, 1H), 7.03 (d, 2H, J = 13 7.5 Hz), 7.13 (dd, 1H, J = 7.5, 1.0 Hz); C NMR (CDCl3, 125 MHz) δ 20.98, 81.13, 85.33, -1 121.91, 126.64, 128.07, 140.93; IR (thin film) 3303s, 2920s, 2101w, 1559s, 1466s, 1379s cm ; + mass spectrum, m/z (% rel intensity) 130 M (69), 115 (100), 102 (9), 89 (8) 89 5-Ethynyl-1,2,3-trimethoxybenzene 235p: To a 1L flame-dried round bottom flask was added CBr4 (50.8 g, 153 mmol), dry CH2Cl2 (200 mL) and the resulting solution was cooled to 0 °C. PPh3 (80.2 g, 306 mmol) in dry CH2Cl2 (200 mL) was added dropwise to the above solution. The resulting solution was stirred at 0 °C for 15 minutes. 3,4,5-Trimethoxybenzaldehyde (20 g, 344 102 mmol) in dry CH2Cl2 (120 mL) was added dropwise. The solution was stirred at 0 °C for 15 minutes. The solvent was removed by rotary evaporation and the resulting slurry was filtered through a plug of silica gel and washed with hexanes:EtOAc (9:1, 500 mL; then 4:1 , 1500 mL) until no dibromo-olefin was left by TLC. The combined organics were concentrated to dryness to give dibromo-olefin (32.2 g, 91.4 mmol), which was dissolved in dry THF (400 mL) and cooled to –78 °C. n-BuLi (2.5 M in hexanes, 110 mL, 274 mmol) was added dropwise and the solution stirred at –78 °C for 30 minutes. NH4Cl (sat. aq. 100 mL) was added and the solution warmed to room temperature. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layer was washed with brine (100 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 280 mm, EtOAc:hexanes 1:9) gave 235p as a white solid (15.8 g, 82.3 mmol, 81%). Rf = 0.33 (1:3 EtOAc/hexanes). Spectral data for 235p: 1 H NMR (CDCl3, 500 MHz) δ 3.01 (s, 1H), 3.83 (s, 6H), 3.84 (s, 3H), 6.71 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 56.11, 60.92, 76.19, 83.67, 109.32, 116.99, 153.02; IR (thin film) 3247s, -1 + 2990s, 1576s, 1456s, 1335s, 1235s, 1129s cm ; mass spectrum, m/z (% rel intensity) 192 M (100), 177 (67), 134 (25), 119 (22), 89 (15). 6.3.2 Preparation of VANOL monomer derivatives 345 5-bromo-3-phenylnaphthalen-1-ol 224d: The reaction of 2-bromo-phenylacetic acid 332d (2.37 g, 11.0 mmol), SOCl2 (2.90 mL, 39.8 mmol), phenylacetylene (1.50 mL, 13.7 mmol) and (i-PrCO)2O (3.70 mL, 22.3 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:2 to 1:1 to 2:1) gave 224d as a yellow solid (2.62 g, 8.76 mmol, 80%). 1 mp 130-131 °C; Rf = 0.31 (CH2Cl2). Spectral data for 224d: H NMR (CDCl3, 500 MHz) δ 5.35 (s,1H), 7.11 (s, 1H), 7.29 (t, 1H, J = 7.5 Hz), 7.39 (t, 1H, J = 7.5 Hz), 7.48 (t, 2H, J = 7.5 Hz), 7.69 (d, 2H, J = 8.0 Hz), 7.80 (d, 1H, J = 7.5 Hz), 8.03 (s, 1H), 8.17 (d, 1H, J = 8.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 109.13, 118.13, 121.57, 122.95, 124.77, 125.41, 127.45, 127.79, 128.90, 131.08, 133.40, 140.22, 140.59, 151.79; IR (thin film) 3239br s, 1626m, 1595s, 1495s, -1 + 1390s, 1263m cm ; HRMS (ESI–) m/z calcd for C16H10OBr (M-H ) 296.9915, meas 296.9921. 346 The reaction of 3-bromo-phenylacetic acid 333d (6.45 g, 30.0 mmol), SOCl2 (8.00 mL, 110 mmol), phenylacetylene (4.0 mL, 36 mmol) and (i-PrCO)2O (10 mL, 60 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:2 to 1:1 to 1:0) gave 225d as an off-white solid (4.19 g, 14.0 mmol, 47%). mp 144-145 °C; Rf = 0.34 (CH2Cl2). Purification of the crude 226d obtained from the first column by a 2nd column chromatography on silica gel (35 mm x 300 mm, EtOAc:hexanes 1:50) gave 226d as a yellow solid (1.71 g, 5.72 1 mmol, 19%). mp 53-54 °C; Rf = 0.62 (CH2Cl2). Spectral data for 225d: H NMR (CDCl3, 500 MHz) δ 5.27 (s, 1H), 7.06 (d, 1H, J = 1.5 Hz), 7.35-7.39 (m, 1H), 7.43-7.48 (m, 2H), 7.51-7.54 (m, 2H), 7.62-7.65 (m, 2H), 7.99-8.00 (m, 1H), 8.04 (d, 1H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 108.81, 117.81, 121.25, 122.05, 123.60, 127.30, 127.77, 128.58, 128.91, 129.88, 136.14, -1 140.29, 140.46, 151.86; IR (thin film) 3330br s, 1576s, 1456s, 1375s cm ; HRMS (ESI–) m/z + calcd for C16H10O79Br (M-H ) 296.9915, meas 296.9906. 347 1 Spectral data for 226d: H NMR (CDCl3, 500 MHz) δ 7.22 (t, 1H, J = 8.0 Hz), 7.36-7.39 (m, 2H), 7.46 (t, 2H, J = 7.5 Hz), 7.60 (d, 1H, J = 7.0 Hz), 7.63 (d, 1H, J = 2.0 Hz), 7.68-7.70 (m, 2H), 7.82 (d, 1H, J = 8.5 Hz), 8.10 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 112.59, 115.21, 118.98, 119.76, 126.36, 127.21, 127.88, 128.88, 129.60, 131.38, 137.43, 139.84, 140.22, 152.94; -1 IR (thin film) 3482br s, 1568s, 1489s, 1368s, 1210s cm ; HRMS (ESI–) m/z calcd for 79 + C16H10O Br (M-H ) 296.9915, meas 296.9923. 7-bromo-3-(4-butylphenyl)naphthalen-1-ol 236b: The reaction of 4-bromo-phenylacetic acid 191d (23.7 g, 110 mmol), SOCl2 (29 mL, 398 mmol), 1-butyl-4-ethynylbenzene 235b (20 g, 127 mmol) and (i-PrCO)2O (37 mL, 223 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:2 to 1:1 to 2:1) gave 236b as a light brown solid (26.5 g, 1 74.6 mmol, 68%). mp 106-109 °C; Rf = 0.21 (2:1 CH2Cl2/hexanes). Spectral data for 236b: H NMR (CDCl3, 500 MHz) δ 0.94 (t, 3H, J = 7.5 Hz), 1.34-1.43 (m, 2H), 1.60-1.67 (m, 2H), 2.65 (t, 2H, J = 7.5 Hz), 5.25 (s, 1H), 7.07 (d, 1H, J = 1.5 Hz), 7.25-7.28 (m, 2H), 7.53-7.57 (m, 4H), 7.69 (d, 1H, J = 8.5 Hz), 8.33 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.94, 22.39, 33.58, 35.31, 109.28, 118.29, 119.10, 124.26, 124.57, 127.05, 128.98, 129.54, 130.23, 133.43, 348 -1 137.78, 139.42, 142.63, 150.82; IR (thin film) 3260br s, 2926s, 1589s, 1406s, 1254s cm ; 79 + HRMS (ESI–) m/z calcd for C20H18O Br (M-H ) 353.0541, meas 353.0539. 7-bromo-3-(3,5-dimethylphenyl)naphthalen-1-ol 236c: The reaction of 4-bromo-phenylacetic acid 191d (4.30 g, 20.0 mmol), SOCl2 (5.3 mL, 73 mmol), 1-ethynyl-3,5-dimethylbenzene 235c (2.60 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 236c as an off-white solid (3.96 g, 1 12.1 mmol, 61%). mp 110-111 °C; Rf = 0.19 (2:1 CH2Cl2/hexanes). Spectral data for 236c: H NMR (CDCl3, 500 MHz) δ 2.39 (s, 6H), 5.22 (s, 1H), 7.01 (s, 1H), 7.07 (d, 1H, J = 1.5 Hz), 7.26 (s, 2H), 7.55 (dd, 1H, J = 9.0, 2.0 Hz), 7.57 (s, 1H), 7.69 (d, 1H, J = 9.0 Hz), 8.33 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 21.40, 109.43, 118.53, 119.13, 124.25, 124.60, 125.16, 129.34, 129.55, 130.21, 133.35, 138.43, 139.67, 140.47, 150.72; IR (thin film) 3509br m, 2918w, -1 + 1587s, 1474s, 1404s, 1267s cm ; mass spectrum, m/z (% rel intensity) 328 M (91, + M (100, 79 81 Br), 326 Br), 202 (42), 163 (20). Anal calcd for C18H15BrO: C, 66.07; H, 4.62. Found: C, 66.00; H, 4.42. 349 7-bromo-3-(4-methoxyphenyl)naphthalen-1-ol 236d: The reaction of 4-bromo-phenylacetic acid 191d (4.30 g, 20.0 mmol), SOCl2 (5.3 mL, 73 mmol), 1-ethynyl-4-methoxybenzene 235d (2.64 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 236d as an off-white solid (1.98 1 g, 6.0 mmol, 30%). mp 168-170 °C; Rf = 0.26 (CH2Cl2). Spectral data for 236d: H NMR (CDCl3, 500 MHz) δ 3.85 (s, 3H), 5.24 (s, 1H), 6.98-7.00 (m, 2H), 7.53-7.55 (m, 2H), 7.56-7.58 (m, 2H), 7.67 (d, 1H, J = 9.0 Hz), 8.32 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 55.40, 109.13, 114.38, 117.87, 118.96, 124.24, 124.37, 128.27, 129.46, 130.25, 132.99, 133.45, -1 139.03, 150.82, 159.48; IR (thin film) 3395br s, 1578s, 1507s, 1402s, 1240s, 1179s cm ; mass + spectrum, m/z (% rel intensity) 330 M (89, 79 81 + Br), 328 M (100, 79 Br), 315 (29, 81 Br), 313 (31, Br), 285 (14), 205 (15). Anal calcd for C17H13BrO2: C, 62.03; H, 3.98. Found: C, 61.83; H, 3.92. 350 7-bromo-3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol 236e: The reaction of 4-bromo-phenylacetic acid 191d (4.30 g, 20.0 mmol), SOCl2 (5.3 mL, 73 mmol), 5-ethynyl-2-methoxy-1,3-dimethylbenzene 235e (3.20 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 236e as an off-white solid (3.56 g, 10.0 mmol, 50%). mp 146-148 °C; Rf = 1 0.22 (CH2Cl2). Spectral data for 236e: H NMR (CDCl3, 500 MHz) δ 2.35 (s, 6H), 3.78 (s, 3H), 5.46 (s, 1H), 6.98 (d, 1H, J = 1.5 Hz), 7.27 (s, 2H), 7.51 (s, 1H), 7.54 (dd, 1H, J = 8.5, 2.0 Hz), 7.67 (d, 1H, J = 9.0 Hz), 8.33 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 16.29, 59.84, 109.29, 118.15, 119.02, 124.28, 124.52, 127.72, 129.49, 130.21, 131.30, 133.38, 136.13, 139.22, -1 150.80, 156.79; IR (thin film) 3341br s, 2928s, 1587s, 1485s, 1402s, 1227s, 1157s cm ; mass + spectrum, m/z (% rel intensity) 358 M (77, 79 Br), 314 (4, 81 Br), 312 (5, 79 81 + Br), 356 M (80, 79 Br), 343 (50, 81 Br), 341 (52, Br), 202 (28), 189 (49), 171 (34), 100 (100). Anal calcd for C19H17BrO2: C, 63.88; H, 4.80. Found: C, 63.73; H, 4.72. 351 7-bromo-3-(4-fluorophenyl)naphthalen-1-ol 236f: The reaction of 4-bromo-phenylacetic acid 191d (4.30 g, 20.0 mmol), SOCl2 (5.3 mL, 73 mmol), 1-ethynyl-4-fluorobenzene 235f (2.40 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 236f as an off-white solid (2.33 g, 1 7.35 mmol, 37%). mp 96-97 °C; Rf = 0.30 (CH2Cl2). Spectral data for 236f: H NMR (CDCl3, 500 MHz) δ 5.30 (s, 1H), 7.02 (d, 1H, J = 2.0 Hz), 7.11-7.17 (m, 2H), .45-7.53 (m, 2H), 7.58 (s, 1H), 7.59-7.64 (m, 2H), 7.82-7.85 (m, 1H), 8.14-8.17 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 2 3 108.27, 115.61 ( J CF = 21 Hz), 118.64, 121.42, 123.47, 125.41, 127.02, 127.97, 128.83 ( J CF = 4 1 7.9 Hz), 134.94, 137.03 ( J CF = 3.3 Hz), 137.91, 151.76, 162.56 ( J CF = 245.4 Hz); -1 19 F NMR (CDCl3, 283 Hz) δ –113.30; IR (thin film) 3399br w, 1507s, 1401s, 1237s cm ; HRMS (ESI+) + m/z calcd for C16H12OF (M+H ) 239.0872, meas 239.0884. 352 7-bromo-3-(3,4,5-trimethoxyphenyl)naphthalen-1-ol 236p: The reaction of 4-bromo-phenylacetic acid 191d (4.30 g, 20.0 mmol), SOCl2 (5.3 mL, 73 mmol), 5-ethynyl-1,2,3-trimethoxybenzene 235p (3.84 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, EtOAc:hexanes 1:4 to 1:2) gave 236p as a yellow solid (3.69 g, 1 9.49 mmol, 47%). mp 177-179 °C; Rf = 0.16 (1:2 EtOAc/hexanes). Spectral data for 236p: H NMR (CDCl3, 500 MHz) δ 3.90 (s, 6H), 3.91 (s, 3H), 5.74 (s, 1H), 6.80 (s, 2H), 6.99 (d, 1H, J = 1.0 Hz), 7.50 (s, 1H), 7.56 (dd, 1H, J = 8.5, 2.0 Hz), 7.69 (d, 1H, J = 9.0 Hz), 8.36 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 56.28, 61.03, 104.71, 109.39, 118.20, 119.26, 124.38, 124.76, 129.47, 130.36, 133.28, 136.73, 139.56, 151.03, 153.53; IR (thin film) 3413br m, 2938m, -1 + 1589s, 1503s, 1406s, 1240s, 1129s cm ; mass spectrum, m/z (% rel intensity) 390 M (14, + 388 M (13, 79 Br), 375 (7, 81 Br), 373 (7, 79 Br), 236 (4, 81 Br), 234 (4, 79 81 Br). Anal calcd for C19H17BrO4: C, 58.63; H, 4.40. Found: C, 58.39; H, 4.19. Procedure R – illustrated for the synthesis of 3-(3,5-dimethylphenyl)naphthalen-1-ol 222c 353 Br), To a 250 mL flame-dried round bottom flask was added phenylacetyl chloride 180 (2.64 mL, 20.0 mmol), 1-ethynyl-3,5-dimethylbenzene 235c (2.60 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) 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. 60 °C, oil bath temperature) and a solution of KOH (6.7 g, 536 mmol) in H2O (26 mL) was then added slowly. This two-phase mixture was stirred at 100 °C overnight. The mixture was cooled to room temperature and ethyl acetate (60 mL) was added and the mixture stirred for 10 min before the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (30 mL × 3) and the combined organic layer was washed with brine (30 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (50 mm × 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 222c as a yellow solid (3.26 g, 13.1 mmol, 66%). mp 104-105 °C; Rf = 0.34 (CH2Cl2). Spectral 1 data for 222c: H NMR (CDCl3, 500 MHz) δ 2.39 (s, 6H), 5.26 (s, 1H), 7.01 (s, 1H), 7.07 (d, 1H, J = 1.5 Hz), 7.29 (s, 2H), 7.44-7.52 (m, 2H), 7.83-7.85 (m, 1H), 8.13-8.16 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 21.43, 108.59, 118.73, 121.42, 123.53, 125.19, 125.24, 126.81, 128.01, 354 129.13, 135.00, 138.34, 139.18, 140.92, 151.59; IR (thin film) 3430br s, 2919s, 1576s, 1456s, -1 + 1400s, 1271s cm ; HRMS (ESI+) m/z calcd for C18H17O (M+H ) 249.1279, meas 249.1268. 3-(4-methoxyphenyl)naphthalen-1-ol 222d: The reaction of phenylacetyl chloride 180 (2.64 mL, 20.0 mmol), 1-ethynyl-4-methoxybenzene 235d (2.64 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 222d as a pale brown solid (2.07 g, 8.28 mmol, 41%). mp 151-152 °C; Rf = 1 0.19 (CH2Cl2). Spectral data for 222d: H NMR (CDCl3, 500 MHz) δ 3.85 (s, 3H), 5.27 (s, 1H), 6.99 (dd, 2H, J = 9.0, 2.0 Hz), 7.05 (d, 1H, J = 1.0 Hz), 7.43-7.51 (m, 2H), 7.58-7.61 (m, 3H), 7.82 (d, 1H, J = 7.5 Hz), 8.12-8.15 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 55.39, 108.26, 114.30, 118.05, 121.40, 123.24, 125.05, 126.84, 127.88, 128.30, 133.43, 135.04, 138.51, 151.65, -1 159.29; IR (thin film) 3357br w, 1587s, 1456s, 1401s, 1250s, 1184s cm ; HRMS (ESI–) m/z + calcd for C17H13O2 (M-H ) 249.0916, meas 249.0921. 355 3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol 222e: The reaction of phenylacetyl chloride 180 (2.64 mL, 20.0 mmol), 5-ethynyl-2-methoxy-1,3-dimethylbenzene 235e (3.20 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 222e as a light yellow solid (3.10 g, 11.1 1 mmol, 56%). mp 156-157 °C; Rf = 0.19 (CH2Cl2). Spectral data for 222e: H NMR (CDCl3, 500 MHz) δ 2.36 (s, 6H), 3.77 (s, 3H), 5.33 (s, 1H), 7.02 (d, 1H, J = 1.5 Hz), 7.31 (s, 2H), 7.43-7.51 (m, 2H), 7.57 (s, 1H), 7.82 (d, 1H, J = 7.5 Hz), 8.13-8.15 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.29, 59.84, 108.39, 118.32, 121.44, 123.38, 125.07, 126.79, 127.75, 127.91, 131.18, 134.96, 136.54, 138.68, 151.63, 156.57; IR (thin film) 3359br s, 2942s, 1576s, 1489s, 1402s, 1230s, -1 + 1157s cm ; HRMS (ESI-) m/z calcd for C19H17O2 (M-H ) 277.1229, meas 277.1224. 356 3-(4-fluorophenyl)naphthalen-1-ol 222f: The reaction of phenylacetyl chloride 180 (2.64 mL, 20.0 mmol), 1-ethynyl-4-fluorobenzene 235f (2.40 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 222f as an off-white solid (2.54 g, 10.6 mmol, 53%). mp 96-97 °C; Rf = 0.30 1 (CH2Cl2). Spectral data for 222f: H NMR (CDCl3, 500 MHz) δ 5.30 (s, 1H), 7.02 (d, 1H, J = 2.0 Hz), 7.11-7.17 (m, 2H), 7.45-7.53 (m, 2H), 7.58 (s, 1H), 7.59-7.64 (m, 2H), 7.82-7.85 (m, 1H), 8.14-8.17 (m, 1H); 13 2 C NMR (CDCl3, 125 MHz) δ 108.27, 115.61 ( J CF = 21 Hz), 118.64, 3 4 121.42, 123.47, 125.41, 127.02, 127.97, 128.83 ( J CF = 7.9 Hz), 134.94, 137.03 ( J CF = 3.3 1 Hz), 137.91, 151.76, 162.56 ( J CF = 245.4 Hz); 19 -1 F NMR (CDCl3, 283 Hz) δ –113.77; IR (thin + film) 3399br w, 1507s, 1401s, 1237s cm ; HRMS (ESI+) m/z calcd for C16H12OF (M+H ) 239.0872, meas 239.0884. 3-(4-bromophenyl)naphthalen-1-ol 222g: The reaction of phenylacetyl chloride 180 (2.64 mL, 20.0 mmol), 1-bromo-4-ethynylbenzene 235g (3.62 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 357 to 2:1 to 1:0) gave 222g as an off-white solid (2.70 g, 9.03 mmol, 45%). mp 168-169 °C; Rf = 1 0.31 (CH2Cl2). Spectral data for 222g: H NMR (CDCl3, 500 MHz) δ 5.36 (s, 1H), 7.01 (d, 1H, J = 1.5 Hz), 7.46-7.54 (m, 4H), 7.55-7.59 (m, 2H), 7.59 (s, 1H), 7.82-7.85 (m, 1H), 8.14-8.17 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 107.97, 118.70, 121.46, 121.70, 123.68, 125.57, 127.09, 128.03, 128.85, 131.92, 134.92, 137.64, 139.83, 151.88; IR (thin film) 3355br w, 1576s, 1493s, -1 79 + 1399s, 1265s cm ; HRMS (ESI+) m/z calcd for C16H10 BrO (M+H ) 296.9915, meas 296.9906. 3-(thiophen-2-yl)naphthalen-1-ol 222s: The reaction of phenylacetyl chloride 180 (3.72 mL, 28.1 mmol), 2-ethynylthiophene 235s (3.04 g, 28.1 mmol) and (i-PrCO)2O (9.33 mL, 56.3 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:2 to 1:1 to 1:0) gave 222g as a brownish pink solid (1.66 g, 7.35 mmol, 37%). mp 128-129 °C; Rf = 0.35 1 (CH2Cl2). Spectral data for 222g: H NMR (CDCl3, 500 MHz) δ 5.35 (s, 1H), 7.07-7.11 (m, 2H), 7.30(dd, 1H, J = 5.0, 1.5 Hz), 7.36 (dd, 1H, J = 3.5, 1.5 Hz), 7.43-7.51 (m, 2H), 7.67 (s, 1H), 7.79-7.82 (m, 1H), 8.11-8.14 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 107.20, 117.36, 121.51, 123.42, 123.77, 125.02, 125.34, 127.14, 127.84, 128.06, 131.95, 134.91, 144.22, 151.69; IR (thin 358 -1 + film) 3320br s, 1599s, 1401s, 1262s cm ; HRMS (ESI–) m/z calcd for C14H9OS (M-H ) 225.0374, meas 225.0377. 3-(thiophen-3-yl)naphthalen-1-ol 222t: The reaction of phenylacetyl chloride 180 (2.64 mL, 20.0 mmol), 3-ethynylthiophene 235t (2.16 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:2 to 1:1 to 1:0) gave 222t as a brownish pink solid (2.58 g, 11.4 mmol, 57%). mp 119-120 °C; Rf = 0.32 1 (CH2Cl2). Spectral data for 222t: H NMR (CDCl3, 500 MHz) δ 5.34 (s, 1H), 7.06 (d, 1H, J = 1.5 Hz), 7.40 (dd, 1H, J = 5.5, 3.0 Hz), 7.45-7.51 (m, 4H), 7.65 (s, 1H), 7.82 (d, 1H, J = 7.5 Hz), 8.14 (d, 1H, J = 8.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 107.84, 117.90, 120.62, 121.43, 123.58, 125.22, 126.31, 126.38, 126.96, 127.88, 133.44, 134.99, 142.05, 151.66; IR (thin film) 3362br s, -1 + 1599s, 1507s, 1418s, 1275s cm ; HRMS (ESI–) m/z calcd for C14H9OS (M-H ) 225.0374, meas 225.0382. 6.3.3 Preparation of C2-VANOL derivatives 359 5,5’-di-bromo VANOL 227d: The synthesis of racemic 227d was performed according to the general procedure (Procedure J) with 5-bromo-3-phenylnaphthalen-1-ol 224d (2.50 g, 8.36 mmol). After cooling down to room temperature, CH2Cl2 (10 mL) and hexanes (20 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) and then filtered through filter paper. The yellow powder was washed with chilled CH2Cl2/hexanes and dried under vacuum to afford a yellow solid (1.32 g). Purification of the product remaining in the mother liquor by column chromatography on silica gel (35 mm x 250 mm, CH2Cl2:hexanes 2:3) gave racemic 227d as a light yellow solid (0.26 g). The total yield is 63% (1.58 g, 2.65 mmol). After de-racemization of racemic 227d (1.19 g, 2.00 mmol) with CuCl (337 mg, 3.40 mmol) and (–)-sparteine (1.64 g, 7.00 mmol), the crude product was purified by column chromatography on silica gel (35 mm × 250 mm, CH2Cl2/hexanes 2:3) to afford (S)-227d as an off-white foamy solid (534 mg, 0.90 mmol, 45%). The optical purity was determined to be >99% ee by HPLC analysis (Chiralcel OD-H column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 0.7 mL/min). Retention times: Rt = 9.68 min for (R)-227d (minor) and Rt = 15.00 min for (S)-227d (major). mp 234-238 °C; Rf = 360 1 0.22 (1:1 CH2Cl2/hexane). Spectral data for 227d: H NMR (CDCl3, 500 MHz) δ 5.78 (s, 2H), 6.63-6.66 (m, 4H), 6.98-7.01 (m, 4H), 7.09-7.13 (m, 2H), 7.36-7.40 (m, 2H), 7.70 (d, 2H, J = 0.5 Hz), 7.86 (dd, 2H, J = 7.5, 1.5 Hz), 8.32-8.35 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 113.29, 121.32, 122.64, 122.70, 124.11, 126.00, 127.05, 127.65, 128.85, 131.75, 133.14, 139.68, 141.88, -1 150.44; IR (thin film) 3512br s, 1653s, 1558m, 1379s, 1240m cm ; HRMS (ESI–) m/z calcd for 79 + 20 C32H19O2 Br2 (M-H ) 592.9752, meas 592.9760. [α] D = –163.6 (c 1.0, CH2Cl2) on 99% ee (S)-227d (HPLC). 6,6’-di-bromo VANOL 228d: The synthesis of racemic 228d was performed according to the general procedure (Procedure J) with 6-bromo-3-phenylnaphthalen-1-ol 225d (2.39 g, 8.00 mmol). Purification by column chromatography on silica gel (35 mm × 300 mm, CH2Cl2/hexanes 1:2) gave racemic 228d as an off-white solid (1.54 g, 2.58 mmol, 65% yield). After de-racemization of racemic 228d (834 mg, 1.40 mmol) with CuCl (236 mg, 2.38 mmol) and (–)-sparteine (1.15 mg, 4.91 mmol), the crude product was purified by column chromatography on silica gel (25 mm × 200 mm, CH2Cl2/hexanes 1:2) to afford (S)-228d as a white solid (577 mg, 0.97 mmol, 69%). The optical purity was determined to be >99% ee by 361 HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 23.98 min for (R)-228d (minor) and Rt = 26.31 min for (S)-228d 1 (major). mp 130-133 °C; Rf = 0.21 (1:1 CH2Cl2/hexanes). Spectral data for 228d: H NMR (CDCl3, 500 MHz) δ 5.78 (s, 2H), 6.56-6.59 (m, 4H), 6.94-6.98 (m, 4H), 7.06-7.10 (m, 2H), 7.20 (s, 2H), 7.60 (dd, 2H, J = 9.0, 2.0 Hz), 7.92 (d, 2H, J = 2.0 Hz), 8.20 (d, 2H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 112.95, 121.06, 121.34, 122.10, 124.70, 127.00, 127.57, 128.76, 129.13, 129.68, 135.73, 139.56, 141.93, 150.53; IR (thin film) 3507br s, 1562s, 1483s, 1381s, -1 79 + 1240s cm ; HRMS (ESI–) m/z calcd for C32H19O2 Br2 (M-H ) 592.9752, meas 592.9760. 20 [α] D = –220.4 (c 1.0, CH2Cl2) on >99% ee (S)-228d (HPLC). 4,4’-di-bromo VANOL 229d: To a 100 mL flame-dried round bottom flask was added (S)-VANOL (350 mg, 0.80 mmol) and dry CH2Cl2 (20 mL). The solution was cooled to 0 °C and Br2 solution (1 M in CH2Cl2, 1.68 mL, 1.68 mmol) was added. The resulting mixture was stirred at 0 °C for 30 minutes. H2O (40 mL) was then added to the mixture. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (20 mL x 3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (25 mm × 250 mm, 362 CH2Cl2/hexanes 2:1) gave 229d as an off-white solid (468 mg, 0.78 mmol, 98%). mp 202-206 1 °C; Rf = 0.29 (2:1 CH2Cl2/hexane). Spectral data for 229d: H NMR (CDCl3, 500 MHz) δ 5.52 (s, 2H), 6.69-6.73 (m, 2H), 6.96-7.03 (m, 4H), 7.13-7.17 (m, 2H), 7.22-7.26 (m, 2H), 7.57-7.61 (m, 2H), 7.64-7.68 (m, 2H), 8.28-8.34 (m, 4H); 13 C NMR (CDCl3, 125 MHz) δ 114.00, 116.01, 123.07, 123.95, 126.53, 126.87, 127.51, 127.55, 127.72, 127.96, 129.03, 132.08, 133.45, 139.37, -1 140.63, 150.04; IR (thin film) 3511br s, 1585s, 1491s, 1375s, 1265s cm ; HRMS (ESI–) m/z 79 + 20 calcd for C32H19O2 Br2 (M-H ) 592.9752, meas 592.9731. [α] D = –114.2 (c 1.0, CH2Cl2). The synthesis of racemic 237b was performed according to the general procedure (Procedure J) with 7-bromo-3-(4-butylphenyl)naphthalen-1-ol 236b (5.09 g, 14.3 mmol). After cooling down to room temperature, CH2Cl2 (30 mL) and hexanes (30 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) and then filtered through filter paper. The yellow powder was washed with chilled CH2Cl2/hexanes and dried under vacuum to afford a yellow solid (2.42 g). Purification of the product remaining in the mother liquor by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2/hexanes 1:2) gave racemic 237b as an off-white solid (1.25 g). The total yield is 72% (3.67 g, 5.18 mmol). After de-racemization of racemic 237b (6.75 g, 9.54 mmol) with 363 CuCl (1.61 g, 16.3 mmol) and (–)-sparteine (7.81 g, 33.4 mmol), the crude product was purified by column chromatography on silica gel (50 mm × 250 mm, CH2Cl2/hexanes 1:3) to afford (S)-237b as an off-white foamy solid (5.38 g, 7.60 mmol, 80%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 23.71 min for (S)-237b (major) and Rt = 28.67 min for (R)-237b (minor). mp 85-88 °C; Rf = 0.19 (1:2 CH2Cl2/hexanes). 1 Spectral data for 237b: H NMR (CDCl3, 500 MHz) δ 0.88 (t, 6H, J = 7.5 Hz), 1.25-1.30 (m, 4H), 1.46-1.51 (m, 4H), 2.46 (t, 4H, J = 7.5 Hz), 5.68 (s, 2H), 6.52 (dd, 4H, J = 6.5, 2.0 Hz), 6.76 (d, 4H, J = 8.0 Hz), 7.29 (s, 2H), 7.59-7.65 (m, 4H), 8.46-8.48 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.89, 22.20, 33.45, 35.12, 113.79, 119.66, 121.74, 123.92, 125.29, 127.64, 128.57, 129.32, 130.92, 133.07, 136.94, 141.11, 141.66, 149.39; IR (thin film) 3519br s, 2928s, 2857s, -1 79 + 1561s, 1487s, 1375s cm ; HRMS (ESI–) m/z calcd for C40H35O2 Br2 (M-H ) 705.1004, meas 20 705.0973. [α] D = –187.5 (c 1.0, CH2Cl2) on >99% ee (S)-237b (HPLC). The synthesis of racemic 237c was performed according to the general procedure (Procedure J) with 7-bromo-3-(3,5-dimethylphenyl)naphthalen-1-ol 236c (2.62 g, 8.01 mmol). Purification by 364 column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:3) gave racemic 237c as a white solid (1.62 g, 2.48 mmol, 62% yield). After de-racemization of racemic 237c (652 mg, 1.00 mmol) with CuCl (168 mg, 1.70 mmol) and (–)-sparteine (819 mg, 3.50 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 1:3) to afford (S)-237c as an off-white foamy solid (488 mg, 0.75 mmol, 75%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 21.79 min for (S)-237c (major) and Rt = 24.01 min for (R)-237c (minor). mp 130-134 °C; Rf = 0.19 (1:2 1 CH2Cl2/hexanes). Spectral data for 237c: H NMR (CDCl3, 500 MHz) δ 2.00 (s, 12H), 5.70 (s, 2H), 6.28 (s, 4H), 6.72 (s, 2H), 7.27 (d, 2H, J = 0.5 Hz), 7.60-7.62 (m, 4H), 8.48-8.49 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 21.09, 113.92, 119.66, 121.56, 123.82, 125.14, 126.68, 128.51, 129.24, 130.90, 132.95, 136.78, 139.60, 141.41, 149.50; IR (thin film) 3517br s, 2919s, 1581s, -1 79 + 1487s, 1373s, 1279s cm ; HRMS (ESI–) m/z calcd for C36H27O2 Br2 (M-H ) 649.0378, meas 20 649.0355. [α] D = –171.4 (c 1.0, CH2Cl2) on >99% ee (S)-237c (HPLC). The synthesis of racemic 237d was performed according to the general procedure (Procedure J) with 7-bromo-3-(4-methoxyphenyl)naphthalen-1-ol 236d (1.58 g, 4.80 mmol). Purification by 365 column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 3:2) gave racemic 237d as a yellow solid (654 mg, 1.00 mmol, 42% yield). After de-racemization of racemic 237d (548 mg, 0.84 mmol) with CuCl (141 mg, 1.42 mmol) and (–)-sparteine (684 mg, 2.92 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 3:2) to afford (S)-237d as a light yellow solid (380 mg, 0.58 mmol, 69%). The optical purity was determined to be >99% ee by HPLC analysis (Chiralcel OD-H column, 90:10 hexane/iPrOH at 254 nm, flow-rate: 0.5 mL/min). Retention times: Rt = 4.68 min for (R)-237d (minor) and Rt = 6.65 min for (S)-237d (major). mp 147-150 °C; Rf = 0.24 (2:1 1 CH2Cl2/hexanes). Spectral data for 237d: H NMR (CDCl3, 500 MHz) δ 3.68 (s, 6H), 5.70 (s, 2H), 6.51-6.52 (m, 4H), 6.57-6.59 (m, 4H), 7.25 (s, 2H), 7.60-7.62 (m, 4H), 8.46-8.47 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 55.17, 113.09, 113.81119.63, 121.71, 123.82, 125.28, 129.28, 129.85, 130.96, 132.26, 133.06, 140.70, 149.41, 158.74; IR (thin film) 3503br s, 2930m,1514s, -1 79 + 1487s, 1375s, 1248s cm ; HRMS (ESI–) m/z calcd for C34H23O4 Br2 (M-H ) 652.9963, meas 20 652.9937. [α] D = –182.6 (c 1.0, CH2Cl2) on >99% ee (S)-237d (HPLC). The synthesis of racemic 237e was performed according to the general procedure (Procedure J) with 7-bromo-3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol 236e (2.50 g, 7.00 mmol). 366 Purification by column chromatography on silica gel (20 mm × 200 mm, CH2Cl2/hexanes 3:2) gave racemic 237e as a light yellow solid (990 mg, 1.39 mmol, 40% yield). After de-racemization of racemic 237e (712 mg, 1.00 mmol) with CuCl (168 mg, 1.70 mmol) and (–)-sparteine (819 mg, 3.50 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 3:2) to afford (S)-237e as a light yellow solid (526 mg, 0.74 mmol, 74%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 44.60 min for (R)-237e (minor) and Rt = 49.09 min for (S)-237e (major). 1 mp 203-206 °C; Rf = 0.33 (CH2Cl2). Spectral data for 237e: H NMR (CDCl3, 500 MHz) δ 1.95 (s, 12H), 3.61 (s, 6H), 5.70 (s, 2H), 6.28 (s, 4H), 7.25 (d, 2H, J = 0.5 Hz), 7.60-7.62 (m, 4H), 8.47-8.48 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 15.89, 59.70, 113.93, 119.64, 121.43, 123.75, 125.12, 129.21, 129.29, 129.68, 130.94, 132.96, 135.20, 140.85, 149.48, 156.20; IR (thin film) -1 79 3513br s, 2930s, 1577s, 1483s, 1375s, 1225s cm ; HRMS (ESI–) m/z calcd for C38H31O4 Br2 + 20 (M-H ) 709.0589, meas 709.0590. [α] D = –176.4 (c 1.0, CH2Cl2) on >99% ee (S)-237e (HPLC). 367 The synthesis of racemic 237f was performed according to the general procedure (Procedure J) with 7-bromo-3-(4-fluorophenyl)naphthalen-1-ol 236f (2.06 g, 6.50 mmol). After cooling down to room temperature, CH2Cl2 (30 mL) was 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) and then filtered through filter paper. The yellow powder was washed with chilled CH2Cl2/hexanes and dried under vacuum to afford a yellow solid (1.19 g). Purification of the product remaining in the mother liquor by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2/hexanes 1:1) gave racemic 237f as a yellow solid (0.25 g). The total yield is 70% (1.44 g, 2.28 mmol). After de-racemization of racemic 237f (632 mg, 1.00 mmol) with CuCl (168 mg, 1.70 mmol) and (–)-sparteine (819 mg, 3.50 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 2:3) to afford (S)-237f as an off-white solid (560 mg, 0.89 mmol, 89%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 29.55 min for (R)-237f (minor) and Rt = 35.61 min for (S)-237f (major). 1 mp 152-158 °C; Rf = 0.24 (1:1 CH2Cl2/hexanes). Spectral data for 237f: H NMR (CDCl3, 500 MHz) δ 5.75 (s, 2H), 6.54-6.56 (m, 4H), 6.65-6.69 (m, 4H), 7.25 (s, 2H), 7.64 (d, 4H, J = 1.0 Hz), 8.50 (d, 2H, J = 1.0 Hz); 13 2 C NMR (CDCl3, 125 MHz) δ 113.26, 114.58 ( J CF = 21 Hz), 120.21, 3 4 121.99, 123.98, 125.31, 129.36, 130.34 ( J CF = 8.1 Hz), 131.35, 133.02, 135.64 ( J CF = 3.3 1 Hz), 139.79, 149.55, 162.06 ( J CF = 245.8 Hz); 19 F NMR (CDCl3, 283 MHz) δ –113.46; IR -1 (thin film) 3517br s, 1512s, 1489s, 1375s, 1235s cm ; mass spectrum, m/z (% rel intensity) 634 368 + M (5, (17, 79 81 81 + Br Br), 632 M (10, Br), 289 (12, 81 81 79 + Br Br), 630 M (7, Br), 287 (13, 79 79 79 Br Br), 425 (5), 317 (21, 81 Br), 315 Br), 227 (65), 212 (83), 196 (100), 159 (100). Anal calcd 20 for C32H18Br2F2O2: C, 60.79; H, 2.87. Found: C, 60.99; H, 2.72. [α] D = –152.7 (c 1.0, CH2Cl2) on >99% ee (S)-237f (HPLC). The synthesis of racemic 223c was performed according to the general procedure (Procedure J) with 3-(3,5-dimethylphenyl)naphthalen-1-ol 222c (992 mg, 4.00 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:2) gave racemic 223c as a light yellow solid (754 mg, 1.52 mmol, 76% yield). After de-racemization of racemic 223c (494 mg, 1.00 mmol) with CuCl (168 mg, 1.70 mmol) and (–)-sparteine (819 mg, 3.50 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 1:2) to afford (S)-223c as a light yellow solid (160 mg, 0.32 mmol, 32%). The optical purity was determined to be >99% ee by HPLC analysis (Chiralcel OD-H column, 99:1 hexane/iPrOH at 254 nm, flow-rate: 0.7 mL/min). Retention times: Rt = 10.14 min for (R)-223c (minor) and Rt = 16.96 min for (S)-223c (major). mp 79-83 °C; Rf = 0.39 (2:1 CH2Cl2/hexanes). 1 Spectral data for 223c: H NMR (CDCl3, 500 MHz) δ 1.99 (s, 12H), 5.78 (s, 2H), 6.33 (d, 4H, J = 1.0 Hz), 6.70 (s, 2H), 7.31 (s, 2H), 7.50-7.55 (m, 4H), 7.74-7.77 (m, 2H), 8.31-8.34 (m, 2H); 369 13 C NMR (CDCl3, 125 MHz) δ 21.05, 113.06, 121.60, 122.64, 122.78, 125.46, 126.82, 127.32, 127.54, 128.19, 134.53, 136.58, 140.13, 141.00, 150.42; IR (thin film) 3513br s, 2921s, 1597s, -1 + 1497s, 1387s, 1277s cm ; HRMS (ESI+) m/z calcd for C36H31O2 (M+H ) 495.2324, meas 20 495.2332. [α] D = –233.9 (c 1.0, CH2Cl2) on >99% ee (S)-223c (HPLC). The synthesis of racemic 223d was performed according to the general procedure (Procedure J) with 3-(4-methoxyphenyl)naphthalen-1-ol 222d (590 mg, 2.36 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, EtOAc/hexanes 1:20 to 1:10) gave racemic 223d as a yellow solid (362 mg, 0.73 mmol, 62% yield). After de-racemization of racemic 223d (299 mg, 0.60 mmol) with CuCl (101 mg, 1.02 mmol) and (–)-sparteine (491 mg, 2.10 mmol), the crude product was purified by column chromatography on silica gel (35 mm × 200 mm, CH2Cl2/hexanes 4:1) to afford (S)-223d as a yellow solid (50 mg, 0.10 mmol, 17%). The optical purity was determined to be >99% ee by HPLC analysis (Chiralpak AS column, 90:10 hexane/iPrOH at 254 nm, flow-rate: 0.5 mL/min). Retention times: Rt = 12.41 min for (S)-223d (major) and Rt = 22.56 min for (R)-223d (minor). mp 212-215 °C; Rf = 0.42 (CH2Cl2). Spectral 1 data for 223d: H NMR (CDCl3, 500 MHz) δ 3.68 (s, 6H), 5.78 (s, 2H), 6.49-6.53 (m, 4H), 370 6.59-6.63 (m, 4H), 7.30 (s, 2H), 7.50-7.57 (m, 4H), 7.75-7.78 (m, 2H), 8.30-8.33 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 55.14, 112.92, 112.93, 121.78, 122.75, 122.78, 125.43, 127.42, 127.58, 129.94, 132.83, 134.62, 140.30, 150.27, 158.46; IR (thin film) 3507br s, 2930s, 1514s, -1 + 1495s, 1383s, 1246s cm ; HRMS (ESI+) m/z calcd for C34H27O4 (M+H ) 499.1909, meas 20 499.1902. [α] D = –242.3 (c 1.0, CH2Cl2) on >99% ee (S)-223d (HPLC). The synthesis of racemic 223e was performed according to the general procedure (Procedure J) with 3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol 222e (1.12 g, 4.00 mmol). Purification by column chromatography on silica gel (35 mm × 250 mm, EtOAc/hexanes 1:20) gave racemic 223e as a light yellow solid (590 mg, 1.06 mmol, 53% yield). After de-racemization of racemic 223e (188 mg, 0.34 mmol) with CuCl (58 mg, 0.59 mmol) and (–)-sparteine (278 mg, 1.19 mmol), the crude product was purified by column chromatography on silica gel (20 mm × 200 mm, CH2Cl2/hexanes 4:1) to afford (S)-223e as a yellow solid (88 mg, 0.16 mmol, 47%). The optical purity was determined to be >99% ee by HPLC analysis (Chiralcel OD-H column, 99:1 hexane/iPrOH at 254 nm, flow-rate: 0.5 mL/min). Retention times: Rt = 24.40 min for (R)-223e (minor) and Rt = 27.43 min for (S)-223e (major). mp 207-210 °C; Rf = 0.32 (CH2Cl2). Spectral 371 1 data for 223e: H NMR (CDCl3, 500 MHz) δ 1.94 (s, 12H), 3.61 (s, 6H), 5.78 (s, 2H), 6.32 (s, 4H), 7.29 (s, 2H), 7.49-7.56 (m, 4H), 7.74-7.77 (m, 2H), 8.30-8.33 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 15.85, 59.69, 113.05, 121.48, 122.62, 122.70, 125.46, 127.37, 127.51, 129.41, 129.44, 134.53, 135.73, 140.41, 150.38, 155.92; IR (thin film) 3515br s, 2930s, 1570s, 1487s, -1 + 1387s, 1225s cm ; HRMS (ESI+) m/z calcd for C36H29O4I2 (M+H ) 779.0155, meas 779.0159. 20 [α] D = –209.2 (c 1.0, CH2Cl2) on >99% ee (S)-223e (HPLC). The synthesis of racemic 223f was performed according to the general procedure (Procedure J) with 3-(4-fluorophenyl)naphthalen-1-ol 222f (952 mg, 4.00 mmol). Purification by column chromatography on silica gel (35 mm × 200 mm, CH2Cl2/hexanes 2:3) gave racemic 223f as an off-white solid (752 mg, 1.58 mmol, 79% yield). After de-racemization of racemic 223f (436 mg, 0.92 mmol) with CuCl (155 mg, 1.57 mmol) and (–)-sparteine (754 mg, 3.22 mmol), the crude product was purified by column chromatography on silica gel (35 mm × 200 mm, CH2Cl2/hexanes 2:3) to afford (S)-223f as an off-white solid (281 mg, 0.59 mmol, 64%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 20.55 min for 372 (R)-223f (minor) and Rt = 24.49 min for (S)-223f (major). mp 107-112 °C; Rf = 0.33 (2:1 1 CH2Cl2/hexanes). Spectral data for 223f: H NMR (CDCl3, 500 MHz) δ 5.83 (s, 2H), 6.57-6.61 (m, 4H), 6.63-6.68 (m, 4H), 7.29 (s, 2H), 7.54-7.60 (m, 4H), 7.77-7.79 (m, 2H), 8.33-8.35 (m, 2H); 13 2 C NMR (CDCl3, 125 MHz) δ 112.40, 114.40 ( J CF = 21.1 Hz), 122.05, 122.78, 122.93, 3 4 125.93, 127.69, 127.77, 130.43 ( J CF = 8.3 Hz), 134.59, 136.16 ( J CF = 3.3 Hz), 139.41, 1 150.42, 161.90 ( J CF = 244.9 Hz); 19 F NMR (CDCl3, 283 Hz) δ –114.15; IR (thin film) 3517br -1 + s, 3058s, 1512s, 1495s, 1385s, 1221s cm ; HRMS (ESI+) m/z calcd for C32H21O2F2 (M+H ) 20 475.1510, meas 475.1504. [α] D = –193.6 (c 1.0, CH2Cl2) on >99% ee (S)-223f (HPLC). The synthesis of racemic 223g was performed according to the general procedure (Procedure J) with 3-(4-bromophenyl)naphthalen-1-ol 222g (1.20 g, 4.00 mmol). Purification by column chromatography on silica gel (35 mm × 250 mm, CH2Cl2/hexanes 1:2 to 2:3) gave racemic 223g as an off-white solid (699 mg, 1.17 mmol, 59% yield). After de-racemization of racemic 223g (596mg, 1.00 mmol) with CuCl (168 mg, 1.70 mmol) and (–)-sparteine (819 mg, 3.50 mmol), the crude product was purified by column chromatography on silica gel (35 mm × 200 mm, CH2Cl2/hexanes 1:2 to 2:3) to afford (S)-223g as an off-white solid (443 mg, 0.74 mmol, 74%). The optical purity was determined to be >99% ee by HPLC analysis (Chiralcel OD-H column, 373 98:2 hexane/iPrOH at 254 nm, flow-rate: 0.7 mL/min). Retention times: Rt = 18.72 min for (S)-223g (major) and Rt = 21.78 min for (R)-223g (minor). mp 143-148 °C; Rf = 0.33 (2:1 1 CH2Cl2/hexanes). Spectral data for 223g: H NMR (CDCl3, 500 MHz) δ 5.82 (s, 2H), 6.48-6.51 (m, 4H), 7.08-7.11 (m, 4H), 7.29 (s, 2H), 7.55-7.61 (m, 4H), 7.78-7.80 (m, 2H), 8.32-8.35 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 112.02, 121.11, 122.12, 122.80, 123.03, 126.11, 127.76, 127.89, 130.49, 130.65, 134.58, 139.06, 139.17, 150.48; IR (thin film) 3505br s, 3052s, 1570s, -1 79 + 1489s, 1385s, 1221s cm ; HRMS (ESI+) m/z calcd for C32H21O2 Br2 (M+H ) 594.9908, 20 meas 594.9921. [α] D = –186.8 (c 1.0, CH2Cl2) on >99% ee (S)-223g (HPLC). The synthesis of racemic 223s was performed according to the general procedure (Procedure J) with 3-(thiophen-2-yl)naphthalen-1-ol 222s (1.70 g, 7.50 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 2:3) gave racemic 223s as a yellow solid (757 mg, 1.68 mmol, 45% yield). After de-racemization of racemic 223s (652 mg, 1.45 mmol) with CuCl (244 mg, 2.46 mmol) and (+)-sparteine (1.19 g, 5.09 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 1:1) to afford (R)-223s as an off-white foamy solid (476 mg, 1.06 mmol, 73%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine 374 column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 30.75 min for (R)-223s (major) and Rt = 34.92 min for (S)-223s (minor). mp 157-159 °C; Rf = 0.37 (2:1 1 CH2Cl2/hexanes). Spectral data for 223s: H NMR (CDCl3, 500 MHz) δ 5.60 (s, 2H), 6.68 (dd, 2H, J = 3.5, 1.0 Hz), 6.73 (dd, 2H, J = 5.0, 1.0 Hz), 7.50-7.54 (m, 2H), 7.56-7.61 (m, 2H), 7.76 (s, 2H), 7.86 (d, 2H, J = 8.0 Hz), 8.24-8.26 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 111.44, 121.47, 122.94, 123.29, 125.91, 126.00, 126.04, 127.03, 127.74, 127.96, 133.07, 134.80, 141.52, -1 151.31; IR (thin film) 3505br s, 1570s, 1491s, 1387s, 1210s cm ; HRMS (ESI–) m/z calcd for + 20 C28H17O2S2 (M-H ) 449.0670, meas 449.0660. [α] D = +124.9 (c 1.0, CH2Cl2) on >99% ee (R)-223s (HPLC). The synthesis of racemic 223t was performed according to the general procedure (Procedure J) with 3-(thiophen-3-yl)naphthalen-1-ol 222t (904 mg, 4.00 mmol). Purification by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:1) gave racemic 223t as a light yellow solid (534 mg, 1.19 mmol, 59% yield). After de-racemization of racemic 223t (360 mg, 0.80 mmol) with CuCl (135 mg, 1.36 mmol) and (+)-sparteine (655 mg, 2.80 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm, 375 CH2Cl2/hexanes 1:1) to afford (R)-223t as an off-white solid (144 mg, 0.32 mmol, 40%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 25.76 min for (R)-223t (major) and Rt = 30.40 min for (S)-223t (minor). mp 188-189 °C; Rf = 0.18 (1:1 1 CH2Cl2/hexanes). Spectral data for 223t: H NMR (CDCl3, 500 MHz) δ 5.68 (s, 2H), 6.62-6.65 (m, 4H), 6.96 (dd, 2H, J = 5.0, 3.5 Hz), 7.50-7.59 (m, 6H), 7.81-7.84 (m, 2H), 8.26-8.29 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 112.45, 121.33, 122.69, 122.83, 123.07, 124.43, 125.71, 127.63, 127.67, 127.94, 134.68, 135.10, 140.46, 150.46; IR (thin film) 3505br s, 1570s, 1495s, 1379s, -1 + 1265s cm ; HRMS (ESI–) m/z calcd for C28H17O2S2 (M-H ) 449.0670, meas 449.0685. 20 [α] D = +155.1 (c 1.0, CH2Cl2) on >99% ee (R)-223t (HPLC). 88 H8-VANOL 234: Acetic acid (4 mL) was added to a 25 mL round bottom flask charged with (S)-VANOL (219 mg, 0.5 mmol) and PtO2·H2O (15 mg, 0.06 mmol). The atmosphere of the flask was evacuated under vacuum and flushed with H2 three times. The mixture was stirred under a balloon pressure H2 atmosphere for 48 h. The reaction mixture was filtered through a pad of Celite, diluted with CH2Cl2 (10 mL), washed with H2O (20 mL), NaHCO3 (sat. aq. 20 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the 376 crude product by column chromatography on silica gel (30 mm x 250 mm, EtOAc/hexanes 1:80) gave 234 as a white foamy solid (148 mg, 0.33 mmol, 66%). mp 72-76 °C; Rf = 0.24 (1:10 1 EtOAc/hexanes). Spectral data for 234: H NMR (CDCl3, 500 MHz) δ 1.76-1.88 (m, 8H), 2.68-2.77 (m, 8H), 5.19 (s, 2H), 6.54 (s, 2H), 6.58-6.61 (m, 4H), 6.98-7.03 (m, 4H), 7.05-7.09 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 22.73, 22.81, 23.23, 29.58, 115.06, 122.99, 123.22, 126.14, 127.29, 128.62, 139.31, 140.31, 140.67, 151.88; IR (thin film) 3468br s, 2930s, 1559s, 1399s, -1 + 1300s, 1229s cm ; HRMS (ESI–) m/z calcd for C32H29O2 (M-H ) 445.2168, meas 445.2173. 20 [α] D = –143.3 (c 1.0, CH2Cl2). Suzuki coupling The reaction of (S)-227d (178 mg, 0.30 mmol), tetrakis(triphosphine)palladium (35 mg, 0.030 mmol), benzene (3 mL), Na2CO3 (aq. 2 M, 1.5 mL), 4-tert-butylphenylboronic acid (214 mg, 1.20 mmol) and ethanol (1.5 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (25 mm x 250 mm, CH2Cl2:hexanes 2:3) 377 gave (S)-227q as a white solid (179 mg, 0.255 mmol, 85%). mp >260 °C; Rf = 0.23 (1:1 1 CH2Cl2/hexane). Spectral data for 227q: H NMR (CDCl3, 500 MHz) δ 1.35 (s, 18H), 5.90 (s, 2H), 6.55-6.58 (m, 4H), 6.91-6.95 (m, 4H), 7.01-7.06 (m, 2H), 7.39-7.47 (m, 10H), 7.52 (dd, 2H, J = 7.0, 1.5 Hz), 7.58-7.62 (m, 2H), 8.38-8.41 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 31.37, 34.56, 112.54, 120.21, 122.07, 123.31, 125.26, 125.27, 126.43, 127.37, 128.81, 128.99, 129.60, 2 132.78, 137.40, 140.07, 140.43, 150.10, 150.47 (1 sp C not located); IR (thin film) 3520s, -1 + 2963s, 1576m, 1483m, 1383s, 1238m cm ; HRMS (ESI–) m/z calcd for C52H45O2 (M-H ) 20 701.3420, meas 701.3439. [α] D = –106.2 (c 1.0, CH2Cl2). The reaction of (S)-227d (149 mg, 0.25 mmol), tetrakis(triphosphine)palladium (29 mg, 0.025 mmol), benzene (2.5 mL), Na2CO3 (aq. 2 M, 1.25 mL), 4-(trifluoromethyl)phenylboronic acid (190 mg, 1.00 mmol) and ethanol (1.25 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:2) gave (S)-227p as a white solid (142 mg, 0.196 mmol, 78%). mp >260 °C; 1 Rf = 0.29 (1:1 CH2Cl2/hexanes). Spectral data for 227p: H NMR (CDCl3, 500 MHz) δ 5.90 (s, 378 2H), 6.54-6.57 (m, 4H), 6.92-6.96 (m, 4H), 7.04-7.08 (m, 2H), 7.29 (s, 2H), 7.51 (dd, 2H, J = 7.5, 1.5 Hz), 7.59 (d, 4H, J = 8.0 Hz), 7.61-7.65 (m, 2H), 7.69 (d, 4H, J = 8.0 Hz), 8.44-8.47 (m, 2H); 13 1 C NMR (CDCl3, 125 MHz) δ 112.79, 119.61, 123.08, 123.12, 124.34 (q, J CF = 255.63 Hz), 3 2 125.29 (q, J CF = 3.9 Hz), 126.74, 127.52, 128.82, 128.90, 129.54 (q, J CF = 31.9 Hz), 130.29, 2 132.43, 138.59, 140.10, 141.06, 144.13, 150.63 (1 sp C not located); 19 F NMR (CDCl3, 283 Hz) -1 δ –60.81; IR (thin film) 3522br s, 1576s, 1485s, 1385s, 1325s, 1240s cm ; HRMS (ESI–) m/z + 20 calcd for C46H27O2F6 (M-H ) 725.1915, meas 725.1891. [α] D = –110.4 (c 1.0, CH2Cl2). The reaction of (S)-228d (178 mg, 0.30 mmol), tetrakis(triphosphine)palladium (35 mg, 0.030 mmol), benzene (3 mL), Na2CO3 (aq. 2 M, 1.5 mL), 4-tert-butylphenylboronic acid (214 mg, 1.20 mmol) and ethanol (1.5 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (20 mm x 200 mm, CH2Cl2:hexanes 1:2) gave (S)-228q as a white solid (110 mg, 0.157 mmol, 53%). mp >260 °C; Rf = 0.26 (1:1 379 1 CH2Cl2/hexanes). Spectral data for 228q: H NMR (CDCl3, 500 MHz) δ 1.39 (s, 18H), 5.85 (s, 2H), 6.68 (dd, 4H, J = 8.0, 1.5 Hz), 6.99 (t, 4H, J = 8.0 Hz), 7.09 (t, 2H, J = 7.5 Hz), 7.37 (s, 2H), 7.52-7.54 (m, 4H), 7.67-7,70 (m, 4H), 7.82 (dd, 2H, J = 9.0, 2.0 Hz), 7.96 (d, 2H, J = 1.5 Hz), 8.40 (d, 2H, J = 8.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 31.38, 34.61, 112.64, 121.88, 122.29, 123.36, 125.27, 125.38, 125.89, 126.66, 127.06, 127.50, 128.90, 134.97, 137.92, 140.09, 140.23, -1 141.13, 150.39, 150.72; IR (thin film) 3521br s, 3031w, 2963s, 1570s, 1489s, 1383s, 1227s cm ; + 20 HRMS (ESI–) m/z calcd for C52H45O2 (M-H ) 701.3420, meas 701.3394. [α] D = –235.9 (c 1.0, CH2Cl2). The reaction of (S)-228d (238 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2 M, 2 mL), 4-(trifluoromethyl)phenylboronic acid (304 mg, 1.60 mmol) and ethanol (2 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 1:2) 380 gave (S)-228p as a white solid (146 mg, 0.201 mmol, 50%). mp >260 °C; Rf = 0.27 (1:1 1 CH2Cl2/hexanes). Spectral data for 228p: H NMR (CDCl3, 500 MHz) δ 5.89 (s, 2H), 6.64-6.68 (m, 4H), 6.98-7.01 (m, 4H), 7.08-7.12 (m, 2H), 7.38 (s, 2H), 7.75 (d, 4H, J = 8.0 Hz), 7.79 (dd, 2H, J = 9.0, 1.5 Hz), 7.83 (d, 4H, J = 8.0 Hz), 7.98 (d, 2H, J = 1.5 Hz), 8.44 (d, 2H, J = 9.0 Hz); 13 1 C NMR (CDCl3, 125 MHz) δ 113.22, 122.35, 122.39, 124.27 (q, J CF = 270.4 Hz), 123.81, 3 2 125.07, 125.86 (q, J CF = 3.9 Hz), 126.09, 126.84,127.56, 127.69, 128.85, 129.67 (q, J CF = 4 32.5 Hz), 134.80, 138.78, 139.90, 141.47, 144.33 (q, J CF = 1.3 Hz), 150.38; 19 F NMR (CDCl3, -1 283 Hz) δ –60.76; IR (thin film) 3521br s, 1561s, 1489s, 1385s, 1325s, 1225s cm ; HRMS + 20 (ESI–) m/z calcd for C46H27O2F6 (M-H ) 725.1915, meas 725.1890. [α] D = –231.4 (c 1.0, CH2Cl2). The reaction of (S)-229d (178 mg, 0.30 mmol), tetrakis(triphosphine)palladium (35 mg, 0.030 mmol), benzene (3 mL), Na2CO3 (aq. 2 M, 1.5 mL), 4-tert-butylphenylboronic acid (214 mg, 1.20 mmol) and ethanol (1.5 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (25 mm x 300 mm, CH2Cl2:hexanes 1:3) gave (S)-229q as a white solid (125 mg, 0.178 mmol, 59%). mp >260 °C; Rf = 0.25 (1:1 381 1 CH2Cl2/hexane). Spectral data for 229q: H NMR (CDCl3, 500 MHz) δ 1.21 (s, 18H), 5.80 (s, 2H), 5.92 (bs, 2H), 6.58 (dd, 2H, J = 8.0, 2.0 Hz), 6.62 (bs, 2H), 6.79 (s, 4H), 6.90 (s, 2H), 6.96-6.99 (m, 4H), 7.21 (dd, 2H, J = 8.0, 2.0 Hz), 7.40-7.44 (m, 2H), 7.51-7.56 (m, 4H), 8.41 (d, 2H, J = 8.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 31.29, 34.32, 113.72, 122.62, 122.91, 123.72, 124.61, 125.29, 125.67, 126.92, 127.05, 130.75, 131.60, 132.56, 134.08, 135.83, 138.58, 139.22, -1 148.89, 149.56; IR (thin film) 3519br s, 2961s, 1576s, 1456s, 1373s, 1210s cm ; HRMS (ESI–) + 20 m/z calcd for C52H45O2 (M-H ) 701.3420, meas 701.3401. [α] D = –1.9 (c 1.0, CH2Cl2). The reaction of (S)-237b (284 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2 M, 4 mL), 4-tert-butylphenylboronic acid (285 mg, 1.60 mmol) and ethanol (2 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 2:5) gave (S)-238b as an off-white solid (162 mg, 0.199 mmol, 50%). mp >260 °C; Rf = 0.22 (1:2 1 CH2Cl2/hexanes). Spectral data for 238b: H NMR (CDCl3, 500 MHz) δ 0.89 (t, 6H, J = 7.5 Hz), 1.27-1.32 (m, 4H), 1.39 (s, 18H), 1.49-1.52 (m, 4H), 2.47 (t, 2H, J = 7.5 Hz), 5.84 (s, 2H), 6.58 382 (dd, 4H, J = 6.5, 2.0 Hz), 6.78 (d, 4H, J = 8.0 Hz), 7.36 (d, 2H, J = 1.0 Hz), 7.52 (dd, 4H, J = 6.5, 2.0 Hz), 7.74 (dd, 4H, J = 6.5, 2.0 Hz), 7.83-7.84 (m, 4H), 8.54 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.91, 22.24, 31.40, 33.52, 34.59, 35.15, 113.30, 120.48, 121.61, 123.18, 125.84, 126.98, 127.08, 127.57, 128.14, 128.69, 133.69, 137.53, 138.09, 138.18, 140.60, 141.26, 150.48, 150.49; -1 IR (thin film) 3499br s, 2957s, 1559s, 1456s, 1388s, 1267s cm ; HRMS (ESI–) m/z calcd for + 20 C60H61O2 (M-H ) 813.4672, meas 813.4709. [α] D = –31.7 (c 1.0, CH2Cl2). The reaction of (S)-237c (261 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2 M, 4 mL), 4-tert-butylphenylboronic acid (285 mg, 1.60 mmol) and ethanol (2 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 2:5) gave (S)-238c as an off-white solid (145 mg, 0.191 mmol, 48%). mp 170-185 °C; Rf = 0.19 (1:2 1 CH2Cl2/hexanes). Spectral data for 238c: H NMR (CDCl3, 500 MHz) δ 1.38 (s, 18H), 2.01 (s, 12H), 5.82 (s, 2H), 6.36 (d, 4H, J = 0.5 Hz), 6.71 (s, 2H), 7.33 (d, 2H, J = 0.5 Hz), 7.52 (dd, 4H, J = 6.5, 2.0 Hz), 7.75 (dd, 4H, J = 7.0, 2.0 Hz), 7.82-7.83 (m, 4H), 8.55 (d, 2H, J = 0.5 Hz); 383 13 C NMR (CDCl3, 125 MHz) δ 21.10, 31.39, 34.59, 113.41, 120.24, 121.36, 123.07, 125.84, 126.82, 126.86, 127.03, 128.06, 128.22, 133.58, 136.62, 137.95, 138.12, 140.17, 140.90, 150.49, 150.65; -1 IR (thin film) 3519br s, 2961s, 1597s, 1495s, 1387s, 1267s cm ; HRMS (ESI–) m/z calcd for + 20 C56H53O2 (M-H ) 757.4046, meas 757.4055. [α] D = –6.2 (c 1.0, CH2Cl2). The reaction of (S)-237e (214 mg, 0.30 mmol), tetrakis(triphosphine)palladium (35 mg, 0.030 mmol), benzene (3 mL), Na2CO3 (aq. 2 M, 1.5 mL), 4-tert-butylphenylboronic acid (214 mg, 1.20 mmol) and ethanol (1.5 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 200 mm, CH2Cl2:hexanes 3:2) gave (S)-238e as an off-white solid (63 mg, 0.077 mmol, 26%). mp 172-178 °C; Rf = 0.40 1 (CH2Cl2). Spectral data for 238e: H NMR (CDCl3, 500 MHz) δ 1.39 (s, 18H), 1.96 (s, 12H), 3.62 (s, 6H), 5.84 (s, 2H), 6.36 (s, 4H), 7.32 (s, 2H), 7.53 (dd, 4H, J = 6.5, 2.0 Hz), 7.76 (dd, 4H, J = 6.5, 2.0 Hz), 7.82-7.83 (m, 4H), 8.55-8.56 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 15.89, 31.39, 34.59, 59.90, 113.44, 120.22, 121.26, 123.02, 125.85, 126.91, 127.03, 128.04, 129.42, 129.49, 133.60, 135.79, 137.96, 138.12, 140.34, 150.50, 150.64, 155.9; IR (thin film) 3519br s, 384 -1 + 2959s, 1559s, 1489s, 1389s, 1223s cm ; HRMS (ESI–) m/z calcd for C58H57O4 (M-H ) 20 817.4257, meas 817.4262. [α] D = –40.8 (c 1.0, CH2Cl2). To a flame-dried 250 mL round bottom flask was added (S)-237b (1.42 g, 2.00 mmol) and dry THF (15 mL). The resulting mixture was cooled to 0 °C and NaH (176 mg, 60% in mineral oil, 4.40 mmol) was added. The mixture was stirred at 0 °C for 15 minutes and MeI (0.8 mL, 12.8 mmol) was added. The mixture was warmed up to room temperature and stirred for additional 24 h. NH4Cl (sat. aq. 4 mL) was added to the mixture and the organic solvent was removed by rotary evaporation. The residue was extracted with CH2Cl2 (5 mL × 3). The combined organic layer was washed with Na2S2O3 (sat. aq. 5 mL × 2), brine (5 mL), and dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (20 mm x 320 mm, CH2Cl2:hexanes 1:4) gave (S)-239b as a white foamy solid (1.30 g, 1.76 mmol, 88%). mp 75-77 °C; Rf = 0.29 (1:2 CH2Cl2/hexanes). Spectral 1 data for 239b: H NMR (CDCl3, 500 MHz) δ 0.91 (t, 6H, J = 7.5 Hz), 1.28-1.33 (m, 4H), 1.49-1.53 (m, 4H), 2.45-2.49 (m, 4H), 3.63 (s, 6H), 6.63 (dd, 4H, J = 6.5, 2.0 Hz), 6.74 (d, 4H, J = 8.0 Hz), 7.50 (s, 2H), 7.57 (dd, 2H, J = 8.5, 2.0 Hz), 7.71 (d, 2H, J = 8.5 Hz), 8.33 (d, 2H, J = 385 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.91, 22.24, 33.58, 35.10, 61.14, 120.02, 124.84, 125.25, 126.37, 127.64, 128.10, 128.72, 129.82, 129.90, 132.99, 137.66, 140.65, 141.17, 153.39; IR (thin film) 2955s, 2928s, 2857s, 1561s, 1480s, 1352s, 1105s cm-1; HRMS (ESI+) m/z 79 20 + calculated for C42H41O2 Br2 (M+H ) 735.1473, found 735.1495. [α] D = –85.4 (c 1.0, CH2Cl2). To a flame-dried 25 mL round bottom flask were added (S)-239b (184 mg, 0.25 mmol), tetrakis(triphosphine)palladium (29 mg, 0.025 mmol) and DME (1.7 mL) under argon. To the stirred mixture were added phenyboronic acid (107 mg, 0.88 mmol) and Na2CO3 (aq. 2 M, 0.7 mL). The mixture was stirred at 90 ºC for 14 h with an argon balloon attached. After cooling down to room temperature, the mixture was filtered through a pad of Celite and washed with CH2Cl2. After removal of the solvent, the residue was dissolved in CH2Cl2 (20 mL) and washed with NH4Cl (sat. aq. 5 mL) and brine (5 mL). The organic layer was separated, dried over MgSO4, filtered through Celite and concentrated to dryness. The residue was purified by column chromatography (silica gel, 20 mm x 250 mm, CH2Cl2:hexanes 1:2). The purified and concentrated product was dissolved in CH2Cl2 (4 mL) and cooled to 0 ºC, BBr3 (1 M in CH2Cl2, 1.5 mL, 1.5 mmol) was added dropwise to the mixture at 0 ºC. The mixture was stirred at room 386 temperature overnight with an argon balloon attached to the flask. The mixture was then cooled to 0 ºC and H2O (8 mL) was added dropwise. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (5 mL×3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (20 mm x 260 mm, CH2Cl2:hexanes 1:2) gave (S)-240ah as a light yellow solid in 74% isolated yield over two steps (130 mg, 0.185 mmol). mp 225-226 °C; Rf = 1 0.26 (1:1 CH2Cl2/hexanes). Spectral data for 240ah: H NMR (CDCl3, 500 MHz) δ 0.89 (t, 6H, J = 7.5 Hz), 1.27-1.32 (m, 4H), 1.47-1.54 (m, 4H), 2.47 (t, 4H, J = 7.5 Hz), 5.84 (s, 2H), 6.59 (d, 4H, J = 8.0 Hz), 6.78 (d, 4H, J = 8.0 Hz), 7.36-7.40 (m, 4H), 7.48-7.52 (m, 4H), 7.78-7.88 (m, 8H), 8.55 (d, 2H, J = 0.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.90, 22.23, 33.51, 35.15, 113.36, 120.75, 121.63, 123.15, 127.02, 127.41, 127.44, 127.59, 128.24, 128.69, 128.89, 133.81, 137.46, 138.25, 140.78, 141.10, 141.33, 150.53; IR (thin film) 3503br s, 2928s, 1559s, 1489s, 1387s, -1 + 1215s cm ; HRMS (ESI–) m/z calculated for C52H45O2 (M-H ) 701.3420, found 701.3411. 20 [α] D = –86.8 (c 1.0, CH2Cl2). 387 To a flame-dried 25 mL round bottom flask were added (S)-239b (184 mg, 0.25 mmol), tetrakis(triphosphine)palladium (29 mg, 0.025 mmol) and DME (1.7 mL) under argon. To the stirred mixture were added anthracene-9-boronic acid (195 mg, 0.88 mmol) and Na2CO3 (aq. 2 M, 0.7 mL). The mixture was stirred at 90 ºC for 14 h with an argon balloon attached. After cooling down to room temperature, the mixture was filtered through a pad of Celite and washed with CH2Cl2. After removal of the solvent, the residue was dissolved in CH2Cl2 (20 mL) and washed with NH4Cl (sat. aq. 5 mL) and brine (5 mL). The organic layer was separated, dried over MgSO4, filtered through Celite and concentrated to dryness. The residue was purified by column chromatography (silica gel, 20 mm x 250 mm, CH2Cl2:hexanes 1:2). The purified and concentrated product was dissolved in CH2Cl2 (4 mL) and cooled to 0 ºC, BBr3 (1 M in CH2Cl2, 1.5 mL, 1.5 mmol) was added dropwise to the mixture at 0 ºC. The mixture was stirred at rt overnight with an argon balloon attached to the flask. The mixture was then cooled to 0 ºC and H2O (8 mL) was added dropwise. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (5 mL×3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (20 mm x 260 mm, CH2Cl2:hexanes 1:2) gave (S)-240x as a light yellow solid in 53% isolated yield over two steps (120 mg, 0.133 mmol). mp 170-172 °C; Rf = 1 0.15 (1:2 CH2Cl2/hexane). Spectral data for 240x: H NMR (CDCl3, 500 MHz) δ 0.96 (t, 6H, J = 7.5 Hz), 1.35-1.40 (m, 4H), 1.56-1.62 (m, 4H), 2.57 (t, 4H, J = 7.5 Hz), 5.87 (s, 2H), 6.69 (d, 4H, J = 8.0 Hz), 6.89 (d, 4H, J = 8.0 Hz), 7.30-7.34 (m, 2H), 7.40-7.50 (m, 8H), 7.61 (dd, 2H, J = 8.5, 2.0 Hz), 7.72 (d, 2H, J = 8.5 Hz), 7.82 (d, 2H, J = 8.5 Hz), 7.98 (d, 2H, J = 8.5 Hz), 388 8.04-8.09 (m, 4H), 8.42 (d, 2H, J = 1.0 Hz), 8.53 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.97, 22.34, 33.63, 35.26, 113.59, 121.84, 122.91, 125.10, 125.14, 125.17, 125.44, 125.51, 126.76, 126.95, 127.64, 127.69, 128.35, 128.47, 128.82, 130.42, 130.53, 131.07, 131.45, 131.49, 133.94, 2 136.03, 136.94, 137.63, 141.11, 141.41, 150.54 (1 sp C not located); IR (thin film) 3520br s, -1 + 3052m, 2928s, 1559s, 1456s, 1387s cm ; HRMS (ESI–) m/z calculated for C68H53O2 (M-H ) 20 901.4046, found 901.4084. [α] D = –497.9 (c 1.0, CH2Cl2). The reaction of (S)-223e (179 mg, 0.30 mmol), tetrakis(triphosphine)palladium (35 mg, 0.030 mmol), benzene (3 mL), Na2CO3 (aq. 2 M, 1.5 mL), phenylboronic acid (146 mg, 1.20 mmol) and ethanol (1.5 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (20 mm x 200 mm, CH2Cl2:hexanes 2:3) gave (S)-223f as a white solid (125 mg, 0.212 mmol, 71%). mp 154-159 °C; Rf = 0.29 (2:1 CH2Cl2/hexanes). 1 Spectral data for 223f: H NMR (CDCl3, 500 MHz) δ 5.90 (s, 2H), 6.70-6.74 (m, 4H), 7.20-7.24 (m, 4H), 7.27-7.32 (m, 2H), 7.36-7.40 (m, 6H), 7.49-7.52 (m, 4H), 7.55-7.60 (m, 4H), 7.78-7.81 (m, 2H), 8.36-8.39 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 112.66, 122.07, 122.84, 123.01, 125.76, 126.11, 126.90, 127.23, 127.60, 127.75, 128.72, 129.34, 134.66, 139.24, 139.26, 140.21, 389 -1 140.63, 150.41; IR (thin film) 3511br s, 3056s, 1570s, 1487s, 1383s, 1221s cm ; HRMS (ESI+) + 20 m/z calcd for C44H31O2 (M+H ) 591.2324, meas 591.2335. [α] D = –167.3 (c 1.0, CH2Cl2). 6.3.4 Preparation of C1-VANOL derivatives Procedure R 13g,73 Oxidative phenol-coupling: To a 250 mL flame-dried three neck round bottom flask equipped with a cooling condenser was added 3-(4-methoxyphenyl)naphthalen-1-ol 222d (1.00 g, 4.00 mmol), 3-phenylnaphthalen-1-ol 175a (2.64 g, 12.0 mmol) and mineral oil (24 mL). Airflow was introduced from one side neck via a needle located one inch above the mixture. The airflow rate is about one bubble per second. The mixture was stirred at 165 °C for 24 h. st Purification of the crude product by column chromatography on silica gel (1 column, 35 mm x nd 250 mm, CH2Cl2:hexanes 1:1; 2 column, 35 mm x 250 mm, EtOAc:hexanes, 1:20) gave racemic 260a as a light yellow solid (980 mg, 2.09 mmol, 52%). 390 13c De-racemization: To a 100 mL round bottom flask was added (–)-sparteine (819 mg, 3.50 mmol), CuCl (168 mg, 1.70 mmol) and MeOH (30 mL) under an atmosphere of air. reaction mixture was sonicated in a water bath for 60 minutes with exposure to air. The The flask was then sealed with a septum and purged with argon, which was introduced by a needle under the surface for 60 minutes. At the same time, to a 500 mL flame-dried round bottom flask was added racemic 260a (468 mg, 1.00 mmol) and CH2Cl2 (120 mL). The resulting solution was purged with argon for 60 minutes under the surface. The green Cu(II)-sparteine solution was then transferred via cannula to the solution of racemic 260a under argon and then the combined mixture was sonicated for 15 minutes and then allowed to stir at room temperature overnight with an argon balloon attached to the flask which was covered with aluminum foil. The reaction was quenched by slow addition of NaHCO3 (sat. aq.13 mL), H2O (50 mL) and most of the organic solvent was removed under reduced pressure. The residue was then extracted with CH2Cl2 (50 mL × 3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (25 mm × 200 mm, EtOAc:hexanes 1:20) gave the product (S)-260a as an off-white foamy solid (82 mg, 0.175 mmol, 18%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 28.22 min for (R)-260a (minor) and Rt = 31.71 min for (S)-260a 1 (major). mp 112-117 °C; Rf = 0.15 (2:1 CH2Cl2/hexanes). Spectral data for 260a: H NMR (CDCl3, 500 MHz) δ 3.69 (s, 3H), 5.78 (s, 1H), 5.81 (s, 1H), 6.49-6.52 (m, 2H), 6.55-6.58 (m, 2H), 6.67 (dd, 2H, J = 8.5, 1.5 Hz), 6.94-6.98 (m, 2H), 7.05 (t, 1H, J = 7.5 Hz), 7.28 (s, 1H), 7.34 391 (s, 1H), 7.50-7.59 (m, 4H), 7.74-7.80 (m, 2H), 8.31-8.35 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 55.39, 112.97, 113.09, 113.19, 121.99, 122.31, 122.97, 123.02, 123.04, 123.16, 125.70, 125.89, 126.84, 127.67, 127.69, 127.74, 127.82, 127.93, 129.08, 130.23, 133.02, 134.82, 134.88, 140.45, 2 140.52, 140.94, 150.55, 158.71 (1 sp C not located); IR (thin film) 3507br s, 3054m, 2930m, -1 + 1570s, 1493s, 1383s, 1246s cm ; HRMS (ESI–) m/z calculated for C33H23O3 (M-H ) 467.1647, 20 found 467.1638. [α] D = –244.2 (c 1.0, CH2Cl2) on >99% ee (S)-260a (HPLC). The synthesis of racemic 260b was performed according to the general procedure (Procedure R) with 3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol 222e (1.11 g, 4 mmol) and 3-phenyl-1-naphthol 175a (2.64 g, 12 mmol) Purification by column chromatography on silica st nd gel (1 column, silica gel, 35 mm x 250 mm, CH2Cl2:hexanes 1:1; 2 column, silica gel, 35 mm x 250 mm, EtOAc:hexanes 1:20) gave racemic 260b as a light yellow solid (998 mg, 2.01 mmol, 50%). After de-racemization of racemic 260b (496 mg, 1.00 mmol) with CuCl (168 mg, 1.70 mmol) and (–)-sparteine (819 mg, 3.50 mmol), the crude product was purified by column 392 chromatography on silica gel (25 mm × 180 mm column, CH2Cl2:hexanes 2:1) to afford (S)-260b as a light yellow solid (142 mg, 0.29 mmol, 29%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 24.21 min for (R)-260b (minor) and Rt = 26.81 min for (S)-260b (major). mp 71-76 °C; Rf = 0.14 (2:1 CH2Cl2/hexanes). Spectral data for 260b: 1 H NMR (CDCl3, 500 MHz) δ 1.92 (s, 6H), 3.61 (s, 3H), 5.80 (s, 1H), 5.83 (s, 1H), 6.20 (s, 2H), 6.64-6.60 (m, 2H), 6.94-6.98 (m, 2H), 7.04-7.08 (m, 1H), 7.28 (s, 1H), 7.32 (s, 1H), 7.51-7.58 (m, 4H), 7.74-7.78 (m, 2H), 8.32-8.35 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 15.73, 59.71, 112.79, 112.91, 121.48, 121.88, 122.66, 122.76, 122.80, 125.49, 125.62, 126.49, 127.26, 127.42, 127.46, 127.56, 127.59, 128.93, 129.46, 129.47, 134.52, 134.57, 135.54, 140.18, 140.46, 140.60, 150.24, 2 150.36, 155.83 (1 sp C not located); IR (thin film) 3510br s, 2930s, 1570s, 1491s, 1385s, 1225s -1 + 20 cm ; HRMS (ESI–) m/z calculated for C17H13O2 (M-H ) 495.1960, found 495.1952. [α] D = –225.0 (c 1.0, CH2Cl2) on >99% ee (S)-260b (HPLC). 393 The synthesis of racemic 260c was performed according to the general procedure (Procedure R) with 3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol 222e (1.11 g, 4 mmol) and 7-bromo-3-phenyl-1-naphthol 175d (3.59 g, 12 mmol) Purification by column chromatography st nd on silica gel (1 column, silica gel, 35 mm x 250 mm, CH2Cl2:hexanes 1:2; 2 column, silica gel, 35 mm x 250 mm, EtOAc:hexanes 1:20) gave racemic 260c as a light yellow solid (537 mg, 0.93 mmol, 23%). After de-racemization of racemic 260c (463 mg, 0.805 mmol) with CuCl (136 mg, 1.37 mmol) and (–)-sparteine (660 mg, 2.82 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm column, CH2Cl2:hexanes 2:1) to afford (S)-260c as an off-white solid (272 mg, 0.47 mmol, 59%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 28.98 min for (R)-260c (minor) and Rt = 32.42 min for (S)-260c (major). mp 124-128 °C; Rf = 0.26 (2:1 CH2Cl2/hexanes). Spectral data for 1 260c: H NMR (CDCl3, 500 MHz) δ 1.94 (s, 6H), 3.61 (s, 3H), 5.75 (s, 1H), 5.82 (s, 1H), 6.18 (s, 2H), 6.62-6.65 (m, 2H), 6.94-6.98 (m, 2H), 7.05-7.09 (m, 1H), 7.27 (s, 1H), 7.28 (s, 1H), 7.51-7.57 (m, 2H), 7.59-7.63 (m, 2H), 7.74-7.77 (m, 1H), 8.31-8.34 (m, 1H), 8.49-8.50 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 15.77, 59.72, 112.55, 114.13, 119.69, 121.61, 121.64, 122.72, 122.79, 123.85, 125.18, 125.60, 126.72, 127.35, 127.57, 127.62, 128.85, 129.24, 129.43, 129.56, 130.86, 132.87, 134.65, 135.41, 139.82, 140.29, 141.21, 149.53, 150.19, 155.93; IR (thin film) -1 3509br s, 3054m, 2932m, 1570s, 1487s, 1375s, 1224s cm ;HRMS (ESI+) m/z calculated for 79 + 20 C35H28O3 Br (M-H ) 575.1222, found 575.1233. [α] D = –234.9 (c 1.0, CH2Cl2) on >99% ee (S)-260c (HPLC). 394 The synthesis of racemic 260d was performed according to the general procedure (Procedure R) with 3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol 222e (1.11 g, 4 mmol) and 7-iodo-3-phenyl-1-naphthol 175m (4.15 g, 12 mmol) Purification by column chromatography on st silica gel (1 column, silica gel, 35 mm x 250 mm, CH2Cl2:hexanes 1:2; 2 nd column, silica gel, 35 mm x 250 mm, EtOAc:hexanes 1:20) gave racemic 260d as a light yellow solid (590 mg, 0.95 mmol, 24%). After de-racemization of racemic 260d (450 mg, 0.723 mmol) with CuCl (122 mg, 1.23 mmol) and (–)-sparteine (593 mg, 2.53 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm column, CH2Cl2:hexanes 2:1) to afford (S)-260d as a light yellow (183 mg, 0.29 mmol, 41%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 30.86 min (minor) for (R)-260d and Rt = 34.17 min for (S)-260d (major). mp 128-132 °C; Rf = 0.26 (2:1 CH2Cl2/hexanes). Spectral data for 1 260d: H NMR (CDCl3, 500 MHz) δ 1.94 (s, 6H), 3.61 (s, 3H), 5.74 (s, 1H), 5.80 (s, 1H), 6.18 (s, 395 2H), 6.63 (dd, 2H, J = 8.0, 1.0 Hz), 6.96 (t, 2H, J = 8.0 Hz), 7.05-7.09 (m, 1H), 7.26 (s, 1H), 7.28 (s, 1H), 7.49 (d, 1H, J = 8.5 Hz), 7.52-7.57 (m, 2H), 7.74-7.79 (m, 2H), 8.31-8.34 (m, 1H), 8.72-8.73 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 15.78, 59.72, 91.08, 112.52, 113.98, 121.66, 122.73, 122.79, 124.27, 125.60, 126.73, 127.35, 127.57, 127.62, 128.84, 129.12, 129.42, 129.57, 2 131.76, 133.14, 134.65, 135.41, 136.03, 139.82, 140.30, 141.42, 149.29, 150.19, 155.94 (1 sp C -1 not located); IR (thin film) 3507br s, 2932m, 1570s, 1485s, 1373s, 1225s cm ; HRMS (ESI+) + 20 m/z calculated for C35H28O3I (M+H ) 623.1083, found 623.1067. [α] D = –223.8 (c 1.0, CH2Cl2) on >99% ee (S)-260d (HPLC). The synthesis of racemic 260e was performed according to the general procedure (Procedure R) with 3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol 222e (1.11 g, 4 mmol) and 7-(tert-butyl)-3-phenylnaphthalen-1-ol 175m (3.31 g, 12 mmol) Purification by column st nd chromatography on silica gel (1 column, silica gel, 35 mm x 250 mm, CH2Cl2:hexanes 1:2; 2 column, silica gel, 35 mm x 300 mm, EtOAc:hexanes 1:20) gave racemic 260e as a light yellow 396 solid (290 mg, 0.53 mmol, 13%). After de-racemization of racemic 260e (127 mg, 0.23 mmol) with CuCl (39 mg, 0.39 mmol) and (–)-sparteine (188 mg, 0.80 mmol), the crude product was purified by column chromatography on silica gel (20 mm × 200 mm column, CH2Cl2:hexanes 2:1) to afford (S)-260e as an off-white solid (80 mg, 0.145 mmol, 63%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 15.47 min for (R)-260e (minor) and Rt = 17.08 min for (S)-260e (major). mp 125-130 °C; Rf = 0.33 (2:1 1 CH2Cl2/hexanes). Spectral data for 260e: H NMR (CDCl3, 500 MHz) δ 1.47 (s, 9H), 1.94, (s, 6H), 3.62 (s, 3H), 5.76 (s, 1H), 5.83 (s, 1H), 6.23 (s, 2H), 6.63-6.66 (m, 2H), 6.95 (t, 2H, J = 7.5 Hz), 7.05 (t, 1H, J = 7.5 Hz), 7.29 (d, 2H, J = 2.0 Hz), 7.51-7.56 (m, 2H), 7.65 (dd, 1H, J = 8.5, 2.0 Hz), 7.72 (d, 1H, J = 8.5 Hz), 7.74-7.77 (m, 1H), 8.27 (d, 1H, J = 1.5 Hz), 8.32-8.35 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 15.76, 31.35, 35.20, 59.71, 112.70, 113.13, 117.56, 121.50, 121.54, 122.66, 122.81, 125.46, 126.37, 127.28, 127.36, 127.40, 127.61, 128.94, 129.48, 129.50, 2 132.82, 134.59, 135.67, 139.86, 140.41, 140.57, 148.62, 150.26, 150.29, 155.91 (2 sp C not -1 located); IR (thin film) 3517br s, 2959s, 1597s, 1487s, 1387s, 1225s cm ; HRMS (ESI+) m/z + 20 calculated for C39H37O3 (M+H ) 553.2743, found 553.2740. [α] D = –214.8 (c 1.0, CH2Cl2) on >99% ee (S)-260e (HPLC). 397 The synthesis of racemic 260o was performed according to the general procedure (Procedure R) with 7-bromo-3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol 236e (1.29 g, 3.60 mmol) and 7-bromo-3-phenyl-1-naphthol 175d (3.23 g, 10.8 mmol) Purification by column chromatography st nd on silica gel (1 column, silica gel, 35 mm x 250 mm, CH2Cl2:hexanes 2:5; 2 column, silica gel, 35 mm x 250 mm, EtOAc:hexanes 1:20) gave racemic 260o as a light yellow solid (1.19 g, 1.82 mmol, 51%). After de-racemization of racemic 260o (785 mg, 1.20 mmol) with CuCl (202 mg, 2.04 mmol) and (+)-sparteine (983 mg, 4.20 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm column, CH2Cl2:hexanes 1:1) to afford (R)-260o as a light yellow solid (770 mg, 1.18 mmol, 98%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 40.65 min for (R)-260o (major) and Rt = 45.82 min for (S)-260o (minor). mp 127-133 °C; Rf = 0.35 (2:1 CH2Cl2/hexanes). Spectral data for 1 260o: H NMR (CDCl3, 500 MHz) δ 1.93 (s, 6H), 3.61 (s, 3H), 5.77 (s, 1H), 5.80 (s, 1H), 6.16 398 (s, 2H), 6.59-6.61 (m, 2H), 6.94-6.98 (m, 2H), 7.06-7.10 (m, 1H), 7.23 (s, 1H), 7.26 (s, 1H), 7.59-7.64 (m, 4H), 8.49 (d, 2H, J = 1.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 15.76, 59.72, 113.73, 113.77, 119.67, 119.82, 121.39, 121.75, 123.81, 123.85, 125.16, 125.26, 126.82, 127.38, 128.78, 129.25, 129.27, 129.34, 129.67, 130.95, 131.00, 132.91, 132.98, 135.02, 139.64, 140.87, -1 141.02, 149.38, 149.48, 156.07; IR (thin film) 3509br s, 2926s, 1561s, 1485s, 1375s, 1225s cm ; 79 + 20 HRMS (ESI–) m/z calcd for C35H25O3 Br2 (M-H ) 651.0170, meas 651.0153. [α] D = +160.8 (c 1.0, CH2Cl2) on >99% ee (R)-260o (HPLC). The reaction of (S)-260c (115 mg, 0.20 mmol), tetrakis(triphosphine)palladium (11.6 mg, 0.013 mmol), benzene (2 mL), Na2CO3 (aq. 2 M, 0.4 mL), 4-tert-butylphenylboronic acid (54 mg, 0.30 mmol) and ethanol (1 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (20 mm x 200 mm, CH2Cl2:hexanes 3:2) gave (S)-260f as an off-white solid (73 mg, 0.116 mmol, 58%). mp 156-161 °C; Rf = 0.38 (2:1 1 CH2Cl2/hexanes). Spectral data for 260f: H NMR (CDCl3, 500 MHz) δ 1.39 (s, 9H), 1.94 (s, 6H), 3.61 (s, 3H), 5.83 (s, 1H), 5.86 (s, 1H), 6.23 (s, 2H), 6.66-6.69 (dm, 2H), 6.95-6.99 (m, 2H), 7.05-7.09 (m, 1H), 7.29 (s, 1H), 7.33 (d, 1H, J = 0.5 Hz), 7.51-7.56 (m, 4H), 7.74-7.78 (m, 3H), 399 7.83-7.84 (m, 2H), 8.33-8.36 (m, 1H), 8.55-8.56 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 15.77, 31.39, 34.59, 59.71, 112.99, 113.18, 120.25, 121.50, 121.62, 122.78, 122.80, 123.14, 125.49, 125.86, 126.50, 126.99, 127.04, 127.29, 127.43, 127.60, 128.09, 128.93, 129.48, 129.50, 133.57, 2 134.60, 135.58, 138.06, 138.11, 140.25, 140.51, 150.28, 150.53, 150.61, 155.90 (1 sp C not -1 located); IR (thin film) 3519br s, 2959s, 1570s, 1491s, 1387s, 1225s cm ; HRMS (ESI+) m/z + 20 calculated for C45H41O3 (M+H ) 629.3056, found 629.3069. [α] D = –219.2 (c 1.0, CH2Cl2) The reaction of (R)-260o (262 mg, 0.40 mmol), tetrakis(triphosphine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2 M, 2 mL), 4-tert-butylphenylboronic acid (285 mg, 1.60 mmol) and ethanol (2 mL) was performed according to Procedure K. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:2) gave (R)-260o as an off-white solid (133 mg, 0.175 mmol, 44%). mp 158-164 °C; Rf = 0.37 (1:1 1 CH2Cl2/hexanes). Spectral data for 260o: H NMR (CDCl3, 500 MHz) δ 1.40 (s, 18H), 1.95 (s, 6H), 3.63 (s, 3H), 5.89 (s, 1H), 5.92 (s, 1H), 6.26 (s, 2H), 6.69-6.71 (m, 2H), 6.97-7.01 (m, 2H), 7.06-7.10 (m, 1H), 7.31 (s, 1H), 7.35 (s, 1H), 7.52-7.56 (m, 4H), 7.74-7.79 (m, 4H), 7.81-7.87 (m, 400 4H), 8.57-8.59 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 15.76, 31.38, 34.58, 59.71, 113.21, 113.31, 120.26, 120.42, 121.24, 121.62, 123.07, 123.13, 125.85, 126.51, 126.97, 127.03, 127.05, 127.31, 128.09, 128.11, 128.93, 129.46, 129.51, 133.57, 133.61, 135.60, 138.05, 138.07, 138.08, 2 138.11, 140.23, 140.37, 140.50, 150.46, 150.50, 150.51, 150.61, 155.87 (2 sp C not located); IR -1 (thin film) 3513br s, 2959s, 1559s, 1458s, 1387s, 1265s cm ; HRMS (ESI–) m/z calcd for + 20 C55H51O3 (M-H ) 759.3838, meas 759.3824. [α] D = +5.7 (c 1.0, CH2Cl2). 401 6.4 Experimental for chapter five 6.4.1 Preparation of aryl alkyne 331x 1,3-di-tert-butyl-5-iodo-2-methoxybenzene 331x: To a 1 L flame-dried flask filled with argon was added 5-bromo-1,3-di-tert-butyl-2-methoxybenzene 330x (34.6 g, 100 mmol) and dry Et2O (250 mL). The mixture was stirred until the bromide was dissolved at room temperature and then the flask was submerged into a –78 ºC bath, followed by slow addition of t-BuLi (118 mL, 200 mmol, 1.7 M in hexanes) and then the solution was stirred at –78 ºC for 1h. At the same time, to a flame-dried 250 mL flask iodine (27.9 g, 110 mmol) was dissolved in dry Et2O (150 mL). The iodine solution was then cooled to –78 ºC and transferred to the aryllithium solution via cannula under argon. The mixture was warmed up gradually to room temperature and stir for an additional 2 h. The reaction was quenched by pouring the reaction mixture slowly into a Na2S2O3 solution (aq. 5%, 200 mL) and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted with Et2O (100 mL × 3). the combined organic layer was washed with H2O (100 mL × 2) and NaCl (aq. sat.), dried over MgSO4 and filtered through Celite. Removal of the solvent by rotary evaporation afforded the crude product as a yellow 1 liquid in 100% yield. The H NMR spectrum of the crude was clean, and it was used in the next 1 step without purification. Spectral data for 331x: H NMR (CDCl3, 500 MHz) δ 1.38 (s, 18H), 402 3.65 (s, 3H), 7.48 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 31.87, 35.76, 64.39, 88.13, 135.68, 146.42, 159.66. 1,3-di-tert-butyl-5-ethynyl-2-methoxybenzene 235x: 112 The reaction of 1,3-di-tert-butyl-5-iodo-2-methoxybenzene 331x from the above and trimethylsilyl acetylene (15.5 mL, 110 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm × 200 mm, hexanes) gave 235x as a colorless solid (22.1 g, 90.6 mmol, 91%). Rf = 0.16 (hexanes). Spectral 1 data for 235x: 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. 6.4.2 Preparation of aryl acetic acids 99 (6-bromonaphthalen-2-yl)methanol 282: To a flame-dried round bottom flask was added methyl 6-bromo-2-naphthoate 281 (31.8 g, 120 mmol) and dry THF (300 mL) under argon. The solution was cooled to 0 °C and DIBAL-H (1 M in heptane, 252 mL, 252 mmol) was added dropwise to the mixture. The mixture was warmed up to room temperature and stirred overnight. 403 The resulting mixture was poured slowly into HCl (4N aq. 200 mL) at 0 °C. The mixture was stirred for 30 min and the organic layer was separated. The organic layer was washed with HCl (4N aq. 48 mL), NaHCO3 (5% aq. 240 mL), and brine (240 mL). The organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. EtOAc (20 mL) and hexanes (160 mL) were added to the product. Filtration by filter paper and drying under vacuum gave 282 99 as a white solid (27.0 g, 114 mmol, 95%). mp 150-151 °C (lit. 152-153 °C). Spectral data for 1 282: H NMR (CDCl3, 500 MHz) δ 1.75 (t, 1H, J = 0.5 Hz), 4.83 (d, 2H, J = 5.5 Hz), 7.48 (dd, 1H J = 8.5, 1.5 Hz), 7.53 (dd, 1H, J = 8.5, 2.0 Hz), 7.68 (d, 1H, J = 8.5 Hz), 7.73 (d, 1H, J = 8.5 Hz), 7.77 (s, 1H), 7.98 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 65.25, 119.83, 125.28, 126.16, 127.42, 129.52, 129.59, 129.78, 131.80, 133.98, 138.85; IR (thin film) 3276s, -1 + 1591s, 1269s, 1129s, 1013s cm ; mass spectrum, m/z (% rel intensity) 238 M (32, + M (35, 79 Br), 209 (9, 81 Br), 207 (12, 79 81 Br), 236 Br), 157 (7), 139 (20), 128 (100). 99 2-bromo-6-(chloromethyl)naphthalene 283: To a 250 mL round bottom flask was added (6-bromonaphthalen-2-yl)methanol 282 (1.90, 8.00 mmol), ZnCl2 (27.2 mg, 0.20 mmol) and DME (20 mL). The reaction mixture was cooled to 0 °C and SOCl2 (1.17 mL, 16 mmol) was added dropwise. The resulting mixture was stirred at 0 °C for 3 h, and then room temperature overnight. The solvent was removed by rotary evaporation. Hexanes (25 mL) was added to the crude product. Filtration by filter paper and drying under vacuum gave 283 as a white solid (2.00 404 99 g, 7.80 mmol, 98%). mp 118-119 °C (lit. 1 130-131 °C). Spectral data for 283: H NMR (CDCl3, 500 MHz) δ 4.71 (s, 2H), 7.51 (dd, 1H, J = 8.5, 2.0 Hz), 7.55 (dd, 1H, J = 8.5, 2.0 Hz), 7.68 (d, 1H, J = 8.5 Hz), 7.74 (d, 1H, J = 8.5 Hz), 7.78 (s, 1H), 7.99 (d, 1H, J = 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 46.27, 120.54, 127.32, 127.43, 127.79, 129.59, 129.82, 129.90, 131.59, -1 + 134.13, 135.35; IR (thin film) 1576s, 1456s cm ; mass spectrum, m/z (% rel intensity) 256 M (23, 81 + Br), 254 M (18, 79 Br), 221 (66, 81 Br), 219 (69, 99 2-(6-bromonaphthalen-2-yl)acetonitrile 284: 79 Br), 139 (64), 111 (22). To a 500 mL round bottom flask was added 2-bromo-6-(chloromethyl)naphthalene 283 (27.1 g, 106 mmol), NaCN (6.76 g, 138 mmol), CH3CN (275 ml) and H2O (33 mL) The mixture was refluxed overnight. After cooling to room temperature, H2O (240 mL) was added to the flask. The organic solvent was removed by rotary evaporation and H2O (320 mL) was added. CH2Cl2 (500 ml) was added to the mixture. The organic layer was separated, dried over MgSO4, filtered through Celite and concentrated to dryness. The crude product was washed with CH2Cl2/hexanes (1:25). Filtration by filter paper and drying under vacuum gave 284 as a light yellow solid (25.6 g, 104 mmol, 98%). mp 117-118 99 °C (lit. 1 118-119 °C). Spectral data for 284: H NMR (CDCl3, 500 MHz) δ 3.88 (s, 2H), 7.39 (dd, 1H, J = 8.5, 2.0 Hz), 7.58 (dd, 1H, J = 9.0, 2.0 Hz), 7.69 (d, 1H, J = 9.0 Hz), 7.76 (d, 1H, J = 9.0 Hz), 7.79 (s, 1H), 7.99 (d, 1H, J = 1.5 Hz); 13 405 C NMR (CDCl3, 125 MHz) δ 23.82, 117.50, 120.58, 126.53, 126.84, 127.78, 128.16, 129.35, 129.84, 130.26, 131.77, 133.77; IR (thin film) -1 1558s, 1456s cm . 99 2-(6-bromonaphthalen-2-yl)acetic acid 286: To a 500 mL round bottom flask was added 2-(6-bromonaphthalen-2-yl)acetonitrile 284 (21.1 g, 86 mmol), H2O (85 mL), acetic acid (115 mL) and H2SO4 (80 mL). The mixture was stirred at 110 °C for 24 h. After cooling to room temperature, the mixture was poured into ice H2O (750 mL). The crude product was filtered by filter paper and washed with H2O (200 mL). The solid was dissolved in acetone, dried over MgSO4, filtered through Celite and concentrated to dryness. Drying under vacuum gave 286 as a 99 tan solid (22.7 g, 86 mmol, 100%). mp 177-179 °C (lit. 1 178-180 °C). Spectral data for 286: H NMR (DMSO-d6, 500 MHz) δ 3.74 (s, 2H), 7.47 (dd, 1H, J = 8.5, 1.5 Hz), 7.61 (dd, 1H, J = 8.5, 2.0 Hz), 7.80 (s, 1H), 7.85 (dd, 2H, J = 9.0, 6.0 Hz), 8.17 (d, 1H, J = 2.0 Hz), 12.39 (s, 1H); 13 C NMR (DMSO-d6, 125 MHz) δ 40.66, 118.70, 126.85, 127.72, 129.01, 129.15, 129.32, 129.68, 131.40, 132.98, 133.49, 172.43. 100 1-(9,10-dihydrophenanthren-2-yl)ethanone 296: 74 one for a related compound: The following procedure was adapted from A solution of 9,10-dihydrophenanthrene (10.5 g, 58.2 mmol) and 406 acetyl chloride (4.14 mL, 58.2 mmol) in CS2 (60 mL) was added dropwise to a mixture of AlCl3 (8.54 g, 64.0 mmol) in CS2 (40 mL) at 0 °C. After stirring at 0 °C for 2 h, the mixture was refluxed overnight. CS2 was then removed by rotary evaporation. Ice H2O (90 mL) and H2SO4 (9 mL) was added to the residue. The mixture was extracted with CH2Cl2 (60 mL x 3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (60 mm × 250 mm, CH2Cl2/hexanes 1:1 to 3:1) gave 296 as a white solid upon storing at the refrigerator (10.8 1 g, 48.6 mmol, 84%). mp 54-57 °C; Rf = 0.21 (1:1 CH2Cl2/hexanes). Spectral data for 296: H NMR (CDCl3, 500 MHz) δ 2.60-2.94 (m, 4H), 7.24-7.30 (m, 2H), 7.32 (td, 1H, J = 8.0, 1.5 Hz), 7.76-7.83 (m, 3H), 7.87 (dd, 1H, J = 8.0, 2.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 26.60, 28.77, 28.90, 123.75, 124.37, 127.14, 127.24, 128.03, 128.32, 128.57, 133.42, 135.77, 137.50, 137.98, -1 139.15, 197.81; IR (thin film) 1684s, 1559s, 1456s cm ; mass spectrum, m/z (% rel intensity) + 222 M (87), 207 (100), 178 (92), 152 (39), 96 (22). 101 1-(phenanthren-2-yl)ethanone 297: related 15 compound: To a The following procedure was adapted from one for a 250 mL round bottom flask was added 1-(9,10-dihydrophenanthren-2-yl)ethanone 296 (222 mg, 1.00 mmol), N-bromosuccinimide (187 mg, 1.05 mmol), benzoyl peroxide (24 mg, 0.10 mmol) and benzene (50 mL). The mixture was refluxed overnight. After cooling to room temperature, the mixture was filtered through a pad of 407 Al2O3 (neutral) and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:1 to 2:1) gave 297 as a white solid (154 mg, 0.70 mmol, 70%). mp 141-143 °C; Rf = 0.20 (2:1 CH2Cl2/hexanes). 1 Spectral data for 297: H NMR (CDCl3, 500 MHz) δ 2.73 (s, 3H), 7.63-7.70 (m, 2H), 7.78-7.79 (m, 2H), 7.88-7.91 (m, 1H), 8.17 (dd, 1H, J = 8.0, 2.0 Hz), 8.45 (d, 1H, J = 2.0 Hz), 8.66-8.71 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 26.74, 123.11, 123.29, 125.12, 127.00, 127.28, 127.75, 127.89, 128.69, 129.65, 129.81, 131.41, 132.96, 133.40, 134.87, 197.95; mass spectrum, m/z (% + rel intensity) 220 M (60), 205 (100), 177 (68), 151 (26), 111 (15). 102 2-phenanthreneacetic acid 298: 77 compound: The following procedure was adapted from one for a related To a 1 L round bottom flask was added 1-(phenanthren-2-yl)ethanone 297 (11.5 g, 52 mmol), morpholine (15.7 mL, 180 mmol), sulfur (3.36 g, 105 mmol) and p-toluene sulfonic acid monohydrate (0.4 g, 2 mmol). The mixture was stirred at 125 ºC for 10 h. After cooling down to room temperature, alcoholic KOH (3M, 87 mL) was added and the mixture was stirred at 110 ºC overnight. After cooling down to room temperature, H2O (75 mL) was added to the mixture. The mixture was acidified with 6N HCl to pH 2. CH2Cl2 (150 mL) was added to the mixture and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (60 mL x 2). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica 408 gel (60 mm x 250 mm column, CH2Cl2/hexanes 1:1, then CH2Cl2, and then acetone/hexanes 1:2 as eluent) gave 298 as a yellow solid (10.6 g, 44.9 mmol, 86%). mp 191-193 °C; Rf = 0.35 (1:1 1 acetone/hexanes). Spectral data for 298: H NMR (DMSO-d6, 500 MHz) δ 3.80 (s, 2H), 7.58-7.64 (m, 2H), 7.65-7.70 (m, 1H), 7.79 (d, 1H, J = 9.0 Hz), 7.83 (d, 1H, J = 8.5 Hz), 7.85 (d, 1H, J = 1.5 Hz), 7.97 (dd, 1H, J = 8.0, 1.5 Hz), 8.76 (d, 1H, J = 8.5 Hz), 8.79 (d, 1H, J = 8.5 Hz), 12.4 (s, 1H); 13 C NMR (DMSO-d6, 125 MHz) δ 40.59, 122.83, 122.90, 126.58, 126.65, 126.86, 126.96, 128.42, 128.45, 128.53, 128.75, 129.64, 131.44, 131.54, 133.67, 172.70; mass spectrum, + m/z (% rel intensity) 236 M (63),191 (100), 189 (43), 165 (11). 6.4.3 Preparation of monomers 2-(3,5-dimethylphenyl)phenanthren-4-ol 287c: The reaction of 2-naphthaleneacetic acid 285 (11.2 g, 60.0 mmol), SOCl2 (16 mL, 219 mmol), 1-ethynyl-3,5-dimethylbenzene 235c (8.58 g, 66.0 mmol) and (i-PrCO)2O (20 mL, 120 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:1 to 2:1) gave 287c as a yellow solid (10.1 g, 409 1 33.8 mmol, 56%). mp 140-142 °C; Rf = 0.18 (1:1 CH2Cl2/hexane). Spectral data for 287c: H NMR (CDCl3, 500 MHz) δ 2.41 (s, 6H), 5.64 (s, 2H), 7.03 (s, 1H), 7.20 (d, 1H, J = 1.5 Hz), 7.34 (s, 2H), 7.55-5.59 (m, 1H), 7.63-7.66 (m, 1H), 7.70 (d, 1H, J = 1.5 Hz), 7.73 (s, 2H), 7.87 (dd, 1H, J = 8.0, 1.0 Hz), 9.61 (d, 1H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 21.44, 112.35, 118.45, 119.88, 125.15, 125.93, 126.62, 127.27, 128.24, 128.32, 128.41, 129.29, 130.19, 132.57, 135.26, 138.42, 139.46, 140.08, 154.49; IR (thin film) 3517s, 2921m, 1597s, 1458s, 1279m, -1 + 1229s cm ; HRMS (ESI–) m/z calculated for C22H17O (M-H ) 297.1279, found 297.1281. 2-(4-methoxy-3,5-dimethylphenyl)phenanthren-4-ol 287e: The reaction of 2-naphthaleneacetic acid 285 (7.44 g, 40.0 mmol), SOCl2 (10.5 mL, 144 mmol), 5-ethynyl-2-methoxy-1,3-dimethylbenzene 235e (6.4 g, 40.0 mmol) and (i-PrCO)2O (13.3 mL, 80.0 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 287e as an off-white solid (4.64 g, 14.1 mmol, 35%). mp 164-165 °C; Rf = 1 0.31 (CH2Cl2). Spectral data for 287e: H NMR (CDCl3, 500 MHz) δ 2.38 (s, 6H), 3.79 (s, 3H), 5.76 (s, 1H), 7.15 (d, 1H, J = 1.5 Hz), 7.36 (s, 2H), 7.54-7.58 (m, 1H), 7.62-7.66 (m, 2H), 7.72 (d, 2H, J = 1.0 Hz), 7.86 (dd, 1H, J = 8.0, 1.5 Hz), 9.61 (dd, 1H, J = 8.5, 0.5 Hz); 410 13 C NMR (CDCl3, 125 MHz) δ 16.31, 59.85, 112.22, 118.32, 119.55, 125.87, 126.60, 127.25, 127.71, 128.23, 128.30, 128.41, 130.25, 131.28, 132.55, 135.26, 135.76, 139.02, 154.60, 156.77; IR (thin film) -1 3341br s, 2934s, 1487s, 1381s, 1265s, 1226s, 1159s cm ; HRMS (ESI–) m/z calculated for + C23H19O2 (M-H ) 327.1385, found 327.1391. 2-(3,5-di-tert-butyl-4-methoxyphenyl)phenanthren-4-ol 287x: The reaction of 2-naphthaleneacetic acid 285 (4.84 g, 26.0 mmol), SOCl2 (6.8 mL, 93 mmol), 1,3-di-tert-butyl-5-ethynyl-2-methoxybenzene 235x (7.03 g, 28.8 mmol) and (i-PrCO)2O (8.7 mL, 52.5 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:1 to 2:1) gave 287x as a light yellow solid (4.65 g, 11.3 mmol, 43%). mp 202-203 °C; Rf 1 = 0.21 (1:1 CH2Cl2/hexanes). Spectral data for 287x: H 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); 13 C 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; 411 -1 IR (thin film) 3521br m, 2961s, 1420s, 1227s cm ; HRMS (ESI–) m/z calculated for C29H31O2 + (M-H ) 411.2324, found 411.2312. 7-bromo-2-phenylphenanthren-4-ol 288a: The reaction of 2-(6-bromonaphthalen-2-yl)acetic acid 286 (4.23 g, 16.0 mmol), SOCl2 (4.3 mL, 58.9 mmol), phenylacetylene 235a (2.4 mL, 21.9 mmol) and (i-PrCO)2O (5.4 mL, 32.5 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:2 to 1:1 to 2:1) gave 288a as a yellow solid (2.54 g, 7.27 mmol, 1 45%). mp 168-169 °C; Rf = 0.23 (2:1 CH2Cl2/hexanes). Spectral data for 288a: H NMR (CDCl3, 500 MHz) δ 5.74 (s, 1H), 7.20 (d, 1H, J = 2.0 Hz), 7.37-7.41 (m, 1H), 7.46-7.50 (m, 2H), 7.62 (d, 1H, J = 9.5 Hz), 7.68-7.72 (m, 4H), 7.74 (d, 1H, J = 8.5 Hz), 8.00 (d, 1H, J = 2.0 Hz), 9.48 (d, 1H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 112.56, 118.22, 119.96, 120.02, 127.23, 127.78, 128.48, 128.78, 128.95, 129.60, 130.24, 130.31, 134.17, 135.11, 139.62, 139.92, 2 79 + 154.42 (1 sp C not located); HRMS (ESI–) m/z calculated for C20H12O Br (M-H ) 347.0072, found 347.0069. 412 7-bromo-2-(4-butylphenyl)phenanthren-4-ol 288b: The reaction of 2-(6-bromonaphthalen-2-yl)acetic acid 286 (6.63 g, 25.0 mmol), SOCl2 (6.7 mL, 92 mmol), 1-butyl-4-ethynylbenzene 235b (5.0 g, 31.6 mmol) and (i-PrCO)2O (8.4 mL, 50.7 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:3 to 1:1 to 2:1) gave 288b as a yellow solid (5.36 g, 13.2 mmol, 53%). mp 140-142 °C; Rf = 0.31 (2:1 1 CH2Cl2/hexanes). Spectral data for 288b: H NMR (CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.5 Hz), 1.35-1.44 (m, 2H), 1.61-1.68 (m, 2H), 2.67 (t, 2H, J = 7.5 Hz), 5.68 (s, 1H), 7.20 (d, 1H, J = 1.5 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.60-7.62 (m, 3H), 7.70 (dd, 2H, J = 9.0, 2.0 Hz), 7.73 (d, 1H, J = 9.0 Hz), 7.99 (d, 1H, J = 2.0 Hz), 9.48 (d, 1H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.95, 22.40, 33.60, 35.33, 112.50, 118.04, 119.80, 119.87, 127.04, 127.16, 128.52, 128.84, 129.04, 129.57, 130.23, 130.29, 134.15, 135.14, 137.19, 139.65, 142.75, 154.39; IR (thin film) 3517s, -1 79 + 2926s, 1559s, 1458s, 1390s, 1231s cm ; HRMS (ESI–) m/z calculated for C20H12O Br (M-H ) 403.0698, found 403.0684. 413 7-bromo-2-(3,5-dimethylphenyl)phenanthren-4-ol 288c: The reaction of 2-(6-bromonaphthalen-2-yl)acetic acid 286 (1.33 g, 5.0 mmol), SOCl2 (1.4 mL, 19 mmol), 1-ethynyl-3,5-dimethylbenzene 235c (0.78 g, 6.0 mmol) and (i-PrCO)2O (1.7 mL, 10 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:2 to 1:1 to 2:1) gave 288c as a yellow solid (864 mg, 2.29 mmol, 46%). mp 203-204 °C; Rf = 0.30 (2:1 1 CH2Cl2/hexanes). Spectral data for 288c: H NMR (CDCl3, 500 MHz) δ 2.41 (s, 6H), 5.73 (s, 1H), 7.03 (s, 1H), 7.21 (d, 1H, J = 1.5 Hz), 7.32 (s, 2H), 7.61 (d, 1H, J = 8.5 Hz), 7.68-7.71 (m, 2H), 7.74 (d, 1H, J = 9.0 Hz), 7.99 (d, 1H, J = 2.0 Hz), 9.48 (d, 1H, J = 9.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 21.43, 112.68, 118.10, 119.87, 119.99, 125.14, 127.13, 128.52, 128.82, 129.43, 129.54, 130.21, 130.29, 134.14, 135.06, 138.48, 139.89, 139.88, 154.32; HRMS (ESI–) 79 + m/z calculated for C22H16O Br (M-H ) 375.0385, found 375.0384. 414 7-bromo-2-(3,5-di-tert-butyl-4-methoxyphenyl)phenanthren-4-ol 288x: The reaction of 2-(6-bromonaphthalen-2-yl)acetic acid 286 (1.33 g, 5.0 mmol), SOCl2 (1.4 mL, 19 mmol), 1,3-di-tert-butyl-5-ethynyl-2-methoxybenzene 235x (1.46 g, 6.0 mmol) and (i-PrCO)2O (1.7 mL, 10 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:2 to 1:1 to 2:1) gave 288x as a yellow solid (614 mg, 1.25 mmol, 25%). mp 192-193 °C; Rf = 0.26 1 (1:1 CH2Cl2/hexanes). Spectral data for 288x: H NMR (CDCl3, 500 MHz) δ 1.50 (s, 18H), 3.75 (s, 3H), 5.69 (s, 1H), 7.19 (d, 1H, J = 2.0 Hz), 7.56 (s, 2H), 7.61-7.64 (m, 2H), 7.70 (dd, 1H, J = 9.0, 2.0 Hz), 7.76 (d, 1H, J = 9.0 Hz), 7.99 (d, 1H, J = 2.0 Hz), 9.49 (d, 1H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 32.17, 35.99, 64.35, 112.73, 117.83, 119.80, 119.81, 125.60, 127.13, 128.52, 128.86, 129.54, 130.21, 130.27, 134.10, 134.18, 135.09, 140.42, 144.23, 154.32, 159.67; -1 IR (thin film) 3512br m, 2961s, 1560s, 1446s, 1227s, 1169s, 1115s cm ; HRMS (ESI–) m/z 79 + calculated for C29H30O2 Br (M-H ) 489.1429, found 489.1447. 415 7-bromo-2-(4-butylphenyl)-4-(methoxymethoxy)phenanthrene 290: To a flame-dried 250 mL round bottom flask was added 7-bromo-2-(4-butylphenyl)phenanthren-4-ol 288b (10.1 g, 24.9 mmol) and dry THF (80 mL) under N2. The resulting solution was cooled to 0 °C and NaH (1.10 g, 60% in mineral oil, 27.5 mmol) was added. The resulting mixture was stirred at 0 °C for 1 h. MOMCl (2.1 mL, 27.8 mmol) was then added to the mixture at 0 °C. The mixture was warmed up to room temperature and stirred for additional 24 h. NH4Cl (sat. aq. 20 mL) was added to the mixture and the organic solvent was removed by rotary evaporation. The two phase residue was extracted with CH2Cl2 (30 mL × 3). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:3) gave 290 as a light yellow solid (10.7 g, 23.8 mmol, 96%). mp 84-85 °C; Rf = 0.31 (1:2 1 CH2Cl2/hexanes). Spectral data for 290: H NMR (CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.5 Hz), 1.35-1.44 (m, 2H), 1.61-1.68 (m, 2H), 2.67 (t, 2H, J = 8.0 Hz), 3.61 (s, 3H), 5.56 (s, 2H), 7.30 (d, 2H, J = 8.5 Hz), 7.61-7.67 (m, 4H), 7.70 (dd, 1H, J = 9.0, 2.5 Hz), 7.74-7.76 (m, 2H), 8.00 (d, 1H, J = 2.5 Hz), 9.51 (d, 1H, J = 9.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.96, 22.39, 33.64, 35.34, 56.56, 95.27, 111.57, 119.74, 119.86, 120.57, 127.02, 127.21, 128.69, 128.75, 129.01, 129.51, 130.10, 130.36, 134.41, 134.75, 137.65, 139.81, 142.67, 156.42; IR (thin film) 2955s, 416 -1 + 2928s, 2857m, 1455s, 1154s, 1046s cm ; mass spectrum, m/z (% rel intensity) 450 M (8, + 448 M (7, 79 Br), 418 (9, 81 Br), 416 (7, 79 81 Br), Br), 337 (7), 281 (37), 252 (25), 131 (25). Anal calcd for C26H25BrO2: C, 69.49; H, 5.61. Found: C, 69.45; H, 5.45. 7-(tert-butyldiphenylsilyl)-2-(4-butylphenyl)phenanthren-4-ol 291: The following procedure was adapted from one for a related compound: 15 To a 250 mL flame-dried round bottom flask was added 7-bromo-2-(4-butylphenyl)-4-(methoxymethoxy)phenanthrene 290 (2.87 g, 6.39 mmol) and dry THF (65 mL) under N2. The resulting solution was cooled to –78 °C and t-BuLi (1.7 M in pentane, 7.7 mL, 13.1 mmol) was added dropwise. The resulting mixture was stirred at –78 °C for 1 h. TBDPSCl (1.8 mL, 7.06 mmol) was then added to the mixture at –78 °C. The mixture was warmed up to room temperature and stirred for an additional 24 h. NaHCO3 (sat. aq. 5 mL) was added to the mixture. The reaction mixture was partitioned between Et2O (60 mL) and NaHCO3 (sat. aq. 60 mL). The organic layer was washed with brine (30 mL), dried over MgSO4, filtered through Celite and concentrated to dryness. The product was partially purified by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:3). The partially purified product was dissolved in a mixture of THF and MeOH (130 mL, 1:1) and Amberlyst 15 (1.6 g) was added. The mixture was stirred at 65 ºC for 15 h under N2 in a balloon. After cooling down to room temperature, the mixture was filtered through filter paper and concentrated to dryness. 417 Purification of the crude product by column chromatography on silica gel (30 mm x 300 mm, CH2Cl2:hexanes 1:2) gave 291 as a white solid in over two steps (1.73 g, 3.07 mmol, 48%). mp 1 176-178 °C; Rf = 0.26 (1:1 CH2Cl2/hexanes). Spectral data for 291: H NMR (CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.5 Hz),1.24 (s, 9H), 1.37-1.42 (m, 2H), 1.61-1.68 (m, 2H), 2.67 (t, 2H, J = 7.5 Hz), 5.74 (s, 1H), 7.20 (d, 1H, J = 2.0 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.34-7.38 (m, 4H), 7.39-7.44 (m, 2H), 7.62-7.66 (m, 8H), 7.69-7.71 (m, 2H), 7.87 (dd, 1H, J = 8.5, 2.0 Hz), 8.06 (d, 1H, J = 1.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.95, 18.92, 22.39, 28.92, 33.61, 35.33, 112.07, 118.21, 119.60, 127.04, 127.16, 127.70, 128.70, 129.00, 129.20, 130.68, 131.70, 132.34, 134.05, 2 134.91, 135.62, 136.64, 137.37, 137.47, 139.46, 142.61, 154.83 (1 sp C not located); IR (thin -1 film) 3526br m, 2930s, 2857s, 1653s, 1558s, 1458s cm ; HRMS (ESI–) m/z calculated for + C40H39OSi (M-H ) 563.2770, found 563.2784. 3-phenethyl-1-naphthol 333: The reaction of phenylacetyl chloride 180 (2.64 mL, 20.0 mmol), but-3-yn-1-ylbenzene (2.60 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to the general procedure (Procedure Q). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 333 as 1 a brown oil (1.80 g, 7.26 mmol, 36%). Rf = 0.36 (CH2Cl2). Spectral data for 333: H NMR 418 (CDCl3, 500 MHz) δ 2.95-3.03 (m, 4H), 5.15 (s, 1H), 6.65 (d, 1H, J = 1.5 Hz), 7.17-7.21 (m, 3H), 7.23 (s, 1H), 7.26-7.30 (m, 2H), 7.39-7.47 (m, 2H), 7.71-7.73 (m, 1H), 8.09-8.11 (m, 1H). 3-(4-butylphenyl)-7-methoxynaphthalen-1-ol 334b: The reaction of 4-methoxy-phenylacetic acid 191g (4.15 g, 25.0 mmol), SOCl2 (6.7 mL, 92 mmol), 1-butyl-4-ethynylbenzene 235b (5.0 g, 31.6 mmol) and (i-PrCO)2O (8.4 mL, 50.7 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 3:1) gave 334b as a brownish yellow solid 1 (3.32 g, 10.8 mmol, 43%). mp 96-99 °C; Rf = 0.24 (CH2Cl2). Spectral data for 334b: H NMR (CDCl3, 500 MHz) δ 0.94 (t, 3H, J = 7.5 Hz), 1.36-1.41 (m, 2H), 1.60-1.67 (m, 2H), 2.65 (t, 2H, J = 7.5 Hz), 3.94 (s, 3H), 5.19 (s, 1H), 7.05 (d, 1H, J = 1.5 Hz), 7.16 (dd, 1H, J = 9.0, 2.5 Hz), 7.25 (d, 2H, J = 8.5 Hz), 7.44 (d, 1H, J = 7.5 Hz), 7.54-7.57 (m, 3H), 7.73 (d, 1H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.96, 22.40, 33.64, 35.29, 55.41, 99.85, 108.83, 118.35, 119.66, 124.30, 126.93, 128.87, 129.55, 130.51, 136.46, 138.24, 142.01, 150.68, 157.40; HRMS (ESI–) + m/z calculated for C21H21O2 (M-H ) 305.1542, found 305.1556. 419 3-(3,5-dimethylphenyl)-7-methoxynaphthalen-1-ol 334c: The reaction of 4-methoxy-phenylacetic acid 191g (8.30 g, 50.0 mmol), SOCl2 (13.3 mL, 182 mmol), 1-ethynyl-3,5-dimethylbenzene 235c (7.15 g, 55.0 mmol) and (i-PrCO)2O (16.8 mL, 101 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:1 to 2:1 to 1:0) gave 334c as a brown solid (7.24 1 g, 26.2 mmol, 52%). mp 103-108 °C; Rf = 0.26 (CH2Cl2). Spectral data for 334c: H NMR (CDCl3, 500 MHz) δ 2.38 (s, 6H), 3.95 (s, 3H), 5.17 (s, 1H), 6.98 (s, 1H), 7.06 (d, 1H, J = 1.5 Hz), 7.16 (dd, 1H, J = 8.5, 2.5 Hz), 7.26 (s, 2H), 7.44 (d, 1H, J = 2.5 Hz), 7.57 (s, 1H), 7.74 (d, 1H, J = 9.0 Hz); 13 C NMR (CDCl3, 125 MHz) δ 21.42, 55.41, 99.87, 109.00, 118.58, 119.64, 124.39, 125.05, 128.83, 129.58, 130.47, 136.72, 138.28, 140.95, 150.64, 157.43; IR (thin film) -1 3405br m, 2919m, 1599s, 1487s, 1267s, 1213s, 1175s cm ; HRMS (ESI–) m/z calculated for + C19H17O2 (M-H ) 277.1229, found 227.1227. 420 2-phenylchrysen-4-ol 335: The reaction of 2-phenanthreneacetic acid 298 (10.4 g, 44.0 mmol), SOCl2 (12 mL, 164 mmol), phenylacetylene (6.6 g, 60.0 mmol) and (i-PrCO)2O (15 mL, 90 mmol) was performed according to the general procedure (Procedure I). Purification of the crude product by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 2:3 to 2:1) gave 335 as a orange solid (3.92 g, 12.3 mmol, 28%). mp 234-239 °C; Rf = 0.19 (2:1 1 CH2Cl2/hexanes). Spectral data for 335: H NMR (DMSO-d6, 500 MHz) δ 7.42 (t, 1H, J = 7.5 Hz), 7.51 (d, 1H, J = 1.5 Hz), 7.54 (t, 2H, J = 8.0 Hz), 7.65-7.69 (m, 1H), 7.70-7.74 (m, 1H), 7.81 (dd, 2H, J = 8.0, 1.0 Hz), 7.89 (d, 1H, J = 2.0 Hz), 8.03-8.06 (m, 2H), 8.11 (d, 1H, J = 9.5 Hz), 8.88 (d, 1H, J = 9.0 Hz), 8.93 (d, 1H, J = 8.5 Hz), 9.90 (d, 1H, J = 9.5 Hz), 10.87 (s, 1H); 13 C NMR (DMSO-d6, 125 MHz) δ 111.12, 117.40, 118.81, 121.98, 123.34, 126.25, 126.28, 126.42, 126.70, 127.66, 127.89, 127.91, 128.23, 128.51, 129.03, 129.67, 131.02, 134.86, 138.31, 2 + 139.54, 156.70 (1 sp C not located); HRMS (ESI–) m/z calculated for C24H15O (M-H ) 319.1123, found 319.1110. 6.4.4 Preparation of VAPOL derivatives 421 The synthesis of racemic 289c was performed according to the general procedure (Procedure J) with 2-(3,5-dimethylphenyl)phenanthren-4-ol 287c (9.37 g, 31.4 mmol). The mixture was stirred at 180 °C for 24 h. After cooling down to room temperature, CH2Cl2 (50 mL) and hexanes (50 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) and then filtered through filter paper. The yellow powder was washed with chilled CH2Cl2/hexanes and dried under vacuum to afford a yellow solid (5.00 g). Purification of the product remaining in the mother liquor by column chromatography on silica gel (50 mm x 250 mm, CH2Cl2:hexanes 1:2) gave racemic 289c as an off-white solid (2.46 g). The total yield is 80% (7.46 g, 12.6 mmol). After de-racemization of racemic 289c (4.75 g, 8.00 mmol) with CuCl (1.35 mg, 13.6 mmol) and (–)-sparteine (6.56 g, 28 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 2:5) to afford (S)-289c as a yellow solid (4.27 g, 7.19 mmol, 90%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 75:25 hexane/iPrOH at 254 nm, flow-rate: 2.0 mL/min). Retention times: Rt = 9.68 min for (R)-289c (minor) and Rt = 13.08 min for (S)-289c (major). mp 135-137 °C; Rf = 0.19 (1:2 422 1 CH2Cl2/hexanes). Spectral data for 289c: H NMR (CDCl3, 500 MHz) δ 1.99 (s, 12H), 6.42 (s, 4H), 6.51 (s, 2H), 6.71 (s, 2H), 7.46 (s, 2H), 7.60-7.64 (m, 2H), 7.65-7.69 (m, 4H), 7.80 (d, 2H, J = 8.5 Hz), 7.92 (dd, 2H, J = 8.5, 1.5 Hz), 9.73 (d, 2H, J = 8.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 21.10, 116.15, 117.96, 122.94, 126.22, 126.76, 126.92, 126.93, 128.36, 128.40, 128.80, 129.11, 130.36, 132.79, 135.17, 136.76, 139.77, 141.88, 153.43; IR (thin film) 3482br s, 2917m, 1559s, -1 + 1456s, 1223s cm ; HRMS (ESI–) m/z calculated for C44H33O2 (M-H ) 593.2481, found 20 593.2498. [α] D = +3.9 (c 1.0, CH2Cl2) on >99% ee (S)-289c (HPLC). The synthesis of racemic 289e was performed according to the general procedure (Procedure J) with 2-(4-methoxy-3,5-dimethylphenyl)phenanthren-4-ol 287e (3.05 g, 9.30 mmol). The mixture was stirred at 180 °C for 24 h. Purification by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 2:1) and then washing with CH2Cl2/hexanes gave racemic 289e as a yellow solid (1.84 g, 2.81 mmol, 60% yield). After de-racemization of racemic 289e (3.25 g, 4.97 mmol) with CuCl (837 mg, 8.45 mmol) and (–)-sparteine (4.08 g, 17.4 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 2:1) to afford (S)-289e as an off-white solid (3.10 g, 4.74 mmol, 95%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 423 75:25 hexane/iPrOH at 254 nm, flow-rate: 2.0 mL/min). Retention times: Rt = 15.13 min for (R)-289e (minor) and Rt = 21.73 min for (S)-289e (major). mp 158-160 °C; Rf = 0.20 (2:1 1 CH2Cl2/hexanes). Spectral data for 289e: H NMR (CDCl3, 500 MHz) δ 1.93 (s, 12H), 3.60 (s, 6H), 6.40 (s, 4H), 6.51 (s, 2H), 7.34 (s, 2H), 7.62 (t, 2H, J = 7.5 Hz), 7.65-7.68 (m, 4H), 7.81 (d, 2H, J = 9.0 Hz), 7.93 (d, 2H, J = 7.5 Hz), 9.72 (d, 2H, J = 8.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 15.89, 59.67, 116.14, 117.88, 122.84, 126.23, 126.91, 126.93, 128.38, 128.77, 129.16, 129.38, 129.66, 130.33, 132.79, 135.19, 135.36, 141.33, 153.43, 156.10; IR (thin film) 3482br s, 2932s, -1 + 1487s, 1372s, 1244s, 1225s,1130s cm ; HRMS (ESI–) m/z calculated for C46H37O4 (M-H ) 20 653.2692, found 653.2712. [α] D = –16.5 (c 1.0, CH2Cl2) on >99% ee (S)-289e (HPLC). The synthesis of racemic 289x was performed according to the general procedure (Procedure J) with 2-(3,5-di-tert-butyl-4-methoxyphenyl)phenanthren-4-ol 287x (4.20 g, 10.2 mmol). The mixture was stirred at 180 °C for 60 h. After cooling down to room temperature, hexanes (25 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) and then filtered through filter paper. The yellow powder was washed with chilled hexanes and dried under vacuum to afford racemic 289x as an orange solid (3.44 g, 4.18 mmol, 82% yield). After de-racemization of racemic 289x (3.39 424 g, 4.12 mmol) with CuCl (693 mg, 7.00 mmol) and (–)-sparteine (3.38 g, 14.4 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:2) to afford (S)-289x as a yellow solid (3.19 g, 3.88 mmol, 94%). The optical purity was determined to be 97% ee by HPLC analysis (Pirkle D-Phenylglycine column, 75:25 hexane/iPrOH at 254 nm, flow-rate: 2.0 mL/min). Retention times: Rt = 10.30 min for (R)-289x (minor) and Rt = 18.67 min for (S)-289x (major). mp 150-153 °C; Rf = 0.26 (1:2 1 CH2Cl2/hexanes). Spectral data for 289x: H NMR (CDCl3, 500 MHz) δ 1.08 (s, 36H), 3.21 (s, 6H), 6.16 (s, 2H), 7.14 (s, 4H), 7.49-7.54 (m, 4H), 7.71-7.77 (m, 6H), 7.82-7.85 (m, 2H), 9.34-9.37 (m, 2H); 13 C NMR (CDCl3, 125 MHz) 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, -1 142.83, 153.19, 158.84; IR (thin film) 3486br s, 2961s, 1412s, 1225s, 1115m cm ; HRMS (ESI–) 20 m/z calculated for C58H62O4 822.4648, found 822.4680. [α] D = –200.4 (c 1.0, CH2Cl2) on >97% ee (S)-289x (HPLC). The synthesis of racemic 292 was performed according to the general procedure (Procedure J) with 7-(tert-butyldiphenylsilyl)-2-(4-butylphenyl)phenanthren-4-ol 291 (1.46 g, 2.58 mmol). The 425 mixture was stirred at 180 °C for 24 h. Purification by column chromatography on silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:4) gave racemic 292 as an off-white solid (812 mg, 0.72 mmol, 56% yield). After de-racemization of racemic 292 (563 mg, 0.50 mmol) with CuCl (84 mg, 0.85 mmol) and (–)-sparteine (0.41 g, 1.75 mmol), the crude product was purified by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 1:3) to afford (S)-292 as an off-white solid (486 mg, 0.43 mmol, 86%). The optical purity was determined to be >99% ee by HPLC analysis (Pirkle D-Phenylglycine column, 75:25 hexane/iPrOH at 254 nm, flow-rate: 2.0 mL/min). Retention times: Rt = 1.91 min for (R)-292 (minor) and Rt = 2.21 min for (S)-292 1 (major). mp 165-167 °C; Rf = 0.19 (1:3 CH2Cl2/hexanes). Spectral data for 292: H NMR (CDCl3, 500 MHz) δ 0.88 (t, 3H, J = 7.5 Hz), 1.21-1.30 (m, 22H), 1.45-1.52 (m, 4H), 2.46 (t, 4H, J = 7.5 Hz), 6.52 (s, 2H), 6.59 (d, 4H, J = 8.0 Hz), 6.76 (d, 4H, J = 8.0 Hz), 7.35-7.45 (m, 14H), 7.64-7.67 (m, 10H), 7.73 (d, 2H, J = 8.5 Hz), 7.91 (dd, 2H, J = 8.5, 1.5 Hz), 8.11 (s, 2H), 9.67 (d, 2H, J = 8.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 13.89, 18.93, 22.20, 28.92, 33.47, 35.12, 115.92, 117.84, 123.15, 126.94, 127.59, 127.64, 127.73, 128.67, 129.25, 129.55, 130.84, 131.92, 132.93, 134.40, 134.82, 135.60, 136.63, 137.02, 137.65, 141.52, 141.88, 153.56; IR (thin film) -1 3490s, 2930s, 2857s, 1558s, 1456s, 1105s cm ; HRMS (ESI+) m/z calculated for + 20 C80H78O2Si2Na (M+Na ) 1149.5438, found 1149.5453. [α] D = +85.3 (c 1.0, CH2Cl2) on >99% ee (S)-292 (HPLC). 6.4.5 Functionalization of VANOL monomer 426 1-methoxy-3-phenylnaphthalene 336: To a flame-dried 250 mL round bottom flask was added 3-phenylnaphthalen-1-ol 175a (3.30 g, 15.0 mmol) and dry THF (75 mL) under N2. The resulting solution was cooled to 0 °C and NaH (0.8 g, 60% in mineral oil, 20 mmol) was added. The resulting mixture was stirred at 0 °C for 15 minutes. MeI (3.8 mL, 61 mmol) was then added to the mixture at 0 °C. The mixture was warmed up to room temperature and stirred for an additional 24 h. NH4Cl (sat. aq. 30 mL) was added to the mixture and the organic solvent was removed by rotary evaporation. The residue was extracted with CH2Cl2 (30 mL × 3). The combined organic layer was washed with Na2S2O3 (sat. aq. 20 mL × 2) and brine (20 mL) and then dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:10) gave 336 as a white solid upon storage (3.44 g, 14.7 mmol, 98%). mp 75-76 °C; Rf = 0.24 (1:4 1 CH2Cl2/hexanes). Spectral data for 336: H NMR (CDCl3, 500 MHz) δ 4.07 (s, 3H), 7.06 (d, 1H, J = 1.5 Hz), 7.36-7.40 (m, 1H), 7.44-7.53 (m, 4H), 7.62 (s, 1H), 7.70-7.73 (m, 2H), 7.84 (dd, 1H, J = 8.0, 0.5 Hz), 8.26 (dd, 1H, J = 8.0, 0.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 55.61, 103.85, 118.42, 121.93, 124.86, 125.24, 126.83, 127.36, 127.44, 127.78, 128.79, 134.64, 138.96, 141.69, -1 155.84; IR (thin film) 3055m, 1581s, 1497s, 1401s, 1233s cm ; HRMS (ESI+) m/z calculated + for C17H15O (M+H ) 235.1123, found 235.1131. 427 To a 250 round bottom flask was added 1-methoxy-3-phenylnaphthalene 336 (3.35 g, 14.3 mmol) and CHCl3 (70 mL). To the stirred solution was added HNO3 (5.5 mL) dropwise. The mixture was stirred at room temperature for 1 h. The resulting mixture was poured into H2O (140 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (70 mL). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (35 mm x 250 mm, CH2Cl2:hexanes 2:3) and then recrystallization from CH2Cl2/hexanes gave 299 as a yellow solid (3.15 g, 11.3 mmol, 79%). mp 115-116 °C; Rf = 0.37 (1:1 CH2Cl2/hexanes). Spectral data 1 for 299: H NMR (CDCl3, 500 MHz) δ 4.05 (s, 3H), 6.75 (s, 1H), 7.41-7.48 (m, 5H), 7.55-7.59 (m, 1H), 7.63-7.67 (m, 1H), 7.78-7.81 (m, 1H), 8.31-8.34 (m, 1H); 13 C NMR (CDCl3, 125 MHz) δ 56.08, 105.10, 121.66, 122.39, 124.62, 125.92, 126.63, 128.09, 128.61, 128.85, 129.31, 133.31, 137.48, 156.59 (1 sp2 C not located); IR (thin film) 3061m, 1595s, 1520s, 1447s, 1354s, 1231s + cm-1; HRMS (ESI+) m/z calculated for C17H14NO3 (M+H ) 280.0974, found 280.0977. 428 To a 100 mL flame-dried round bottom flask was added 3-phenylnaphthalen-1-ol 175a (220 mg, 1.00 mmol), N-bromosuccinimide (178 g, 1.00 mmol) and dry CH3CN (10 mL). The mixture was stirred at room temperature for 2 h. The mixture was treated with HCl (4N aq. 10 mL) and the organic solvent was removed by rotary evaporation. The residue was extracted with CH2Cl2 (10 mL x 3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. The crude product was dissolved in dry THF (5 mL). The resulting solution was cooled to 0 °C and NaH (80 mg, 60% in mineral oil, 2.0 mmol) was added. The resulting mixture was stirred at 0 °C for 15 minutes. MeI (0.5 mL, 8.0 mmol) was then added to the mixture at 0 °C. The mixture was warmed up to room temperature and stirred for an additional 24 h. NH4Cl (sat. aq. 3 mL) was added to the mixture and the organic solvent was removed by rotary evaporation. The residue was extracted with CH2Cl2 (3 mL × 3). The combined organic layer was washed with Na2S2O3 (sat. aq. 3 mL × 2) and brine (3 mL) and then dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (2.5 mm x 300 mm, CH2Cl2:hexanes 1:30) gave 300 as a white solid upon storage (270 mg, 0.86 mmol, 86%). mp 80-82 °C; Rf = 0.34 (1:3 1 CH2Cl2/hexanes). Spectral data for 300: H NMR (CDCl3, 500 MHz) δ 3.98 (s, 3H), 6.78 (s, 1H), 7.40-7.48 (m, 5H), 7.51-7.55 (m, 1H), 7.61-7.65 (m, 1H), 8.29 (dd, 1H, J = 8.5, 1.0 Hz), 8.35 (d, 1H, J = 8.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 55.76, 107.13, 113.16, 122.23, 125.87, 125.91, 127.54, 127.63, 128.00, 128.17, 129.56, 132.95, 140.55, 142.83, 154.63; IR (thin film) -1 79 + 3059m, 1593s, 1499s, 1387s, 1227s cm ; HRMS (EI+) m/z calculated for C17H13O Br (M ) 312.0150, found 312.0152. 429 1-iodo-4-methoxy-2-phenylnaphthalene 301: To a 100 mL flame-dried round bottom flask was added 1-methoxy-3-phenylnaphthalene 336 (1.40 g, 6.00 mmol), N-iodosuccinimide (1.48 g, 6.6 mmol), In(OTf)3 (337 mg, 0.60 mmol) and dry CH3CN (36 mL). The flask was then wrapped with aluminum foil. The mixture was stirred at room temperature for 12 h and H2O (120 mL) was then added. The organic solvent was removed by rotary evaporation. The residue was extracted with CH2Cl2 (120 mL x 3). The combined organic layer was washed with Na2S2O3 (sat. aq. 120 mL) and brine (120 mL) and then dried over MgSO4, filtered through Celite and concentrated to dryness. Purification of the crude product by column chromatography on silica gel (30 mm x 250 mm, CH2Cl2:hexanes 1:8) gave 301 as a light yellow solid (2.09 g, 5.81 mmol, 1 97%). mp 94-95 °C; Rf = 0.29 (1:4 CH2Cl2/hexanes). Spectral data for 301: H NMR (CDCl3, 500 MHz) δ 3.97 (s, 3H), 6.81 (s, 1H), 7.37-7.39 (m, 2H), 7.41-7.48 (m, 3H), 7.51 (t, 1H, J = 7.5 Hz), 7.59-7.63 (m, 1H), 8.24-8.29 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 55.73, 92.85, 106.59, 122.26, 125.37, 125.93, 127.59, 127.97, 128.60, 129.41, 132.95, 135.22, 145.91, 146.50, 155.54; -1 + IR (thin film) 1591s, 1499s, 1381s, 1227s cm ; HRMS (EI+) m/z calculated for C17H13OI (M ) 360.0011, found 360.0013. 6.4.6 Asymmetric transfer hydrogenation of 2-pentylquinoline 430 2-pentylquinoline 302 was kindly provided by Prof. Aaron Odom. 110 The requisite Hantzsch ester 337 were prepared according to, or in a similar manner as, previously published 111 procedures. The (R)-VAPOL BOROX catalyst was prepared according to Procedure G with (R)-VAPOL 2,6-dimethylphenol, BH3•SMe2 and H2O. (R)-2-pentyl-1,2,3,4-tetrahydroquinoline 303: A small vial (3.7 mL), fitted with a Teflon liner, was flame dried and cooled under argon. 2-pentylquinoline 302 (10 mg, 0.05 mmol, 1 equiv) was added from a stock solution in CH2Cl2. The vial was directly subjected to gradual high vacuum to remove the CH2Cl2. Hantzsch ester 337 was then added (31 mg, 0.12 mmol, 2.4 equiv) to the vial. The vial was evacuated and back-filled with argon. 10 mol% of the (R)-VAPOL BOROX catalyst was added from a stock solution in benzene (1 mL). The reaction mixture was flushed with argon above the solvent surface; the vial was capped and stirred at 60 °C for 12 h. The reaction was judged complete by TLC. The crude reaction mixture was subjected to rotary evaporation till dryness and finally to high vacuum to afford crude 303. Purification of the crude product by column chromatography on silica gel (25 mm x 300 mm, EtOAc:hexanes 1:20) gave 303 as a colorless oil in >99% isolated yield (10 mg, 0.05 mmol). The optical purity was 431 determined to be >78% ee by HPLC analysis (Chiralpak AS column, 99:1 hexane/iPrOH at 222 nm, flow-rate: 0.7 mL/min). Retention times: Rt = 6.14 min for (S)-303 (minor) and Rt = 6.89 1 min for (R)-303 (major). Rf = 0.43 (1:5 EtOAc/hexanes). Spectral data for 303: H NMR (CDCl3, 600 MHz) δ 0.89 (t, 3H, J = 7.2 Hz), 1.27-1.42 (m, 6H), 1.45-1.49 (m, 2H), 1.54-1.62 (m, 1H), 1.92-1.97 (m, 1H), 2.68-2.74 (m, 1H), 2.76-2.83 (m, 1H), 3.20-3.24 (m, 1H), 3.74 (bs, 1H), 6.46 (d, 1H, J = 7.2 Hz), 6.58 (t, 1H, J = 7.2 Hz), 6.92-6.95 (m, 2H); 13 C NMR (CDCl3, 150 MHz) δ 14.04, 22.63, 25.39, 26.43, 28.12, 31.95, 36.68, 51.59, 114.00, 116.85, 121.38, 126.68, 129.23, 144.73. 6.4.7 Preparation of squaramide-DMAP-BINAM 107 2-chloro-N,N-dimethylpyridin-4-amine 305: To a 50 mL round bottom flask was added 2,4-dichloropyridine 304 (2.61 g, 17.6 mmol) and dimethylamine (40% aq. 17.6 mL) under N2. The mixture was stirred at 50 °C for 20 h under N2. The crude product was extracted with Et2O (20 mL x 3). The combined organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. Recrystallization from CHCl3 (two crops) gave 305 as a white solid 1 (1.89 g, 12.1 mmol, 69%). Spectral data for 305: H NMR (CDCl3, 600 MHz) δ 2.98 (s, 6H), 6.39 (dd, 1H, J = 9.5, 2.0 Hz), 6.46 (d, 1H, J = 2.0 Hz), 7.95 (d, 1H, J = 5.0 Hz); (CDCl3, 150 MHz) δ 39.25, 105.43, 105.84, 149.06, 152.31, 156.09. 432 13 C NMR 113 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione 308: To a 25 mL flame-dried round bottom flask was added 3,4-dimethoxy-3-cyclobutene-1,2-dione 306 (544 mg, 3.83 mmol) and MeOH (5.4 mL). To the solution was added 3,5-bis(trifluoromethyl)aniline 307 (623 µL, 4.02 mmol). The mixture was stirred at room temperature for 48 h under argon protection. Filtration by filter paper gave the first crop. The filtrate was concentrated to dryness. The crude product was washed with CH2Cl2/hexanes and filtered by filter paper to afford the second crop. 308 was obtained as a light yellow solid (1.18 g, 3.48 mmol, 91%). mp 186-188 °C 113 (lit. 1 179-181 °C). Spectral data for 308: H NMR (DMSO-d6, 600 MHz) δ 4.40 (s, 3H), 7.77 (s, 1H), 8.03 (s, 2H), 11.17 (s, 1H); 13 C NMR (CDCl3, 150 MHz) δ 39.25, 105.43, 105.84, 149.06, 152.31, 156.09. 107 N2-(2'-amino-[1,1'-binaphthalen]-2-yl)-N4,N4-dimethylpyridine-2,4-diamine 310: To a 25 mL flame-dried Schlenk flask was added (R)-BINAM 309 (457 mg, 1.61 mmol), Pd2dba3 (110 m, 0.12 mmol), dppp (99 mg, 0.24 mmol) and NaOtBu (232 mg, 2.42 mmol). Dry toluene (13 mL) and 2-chloro-N,N-dimethylpyridin-4-amine 305 (251 mg, 1.61 mmol) were added to the mixture. 433 The mixture was freeze-thawed twice. The mixture was stirred at 80 °C for 36 h. The mixture was cooled to room temperature and filtered through a pad of Celite (rinsed with EtOAc). After removal of the solvent, the residue was partitioned between CH2Cl2 (30 mL) and H2O (30 mL). The organic layer was dried over MgSO4, filtered through Celite and concentrated to dryness. st Purification of the crude product by column chromatography on silica gel (1 column, 25 mm x nd 200 mm, MeOH: CH2Cl2 1:14; 2 column, 25 mm x 200 mm, EtOAc:hexanes 1:2 to 1:1 to 1:0) gave 310 as a light yellow solid (331 mg, 0.82 mmol, 51%). Rf = 0.19 (1:14 MeOH/ CH2Cl2). 1 Spectral data for 310: H NMR (CDCl3, 600 MHz) δ 2.88 (s, 6H), 3.70 (bs, 1H), 5.87 (d, 1H, J = 2.0 Hz), 6.08 (dd, 1H, J = 5.0, 2.0 Hz), 6.25 (bs, 1H), 7.03 (d, 1H, J = 7.0 Hz), 7.10 (d, 1H, J = 7.5 Hz), 7.15 (td, 1H, J = 7.0, 1.0 Hz), 7.19-7.21 (m, 2H), 7.31 (td, 1H, J = 6.5, 0.5 Hz), 7.76-7.81 (m, 3H), 7.84 (d, 1H, J = 6.5 Hz), 7.92 (d, 1H, J = 6.5 Hz), 8.24 (d, 1H, J = 7.5 Hz); 13 C NMR (CDCl3, 150 MHz) δ 39.25, 91.16, 101.28, 111.99, 118.31, 120.50, 122.39, 123.89, 123.95, 125.00, 126.66, 126.89, 128.03, 128.11, 128.36, 128.84, 129.77, 130.12, 133.50, 134.00, 2 138.12, 142.79, 147.66, 156.02, 156.13 (2 sp C not located). To a 25 mL round bottom flask was added amine 310 (162 mg, 0.400 mmol), CH2Cl2 (0.4 mL) and MeOH (4 mL). Amine 308 (271 mg, 0.80 mmol) was then added to the mixture. The 434 resulting mixture was stirred at room temperature for 48 h. Purification of the crude product by column chromatography on silica gel (25 mm x 300 mm, EtOAc/hexanes 1:2 to 2:1) gave 311 as a yellow solid (261 mg, 0.367 mmol, 92%). mp 181-187 °C; Rf = 0.38 (EtOAc). Spectral data for 1 311: H NMR (DMSO-d6, 500 MHz) δ 2.66 (s, 6H), 5.76 (d, 1H, J = 7.0 Hz), 5.92 (d, 1H, J = 4.5 Hz), 6.92 (d, 1H, J = 8.5 Hz), 7.00 (d, 1H, J = 9.0 Hz), 7.24 (t, 1H, J = 7.5 Hz), 7.30 (t, 1H, J = 7.5 Hz), 7.37-7.41 (m, 2H), 7.47 (t, 1H, J = 7.5 Hz), 7.63-7.66 (m, 2H), 7.89 (s, 2H), 7.97-8.05 (m, 4H), 8.10 (d, 1H, J = 9.0 Hz). 13 C NMR (DMSO-d6, 500 MHz) δ 38.48, 89.71, 100.59, 114.91, 118.38, 119.87, 122.05, 123.50, 124.22, 124.30, 125.03, 125.33, 125.70, 126.42, 126.78, 128.25, 128.59, 128.79, 130.26, 130.70, 130.96, 131.22, 131.47, 132.78, 133.29, 134.33, 138.12, 2 140.65, 155.41, 163.62, 167.13, 181.80, 182.65 (1 sp C not located). HRMS (ESI–) m/z + calculated for C39H26N5O3F6 (M-H ) 710.1991, found 710.1979. 6.4.8 Asymmetric addition of 1-nitropropane to nitrostyrene To a 25 mL flame-dried round bottom flask was added nitrostyrene (74.5 mg, 0.50 mmol), 311 (7.1 mg, 0.010 mmol) and dry toluene (1.25 mL). 1-nitropropane (1.25 mL, 14 mmol) was added 1 and the resulting mixture was stirred at for 80 h. Syn:anti = 88:12 was determined from the H NMR spectrum of the crude reaction mixture. Purification of the crude product by column chromatography on silica gel (25 mm x 250 mm, EtOAc/hexanes 1:6) gave syn-311 as a clear oil 435 (83 mg). The total yield of syn- and anti-311 was 79% (94 mg, 0.395 mmol). Spectral data for 1 311: H NMR (CDCl3, 500 MHz) δ 1.00 (t, 3H, J = 7.5 Hz), 1.82-1.88 (m, 1H), 1.96-2.03 (m, 1H), 4.00-4.05 (m, 1H), 4.73-4.79 (m, 2H), 4.84-4.89 (m, 1H), 7.12-7.15 (m, 2H), 7.31-7.34 (m, 3H); 13 C NMR (CDCl3, 125 MHz) δ 10.32, 24.28, 46.47, 76.23, 90.97, 127.87, 129.08, 129.27, 133.69. 6.4.9 One-pot imine formation-AZ reaction Procedure I: 26g Illustrated for (2R,3R)-ethyl1-benzhydryl-3-phenylaziridine-2-carboxylate 31 To a 25 mL flame-dried round bottom flask filled with argon was added benzhydrylamine (183 mg, 1 mmol), 4Å MS (1 g) and dry toluene (2 mL). After stirring for 2 minutes, benzaldhyde 27 (116 mg, 1.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 h under the protection of argon. At the same time the catalyst was prepared in situ: to a flame-dried 25 mL Schlenk flask filled with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and triphenyl borate (116 mg, 0.4 mmol). The mixture was dissolved in dry toluene (2 mL). After the addition of H2O (0.9 mg, 0.1 mmol), the Shlenk flask was sealed and heated at 80 ºC for 1 hour. Then a vacuum (0.5 mm Hg) was applied for half an hour with continual heating at 80 ºC. The Schlenk flask containing the catalyst was cooled to room temperature and then dry toluene (2 mL) was 436 added. The catalyst solution was transferred via syringe to the round bottom flask containing imine generated in situ. After 5 minutes, EDA (114uL, 1.1 mmol) was added. The mixture was stirred at room temperature for 40 hours. Purification of the crude product by column chromatography on silica gel (35 mm x 400 mm column, EtOAc/hexanes 1:19) gave 31 as a white solid in 66% isolated yield (235 mg, 0.66 mmol) with 93% ee by HPLC analysis. Procedure II: 26g Illustrated for (2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 31 To a 25 mL round bottom flask filled with argon was added benzhydrylamine (183 mg, 1 mmol), 4Å MS (1 g) and dry toluene (2 mL). After stirring for 2 minutes, benzaldhyde 27 (116 mg, 1.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 h under the protection of argon. To a 25 mL round bottom flask was added (S)-VAPOL (54 mg, 0.1 mmol) and triphenyl borate (116 mg, 0.4 mmol). The mixture was dissolved in dry toluene (2 mL). This solution was then transferred via syringe to the round bottom flask containing imine generated in situ. After 5 minutes, EDA (114uL, 1.1 mmol) was added. The mixture was stirred at room temperature for 40 h. Purification of the crude product by column chromatography on silica gel (35 mm x 400 mm column, EtOAc/hexanes 1:19) gave 31 as a white solid in 70% isolated yield (251 mg, 0.70 mmol) with 94% ee by HPLC analysis. 437 Procedure III: 26g Illustrated for (2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 31 To a 10 mL round bottom flak was added imine 9a (271 mg, 1.0 mmol), (S)-VAPOL (27 mg, 0.05 mmol), triphenyl borate (43.5 mg, 0.15 mol). 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