I. CATALYTIC ASYMMETRIC HALOFUNCTIONALIZATION OF OLEFINS: REACTION DISCOVERY AND MECHANISTIC STUDIES  II. DEVELOPMENT OF NEW TRANSFORMATIONS FOR FURTHER MODIFICATION OF AZIRIDINES  By  Nastaran Salehi Marzijarani               A DISSERTATION  Submitted to  Michigan State University in partial fulfillment of the requirements  for the degree of   ChemistryÑDoctor of Philosophy  2016  ABSTRACT  I. CATALYTIC ASYMMETRIC HALOFUNCTIONALIZATION OF OLEFINS: REACTION DISCOVERY AND MECHANISTIC STUDIES  II. DEVELOPMENT OF NEW TRANSFORMATIONS FOR FURTHER MODIFICATION OF AZIRIDINES  By  Nastaran Salehi Marzijarani  My doctorate research work with Professor Borhan has focused on various aspects of synthetic, mechanistic and physical organic chemistry. These include reaction discovery and optimization, reaction kinetics, mechanistic studies, and computational methods. My work in the area of physical organic chemistry has defined and explored a new parameter; the halenium affinity (HalA) scale, used to predict the reactivity of various functionalities, and exemplified with over 500 molecules and halenium sources. Various studies were also carried out to understand the mechanistic aspects of chlorocyclization events. My synthetic chemistry studies entail the development of new methodologies toward the preparation of highly functionalized pyrrolidines and piperidines, as well as development of new diastereoselective and enantioselective halofunctionalization reactions.  !"""!!!!!!!!!!!!!!!!!!!!To my parents, my brothers, and my teachers for always believing in me.   iv ACKNOWLEDGMENTS  Completing my dissertation could not have been possible without the help of so many people. I would like to express my gratitude to Prof. Babak Borhan for providing me with this research opportunity, supplying insightful advice concerning this project, and most importantly for his friendship and help he provided during my 6 years in East Lansing. His mentorship has provided me with experiences that allowed me to grow not only as an independent scientist and thinker but also as a teacher and a mentor. It is an honor for me to thank my committee members, Prof. Robert Maleczka, Prof. James Jackson, and Prof. Daniel Jones for their wonderful support and advice. I would also like to send my thanks to other faculty and staff specifically Dr. Richard Staples for his X-ray crystallography expertise, Prof. Daniel Jones and Dr. Lijun Chen for Mass spectrometry, and Dr. Daniel Holmes for his help with NMR analysis. Lastly, I offer my regards and blessings to all of those who supported me during my journey including my friends, my undergraduates, and all of the members of BorhanÕs research group. I especially like to thank Chrysoula, Arvind, and Kumar for their help, support, and friendly advice through out my education.  Most importantly, I am very grateful to my parents, brothers, and the rest of my family for always giving me love and support.        v TABLE OF CONTENTS    LIST OF TABLES ............................................................................................ xi LIST OF FIGURES ........................................................................................ xiv LIST OF SCHEMES .................................................................................... xviii KEYS TO SYMBOLS AND ABBREVIATIONS ............................................. xxii Chapter I: Halenium Affinity (HalA) Scale - A New Quantitative Parameter  ......................................................................................................................... 1  I-1 Introduction ........................................................................................... 1 I-2 Guide to halenium affinity (HalA) calculations ...................................... 4 I-3 The halenium affinity table and trends .................................................. 7 I-4 Experimental analysis of HalA parameter ........................................... 53 I-4-A General procedure ................................................................. 53 I-4-B Screening of chlorenium sources for the formation of chloropyridinium complexes of 1a ......................................... 53 I-4-C Titration of chloropyridinium complex 1a with various halenium sources .................................................................................. 57 I-4-D Titration studies of pyridine derivatives with CDSC ............... 62 I-4-E Qualitative analysis of competition experiments between pyridine derivatives ................................................................ 65 I-4-F Quantitative analysis of competition experiments between pyridine derivatives ................................................................ 68 I-4-F1 1H-NMR analysis of chlorination of 4-methyl-2,6-di-tert-butyl-pyridine (1c) .......................................................... 69 I-4-F2 Titration of pyridine 1c with various amounts of CDSC . 71 I-4-F3 Titration of pyridine 1c with various halenium sources .. 72  I-4-G Quantitative analysis via competition experiments between 1a and 1c ................................................................................... 74 I-4-H Quantitative analysis via competition experiments between sterically hindered pyridines .................................................. 76 I-4-I Competition study for chlorenium ion transfer from 1c-Cl to pyridine derivatives (a quantitative trend) .............................. 80 I-4-J Control experiments ............................................................... 83 I-4-J1 Control experiment #1 ................................................... 85 I-4-J2 Control experiment #2 ................................................... 86 I-4-J3 Control experiment #3 ................................................... 88 I-5 Conclusion .......................................................................................... 88 REFERENCES .............................................................................................. 91    vi Chapter II: Mechanistic Investigations of Asymmetric Halocyclizations Reactions of Olefins .................................................................................... 97 II-1 Introduction ........................................................................................ 97 II-2 Intramolecular organocatalytic halocyclization reactions of olefins .. 100 II-3 Mechanistic studies on cinchona alkaloid-catalyzed halocyclizations reactions-A critical perspective ........................................................ 110 II-4 Detailed stereochemical investigations of chlorocyclization reactions!. ..................................................................................... 129 II-5 Labeling studies ............................................................................... 132 II-6 Absolute stereochemical determination ........................................... 134 II-7 Stereochemical outcomes of uncatalyzed reactions ........................ 139 II-7A Calculations to determine diastereotopic ratio of labeled cyclized products via non-catalyzed pathway ..................... 141 II-7B Effects of chlorenium sources on stereochemical outcomes of uncatalyzed reactions .......................................................... 143 II-7C Effects of reaction solvent on stereochemical outcomes of uncatalyzed reactions .......................................................... 145 II-7D Effects of reaction concentration on stereochemical outcomes of uncatalyzed reactions ...................................................... 147 II-7E Effects of the nucleophile on stereochemical outcomes of uncatalyzed reactions .......................................................... 151 II-8 Stereochemical outcomes of asymmetric chlorocyclization  reactions .......................................................................................... 153 II-8A Calculations to determine the quantity of the four isomeric products 2b-D obtained through (DHQD)2PHAL catalyzed chlorocyclization .................................................................. 153 II-8B Stereochemical outcomes of asymmetric chlorolactonization reactions .............................................................................. 158 II-8C Stereochemical outcomes of asymmetric chloro amidoalkene cyclization ............................................................................ 159 II-8D Stereochemical outcomes of asymmetric chlorocyclization of carbamates .......................................................................... 161 II-8E Effects of chlorenium sources on stereochemical outcomes of asymmetric chloro amidoalkene cyclization ........................ 164 II-8F Structure enantioselectivity relationship studies of cinchona alkaloid dimers in stereochemical outcomes of asymmetric chloro amidoalkene cyclization ............................................ 166 II-9 Control experiment ........................................................................... 169 II-10 Conclusion ..................................................................................... 172 II-11 Experimental results ...................................................................... 175 II-11A General remark .................................................................. 175 II-11B General procedure for the catalytic asymmetric chlorocyclization of unsaturated amide 1b ......................... 176 II-11C Procedure for the synthesis of unsaturated amide substrate 1b ....................................................................................... 177 II-11D Procedure for synthesis of labeled amide substrate 1b-D . 180   vii II-11E Procedure for the non-symmetric chlorocyclization of labeled unsaturated amide 1b-D .................................................... 183 II-11F General procedure for the synthesis of labeled substrates 9b-D to 11b-D ......................................................................... 185 II-11G General procedure for the non-asymmetric chlorocyclization of labeled II-23 to II-25 ....................................................... 185 II-11H Procedure for the catalytic asymmetric chlorocyclization of labeled unsaturated amide1b-D ......................................... 187 II-11I General procedure for synthesis of labeled epoxy alcohol 3b and 3b-D ............................................................................ 188 II-11J General procedure for the synthesis of carbamate substrate 1c ....................................................................................... 191 II-11K General procedure for the catalytic asymmetric chlorocyclization of carbamates in n-PrOH ........................ 192 II-11L general procedure for the catalytic asymmetric chlorocyclization of carbamates in CHCl3:Hexane ............. 193 II-11M Procedure for synthesis of labeled carbamate substrate  1c-D ................................................................................... 194 II-11N Procedure for the racemic chlorocyclization of labeled unsaturated carbamate 1c-D ............................................. 195 II-11O Procedure for the catalytic asymmetric chlorocyclization of labeled unsaturated carbamate 1c-D ................................. 196 II-11P Absolute stereochemical assignment at the deuterated center of substrate 2c-D and ent-2c-D  ........................................ 197 REFERENCES  ........................................................................................... 202  Chapter III: Organocatalytic Asymmetric Halofunctionalization of Alleneamides ............................................................................................. 216 III-1 Introduction ..................................................................................... 216 III-2 Solvent screen for asymmetric chlorocyclization of alleneamides .. 223 III-3 Halogen source and catalyst screen for asymmetric chlorocyclization of alleneamides .............................................................................. 227 III-4 Effect of concentration and catalyst loadings for asymmetric chlorocyclization of alleneamides ................................................... 229 III-5 Substrate scope for asymmetric chlorocyclization of alleneamides 230 III-5A Further investigation of the optimized reaction condition for chlorocyclization of alleneamides ........................................ 234 III-5B Practicality of asymmetric intramolecular chlorocyclization of alleneamides ....................................................................... 238 III-6 Asymmetric intramolecular organocatalytic chlorocyclization of dialleneamides ............................................................................... 240 III-6A Stereochemical determination of III-22 isomer .................... 243 III-7 Intermolecular asymmetric halofunctionalization of alleneamides .. 246 III-8 Synthesis of alleneamides and elaboration of cyclized chlorovinyl oxazolines ...................................................................................... 257 III-9 Computational calculation of chlorenium affinity (HalA(Cl)) for allene   viii substrates ....................................................................................... 257 III-10 Kinetic analysis of chlorocyclization of alleneamides .................... 268 III-11 Future direction ............................................................................. 270 III-12 Conclusion .................................................................................... 282 III-13 Experimentals ............................................................................... 283 III-13-A General procedure for the preparation of products .......... 284 III-13-A1 General procedure for catalytic asymmetric intramolecular chloro- or bromocyclization of alleneamides ........................................................... 284 III-13-A2 Analytical data for the chlorocyclized oxazoline products .................................................................. 285 III-13-A3 Analytical data for the mono- and double cyclized bis-oxazoline products .................................................. 297 III-13-A4 Analytical data for the bromocyclized oxazoline products .................................................................. 300 III-13-A5 Analytical data for the chlorocyclized oxazolidinone products .................................................................. 301 III-13-A6 General procedure for catalytic asymmetric intermolecular dichlorination of unsaturated terminal alleneamides ........................................................... 303 III-13-A7 Analytical data for the dichlorinated products ......... 304 III-13-A8 General procedure for catalytic asymmetric intermolecular haloetherification/halohydrin formation of unsaturated terminal alleneamides ..................... 306 III-13-A9 Analytical data for the halohydrin or haloether products       ................................................................................ 307 III-13-B General procedure for the preparation of starting materials ..        ........................................................................................ 312 III-13-B1 General procedure for synthesis of monosubstituted alleneamide starting materials ................................ 312 III-13-B2 Analytical data for monosubstituted alleneamide starting materials ..................................................... 313 III-13-B3 General procedure for synthesis of elongated monosubstituted alleneamide starting materials ..... 318 III-13-B4 Analytical data for elongated monosubstituted alleneamide starting materials ................................ 320 III-13-B5 General procedure for synthesis of disubstituted alleneamide starting materials ................................ 322 III-13-B6 Analytical data for disubstituted alleneamide starting materials .................................................................. 326 III-13-B7 General procedure for synthesis of monosubstituted dialleneamide starting materials .............................. 329 III-13-B8 Analytical data for monosubstituted dialleneamide starting materials ..................................................... 331 III-13-B9 General procedure for synthesis of disubstituted allenecarbamate starting materials ......................... 333   ix III-13-B10 Analytical data for disubstituted allenecarbamate starting materials ..................................................... 333 REFERENCES ............................................................................................ 335  Chapter IV: Elaboration of Aziridinols Toward Pyrrolidines And Piperidine Compounds ............................................................................. 341 IV-1 Introduction ..................................................................................... 341 IV-2 3,4-Dihydroxypyrrolidines via modified tandem aza-Payne/hydroamination pathway ..................................................... 344 IV-3 Diastereoselective Baylis-Hillman/aza-Payne/conjugate addition reaction .......................................................................................... 360 IV-4 Conclusion and future direction ...................................................... 370 IV-5 Experimental ................................................................................... 371 REFERENCES ............................................................................................ 421  Chapter V: Halenium Induced 1,3-Benzoate Transposition Of Tertiary Allylic Amides ............................................................................................ 426 V-1 Introduction ...................................................................................... 426 V-2 Optimization of reaction conditions for the synthesis of chloroesters ....        ....................................................................................................... 429 V-3 Effects of catalyst and additive on the rate of the reaction .............. 432 V-4 Substrate scope for chlorenium induced benzoyl transposition of unsaturated tertiary amides ............................................................. 435 V-5 Benzoyl transposition of tertiary amides using different electrophilic sources ............................................................................................ 442 V-6 Mechanistic rationale on the formation of benzoyl-transposed haloesters or halohydrins ................................................................ 445 V-7 Synthesis of unsaturated tertiary amides ........................................ 447 V-8 Future direction ................................................................................ 448 V-9 Conclusion ....................................................................................... 450 V-10 Experimental .................................................................................. 451 V-10A General procedure for synthesis of vic-halohydrin esters .. 451 V-10B1 General procedure for synthesis of starting materials (path A) ..................................................................................... 465 V-10B2 General procedure for synthesis of starting materials (path B) ..................................................................................... 471 V-10B3 General procedure for synthesis of starting materials (path C) ..................................................................................... 473 V-10B4 General procedure for synthesis of starting materials (path D) ..................................................................................... 476 REFERENCES  ........................................................................................ 478  Chapter VI: Asymmetric Organocatalytic Chlorocyclization of Phenols ...   ..................................................................................................................... 485 VI-1 Introduction ..................................................................................... 485 VI-2 Optimization of asymmetric organocatalytic chlorocyclization of   x phenols ........................................................................................... 491 VI-3 General schemes for the synthesis of starting materials ................ 512 VI-4 Conclusion ...................................................................................... 514 VI-5 Experimental ................................................................................... 515 VI-5A General procedure for synthesis of chlorocyclized chromane products ............................................................................. 516 VI-5B General procedure for synthesis of phenols through path A    ........................................................................................... 522 VI-5C General procedure for synthesis of phenols through path B   ........................................................................................... 523 VI-5D Procedure for synthesis of protected phenols .................... 531 VI-5E Procedure for synthesis of catalyst VI-21 ........................... 533 REFERENCES  ........................................................................................... 536                                xi LIST OF TABLES  Table I-1 Calculated HalA values for alkynes, alkenes, and aromatic compounds ...................................................................................... 9  Table I-2 Calculated HalA values for sulfur based acceptors ....................... 25 Table I-3 Calculated HalA values for oxygen based acceptors ..................... 28 Table I-4 Calculated HalA values for nitrogen based acceptors ................... 33 Table I-5 Calculated HalA values for phosphine based acceptors ................ 44 Table I-6 Absolute and relative HalA values (gas phase) of 1a in comparison to different halenium sources ........................................................ 61  Table I-7 Absolute and relative HalA values in kcal/mol obtained from gas phase and (SM8-acetone) calculation of pyridine derivatives 1a-j in comparison to diethyl sulfide-mimicking CDSC ............................. 64  Table I-8 Absolute and relative HalA values in kcal/mol (SM8-acetone) of pyridines derivatives 1a-j ............................................................... 67  Table I-9 Absolute HalA values and experimentally observed ratios of 1c and 1c-X using different halenium ion sources .................................... 73  Table I-10 Data for titration of 1c-Cl with 1b ................................................. 78 Table I-11 Effect of temperature on equilibrium ratios of 1b-Cl and 1c-Cl in presence of their free bases 1b and 1c  ..................................... 79  Table I-12 Data for observed equilibrium ratios when 1.0 equiv of 1c is added to chloropyridinium derivatives 1(a-j)-Cl ..................................... 83   Table II-1 Effects of chlorenium sources on syn/anti diastereomeric ratio .. 145 Table II-2 Effects of solvents on syn/anti diastereomeric ratio .................... 147 Table II-3 Effects of reactant concentrations on syn/anti diastereomeric ratio ..     ................................................................................................... 149  Table II-4 Effects of nucleophile on the diastereomeric syn/anti ratios ....... 152 Table II-5 Asymmetric chlorocyclization of amide 1b-D in the presence of   xii cinchona alkaloids dimers .......................................................... 167  Table II-6 E/Z ratios of recovered starting materials at various conversions        ................................................................................................... 170  Table III-1 Solvent and additive screening for chlorocyclization of alleneamides ............................................................................. 224  Table III-2 Co-solvent screening for chlorocyclization of alleneamides ...... 226 Table III-3 Halogen source/catalyst screening for chlorocyclization of alleneamides ............................................................................. 228  Table III-4 Concentration and catalyst loading screening for chlorocyclization of alleneamides ......................................................................... 230  Table III-5 Optimizing the conditions for substrates III-7 and III-8 ............... 235 Table III-6 Optimizing the conditions for substrates III-20 and III-21 ........... 236 Table III-7 Optimizing the conditions for substrate III-15 ............................. 238 Table III-8 Lowering the catalyst loading for III-17 ...................................... 239 Table III-9 Optimization of the reaction conditions for III-22 to reduce the formation of meso-bisoxazoline-III-22 ....................................... 243  Table III-10 HPLC traces and integration of III-22 isomers in conditions A-D   ................................................................................................ 244  Table III-11 Optimization of intermolecular asymmetric dichlorination of III-8a   ................................................................................................ 249  Table III-12 Optimization of intermolecular asymmetric haloetherification .. 251 Table III-13 Optimization of intermolecular asymmetric halohydroxylation . 254 Table III-14 Calculated HalA (Cl) values for various allenes ....................... 264 Table III-15 ÒDifferent excessÓ protocol for asymmetric chlorocyclization of alleneamide III-5a .................................................................... 269  Table III-16 Optimization of asymmetric bromocyclization of alleneamides   ................................................................................................ 272  Table III-17 Kinetic resolution of alleneamide III-53 .................................... 275   xiii Table IV-1 Optimization of reaction conditions for the synthesis of N-Ts enamide carbonate IV-10 ......................................................... 348  Table IV-2 Optimization of reaction conditions for the synthesis of N-Ts enamide carbonate IV-11 from aziridine alcohol IV-11a ........... 351  Table IV-3 Examining the role of catalyst .................................................... 353 Table V-1 Initial chlorine screening for formation of chloroester V-5 .......... 430 Table V-2 Screening of various quenching conditions or additives for formation of chloroester V-5 ....................................................... 431  Table V-3 Effect of solvent on formation of chloroester V-5 ........................ 432 Table V-4 Effect of catalyst on the rate of formation of chloroester V-5 ...... 433 Table V-5 Effect of moisture on the rate of formation of chloroester V-5 .... 434 Table V-6 Benzoyl transposition of aliphatic olefins .................................... 437 Table VI-1 Catalyst screening (1) for chlorocyclization of VI-9 ................... 492 Table VI-2 Catalyst screening (2) for chlorocyclization of VI-9 ................... 494 Table VI-3 Catalyst screening (3) for chlorocyclization of VI-9 ................... 495 Table VI-4 Screening of various chlorine sources ....................................... 497 Table VI-5 Screening of various solvents .................................................... 498 Table VI-6 Effects of temperature and screening of additives .................... 500 Table VI-7 Effects of concentration and catalyst loading (1) ....................... 502 Table VI-8 Effects of concentration and catalyst loading (2) ....................... 504 Table VI-9 Screening of various co-solvents and temperatures ................. 506       xiv LIST OF FIGURES  Figure I-1 The trend in HalA values of substituted posphines ...................... 48 Figure I-2 The trend in HalA values of cyclic sulfides and amines ............... 49 Figure I-3 The trend in HalA values of terminal olefins ................................. 50 Figure I-4 The trend in HalA values of cycloalkenes .................................... 52 Figure I-5 Theoretically estimated relative HalAÕs for pyridine 1a in comparison to the counterions of commonly employed chlorenium sources ......................................................................................... 54  Figure I-6 Overlay of 1H NMR (500 MHz, acetone-d6) spectra (a-f) ............. 58 Figure I-7 Spectra a-f depict 1H NMR data for titration of 1a with CDSC ..... 60 Figure I-8 Plot for titration of pyridines 1a-i with various CDSC representing the chemical shift change of C3-H (ppm) as a function of added CDSC ........................................................................................... 63  Figure I-9 1H NMR spectra of 1c at different temperatures under substoichiometric amounts (0.5 equiv) of CDSC ......................... 70  Figure I-10 Titration data for chlorination of 1c with CDSC .......................... 72 Figure I-11 Quantification of HalA assessment via competitive chlorination between 1c and 1a ..................................................................... 75  Figure I-12 Plot for mol fraction (%) of 1a-Cl and 1c-Cl vs equiv of 1a added (left) ............................................................................................. 75  Figure I-13 Overlay of 1H NMR spectra displaying the titration of 1b-Cl with 1c ................................................................................................ 77  Figure I-14 Plot for mol fraction (%) of 1b-Cl and 1c-Cl vs equiv of 1c added  .................................................................................................. 78  Figure I-15 Comparison of !HalA (Cl) (B3LYP/6-31G*) with experimental results of equilibrium studies between 1c-Cl (prepared in situ using 1.0 equiv CDSC) in presence of 1.0 equiv of pyridines 1b-h    .................................................................................................. 81    xv Figure I-16 Overlay of 1H NMR spectra displaying equilibrium ratios when chloropyridinium derivatives 1(a-f)-Cl were treated with 1.0 equiv of 1c .......................................................................................... 82  Figure I-17 Overlay of 1H NMR spectra of 1c-Cl, 1c-HCl, and 1c displaying their relative chemical shifts ...................................................... 84  Figure I-18 Overlay of 1H NMR spectra displaying the protonated salt (1c-HSbCl6) and the analogous chlorinated salt (1c-Cl) in the presence of the free base (1c) in acetone-d6 at room temperature ............................................................................... 86  Figure I-19 Competition for chlorenium ion capture between 1b and 1c at -90 ¡C in THF as a solvent .............................................................. 87  Figure I-20 Chlorolactonization of 17 using 1c-Cl as an active chlorenium source ........................................................................................ 88  Figure I-21 The HalA (Cl) scale based on theoretical estimates of over 500 chlorenium ion acceptors .......................................................... 90  Figure II-1 Four lowest energy conformations for quinidine ........................ 119 Figure II-2 Effects of oxygen alkylation and acylation on energy conformations of quinidine ........................................................ 120  Figure II-3 Asymmetric chlorocyclization of alkenoic acid 1a (Reaction A), unsaturated amide 1b (Reaction B), carbamate 1c under two different conditions (Reaction C and CÕ) ................................... 121  Figure II-4 Co-planar atoms shown in (DHQD)2PHAL ................................ 126 Figure II-5 Summary of SER study of chlorolactonization (Reaction A), chlorocyclization of amides (Reaction B), chlorocyclization of carbamates in n-CHCl3:Hex (Reaction C), and n-PrOH (Reaction CÕ) catalyzed by (DHQD)2PHAL ............................................... 128  Figure II-6 Asymmetric chlorocyclization of alkenoic acid 1a (Reaction A), unsaturated amide 1b (Reaction B), carbamate 1c under two different conditions (Reaction C and CÕ) ................................... 130  Figure II-7 Summary of stereochemical assignments coupled with the NMR spectra of the epoxides ............................................................. 138  Figure II-8 Summary of stereochemical assignments of uncatalyzed reactions   .................................................................................................. 140   xvi Figure II-9 The plot of anti/syn ratios vs concentration of 1b-D .................. 150 Figure II-10 Putative models for syn (a) and anti (b) addition ..................... 151 Figure II-11 (DHQD)2PHAL catalyzed chlorocyclization of 1a-D (Reaction A)   ................................................................................................ 159  Figure II-12 (DHQD)2PHAL catalyzed chloro amidoalkene cyclization of 1b-D (Reaction B) ............................................................................ 160  Figure II-13 Chlorocyclization of carbamate 1c-D yields the anti product as the major isomer in 1:1 chloroform:hexanes (Reaction C, top), and the syn  product as the major isomer in n-PrOH (Reaction CÕ, bottom) ............................................................................... 163  Figure II-14 Asymmetric chlorocyclization of amide 1b-D in presence of DiChT ...................................................................................... 164  Figure II-15 Asymmetric chlorocyclization of amide 1b-D in presence of TCCA ....................................................................................... 165  Figure II-16 SER studies of cinchona alkaloid dimers (DHQD)2NAPH (top) and (DHQD)2DAC (bottom) on chloro amidoalkene cyclization of labeled amide 1b-D ................................................................. 168  Figure II-17 Summary of stereochemical outcomes for Reactions A, B, C, and CÕ ............................................................................................. 174  Figure II-18 The X-ray structure of II-32 ..................................................... 197  Figure III-1 Comparison of halocyclizations for olefins (a) versus allenes (b)   ................................................................................................ 217  Figure III-2 Asymmetric bromolactonization of allenoic acids developed by Hennecke group ....................................................................... 219  Figure III-3 Asymmetric iodolactonization of allenoic acids developed by Fujioka group ............................................................................ 221  Figure III-4 Asymmetric semipinacol rearrangement of allenols developed by Ma group ................................................................................... 222  Figure III-5 Asymmetric amino bromination of allenes developed by Toste group ......................................................................................... 222  Figure III-6 Geometry minimized structures with calculated HalA (Cl)   xvii (B3LYP/6-31G*) with anchimeric assistance of neighboring groups ..................................................................................... 267  Figure III-7 Linear correlation between rate/[allene]-0.45 versus [DCDMH]2.18 for asymmetric chlorocyclization of alleneamides at different excesses (DE) of 0.0, 0.020, and 0.048 .................................. 270  Figure IV-1 The alkoxide intermediate leads to a semipinacol rearranged aldehyde product without any evidence of an aza-Payne rearranged process under the reaction conditions .................. 347  Figure VI-1 Rate of uncatalyzed reaction monitored by GC ....................... 505 Figure VI-2 Comparison of rates of reaction under three different conditions A-C .......................................................................................... 508  Figure VI-3 Dependence of induction of VI-10 on various conversions ...... 510                 xviii LIST OF SCHEMES  Scheme II-1 Summary of asymmetric functionalization of unactivated olefins   ................................................................................................. 98  Scheme II-2 Sub-structure of all organocatalysts used in asymmetric halofunctionalization of olefins ............................................... 101  Scheme II-3 Intramolecular organocatalytic asymmetric halofunctionalization reactions ................................................................................. 104  Scheme II-4 a) naturally occurring cinchona alkaloids b) dimeric cinchona alkaloids used in asymmetric halofunctionalization reactions ......    ............................................................................................... 109  Scheme II-5 Overview of three strategies to obtain high enantioinduction in halocyclizations reactions ...................................................... 115  Scheme II-6 General catalytic and enantioselective strategies in halocyclizations reactions ...................................................... 117  Scheme II-7 a) asymmetric chlorolactonization reaction, b) proposed mode of binding in associative hydantoin/catalyst complex, c) Asymmetric chlorolactonization reaction using chiral hydantoin ..    ............................................................................................... 124  Scheme II-8 Two plausible intermediate: open form (formation of two diastereomers), and bridged form (formation of one diastereomer) ......................................................................... 133  Scheme II-9 Synthesis of 1b-D and 1c-D starting from propargyl bromide ......    ............................................................................................... 134  Scheme II-10 Chlorocyclization of deuterated substrates ........................... 135  Scheme II-11 Absolute stereochemical assignment at the deuterated center (C-6) for substrate 2b-D ........................................................ 136  Scheme II-12 Absolute stereochemical assignment at the deuterated center (C-6) for substrates 2c-D (top) and ent-2c-D (bottom) ......... 137  Scheme II-13 1H NMR of labeled 2b-D, cyclized under non-catalyzed condition ............................................................................... 141    xix Scheme II-14 Face selectivity in chlorine delivery was measured by using chiral HPLC and 1H NMR ..................................................... 157  Scheme II-15 1H NMR spectrum of the major enantiomer 5R-2b-D, cyclized under catalyzed condition ..................................................... 158  Scheme II-16 Possibility of the formation of the isomerized starting material ...    .............................................................................................. 169  Scheme III-1 Substrate scope for the intramolecular chlorocyclization of alleneamides ......................................................................... 231  Scheme III-2 Substrate scope for the intramolecular chlorocyclization of dialleneamides ...................................................................... 242  Scheme III-3 General scheme for intermolecular and intramolecular halofunctionalization of alleneamides ................................... 247  Scheme III-4 Optimized conditions for asymmetric chloroetherification (A), dichlorination (C), chlorohydroxylation (B), and bromohydroxylation (BÕ) ........................................................ 255  Scheme III-5 Substrate scope for asymmetric chloroetherification (condition A), dichlorination (condition C), chlorohydroxylation (condition B), and bromohydroxylation (condition BÕ) of mono- and disubstituted alleneamides ................................................... 258  Scheme III-6 General scheme for synthesis of mono-substituted alleneamides ......................................................................... 259  Scheme III-7 General scheme for synthesis of di-alleneamides ................. 260 Scheme III-8 General scheme for synthesis of di-substituted alleneamides ....    .............................................................................................. 261  Scheme III-9 Elaboration of chlorovinyl oxazolines through Suzuki coupling (a), Sonogashira coupling (b), and hydrogenation reactions (c)   .............................................................................................. 262  Scheme III-10 Asymmetric chlorocyclization of allene carbamates ............ 273 Scheme III-11 Chloroetherification of alleneamides with 3 MeOH incorporation ........................................................................ 274  Scheme III-12 Efforts toward the synthesis of tri-substituted alleneamide with terminal diphenyl group ....................................................... 276   xx Scheme III-13 Efforts toward the synthesis of tri-substituted alleneamide with terminal dimethyl group ....................................................... 277  Scheme III-14 Efforts toward the synthesis of tri-substituted alleneamide with terminal cyclohexyl group .................................................... 278  Scheme III-15 Efforts for the synthesis of 1,3-di-substituted alleneamide .. 280 Scheme III-16 Synthesis of tri-substituted alleneamide III-82 ..................... 281 Scheme III-17 Synthesis of tri-substituted alleneamide III-87 ..................... 281 Scheme IV-1 One-pot conversion of 2,3-aziridin-1-ols to 2,3-substituted pyrrolidines ........................................................................... 342  Scheme IV-2 High syn diastereoselectivity for the formation of aziridinols; followed by a one-pot tandem aza-Payne/hydroamination reaction ................................................................................. 344  Scheme IV-3 Modification of tandem aza-Payne/hydroamination reaction by a latent nucleophile CO2 .......................................................... 345  Scheme IV-4 Substrate scope for the synthesis of N-Ts enamide carbonates from silyl aziridine alcohols ................................................... 349  Scheme IV-5 Substrate scope for the synthesis of N-Ts enamide carbonates from aziridine alcohols .......................................................... 352  Scheme IV-6 Alkoxide trap of CO2 and subsequent aziridine ring opening of primary and secondary alcohols ........................................... 355  Scheme IV-7 Role of NaHCO3 in the formation of IV-11 ............................. 356 Scheme IV-8 Mechanistic rationale for the synthesis of enamide epoxide and carbonate products ............................................................... 357  Scheme IV-9 Modification of tandem aza-Payne/hydroamination reaction toward the synthesis of piperidines ....................................... 362  Scheme IV-10 Substrate scope for Baylis-Hillman reaction of aziridine carboxaldehydes ................................................................ 365  Scheme IV-11 Substrate scope for aza-Payne/conjugate addition reaction of Baylis-Hillman adducts ....................................................... 367     xxi Scheme IV-12 One-pot synthesis of dehydropiperidines via Baylis-Hillman/aza-Payne/conjugate addition reactions ............... 369  Scheme V-1 General scheme for halofunctionalization of olefins ............... 427 Scheme V-2 Accidental formation of halohydrin ester V-3 ......................... 428 Scheme V-3 Substrate scope for the formation of chloroester products .... 435 Scheme V-4 Benzoyl transposition of aliphatic olefins ............................... 439 Scheme V-5 Derivatization study (a), 1H NMR (b), and 2D-COSY spectra (c) .    ............................................................................................... 440  Scheme V-6 Benzoyl transposition of V-16 and V-18 ................................. 442 Scheme V-7 Substrate scope for the formation of bromoester products .... 444 Scheme V-8 Bromo-induced benzoyl transposition of aliphatic olefin V-11 ......    ............................................................................................... 445  Scheme V-9 Mechanistic rationale on formation of haloesters and halohydrins ............................................................................. 446  Scheme V-10 Synthesis of unsaturated amides ......................................... 447 Scheme V-11 Synthesis of substituted amide V-32 and formation of chloroester V-33 .................................................................. 449  Scheme VI-1 Use of asymmetric chlorocyclization reactions in synthesis of natural products .................................................................... 487  Scheme VI-2 Toward the racemic synthesis of napyradiomycin A1 ........... 490 Scheme VI-3 Chlorocyclization of protected phenols ................................. 512 Scheme VI-4 General scheme for synthesis of 1,2,4-substituted phenols .......   .............................................................................................. 512  Scheme VI-5 General scheme for synthesis of unsaturated phenols ......... 514      xxii KEYS TO SYMBOLS AND ABBREVIATIONS   † angstrom ["] specific rotation # chemical shift Ac acetic, acetate, acetyl APCI atmospheric pressure chemical ionization Aq aqueous Ar aryl B bottom face attack BA benzoic acid BDSB bromodiethylsulfonium bromopentachloroantimonate  BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Bn benzyl BOC tert-butoxycarbonyl BOX bisoxazoline Bu butyl BuOH butanol Bz benzoyl CAN ceric ammonium nitrate CD cinchonidine CDSC chlorodiethylsulfonium hexachloroantimonate  ChT chloramineT   xxiii CN cinchonine COSY correlation spectroscopy D diastereomer DABCO 1,4-diazabicyclo[2,2,2]octane DAST diethylaminosulfur trifluoride DBDMH 1,3-dibromo-5,5-dimethylhydantoin DBU 1,8-diazabicyclo[5,4,0]undec-7-ene DCC N,NÕ-dicyclohexylcarbodiimide DCDMH 1,3-dichloro-5,5-dimethylhydantoin DCDPH 1,3-dichloro-5,5-diphenylhydantoin DCE dichloroethane DCH 1,3-dichlorohydantoin DCM dichloromethane DE different excess DFT density functional theory DHP dihydropyran (DHQ)2AQN dihydroquinine(anthraquinone-1,4-diyl)diether (DHQ)2PHAL dihydroquinine 1,4-phthalazinediyl diether (DHQD)2PHAL dihydroquinidine 1,4-phthalazinediyl diether (DHQD)2PYR dihydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether DIAD diisopropyl diazadicarboxylate DiChT dichloramineT DMAP 4-dimethylaminopyridine   xxiv DMF N,N-dimethylformamide DMP Dess-martin periodinane DMP-tris 2,3-dimethylphenyl DMSO dimethyl sulfoxide dr diastereomeric ratio DTBP 2,6-di-tert-butyl-pyridine EDG electron donating group ee enantioselectivity elec electronic En enantiomer ent enantiomer EI electron ionization ESI electronspray ionization Et ethyl EtOAc ethyl acetate Et2O diethyl ether EtOH ethanol EWG electron withdrawing group GC gas chromatography h hour HalA halenium affinity Hex hexanes HFIP hexafluoroisopropanol   xxv HMBC heteronuclear multiple bond coherence HMPA hexamethylphosphoramide HMQC heteronuclear multiple quantum coherence  HOMO highest occupied molecular orbital HPLC high-performance liquid chromatography HRMS high-resolution mass spectrometry HSQC heteronuclear single quantum coherence Hz Hertz IDSI iododiethylsulfonium iodopentachloroantimonate  LB Lewis base LC-MS liquid chromatography-mass spectrometry LDA lithium diisopropylamide LUMO lowest unoccupied molecular orbital Me methyl MeCN acetonitrile MeOH methanol MHz megahertz min minutes M.P. melting point ms molecular sieve MS mass spectrometry Ms mesyl NBL N-bromolactam   xxvi NBS N-bromosuccinimide NCP N-chlorophthalamide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMR nuclear magnetic resonance NOESY nuclear overhauser effect spectroscopy Nuc (Nu) nucleophile NuE external nucleophile PA propargyl amine PEG polyethylene glycol Ph phenyl PhthH phthalimide PMA phosphomolybdic acid PNB p-nitrobenzoate ppm parts per million Pr propyl PrOH propanol Py pyridine QD quinidine QN quinine Q-TOF quadrupole time-of-flight R substituent RDS rate determining step   xxvii ROESY rotating-frame overhauser effect spectroscopy RPKA reaction progress kinetic analysis rt room temperature RT retention time rxn reaction SelectFluor 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis tetrafluoroborate  SER structure enantioselectivity relationship SN nucleophilic substitution Sub substrate T top face attack TBAI tetra-n-butyl-ammonium iodide TBAF tetra-n-butyl-ammonium fluoride TBAOMe tetra-n-butyl-ammonium methoxide TBS tert-butyldimethylsilyl TCCA trichloroisocyanuric acid Tf triflyl TFE trifluoroethanol THF tetrahydrofuran THP tetrahydropyran TLC thin layer chromatography TMS trimethylsilyl Ts tosyl UV ultraviolet   xxviii vib vibrational X halenium XRD X-ray diffractometer XtalFluor-E (XtF) (diethylamino)difluorosulfonium tetrafluoroborate ZPE zero-point energy !"!Chapter I: Halenium Affinity (HalA) Scale - A New Quantitative Parameter I-1 Introduction  The carbon-carbon double bond is arguably one of the most versatile functional groups in organic chemistry. An enormous body of literature is devoted to the transformation of alkenes into diverse and versatile functionalities.1 Most if not all of these reactions rely on the electrophilic activation of the alkene functionality at some stage during the reaction. Nonetheless, the enantioselective activation of alkenes by halenium ions Ð one of the stereotypical electrophiles Ð has, until recently, met with little or no success.2-7  Electrophilic activation of alkenes via halenium ion attack has been extensively studied for its ability to forge C-C, C-O, C-N, and C-X bonds. The past decade has witnessed explosive growth, especially in the field of stereoselective halofunctionalization of alkenes.2, 3, 5, 8, 9 Despite this rapid expansion and great synthetic utility, the field is still in its infancy and has yet to witness benchmarks analogous in generality and utility to asymmetric epoxidations, dihydroxylations, aminohydroxylations, hydrogenations, cyclopropanations, hydrometalations, oxidative cleavage, and aziridinations, among others.10, 11 Several studies have probed the mechanistic underpinnings of halenium ion reactions,8, 12-19 In fact, catalytic asymmetric halofunctionalization of alkenes has remained an ill-explored and long sought after transformation in organic chemistry in spite of its tremendous potential !#!synthetic utility. The factors that dictate the kinetic and stereochemical stability of chiral halonium ions have been well studied (with the seminal studies dating back to the 1960Õs).15, 17, 18, 20 Rapid stereochemical degradation of chiral halonium ions due to degenerate olefin to olefin halogen transfer12, 19 as well as unwanted isomerization processes13, 14 have precluded the development of synthetically useful asymmetric alkene halogenation reactions.  Exploration of late stage alkene halogenation reactions in total synthesis of complex natural products has remained unexplored thus far, as have many useful reactions such as enantioselective C-C bond formation and intermolecular nucleophilic capture of chiral halonium ions. Central to addressing these challenges is to complement the conventional trial-and-error or brute force screening approaches with predictive models for reaction discovery. To expedite discovery of new reactions in this area, an organizing framework is needed. Reflecting on our own synthetic21-25 and mechanistic26, 27 ventures, we note the parallels between protonation and halogenation of alkenes. The field will be well served by a scale like the familiar pKa tables, to classify and order the halenium ion affinities of various functional groups. Herein we present such a scale, computationally derived but validated by experiments, that quantitatively predicts not only the interactions of halenium ions with various Lewis base acceptors, but also the processes that ensue after the capture of halenium ion by a substrate molecule. We tried to !$!understand the mechanistic nuances that dictate the stereo-, regio- and chemoselectivity of electrophilic alkene halogenations. As a result, we have introduced the halenium affinity (HalA) parameter as a quantitative descriptor of the bond strengths of various functional groups to halenium ions.  We begin by addressing a question that is fundamental to all alkene halogenation reactions Ð How easily does a given alkene capture a halenium ion? More specifically, how can we quantify the propensity of an alkene to undergo halogenation using reliable and predictable means? We approached this question using theoretical means by comparing protonation and halogenation chemistry.  The HalA values will allow for the rapid and quantitative determination of the propensity of various functional groups to react with halenium sources. The HalA scale ranks potential halenium ion acceptors based on their ability to stabilize a Ôfree halenium ionÕ. As a class, halenium ion donors are electrophilic reagents that offer access to complex and useful molecular motifs. Oxidation, addition to !-bonds, halogenation of aromatics, and activation of heteroatoms are among their core reaction modes. The electronegativity, bonding flexibility, and delivery reagents for halogen cations strongly modulate their selectivities. For instance, some chlorenium donors are effective alcohol oxidants,28, 29 whereas suitably chosen iodenium reagents achieve mild activations to form selected glycosidic bonds without oxidation of alcoholic functionalities.30-32 The key to this diversity of reactivity !%!lies in the variable interactions of halenium ions with different functional groups. Alkenes in particular but other Lewis bases as well, such as amines, amides, carbonyls and ether oxygens, etc. have been classified on the HalA scale. This indirect approach enables a rapid and straightforward prediction of the chemoselectivity for systems involved in halofunctionalization reactions that have multiple nucleophilic sites. Deciphering absolute as well as relative halogen affinities will prove particularly useful in the development of C-C bond formation reactions where the nucleophile and the initial site of halogenation are both carbon centered.  I-2 Guide to halenium affinity (HalA) calculations We envisioned theoretical means of predicting the ease of halogenation of an acceptor group by drawing parallels between protonation and halogenation chemistry. While there is ample literature precedent for determination and applications of proton affinity values, an analogous approach with halenium ions (perhaps surprisingly) finds no such precedence. In analogy to ab initio derived proton affinities,33 the Halenium Affinity (HalA) was evaluated by with the aid of experiments and theoretical calculations. We define the computationally evaluated HalA as the molar enthalpy change for a given Lewis base (:LB) upon its attachment to a halenium ion (X+), as shown below:  !&!!"#$!!!!!!"!#!!!!"#!!!!!"#!!!!"!!                              EÕ(vib) (T) =   where;  !E(elec) = E(electronic)(X-LB adduct) Ð [E(electronic)(:LB) + E(electronic) (X+)]; zero point energy change !ZPE = ZPE(X-LB adduct) Ð ZPE(:LB); !EÕ(vib) = EÕ(vib)(X-LB adduct) Ð EÕ(vib)(:LB) i.e. difference in temperature dependence of vibrational energy; N is AvogadroÕs number, h is PlanckÕs constant, and ni is the ith vibrational frequency. Finally, the 5/2 RT quantity accounts for translational degrees of freedom and the ideal gas value for the change from two particles to one.  The acceptor fragment (Lewis base) may be neutral or anionic (i.e. the X-LB complex is cationic or neutral), leading to two distinct cases:  "Hrxn(X+  +  :LB  !  X-LB+)  or  "Hrxn(X+  +  :LBÐ  !  X-LB)  The HalA values (gas phase) in kcal/mol are derived at T = 298.15 K (unless noted otherwise) assuming ideal gas behavior. Ab initio assessments may provide accurate HalA values, but their computational expense quickly becomes impractical with increasing molecular size. A Density Functional Theory (DFT) approach is affordable and widely available to most organic chemists who wish to evaluate HalA values and apply them in the planning of halofunctionalization reactions. Our NhvieNhvi/RT!1i=13n!6"!'!combined theoretical-experimental optimizations for the best compromise between computational expense and reliability of HalA values, have led us to the application of the following basis sets based on the halenium ion under consideration: a.) [B3LYP/6-31G*] for fluorenium, chlorenium and bromenium ions. b.) [B3LYP/6-31G*/LANL2DZ] for iodenium ion. To calculate HalA values from theory for gas phase reactions (appropriate solvent models can be applied if necessary) the following steps were followed: 1. An appropriate basis set was chosen based on the halenium ion under consideration. 2. The Lewis base was initially subjected to a conformational search at the level of theory decided from step 1. To confirm that each structure was a true minimum, vibrational analyses were performed. If necessary, the lowest energy conformer was re-subjected to a full geometry optimization to verify convergence. 3. The halenium ion (in its triplet state) was also subjected to the same level of theory for a geometry optimization. 4. The Lewis base-halenium ion adduct was then subjected to step 2 as described above. If there were multiple nucleophilic sites within the same Lewis base then separate calculations were initiated with appropriate attachment of the halenium ion to each nucleophilic site. 5. The following three values were extracted from each of the output files for geometry minimized Lewis base (lowest energy conformer) and the !(!Lewis base-halenium ion adduct/complex: a.) electronic energy (E), b.) zero point energy (ZPE) and, c.) temperature dependence of vibrational energy EÕ(vib). The electronic energy of the halenium ion was also obtained from its corresponding output file.  6. Finally, these values (converted to kcal/mol) were substituted in the following equation to obtain the HalA (X) for the Lewis base. !"#$!!!!!!"!#!!!!"#!!!!!"#!!!!"!! HalA calculations intrinsically account for the influences of subtle electronic and steric variations, as well as the less predictable anchimeric and stereoelectronic effects providing quantitative assessments beyond simple Ôchemical intuitionÕ. I-3 The halenium affinity table and trends The Halenium affinity table provides over 500 calculated HalA (Cl) values for various halenium acceptors that are categorized based on functional groups. HalA values of alkenes, alkynes, and aromatic based acceptors are shown in Tables I-1. HalA of sulfur and oxygen based compound are presented in Tables I-2 and I-3, respectively. Nitrogen and phosphine compounds were also investigated as shown in Tables I-4, and I-5, respectively. Each category includes an organized trend of HalA values for acceptors based on their ring size, substitution pattern, nucleophilicity etc. For ease of searching a category of acceptors or even a particular acceptor, the table also provides labels and molecular formulas. The labels are based on !)!the functionalities and/or the acceptor atom. For instance, morpholine incorporates nitrogen and oxygen atoms serving as halenium ion acceptors, searching the document under the label ÔNOÕ will lead to a quick recognition of compounds incorporating Nitrogen and Oxygen atoms that have been evaluated for halenium affinity (e.g. N-methyl morpholine, 4-hydroxypyridine, methoxypyridines, amides etc.).   !*! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) A1 ethyne  C1-C2 114.5 1.902 A2 prop-1-yne  C1 136.9 1.722 A3 but-2-yne  C2 143.3 1.768 A4 but-1-yne  C1 142.0 1.724 A5 3-methylbut-1-yne  C1 181.9 1.681 A6 3,3-dimethylbut-1-yne  C1 192.0 1.689 A7 2,2,5,5-tetramethylhex-3-yne  C3 156.6 1.781 A8 ethynylbenzene  C1 168.1 1.727 A9 prop-2-yn-1-ylbenzene  C3 195.0 1.703 A10 1,2-diphenylethyne  C1 169.3 1.674 A11 (3,3-dimethylbut-1-yn-1-yl)benzene  C2 172.6 1.755 A12 ethynyltrimethylsilane  C1 187.0 1.833 A13 trimethyl(prop-1-yn-1-yl)silane  C2 148.6 1.789 A14 trimethyl(prop-2-yn-1-yl)silane  C3 171.9 1.727 A15 ethynylcyclopropane  C2 164.9 1.721 A16 prop-1-yn-1-ylcyclopropane  C2 168.0 1.743 A17 cyclooctyne  C1-C2 164.0 1.749 A18 ethynamine  C2 177.1 1.709 A19 N-methylethynamine  C2 187.4 1.713 A20 N,N-dimethylethynamine  C2 195.0 1.718 AO42 methoxyethyne  C2 O 162.8 NA 1.717 NA  Table I-1 Calculated HalA values for alkynes, alkenes, and aromatic compounds. !"+! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) A21 1-methoxyprop-1-yne  C2 202.9 1.738 AO43 (ethoxyethynyl) trimethylsilane  C1 O 175.9 NA 1.732 NA A22 N-ethynylacetamide  C2 172.3 1.712 A23 propiolamide  C2-C3 146.4 1.699 A24 but-3-yn-2-one  C3-C4 138.7 1.692 A25 pent-3-yn-2-one  C3-C4 140.2 1.696 A26 1,3-diphenylprop-2-yn-1-one  C2 167.8 1.730 A27 but-2-ynoic acid  C2-C3 133.3 1.720 A28 propiolic acid  C2-C3 125.6 1.697 A29 methyl propiolate  C2-C3 135.1 1.695 A30 methyl but-2-ynoate  C2 154.8 1.687 A31 methyl 3-methoxypropiolate  C2 162.4 1.711  Table I-1 (contÕd) !""! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl  distance (†) A32 ethynyl acetate  C2 170.8 1.731 A33 buta-1,3-diyne  C1 140.7 1.705 AO41 (ethynyloxy)ethyne  C2 O 144.2 NA 1.715 NA A34 hexa-2,4-diyne  C2 160.1 1.733 A35 1,4-diphenylbuta-1,3-diyne  C1 177.4 1.751 A36 hexa-1,3,5-triyne  C3 C1 134.8 156.5 1.733 1.707 A37 but-1-en-3-yne  C4 C1 151.6 142.1 1.721 1.828 A38 (E)-hex-2-en-4-yne  C5 C2 168.6 160.0 1.745 1.848 A39 (Z)-hex-2-en-4-yne  C5 C2 166.2 159.3 1.747 1.855 A40 pent-1-en-4-yne  C5 C1 168.5 147.9 1.683 1.811 A41 (E)-hept-2-en-5-yne  C6 C2 203.6 162.1 1.711 1.829 A42 (Z)-hept-2-en-5-yne  C6 C2 169.4 162.4 1.745 1.830 A43 1-ethynyl-4-vinylbenzene  C1 C2 177.1 171.2 1.733 1.815 A44 ethene  C1-C2 136.2 1.892 A45 prop-1-ene  C1-C2 146.0 1.862 A46 but-1-ene  C1-C2 148.4 1.855  Table I-1 (contÕd) !"#! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) A47 3-methylbut-1-ene  C1-C2 150.9 1.848 A48 3,3-dimethylbut-1-ene  C1 153.6 1.836 A49 styrene  C1 167.4 1.815 A50 3-phenylpropene  C1 165.0 1.804 AO11* prop-2-en-1-ol  O C3 109.8 147.4 1.746 1.799 A51 prop-2-ene-1,1-diyldibenzene  C3 181.1 1.808 AO37 ethoxyethene  C2 O 165.5 NA 1.808 NA A52 N-ethylethenamine  C2 193.0 1.801 A53 N-vinylacetamide  C2 169.7 1.804 A54 acrylamide  C2-C3 135.4 1.882 A55 methyl acrylate  C2-C3 133.1 1.882 A56 acrylic acid  C2-C3 128.0 1.884 A57 vinyl acetate  C2 158.9 1.806 A58 but-3-en-2-one  C3-C4 133.4 1.882 AS20 phenyl(vinyl)sulfane  S C2 159.4 171.5 2.089 1.811 A59 2-methylprop-1-ene  C1 155.8 1.831 A60 3-methylenepentane  C1 161.6 1.824 *Addition of Cl+ to the olefin leads to the epoxide during geometry optimization. Table I-1 (contÕd) !"$! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) A61 2,4-dimethyl-3-methylenepentane  C1 202.9 1.818 A62 2,2,4,4-tetramethyl-3-methylenepentane  C1 165.7 1.819 A63 a-methylstyrene  C1 173.7 1.813 AO39 2-ethoxyprop-1-ene  C1 O 176.9 NA 1.808 NA A64 N-ethylprop-1-en-2-amine  C1 200.9 1.802 A65 ethene-1,1-diyldibenzene  C2 182.2 1.814 A66 trans-but-2-ene  C2-C3 153.7 1.955 A67 cis-but-2-ene  C2-C3 154.1 1.957 A68 trans-2,2,5,5-tetramethylhex-3-ene  C3-C4 163.2 1.972 A69 cis-2,2,5,5-tetramethylhex-3-ene  C3-C4 162.9 1.957 A70 (E)-(3,3-dimethylbut-1-en-1-yl)benzene  C2 C1 171.7 172.9 1.846 1.848 A71 b-methylstyrene  C2 170.1 1.838 A72 trans-stilbene  C1 169.7 1.815 A73 cis-stilbene  C1 168.1 1.846 A74 (E)-N-ethylprop-1-en-1-amine  C2 196.1 1.821 AO38 (E)-1-ethoxyprop-1-ene  C2 O 171.3 NA 1.835 NA  Table I-1 (contÕd) !"%! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) A75 (E)-pent-3-en-2-one  C3-C4 141.1 1.883 A76 (E)-1,3-diphenyl-2-propene-1-one (chalcone)  C2 168.9 1.781 A77 (E)-but-2-enoic acid  C2-C3 136.5 1.874 A78 (Z)-but-2-enoic acid  C2-C3 136.9 1.871 A79 (E)-methyl but-2-enoate  C2-C3 140.4 1.881 A80 (Z)-methyl but-2-enoate  C2-C3 141.1 1.876 AO40 (E)-methyl 3-methoxyacrylate  C2 O 160.6 NA 1.787 NA A81 2-methylbut-2-ene  C3 161.0 1.887 A82 2-methylpent-2-ene  C3 166.3 1.870 A83 2,3-dimethylbut-2-ene  C2-C3 166.3 2.001 A84 (E)-2,3-diphenyl-2-butene  C2 170.2 1.874 A85 (Z)-2,3-diphenyl-2-butene  C2 174.7 1.867 A86 cyclopropene  C1-C2 141.1 1.899 A87 cyclobutene  C1-C2 147.9 1.935 A88 cyclopentene  C1-C2 155.5 1.958  Table I-1 (contÕd) !"&! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) A89 cyclohexene  C1-C2 154.8 1.962 A90 cycloheptene  C1-C2 156.9 1.962 A91 cis-cyclooctene  C1-C2 159.2 1.827 A92 trans-cyclooctene  C1-C2 170.3 1.970 A93 bicyclo[2.2.0]hex-1(4)-ene  C1-C4 162.2 1.950 A94 1,2,3,4,5,6-hexahydropentalene  C1-C5 169.1 2.005 A95 1,2,3,4,5,6,7,8-octahydronaphthalene  C1-C6 165.2 2.029 A96 methylenecyclopropane  C1 147.9 1.871 A97 methylenecyclobutane  C1 155.9 1.830 A98 methylenecyclopentane  C1 161.5 1.819 A99 methylenecyclohexane  C1 162.1 1.822 A100 cycloprop-2-enone  C2-C3 101.1 1.875 A101 cyclobut-2-enone  C2-C3 127.2 1.896 A102 cyclopent-2-enone  C2-C3 131.9 1.893 A103 cyclohex-2-enone  C2-C3 137.7 1.891 A104 cyclohept-2-enone  C2-C3 140.1 1.906  Table I-1 (contÕd) !"'! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) A105 1-methylcyclohex-1-ene  C2 162.2 1.867 A106 1,2-dimethylcyclohex-1-ene  C1-C2 166.1 1.974 A107 1-methoxycyclohex-1-ene  C2 180.2 1.830 A108 [1,1'-bi(cyclohexane)]-1,1'-diene  C2 181.4 1.835 A109 2,3,4,5-tetrahydro-1,1'-biphenyl  C2 177.5 1.830 A110 1,2-dihydronaphthalene  C2 173.7 1.842 A111 1H-indene  C2 170.4 1.813 A112 2,3-dihydrofuran  C3 169.9 1.822 A113 3,4-dihydro-2H-pyran  C3 169.2 1.810 A114 2,3-dihydro-1,4-dioxine  C3 164.6 1.878 A115 1-methyl-2,3-dihydro-1H-pyrrole  C4 201.7 1.819 A116 1-methyl-1,2,3,4-tetrahydropyridine  C5 200.0 1.812  Table I-1 (contÕd) !"(! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) ANO44 4-methyl-3,4-dihydro-2H-1,4-oxazine  C5 O N 196.1 NA NA 1.851 NA NA A117 cyclobuta-1,3-diene  C1 193.4 1.754 A118 cyclopenta-1,3-diene  C1 162.4 1.804 A119 cyclohexa-1,4-diene  C1-C2 153.6 1.960 A120 1,5-dimethylcyclohexa-1,4-diene  C2 162.2 1.887 A121* trans-cyclohexa-2,5-diene-1,4-diol  C2  165.4 1.799 A122 para-benzoquinone  C2-C3 118.4 1.918 A123 bicyclo[2.2.1]hept-2-ene  C2-C3 161.0 1.960 A124 bicyclo[2.2.2]oct-2-ene  C2-C3 158.2 1.953 A125 7,7-dimethylbicyclo[2.2.1]hept-2-ene  C2-C3 155.7 1.969 A126** bicyclo[2.2.2]octa-2,5-diene  C2 174.1 1.792 A127 bicyclo[2.2.1]hepta-2,5-diene  C2 175.1 1.783 A128 7,7-dimethylbicyclo[2.2.1]hepta-2,5-diene  C2 180.7 1.795 *Addition of Cl+ to the olefin leads to the epoxide during geometry optimization. **Addition of Cl+ to the olefin results in anchimeric assistance of the other olefin leading to a C-C bond formation. Table I-1 (contÕd) !")! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) AN66 1-azabicyclo[2.2.2]oct-2-ene  C2-C3 N 152.6 168.2 1.924 1.780 AN64 7-methyl-7-azabicyclo[2.2.1]hept-2-ene  N (N-Cl syn to C=C) N (N-Cl anti to C=C) C2 169.0 170.8 188.4 1.796 1.794 1.781 A129 buta-1,3-diene  C1 149.8 1.822 A130 (2E,4E)-hexadiene  C2 165.1 1.839 A131 (2Z,4Z)-hexadiene  C2 167.2 1.850 A132 2,3-dimethylbuta-1,3-diene  C1 163.8 1.818 A133 (E)-hexa-1,3,5-triene  C1 C3-C4 171.8 152.8 1.815 1.981 A134 (3E,5E)-octa-1,3,5,7-tetraene  C1 C3 184.7 168.0 1.814 1.854 A135 (3E,5E,7E)-deca-1,3,5,7,9-pentaene  C1 C3 C5 194.1 178.8 169.9 1.817 1.847 1.820 A136 (3E,5E,7E,9E)-dodeca-1,3,5,7,9,11-hexaene  C1 C3 C5 200.7 186.8 179.3 1.819 1.848 1.843 A137 (E)-2,6-dimethylnona-2,6-diene  C3 C7 164.5 170.3 1.918 1.850 A138 (6E,10E)-2,6,10-trimethyltrideca-2,6,10-triene  C3 C7 C11 167.7 171.5 172.3 1.929 1.853 1.837  Table I-1 (contÕd) !"*! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) A139 cyclohexa-1,3-dien-5-yne  C5 170.8 1.698 A140 benzene  C 139.0 1.805 AO141 nitrobenzene  O C3 118.2 121.8 1.709 1.804 A142 hexafluorobenzene  C 121.4 1.797 A143 fluorobenzene  C2 C4 137.9 141.0 1.807 1.814 A144 chlorobenzene  C2 C4 136.6 139.5 1.815 1.816 A145 bromobenzene  C2 C4 137.1 140.1 1.815 1.820 A146 iodobenzene  C2 C4 139.3 142.2 1.822 1.821 A147 toluene  C2 C4 147.2 148.4 1.803 1.812 A148 cumene  C4 150.7 1.816 A149 tert-butylbenzene  C2 C4 146.6 151.5 1.842 1.817 A150 o-xylene  C4 151.2 1.817 A151 m-xylene  C2 C4 153.0 155.5 1.831 1.813  Table I-1 (contÕd) !#+! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) A152 p-xylene  C2 150.7 1.805 AO153 anisole  C2 O 155.6 112.1 1.826 2.026 A154 1,2-dimethoxybenzene  C3 C4 161.3 166.7 1.821 1.830 A155 1,3-dimethoxybenzene  C2 C4 171.3 174.3 1.819 1.821 A156 1,4-dimethoxybenzene  C2 158.4 1.825 AS3 benzenethiol  C2 C4 S 149.2 152.9 146.8 1.804 1.824 2.089 AO12 phenol  C2 O 152.3 106.3 1.814 2.138 AO13 p-cresol  C2 O 157.9 113.9 1.806 2.205 AO14 4-(tert-butyl)phenol  C2 O 159.1 116.5 1.818 2.247 AO15 4-methoxyphenol  C2 C3 O1 156.0 158.4 124.8 1.807 1.877 2.326 AO16 2,4,6-trimethylphenol  C3 O 159.3 124.6 1.816 2.321 AO17* 4-fluorophenol  C1 C2 O 137.4 146.1 NA 1.886 1.821 NA  *Attempts at geometry optimization of the structure in which Cl+ was attached to OH resulted in the migration of the halogen to C1.   Table I-1 (contÕd) !#"! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) AO18 4-chlorophenol  C2 O 145.3 106.4 1.816 2.211 AO19 4-bromophenol  C2 O 145.7 107.2 1.816 2.222 AO20 4-iodophenol  C2 O 147.2 110.1 1.816 2.240 AO21 hydroquinone  C2 O 153.9 120.5 1.807 2.216 AO22 resorcinol  C2 C4 O 162.4 165.9 108.4 1.816 1.816 2.178 AO23* pyrocatechol  C3 C4 O 152.9 154.1 NA 1.808 1.823 NA AO157 2-hydroxybenzaldehyde  C5 O 149.5 125.3 1.822 1.727 AO158 2-hydroxybenzoic acid  C5 O 153.7 124.7 1.823 1.731 A159 benzoic acid  C3 133.7 1.804 A160 methyl benzoate  C3 137.2 1.807 A161 acetophenone  C2 C3 134.8 134.7 1.830 1.803 AN162 benzamide  C3 N 137.2 133.0 1.808 1.763 *Attempts at geometry optimization of the structure in which Cl+ was attached to OH resulted in the migration of the halogen to C3. Table I-1 (contÕd) !##! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) A163 2-acetoxybenzoic acid  C3 C5 C6 135.8 137.0 116.8 1.818 1.819 1.836 AN164 2-aminobenzoic acid  C5 N 168.6 150.0 1.827 1.810 A165 N-phenylacetamide  C4 162.2 1.824 A166 benzenesulfonic acid  C2 C3 123.8 126.1 1.814 1.803 A167 naphthalene  C1 C2 156.5 152.8 1.834 1.827 A168 1,1'-biphenyl  C2 154.9 1.833 A169 anthracene  C9 175.7 1.848 A170 phenanthrene  C9 161.4 1.854 AN104 1H-imidazole  N1 107.7 1.791 N3 159.5 1.704 C2 151.8 1.770 C4 149.9 1.792 AN105 1H-pyrrole  N1 C2 C3 122.2 169.8 162.0 1.796 1.785 1.801  Table I-1 (contÕd) !#$! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) ANP27 5-(dimethylphosphino)-1-phenyl-1H-pyrazole  P 205.9 2.036 N2 160.4 1.696 N1 NA Cl transfer to C3 C5 160.1 1.780 C4 171.2 1.805 C3 159.3 1.798 ANP28 2-(di-tert-butylphosphino)-1-phenyl-1H-pyrrole  P 217.9 2.038 N 131.8 1.830 C2 173.8 1.798 C3 177.6 1.817 AN106 1H-indole  N1 135.1 1.829 C2 170.1 1.801 C3 173.8 1.812 AN107 6-methoxyquinoline  N 167.0 1.734 C5 165.9 1.838 C7 153.2 1.829 C9 142.1 1.892 AN108 7H-purine  N1 154.2 1.728 N2 156.6 1.723 N3 151.7 1.702 N5 106.2 1.803 C4 128.2 1.775 ANS10 1H-pyrazolo[3,4-d]pyrimidine-4-thiol  S 132.3 2.059 N5 147.8 1.730 N7 148.2 1.723 N1 115.5 1.772 N2 140.3 1.694 ANS9 4H-1,2,4-triazole-3-thiol  S 128.7 2.086 N4 96.5 1.782 C5 145.3 1.769 N2 153.0 1.695  Table I-1 (contÕd) !#%! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) AOP25 4-chlorodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine  P 181.0 1.984 O NA Cl transfer to C1 C1 152.0 1.886 AN109 1H-benzimidazole  N1 122.4 1.811 C2 153.7 1.782 N3 163.0 1.703 AP29 tri(furan-2-yl)phosphine  P 205.5 2.046 C2 180.6 1.706 C3 165.2 1.807 C4 154.6 1.827 C5 178.2 1.778  Table I-1 (contÕd) !#&! Table I-2 Calculated HalA values for sulfur based acceptors. Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) S1 ethanethiol  S 141.1 2.034 S2 2-methylpropane-2-thiol  S 149.4 2.037 AS3 benzenethiol  S C2 C4 146.8 149.2 152.9 2.089 1.804 1.824 OS4 2-methoxyethanethiol  S O 149.1 107.0 2.044 1.757 OS5 2-mercapto-2-methylpropanoic acid  S 142.9 2.071 O1 119.4 1.751 NOS6 2-amino-3-mercaptopropanoic acid  S 175.6 2.070 O1 107.5 1.747 N 139.7 1.777 NS7 4-(dimethyl amino)benzenethiol  S 167.6 2.213 N 157.3 1.976 NS8 2-(1,4,5,6-tetrahydropyrimidin-2-yl)benzenethiol  S 180.5 2.103 N1 156.4 1.793 N3 181.4 1.725 ANS9 4H-1,2,4-triazole-3-thiol  S 128.7 2.086 N4 96.5 1.782 C5 145.3 1.769 N2 153.0 1.695 ANS10 1H-pyrazolo[3,4-d]pyrimidine-4-thiol  S 132.3 2.059 N5 147.8 1.730 N7 148.2 1.723 N1 115.5 1.772 N2 140.3 1.694 S11 dimethylsulfane  S 153.3 2.037 S12 diethylsulfane  S 161.3 2.042 !!#'! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) S13 thiirane  S 147.3 2.031 S14 thietane  S 155.2 2.027 S15 tetrahydrothiophene  S 159.1 2.045 S16 tetrahydro-2H- thiopyran  S 161.5 2.041 S17 di-tert-butylsulfane  S 170.7 2.048 S18 diphenylsulfane  S 163.5 2.094 S19 dibenzylsulfane  S 168.1 2.050 AS20 phenyl(vinyl)sulfane  S C2 159.4 171.5 2.089 1.811 S21 trimethyl(phenylthio)silane  S 165.8 2.087 S22 4-nitrophenyl hypochlorothioite  S 142.7 2.047 OS23 S-tert-butyl carbonochloridothioate  S O 136.6 105.9 2.024 1.742 OS24 (methylsulfinyl)cyclopentane  O 144.6 1.747 OS25 S-phenyl benzenesulfonothioate  S1 O 156.2 126.6 2.058 1.744 NS26 benzothioamide  S N 175.8 129.3 2.056 1.796 NS27 thiourea  S N 169.6 NA 2.045 NA  Table I-2 (contÕd) !#(!   Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) NS28 1,3-dimethylthiourea  S N 173.2 NA 2.056 NA NS29 1,1,3,3-tetramethylthiourea  S N 181.9 NA 2.059 NA NS30 1,3-diphenylthiourea  S N 180.2 NA 2.058 NA S31 triphenylphosphine sulfide  S 184.2 2.075 S32 carbon disulfide  S 109.1 2.052 S33 1,2-dimethyldisulfane  S 150.1 2.078 S34 1,2-diphenyldiselane  Se 173.2 2.222 S35 diphenylselane  Se 173.1 2.210 NS36 (Z)-N-(3,5-bis(trifluoromethyl)phenyl)-4-(dimethyliminio)pyridine-1(4H)-carbimidothioate   S N1 189.3 172.5 2.079 1.777 !Table I-2 (contÕd) !#)! Table I-3 Calculated HalA values for oxygen based acceptors. Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) O1 water H2O O 81.0 1.774 O2 methanol  O 98.3 1.762 O3 ethanol  O 104.9 1.757 O4 propan-2-ol  O 110.5 1.751 O5 butan-1-ol  O 106.1 1.753 O6 2-methylpropan-2-ol  O 117.4 1.731 O7 cyclopropanol  O 104.9 1.805 O8 cyclobutanol  O 109.9 1.766 O9 cyclopentanol  O 113.5 1.750 O10 cyclohexanol  O 114.3 1.747 AO11* prop-2-en-1-ol  O C3 109.8 147.4 1.746 1.799 AO12 phenol  O C2 106.3 152.3 2.138 1.814 AO13 p-cresol  O C2 113.9 157.9 2.205 1.806 AO14 4-(tert-butyl)phenol  O C2 116.5 159.1 2.247 1.818 AO15 4-methoxyphenol  O1 C2 C3 124.8 156.0 158.4 2.326 1.807 1.877 AO16 2,4,6-trimethylphenol  O C3 124.6 159.3 2.321 1.816 AO17** 4-fluorophenol  C1 C2 O 137.4 146.1 NA 1.886 1.821 NA AO18 4-chlorophenol  O C2 106.4 145.3 2.211 1.816 *Addition of Cl+ to the olefin leads to the epoxide during geometry optimization. **Attempts for the geometry optimization of the structure in which Cl+ was attached to OH resulted in the migration of the halogen to C2.    !#*! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) AO19 4-bromophenol  O C2 107.2 145.7 2.222 1.816 AO20 4-iodophenol  C2 O 147.2 110.1 1.816 2.240 AO21 hydroquinone  O C2 120.5 153.9 2.216 1.807 AO22 resorcinol  O C2 C4 108.4 162.4 165.9 2.178 1.816 1.816 AO23* pyrocatechol  O C3 C4 NA 152.9 154.1 NA 1.808 1.823 AO157 2-hydroxybenzaldehyde  O C5 125.3 149.5 1.727 1.822 AO158 2-hydroxybenzoic acid  O C5 124.7 153.7 1.731 1.823 NO24 pyridin-4-ol  O 90.3 1.917 N 161.7 1.725 O25 phenylmethanol  O 118.4 1.786 OP16 phosphinetriyltrimethanol  O 123.6 1.757 P 191.3 2.017 NO26 3-hydroxy-2-(4-methylphenylsulfonamido) butanoic acid  O1 137.0 1.779 N 138.5 1.749 NO27 hydroxylamine  O 95.0 1.883 N 131.2 1.784 *Attempts for the geometry optimization of the structure in which Cl+ was attached to OH resulted in the migration of the halogen to C3.   !Table I-3 (contÕd) !$+! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) NO28 2-aminoethanol  O 148.2 1.725 N 153.5 1.763 NO55 2-(dimethylamino)ethanol  O N 158.0 161.8 1.725 1.807 O29 ethane-1,2-diol  O 117.4 1.745 O30 propane-1,3-diol  O 129.9 1.743 NO31 N-methylhydroxylamine  O N 106.7 142.9 2.006 1.798 NO32 N,N-dimethylhydroxylamine  N O 150.5 117.4 1.798 1.798 AO141 nitrobenzene  O C3 118.2 121.8 1.709 1.804 O33 methoxymethane  O 107.9 1.760 O34 2-isopropoxypropane  O 123.8 1.743 AO153 anisole  O C1 112.1 155.6 2.026 1.826 O35 oxydibenzene  O 115.0 2.240 O36 (oxybis(methylene)) dibenzene  O 129.2 1.762 AO37 ethoxyethene  O C2 NA 165.5 NA 1.808 AO38 (E)-1-ethoxyprop-1-ene  O C2 NA 171.3 NA 1.835 !Table I-3 (contÕd) !$"! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) AO39 2-ethoxyprop-1-ene  O C1 NA 176.9 NA 1.806 AO40 (E)-methyl  3-methoxyacrylate  O C2 NA 160.6 NA 1.787 AO41 (ethynyloxy)ethyne  C2 O 144.2 NA 1.715 NA AO42 methoxyethyne  C2 O 162.8 NA 1.717 NA AO43 (ethoxyethynyl) trimethylsilane  C2 O 175.9 NA 1.732 NA ANO44 4-methyl-3,4- dihydro-2H-1,4-oxazine  C5 N O 196.1 NA NA 1.851 NA NA NO45 morpholine  O (eq) N (ax) N (eq) 117.8 156.0 157.5 1.883 1.791 1.790 NO46 4-methylmorpholine  O N (ax) N (eq) 118.5 159.7 158.5 1.804 1.804 1.811 OP17 trimethyl phosphite  O 130.9 1.740 P 202.1 2.006 OP18 triethyl phosphite  O 135.7 1.742 P 209.1 2.013 OP19 triphenyl phosphite  O 128.1 1.846 P 198.4 2.000 AOP25 4-chlorodinaphtho[2,1-d:1',2'f][1,3,2] dioxaphosphepine  O NA Cl transfer to C1 P 181.0 1.985, 1.84 C1 152.0 1.886 !Table I-3 (contÕd) !$#! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) O47 oxirane  O 104.4 1.752 O48 cis-2,3-dimethyloxirane  O (syn) 117.6 1.738 O (anti) 119.8 1.746 O49 trans-2,3-dimethyloxirane  O 118.6 1.742 O50 trans-2,3-di-tert-butyloxirane  O 122.5 1.742 O51 trans-2,3-diphenyloxirane  O 141.4 1.743 O52 trans-2,3-dibenzyloxirane  O 124.5 1.754 OS5 2-mercapto-2-methyl          propanoic acid  O1 119.4 1.751 S 142.9 2.071 NOS6 2-amino-3-mercapto         propanoic acid  O1 107.5 1.747 S 175.6 2.070 N 139.7 1.777 OS23 S-tert-butyl  carbonochloridothioate  O 105.9 1.742 S 136.6 2.024 OP24 diphenyl(phenylsulfonyl) phosphine  O 141.7 1.739 P 198.8 2.030 OS24 (methylsulfinyl) cyclopentane  O 144.6 1.747 OS25 S-phenyl benzenesulfonothioate  O 126.6 1.744 S1 156.2 2.058 !Table I-3 (contÕd) !$$! Table I-4 Calculated HalA values for nitrogen based acceptors. Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) N1 ammonia NH3 N 132.5 1.764 N2 methanamine  N 146.7 1.773 N3 ethanamine  N 151.0 1.772 N4 propan-2-amine  N 154.3 1.772 N5 2-methylpropan-2-amine  N 156.9 1.774 N6 prop-2-yn-1-amine  N 146.1 1.773 N7 prop-2-en-1-amine  N 152.8 1.778 N8 but-3-en-2-amine  N 153.4 1.780 N9 cyclohexanamine  N (eq) 157.8 1.777 N10 aniline  N 146.8 1.865 N11 phenylmethanamine  N 157.8 1.788 N12 naphthalen-1-amine  N 153.5 2.072 N13 naphthalen-2-amine  N 152.2 2.004 AN164 2-aminobenzoic acid  N C5 150.0 168.6 1.810 1.827 N14 cyanamide  N1 93.7 1.858 N2 125.4 1.637 N15 2-aminoacetic acid  N 146.7 1.764 N16 methyl 2-aminoacetate  N 146.0 1.778 NOS6 2-amino-3-mercaptopropanoic acid  N 139.7 1.777 O1 107.5 1.747 S 175.6 2.070 NS26 benzothioamide  N 129.3 1.796 S 175.8 2.056 NO27 hydroxylamine  N 131.2 1.784 O 95.0 1.883  !$%! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) NO28 2-aminoethanol  N 153.5 1.763 O 148.2 1.725 N17 hydrazine  N 147.7 1.858 N18 ethane-1,2-diamine  N 164.2 1.758 N19 naphthalene-1,8-diamine  N 168.4 1.835 N20 guanidine  N 173.9 1.709 N21 methanesulfonamide  N 124.9 1.747 N22 Trifluoromethane sulfonamide  N 113.8 1.744 N23 4-methyl benzenesulfonamide  N 142.8 1.744 N24 dimethylamine  N 155.6 1.786 N25 diethylamine  N 161.7 1.786 N26 diisopropylamine  N 164.7 1.793 N27 di-tert-butylamine  N 164.7 1.797 N28 bis(trimethylsilyl)amine  N 162.6 1.798 N29 diphenylamine  N 151.3 1.901 N30 dibenzylamine  N 167.4 1.785 N31 N-methylprop-2-en-1-amine  N 153.7 1.780 NO31 N-methylhydroxylamine  N 142.9 1.798 O 106.7 2.006  Table I-4 (contÕd) !$&! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) N32 methylhydrazine  N1 159.0 1.870 N33 N1-methylethane-1,2-diamine  N1 171.1 1.781 N34 N1,N2-dimethylethane-1,2-diamine  N 170.9 1.782 N35 1,2-dimethylhydrazine  N 163.1 1.939 N36 1,2-diphenylhydrazine  N 161.7 2.196 AN162 benzamide  C3 N 137.2 133.0 1.808 1.763 NS26 benzothioamide  S N 175.8 129.3 2.056 1.796 NS27 thiourea  S N 169.6 NA 2.045 NA NS28 1,3-dimethylthiourea  N S NA 173.2 NA 2.056 NS29 1,1,3,3-tetramethylthiourea  S N 181.9 NA 2.059 NA NS30 1,3-diphenylthiourea  S N 180.2 NA 2.058 NA N37 aziridine  N 150.5 1.740 N38 azetidine  N 161.8 1.761 N39 pyrrolidine  N 162.3 1.770 N40 piperidine  N (ax) 162.7 1.789 N (eq) 164.3  1.785 NO45 morpholine  N (ax) 156.0 1.791 N (eq) 157.5  1.790 O (eq) 117.8 1.883  Table I-4 (contÕd) !$'! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) N41 cis-2,6-dimethylpiperidine  N (ax) 165.5 1.789 N (eq) 166.2 1.794 N42 trans-2,6-dimethylpiperidine  N (ax) 167.5 1.791 N (eq) 167.5 1.791 N43 2,2,6,6-tetramethylpiperidine  N (ax) 163.5 1.797 N (eq) 168.9 1.798 N44 7-azabicyclo[2.2.1] heptane  N 166.9 1.766 N45 indoline  N 158.8 1.869 N46 1,2,3,4-tetrahydroquinoline  N 155.4 1.832 N47 1,2,3,4-tetrahydroisoquinoline  N (ax) 162.1 1.788 N (eq) 163.9 1.786 NO26 3-hydroxy-2-(4-methylphenyl sulfonamido) butanoic acid  N 138.5 1.749 O1 137.0 1.779 N48 trimethylamine  N 160.1 1.799 N49 triethylamine  N 167.7 1.805  Table I-4 (contÕd) !$(! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) N50 triisopropylamine  N 160.4 1.834 N51 N-ethyl-N-isopropylpropan-2-amine  N 166.3 1.820 N52 tri-tert-butylamine  N 169.2 1.800 N53 triphenylamine  N 202.9 2.409 N54 tribenzylamine  N 170.1 1.794 NO32 N,N-dimethyl hydroxylamine  N O 150.5 117.4 1.798 1.798 NO55 2-(dimethylamino)ethanol  N O 161.8 158.0 1.807 1.725 N56 N1,N1,N2,N2-tetramethylethane -1,2-diamine  N 164.4 1.802 N57 1,1,2,2-tetramethylhydrazine  N 168.9 2.068 NP20 N,N,N',N',1-pentamethylphosphine diamine  N 177.8 1.792 P 219.9 2.045 N58 1-methylaziridine  N 157.4 1.758 N59 1-methylazetidine  N 164.3 1.785 N60 1-methylpyrrolidine  N 165.4 1.799 N61 1-methylpiperidine  N (ax) 165.9 1.803 N (eq) 165.1 1.804  Table I-4 (contÕd) !$)! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) N62 1-phenylpiperidine  N 161.8 1.838 NO46 4-methylmorpholine  N (ax) 159.7 1.804 N (eq) 158.5 1.811 O (eq) 118.5 1.804 ANO44 4-methyl-3,4-dihydro- 2H-1,4-oxazine  N NA NA O NA NA C5 196.1 1.851 N63 7-methyl-7-azabicyclo[2.2.1]heptane  N 169.0 1.793 AN64 7-methyl-7-azabicyclo[2.2.1] hept-2-ene  N (Cl syn to C=C) 169.0 1.796 N (Cl anti to C=C) C2 170.8 188.4 1.794 1.781 N65 quinuclidine  N 171.3 1.791 AN66 1-azabicyclo[2.2.2]oct-2-ene  C2-C3 N 152.6 168.2 1.924 1.780 N67 1,4-diazabicyclo[2.2.2]octane  N (1st-Cl) 167.5  1.796 N (2nd-Cl) 55.3  1.783 N68 1,3,5,7-Tetraazatricyclo[3.3.1.13,7] decane (HMTA)  N 169.6 1.773 NP22 1,3,5-triaza-7-phosphaadamantane  N 170.0 1.800 P 200.5 2.021 N69 1,5-diazabicyclo [4.3.0] non-5-ene (DBN)  N1 148.6 1.806 N2 184.9 1.723 N70 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU)  N1 148.9 1.816 N2 184.2 1.730 NS8 2-(1,4,5,6-tetrahydro pyrimidin-2-yl)benzenethiol  S 180.5 2.103 N1 156.4 1.793 N3 181.4 1.725  Table I-4 (contÕd) !$*! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) NP23 N-(triphenyl phosphoranylidene) aniline  N 189.3 1.773 N71 Sparteine  N 171.8 1.817 N72 1-methylindoline  N 162.1 1.876 N73 1-methyl-1,2,3,4-tetrahydroquinoline  N (pseudo-ax) N (pseudo-eq) 161.0 159.7 1.866 1.837 N74 2-methyl-1,2,3,4-tetrahydroisoquinoline  N 165.5 1.803 N75 N1,N1,N8,N8-tetramethyl naphthalene- 1,8-diamine  N 154.4 1.844 N76 N,N-dimethylaniline  N 156.8 1.843 NS7 4-(dimethylamino) benzenethiol  N 157.3 1.976 S 167.6 2.213 N77 pyridine  N 157.3 1.728 N78 2-methylpyridine  N 161.3 1.732 N79 3-methylpyridine  N 160.8 1.730 N80 4-methylpyridine  N 161.8 1.727 N81 2,6-dimethylpyridine  N 164.4 1.736 N82 2,6-di-tert-butylpyridine  N N (SM8-acetone) 150.5 126.1 1.743 1.749  Table I-4 (contÕd) !%+! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) N83 2,4,6-trimethylpyridine  N N (SM8-acetone) 168.2 148.2 1.735 1.743 N84 2,6-di-tert-butyl-4-methylpyridine  N N (SM8-acetone) 153.1 127.2 1.742 1.742 N85 2-methoxypyridine  N 161.9 1.725 N86 3-methoxypyridine  N 160.9 1.731 N87 4-methoxypyridine  N 165.2 1.725 N88 N,N-dimethylpyridin-4-amine  N1 N1 (SM8-acetone) 176.0 154.3 1.724 1.732 N2 145.7 1.823 NO24 4-hydroxypyridine  N 161.7 1.725 O 90.3 1.917 N89 4-(tert-butyl)pyridine  N N (SM8-acetone) 164.6 146.3 1.727 1.737 N90 4-phenylpyridine  N N (SM8-acetone) 165.7 145.7 1.725 1.735 N91 4-benzylpyridine  N 164.7 1.728 N92 4-bromopyridine  N N (SM8-acetone) 153.4 138.8 1.726 1.735 N93 4-chloropyridine  N 152.9 1.726 N94 4-cyanopyridine  N1 N1 (SM8-acetone) 145.2 138.0 1.725 1.737 N2 120.5 1.614 N95 4-(trifluoromethyl)pyridine  N N (SM8-acetone) 149.3 137.2 1.726 1.736  Table I-4 (contÕd) !%"! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) N96 pyridine-4-carbaldehye  N N (SM8-acetone) 150.8 140.8 1.726 1.737 N97 4-pyridyl methyl ketone  N 154.6 1.726 N98 quinoline  N 163.3 1.733 N99 isoquinoline  N 164.7 1.728 N100 pyridazine  N 154.4 1.728 N101 pyrimidine  N 146.7 1.729 N102 pyrazine  N 144.2 1.727 N103 1,3,5-triazine  N 135.0 1.725 AN104 1H-imidazole  N1 107.7 1.791 N3 159.5 1.704 C2 151.8 1.770 C4 149.9 1.792 ANP27 5-(dimethylphosphino)-1-phenyl-1H-pyrazole  P 205.9 2.036 N2 160.4 1.696 N1 NA Cl transfers to C3 C5 160.1 1.780 C4 171.2 1.805 C3 159.3 1.798 ANP28 2-(di-tert-butylphosphino)-1-phenyl-1H-pyrrole  P 217.9 2.038 N 131.8 1.830 C2 173.8 1.798 C3 177.6 1.817 C4 177.3 1.811 C5 185.6 1.793 AN105 1H-pyrrole  N1 C2 C3 122.2 169.8 162.0 1.796 1.785 1.801  Table I-4 (contÕd) !%#! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) AN106 1H-indole  N1 135.1 1.829 C2 170.1 1.801 C3 173.8 1.812 AN107 6-methoxyquinoline  N 167.0 1.734 C5 165.9 1.838 C7 153.2 1.829 C9 142.1 1.892 AN108 7H-purine  N1 154.2 1.728 N2 156.6 1.723 N3 151.7 1.702 N5 106.2 1.803 C4 128.2 1.775 ANS10 1H-pyrazolo[3,4-d]pyrimidine-4-thiol  S 132.3 2.059 N5 147.8 1.730 N7 148.2 1.723 N1 115.5 1.772 N2 140.3 1.694 ANS9 4H-1,2,4-triazole-3-thiol  S 128.7 2.086 N4 96.5 1.782 C5 145.3 1.769 N2 153.0 1.695 AN109 1H-benzimidazole  N1 122.4 1.811 C2 153.7 1.782 N3 163.0 1.703 N110 phthalazine  N 164.9 1.726 N111 1,4-dimethoxyphthalazine  N 162.7 1.731 NS36 Z)-N-(3,5-bis(trifluoromethyl) phenyl)-4-(dimethyliminio) pyridine-1(4H)-carbimidothioate  S N1 189.3 172.5 2.079 1.777  Table I-4 (contÕd) !%$! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) N112 3,5-dichloro-2,4,6-trioxo-1,3,5-triazinan-1-ide  N N (SM8-acetone) 252.1 148.1 1.715 1.715 N113 3-chloro-2,5-dioxoimidazolidin-1-ide  N 273.6 1.703 N114 3-chloro-4,4-dimethyl-2,5-dioxoimidazolidin-1-ide  N N (SM8-acetone) 275.7 168.3 1.705 1.708 N115 2,5-dioxopyrrolidin-1-ide  N N (SM8-acetone) 290.1 181.1 1.707 1.716 N116 3-oxo-3H-benzo[d]isothiazol-2-ide 1,1-dioxide  N 265.0 1.712 N117 1,3-dioxoisoindolin-2-ide  N N (SM8-acetone) 286.7 177.7 1.702 1.705 N118 chloro(tosyl)amide  N 273.3 1.778 N119 (1-carboxy-2-hydroxypropyl)(tosyl) amide  N 268.2 1.768  Table I-4 (contÕd) !%%! Table I-5 Calculated HalA values for phosphine based acceptors. Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) P1 phosphine  P 156.0 1.978 P2 phenylphosphine  P 184.6 2.012 P3 trichlorophosphine  P 142.6 1.980 P4 trimethylphosphine  P 205.9 2.015 P5 tert-butyl diisopropylphosphine  P 220.5 2.039 P6 triphenylphosphine  P 215.0 2.049 P7 tribenzylphosphine  P 215.0 2.022 P8 tri(naphthalen-1-yl)phosphine  P 221.3 2.057 P9 tri-o-tolylphosphine  P 214.5 2.055        !%&! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) P10 tris(4-methoxyphenyl) phosphine  P 227.8 2.066 P11 tris(4-chlorophenyl) phosphine  P 207.7 2.049 P12 tris(4-fluorophenyl)phosphine  P 211.3 2.051 P13 Tricyclopentyl phosphine  P 222.2 2.037 P14 tricyclohexylphosphine  P 223.5 2.046 P15 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl) disilaphosphane  P 216.7 2.091 OP16 Phosphinetriyl trimethanol  P 191.3 2.017 O 123.6 1.757 OP17 trimethyl phosphite  P 202.1 2.006 O 130.9 1.740        Table I-5 (contÕd) !%'! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) OP18 triethyl phosphite  P 209.1 2.013 O 135.7 1.742 OP19 triphenyl phosphite  P 198.4 2.000 O 128.1 1.846 NP20 N,N,N',N',1-pentamethyl phosphine diamine  P 219.9 2.045 N 177.8 1.792 NP21 N,N,N',N',N'',N''-hexamethylphosphine triamine  P 221.4 2.075 N 180.2 1.792 NP22 1,3,5-triaza-7-phosphaadamantane  P 200.5 2.021 N 170.0 1.800 NP23 N-(triphenyl phosphoranylidene)aniline  N 189.3 1.773 OP24 diphenyl(phenylsulfonyl) phosphine  P 198.7 2.030 O 141.7 1.739 AOP25 4-chlorodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine  P 181.0 1.984 O NA Cl transfers to C1 C1 152.0 1.886 NP26 5-(dichlorophosphino)-5H-dibenzo[b,f]azepine  P 175.3 2.001 N NA Cl transfers to P        Table I-5 (contÕd) !%(! Label Name Structure Binding Site Cl+ affinity kcal/mol X-Cl distance (†) ANP27 5-(dimethylphosphino)-1-phenyl-1H-pyrazole  P 205.9 2.036 N2 160.4 1.696 N1 NA Cl transfers to C3 C5 160.1 1.780 C4 171.2 1.805 C3 159.3 1.798 ANP28 2-(di-tert-butylphosphino)-1-phenyl-1H-pyrrole  P 217.9 2.038 N 131.8 1.830 C2 173.8 1.798 C3 177.6 1.817 C4 177.3 1.811 C5 185.6 1.793 AP29 tri(furan-2-yl)phosphine  P 205.5 2.046 C3 165.2 1.807 C4 154.6 1.827 C5 178.2 1.778 P30 1,2-bis(diphenyl phosphino)ethane  P 217.6 2.041 P31 1,2-bis(dichloro phosphino)benzene  P 162.2 1.988        Table I-5 (contÕd) !%)!Apart from simply being a listing of HalA (Cl) values, the data also provides the reader with useful and handy trends that can be interpreted based on their ring size, steric strain etc. Figures I-1 to I-4 illustrate a few of several such trends.  The relationship of sterics incorporated in substituted phosphines to their electron donating ability can be best described by TolmanÕs concept of cone angles.34 To represent the trend of halenium affinities in phosphines, we have employed the cone angle where the metal center is replaced by a chlorine atom (Figure I-1). As shown above, the increasing steric demand of the substituents on phosphine leads to an increased internal angle (!1) for R-P-R (P1-93.4¡ <P2-93.0¡ < P6-102.6¡ < P8-103.0¡< P5-107.4¡) eventually shifting the trigonal pyramidal geometry of the phosphine towards trigonal RPRRClRPRRCl!1Tolman's cone angle(!2)PHHH P1PHPhH P2PPhPhPh P6P5<<<P1-naph1-naph1-naph P8<Pt-Bui-Pri-PrLabel!1!2HalA (Cl)156.0184.6215.0220.5221.393.4¡93.0¡102.6¡107.4¡103.0¡48.0¡51.0¡106.1¡146.1¡123.5¡Figure I-1 The trend in HalA values of substituted phosphines. !%*!planar. Thus in sterically bulky phosphines, the R-P bond gains more ÔsÕ character leading to higher ÔpÕ character in the lone pair. A lone pair with more ÔpÕ character is less tightly bound to the nucleus and displays enhanced nucleophilicity for the free phosphine. Meanwhile, as substituent bulk increases, the strain in the larger cone angle (!2) cases of the halo-phosphonium ion opposes this effect, leading to a leveling off of the rate of increase in the HalA (Cl) values.    ClXnXnClS13S14 S15S16<<<SSSSNMeNMeNMeNMeN58N59N60N61<<<Label!"C-N-C (!)N-Cl (†)HalA (Cl)(Kcal/mol)61.4¼1.76157.490.5¼1.79164.3104.6¼1.80165.4111.7¼1.80165.9Label"C-S-C (!)HalA (Cl)(Kcal/mol)147.3155.2159.1161.547.5¼76.6¼93.7¼97.8¼Figure I-2 The trend in HalA values of cyclic sulfides and amines. !&+!A similar trend of HalA (Cl) is observed for compounds S13 to S16 and N58 to N61 (Figure I-2). With increasing ring size, the angle strain for C-N-C or C-S-C (!) is relieved. The increase in ÔpÕ character of the lone pair with increasing ring size enhances the nucleophilicity of the heteroatoms and hence their halenium affinity. In contrast, as we go from left to right the increasing ÔpÕ character of the lone pair results in a longer bond to the chlorine atom (intrinsic effect due to the geometry). This can be seen from increasing N-Cl distance in the chlorinated analogs. Among the compounds shown above, the lone pair electrons in S13 and N58 are tightly bound to the nucleus as they have the highest ÔsÕ character and hence the resulting S-Cl or N-Cl bond is the strongest.    ClCl A44136.2A45146.0A46148.4A47150.9<<< A48153.6<< A49167.4MeEti-Prt-BuPhClMeClEtCli-PrClt-BuClPhA45-ClA46-ClA47-ClA48-ClA44-ClA49-ClHalA (Cl)(Kcal/mol)ClR!2!1Label!1!267.3¼67.3¼61.8¼74.4¼60.5¼76.1¼58.7¼78.7¼54.9¼84.2¼43.6¼102.2¼1.89 †2.03 †1.86 †2.07 †1.86 †2.12 †1.85 †2.23 †1.84 †2.6 †1.82 †"+"+"+"+"+"+"+"+Figure I-3 The trend in HalA values of terminal olefins. !&"!The ascending trend of HalA (Cl) values in Figure I-3 (as anticipated) displays the increasing reluctance of chlorenium ion to form a three membered cyclic intermediate (chloriranium ion) with the increasing inductive and hyperconjugative donating effects of the substituent on the terminal olefin. Ethylene (A44) by itself forms a symmetrically bridged chloriranium ion A44-Cl. The increasing donating effect of the substituents (A45-A48) distorts this symmetry as indicated by the C-Cl distances and the bond angles !1 and !2. The phenyl ring in styrene (A49) stabilizes the chlorenium ion via resonance electron donation. The delocalization of this positive charge results in the corresponding chloromethyl carbenium ion A49-Cl.26, 35 In the next example (Figure I-4) forming a chlorenium ion adduct of the below cycloalkenes leads to re-hybridization of the olefinic carbons from sp2 ("C-C=C = 120¡) to hybridization between sp2 and sp3 (similar to oxirane carbons). The initial strain introduced due to the presence of olefinic carbons (in the parent cycloalkene) can be relieved to a certain extent if the concomitant re-hybridization in its chlorenium adduct leads to a bond angle (!2) that is close to the corresponding bond angle (!) in the parent cycloalkane. As shown above, the HalA values of the cycloalkenes increase with the ring size, except for A88 and A89. Cyclopropene (A86) incorporates a higher ring strain and angular strain !1 = 64.6¡ (55.4¡ deviation from the normal bond angle of 120¡ for an sp2 carbon). Formation of the chlorenium ion adduct A86-Cl, alleviates this strain to a certain extent as !2 (61.7¡) !&#!approaches the natural bond angle in cyclopropane (! = 60.0¡) via partial hybridization of the sp2 carbons. Though cyclobutene undergoes similar changes in its bond angles upon formation of A87-Cl, it has a relatively higher HalA. A switch in the trend of HalA (Cl) values is observed for cyclopentene (A88) and cyclohexene (A89). Their orbital energies being similar, the only difference arises due to the change in angle strain upon formation of A88-Cl and A89-Cl. The resulting hybridization in A88-Cl brings !2 (109.2¡) closer to the bond angle in the parent cyclopentane (! = 103.3¡, !2 Ð! = 5.9¡) in comparison to formation of A89-Cl, which results in elevated angle strain as !2 (120.8¡) deviates further from cyclohexane (! = 111.5¡, !2 Ð! = 9.3¡). Finally, as !1 increases with increasing ring size (!1-A91), the corresponding change in the geometry of the olefin escalates its nucleophilicity. <<<<<ClClClClClClClA89-ClA90-ClA91-ClA86-ClA87-ClA88-ClHalA (Cl)(Kcal/mol)Cl!1!2(  )n(  )n!1!2A86141.1A87147.9A88155.5A89154.8A90156.9A91159.264.6¼61.7¼94.4¼91.9¼112.1¼109.2¼123.5¼120.8¼128.0¼125.2¼131.5¼130.1¼HOMO(LUMO)-9.6 eV(4.9 eV)-9.4 eV(5.1 eV)-9.1 eV(5.2 eV)-9.1 eV(5.2 eV)-9.1 eV(5.1 eV)-9.1 eV(5.0 eV)! for parent cycloalkane60.0¼89.4¼103.3¼111.5¼~116.0¼~117.0¼Figure I-4 The trend in HalA values of cycloalkenes. !&$!I-4 Experimental analysis of HalA parameter I-4-A General Procedure Halenium sources used in this study: N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) and N-chlorophthalimide (NCP) were re-crystallized prior to use. Chlorodiethylsulfonium hexachloroantimonate (CDSC), bromodiethylsulfonium bromopentachloroantimonate (BDSB), iododiethylsulfonium iodopentachloroantimonate (IDSI) were synthesized as reported previously.36 Substituted pyridines were distilled and stored over KOH prior to use (except 4-bromopyridine which was distilled immediately after basification of its commercially available HCl salt and used right away). All other commercially available reagents and solvents were used as received unless otherwise mentioned. I-4-B Screening of chlorenium sources for the formation of chloropyridinium complexes of 1a In order to determine how well experimental results agree with the theoretically predicted HalA values, we initiated studies on the possibility for the formation of chloropyridinium complexes via 1H NMR. These salts have been well characterized and reported as potent halenium sources. The corresponding bromenium and iodenium salts are stable even at room temperature,37-44 and the chlorenium analogs, though unstable to isolation, !&%!have been characterized and observed via ESI studies.45 Substituted pyridines (1) were chosen as halenium acceptors for preliminary 1H NMR studies (see Figure I-5). Treatment of 1 (acceptor) with chlorenium sources (Cl+ donors) forms the chloro-pyridinium ion (1-Cl) with expulsion of the donor counter ion. For such a transfer of halenium ion to proceed, the HalA (Cl) of 1 should be higher than that of the corresponding donor counter ion.  In this respect, 2,4,6-trimethylpyridine 1a was initially chosen as a model substrate and acetone-d6 was identified as the optimum solvent of choice. The corresponding halo-pyridinium salts of 1a displayed low solubility in other commercially available deuterated solvents. Halo-pyridinium salts of Figure I-5 aTheoretically estimated relative HalAÕs for pyridine 1a in comparison to the counterions of commonly employed chlorenium sources (B3LYP/6-31G*/SM8 acetone).  NOO32.8NNOOCl20.1NNNOClClOONOO29.5-0.1or!HalAa (Cl) Kcal/molHalenium IonAcceptorsN0.0(197.5)NRDonorClNRDonorClNRDonorClNRDonorCl1a11-Cl11-Cl(i)(ii)ABCD!&&!1a were found to be soluble in tetrahydrofuran-d8 (THF), but this solvent was prohibitively expensive for the large number of planned experiments. Furthermore, the possibility of chlorination of acetone under reaction conditions was ruled out based on three control experiments (see Section I-4-J for further discussion), thus assuring that acetone is not a reactive solvent. Figure I-5 depicts the theoretical HalA (Cl) values for counter ions of commonly employed chlorenium sources in comparison to 1a. Based on these estimates, the equilibrium for reaction (i) should favor the reactant side as the anions A-C have a significantly higher HalA than 1a.  Furthermore, based on the estimated HalA for the least nucleophilic anion D, the chlorenium ion is probably shared (but not completely transferred) between 1a and anion D. To verify these predictions, 1a was treated with the corresponding halenium sources and the interactions were assessed via the downfield 1H NMR shift of the C3-H resonance.  As a gauge to experimentally predict the extent of halenium ion transfer, we referred to the observed chemical shift difference between the free base-1a (C3-H at 6.82 ppm) and its protonated salt 1a-H (C3-H at 7.66 ppm) in acetone-d6 (#ppm = 0.84) at room temperature (Note: To ensure a fair comparison between the protonated and chlorinated pyridiniums, the same counter anion-SbCl6# was employed). Figure I-6 shows the experimental 1H NMR spectrum of 1a (spectrum a) upon treatment with stoichiometric amounts of different chlorenium ion sources (spectra b-f). !&'!Spectra b-d clearly shows that pyridine 1a with a HalA (Cl) = 197.5 Kcal/mol is incapable of abstracting a chlorenium ion from commonly employed imide based chlorenium donors (such as NCS, DCDMH, and NCP) whose counterions have higher HalA (Cl) values (i.e. >197.5 Kcal/mol). Even TCCA, the most potent chlorenium source among the imide based chlorenium donors, results in only a 0.1 ppm downfield shift of C3-H of 1a indicating halogen bonding (tight Van der Waals complex) rather than complete chlorenium ion transfer (see spectrum e).45 Since reaction of neutral species to form ionic products would always be energetically uphill in an organic solvent, transfer of chlorenium ion to 1a calls for the use of a cationic chlorenium reagent (see reaction (ii), Figure I-5). With this aim, CDSC, whose conjugate leaving group has a lower estimated HalA (Cl) value (161.3 Kcal/mol, gas phase) than 1a was employed (Note: B3LYP/6-31G*/SM8 is not compatible for the antimony (VI) chloride counterion associated with CDSC. Hence we resorted on comparison of gas phase HalA (Cl) values of diethyl sulfide and 1a. Gas phase HalA (Cl) value of 1a is 168.2 kcal/mol whereas diethyl sulfide estimates HalA value of 161.3 kcal/mol). Chlorodiethylsulfonium antimony (V) hexachloride (CDSC),36 proved to be the most effective chlorenium ion source in the formation of 1a-Cl. The resulting chlorpyridinium 1a-Cl, displayed a downfield shift of C3-H at 7.69 ppm (#ppm = 0.87). This reagent effects the formation of 1a-Cl as indicated by the 0.9 ppm downfield shift of C3-H of 1a (spectrum f) ensuing a complete transfer of !&(!the chlorenium ion to 1a (Note: We were aware of the possibility that treatment of pyridines with halenium sources in acetone may lead to protonation (rather than chlorination) of the pyridinium nitrogen atom yielding $-chloroacetone as a byproduct. This possiblity was ruled out based on our control experiments that will be discussed in  full details in Section 1-4-J).46 These experimental results complement the theoretical HalA predictions. I-4-C Titration of chloropyridinium complex 1a with various halenium sources The formation of halo-pyridinium complex (1a-X) was also monitored by observing the chemical shift (ppm) change of the C3-H aromatic hydrogens of 1a upon titraion with various amounts of halenium sources (X+)  (Figure I-7). Halenium ion sources such as NCS, NCP, dichloramine-T and TCCA with HalA values lower than 1a did not fully transfer halenium ion to 1a, whereas XtalFluor-E¨, CDSC, BDSB, and IDSI did form the halo-pyridinium salts. A significant downfield shift of C3-H is evident when 1.0 equivalent of the latter halenium sources are added to 1a (since the extent of positive charge localized on the pyridine nucleus is the same in the halo-pyridinium salts 1a-F, 1a-Cl, 1a-Br and 1a-I, the extent of downfield chemical shift observed for C3-H was also the same upon addition of 1.0 equiv of halenium sources). No further observable change in the chemical shift of C3-H (of 1a-Cl) were observed as the titration is extended beyond 1.0 equiv of the halenium source (indication for the formation of 1:1 complex). Based on the !&)!HalA values, like NCS, DCDMH, dichloramine-T, and N-chlorophthalimide sources (Figure I-6), TCCA and DAST do not have the ability to completely transfer X+ ion, resulting only in stronger halogen bonding that leads to a 0.16 Figure I-6 Overlay of 1H NMR (500 MHz, acetone-d6) spectra (a-f). Spectrum a represents a section of 1H NMR displaying the C3-H of 1a, whereas overlay of spectra b-f represents the same section of spectrum upon treatment of 1a with different chlorenium sources. NCS (N-chlorosuccinimide), DCDMH (1,3-dichloro-5,5-dimethylhydantoin), NCP (N-chlorophthalimide), TCCA (trichloroisocyanuric acid), CDSC (chlorodiethylsulfonium antimony (VI) chloride). a. b. c. d. e. f. 2,4,6-trimethylpyridine- (1a) C3-H (1a) + 1.0 equiv. NCS (1a) +  1.0 equiv. DCDMH  (1a) +  1.0 equiv. NCP  (1a) +  1.0 equiv. CDSC  (1a) +  1.0 equiv. TCCA  NNOOClNNOOClNNNOOClClNNNOClClOONClNH6.82 ppm1aNH7.69 ppmCl1a-ClS!&*!and 0.34 ppm downfield shift of C3-H, respectively (Figure I-7).  Addition of up to 5.0 equiv of TCCA (i.e. 15.0 equiv of active chlorenium ion) did not shift C3-H further downfield. However, with this excess of halogenating reagent, new peaks appeared in the aromatic region of the 1H-NMR spectrum, suggesting side reactions such as benzylic chlorination. EI-MS studies on the crude mixture displayed masses for mono, di- and tri-chlorinated 1a. Radical chlorination of the aromatic ring can be ruled out since the same product was obtained when the experiment was repeated in the dark.  !'+! 2,4,6-trimethylpyridine- (1a) C3-H (1a) + 0.3 equiv. CDSC (1a) + 0.5 equiv. CDSC (1a) + 0.7 equiv. CDSC (1a) + 0.9 equiv. CDSC (1a) + 1.0 equiv. CDSC a. b. c. d. e. f. NMeMeMeX+ sourceacetone-d6NMeMeMeXHH6.82 ppm7.69 ppm1a1a-ClFigure I-7 Spectra a-f depict 1H NMR data for titration of 1a with CDSC. The plot below shows change in chemical shift of C3-H of 1a upon titration with different halenium sources. CDSC (chlorodiethylsulfonium antimony (VI) chloride), BDSB (bromodiethylsulfonium antimony (VI) halide), IDSI (iododiethylsulfonium antimony (VI) halide), XtF (Xtalfluor-E¨).  6.877.27.47.67.800.511.521a + CDSC1a + BDSB1a + IDSI1a + TCCA1a + DAST1a + XtFChemical Shift (C3-H ppm, 1a)Equiv of Halenium SourceSClSbCl6SBrSbCl5BrSISbCl5INNNOOOClClClNSFFFNSFFBF4CDSCBDSBIDSITCCADASTXtF!'"! NCS, DCDMH, NCP, TCCA, and dichloramine-T, and have 121.9, 107.5, 118.5, 83.9, and 105.1 (kcal/mol) higher gas phase chlorenium affinities than trimethyl pyridine, respectively (Table I-6, entries 3-7). These large differences are corroborated by the experimental data and explain why the corresponding halo-pyridinium complexes are not formed. In organic solvents, conversion of neutral species into charged products is typically uphill in energy, so the conjugate anion of the halenium ion donor will always be more potent acceptor than 1a. Thus, it is no surprise that chlorenium ion transfer from neutral donors to substituted pyridines to yield halo-pyridiniums is unlikely. Therefore, for all subsequent experiments, CDSC was employed as the chlorenium donor, BDSB as the Br+ donor and IDSI as the I+ donor; the corresponding gas phase HalA values (gas phase) are 161.3, 133.2, and 96.7 kcal/mol, respectively (Table I-6, entries 8-10).  Table I-6 Absolute and relative HalA values (gas phase) of 1a in comparison to different halenium sources. Since SM8 is not compatible for elements >Kr, the gas phase HalA values are depicted for comparison of the halenium (F, Cl, Br and I) sources. Entry Halenium source Halenium Ion (X) HalA (X) of 1a (kcal/mol) HalA (X) of halenium ion source (kcal/mol) !HalA  (kcal/mol) 1 DAST F+ 288.8 432.2 143.4 2 XtF F+ 288.8 294.7 5.9 3 NCS Cl+ 168.2 290.1 121.9 4 DCDMH Cl+ 168.2 275.7 107.5 5 NCP Cl+ 168.2 286.7 118.5 6 Dich-T Cl+ 168.2 273.3 105.1 7 TCCA Cl+ 168.2 253.0 84.8 8 CDSC Cl+ 168.2 161.3 -6.9 9 BDSB Br+ 179.4 133.2 -46.2 10 IDSI I+ 141.1 96.7 -44.4 !!'#!I-4-D Titration studies of pyridine derivatives with CDSC Apart from 1a, several substituted pyridines with varying electronic and steric profiles were subjected to similar analysis using fluorenium, chlorenium, bromenium and iodenium sources to further evaluate HalA estimations. Substituted pyridines 4-phenylpyridine (1h), 4-cyanopyridine (1f), pyridine 4-carbaldehyde (1i), 4-trifluoromethylpyridine (1e), and 4-dimethylaminopyridine (1j) were titrated with CDSC (0.0-2.0 equiv) in acetone-d6 at room temperature (Figure I-8). In all these cases the formation of a 1:1 complex of Lewis base:halenium ion was confirmed via 1H NMR analysis!The range of HalA (Cl) values (gas phase) for these pyridines spans from 145.2 to 176.0 kcal/mol. B3LYP/6-31G*/SM8 is not compatible for the antimony (VI) chloride counterion associated with CDSC, hence we resorted to comparing gas phase HalA (Cl) values of diethyl sulfide and substituted pyridines. The gas phase HalA (Cl) values are 161.3 for diethyl sulfide and 168.2 for 1a. Figure I-8 depicts the downfield shifts of the pyridinesÕ C3-H resonances as they are titrated with CDSC (0.0-2.0 equiv), forming chloro-pyridinium complexes. In all cases the formation of a 1:1 complex of Lewis base:halonium ion was confirmed on the basis of the unchanged chemical shifts of C3-H beyond addition of a stoichiometric equivalent of CDSC. [Note: The titration of 1f with CDSC was studied under diluted conditions (less than 10 mM solutions). An unknown complex (with fixed chemical shifts of 8.8, and 9.8 ppm) was formed at higher concentrations upon CDSC titration. The !'$!unknown complex formed at higher concentrations could be removed upon dilution but did not change over time.]  As Table I-7 shows, halenium ion transfer to substituted pyridines can be easily monitored from the downfield chemical shift change of the aromatic proton (meta proton, C3-H). The most electron rich pyridine 1j (DMAP) shows an attenuated shift as a result of the electron donating C4-N,N-dimethylamine, which prior to chlorenium transfer alters the chemical shift of the C3-H significantly in comparison to other substituted pyridines.  The observed chemical shift change between the free pyridine derivatives and their protonated analogs (~1 ppm downfield), closely matches those observed upon treatment of pyridine derivatives 1a-j with 1.0 equiv of Figure I-8 Plot for titration of pyridines 1a-i with various CDSC representing the chemical shift change of C3-H (ppm) as a function of added CDSC. The biphasic nature of the data for the titration of 1a is illustrated by two straight lines.   NCDSCacetone-d6NClR1R1NMeMeMe1aNCF31eNCN1fNPh1hNCHO1iNN1j6.577.588.5900.511.521a1h1f1i1e1jChemical Shift (C3-H ppm)Equiv of CDSC!'%!CDSC. This clearly suggests complete chlorenium atom transfer to the nitrogen in all these pyridines to form the corresponding chloropyridinium salts. However, the exact chemistry of Cl+ delivery by CDSC is not completely understood. The range of HalA (Cl) values (SM8-acetone) for the pyridines in Table I-7 spans from 137.2 to 154.3 kcal/mol, while that simply calculated for diethyl sulfide is 151.6, yet as noted above, complete chlorenium transfer is clearly indicated by the NMR results. Exploratory studies for providing explanations to probe the differential ion pairing of the SbCl6Ð counterion with Et2SCl+ versus the chloropyridinium cations are not possible presently since the SM8 solvent model included in the Spartan code does not extend to antimony. Hence, we focused our analysis on comparisons of the HalA values within the same class (i.e. the pyridine derivatives in this case) of Lewis bases.  Table I-7 Absolute and relative HalA values in kcal/mol obtained from gas phase and (SM8-acetone) calculation of pyridine derivatives 1a-j in comparison to diethyl sulfide-mimicking CDSC.a The "HalA values displayed below represent the difference in HalA (Cl) values between the pyridine derivatives and diethyl sulfide. The HalA value of diethyl sulfide is 161.3 kcal/mol (gas phase) and 151.6 kcal/mol (SM8-acetone). Entry Pyridine derivatives HalA  gas phase  HalA SM8-acetone !HalA  gas phase  !HalA  SM8-acetonea !ppm  (C3-H) 1 1j (4-NMe2) 176.0 154.3 14.7 2.7 0.576 2 1a (2,4,6-trimethyl) 168.2 148.2 6.9 -3.4 0.868 3 1h (4-Ph) 165.7 145.7 4.4 -5.9 0.936 4 1i (4-CHO) 150.8 140.8 -10.5 -10.8 0.921 5 1f (4-CN) 145.2 138.0 -16.1 -13.6 1.048 6 1e (4-CF3) 149.3 137.2 -12.0 -14.4 1.050 !!'&!I-4-E Qualitative analysis of competition experiments between pyridine derivatives To validate the HalA scale in a more conclusive manner, the equilibrium of various substituted chloropyridiniums were investigated (Table I-8). In a typical experiment, a stock solution of CDSC (1.0 equiv) was added at room temperature to an acetone-d6 solution of pyridine A (1.0 equiv), which has a lower calculated HalA than diethyl sulfide. Complete formation of the chloro-pyridinium complex (A-Cl) was then confirmed by 1H NMR analysis. To this complex (A-Cl), pyridine B (1.0 equiv), chosen to have a higher calculated HalA value than A, was added to generate B-Cl via abstraction of chlorenium ion from A-Cl. The established equilibrium was then analyzed via 1H-NMR analysis. The amount of each chlorinated pyridine derivative was determined by examining the chemical shift change of C3-H and correlating it with the titration data of each substituted pyridine with CDSC (Figure I-8). For example, in the competition between 1e and 1a, C3-H for 1e-Cl under the equilibrium mixture resonates at 8.27 ppm. Using linear interpolation based on the biphasic behavior seen between the limiting chemical shifts observed in 1H NMR for unchlorinated and chlorinated pyridines in titrations with CDSC, this shift indicates that 0.35 mol fraction of 1e is chlorinated. Similarly, C3-H of 1a, resonating at 7.67 ppm correlates to a 0.80 mol fraction of 1a. (Note: the sum of the individual mole fractions is over 100% (0.35 + 0.80 = 1.15); this can be attributed to the fact that the actual chemical shift observed for !''!C3-H under sub-stoichiometric amounts of halenium source is influenced by dimerization). Table I-8 shows the fraction of chlorinated pyridine A and B, extracted from the titration curves in Figure I-8 based on the changes in the chemical shifts of C3-H aromatic proton of the substituted pyridines. This shows a correlation between the calculated chlorenium affinities and experimental results. As anticipated, pyridine B with higher HalA value yields a greater ratio of BCl:B. This is a fair qualitative comparison to display the transfer of chlorenium ion from pyridine A (with a relatively lower HalA) to pyridine B exhibiting a relatively higher HalA value. Pyridine derivative 1a has 18.9 and 23.0 kcal/mol higher HalA than 1e and 1f, respectively, and thus the chlorenium ion is mostly transferred to 1a (with 0.80 equivalents chlorinated, Table I-8, entry 1 and 2). The smallest difference in the fraction of chlorinated complex is observed between 1f and 1e (0.56 versus 0.52, Table I-8, entry 3). This is in complete agreement with the HalA values of the two pyridines. HalA (Cl) of 1f is 138.0 kcal/mol and HalA (Cl) of 1e is 137.2 kcal/mol. These experiments qualitatively display the correlation between theoretically calculated HalA values and the fraction of chlorinated pyridine observed by 1H NMR. However, these experimental results cannot be used for quantitative analysis. As shown in Figures I-7 and I-8, the titration curves are nonlinear prior to addition of full stoichiometric equivalent amounts of halenium ion sources (CDSC, BDSB and IDSI), clearly suggesting the possibility of dimerization. This dimerization was confirmed when treatment of !'(!1a with 0.5 equivalents of BDSB (or IDSI) in CDCl3 displayed a downfield shift of the C3-H to 7.2 ppm. The extent of this shift is in accordance with the reported halogenated dimers of 1a.40 The tendency of halo-pyridinium to undergo dimerization with the free base when subjected to sub-stoichiometric amounts of halenium source limits quantitative analysis.37 Moreover, the rapid exchange of chlorenium ion between the chlorinated and non-chlorinated acceptors does not allow for a direct measure of the quantity of each species via integration.    Table I-8 Absolute and relative HalA values in kcal/mol (SM8-acetone) of pyridine derivatives 1a-j.  Entry Pyridine derivatives (A) HalA (kcal/mol) of pyridines (A) (ACl/A) Pyridine derivatives (B) HalA (kcal/mol) of pyridines B (BCl/B) 1 1e (4-CF3) 137.2 0.35 1a (2,4,6-trimethyl) 148.2 0.80 2 1f (4-CN) 138.0 0.37 1a (2,4,6-trimethyl) 148.2 0.80 3 1f (4-CN) 138.0 0.52 1e (4-CF3) 137.2 0.56 4 1e (4-CF3) 137.2 0.04 1j (4-NMe2)  154.3 0.75 5 1a (2,4,6-trimethyl) 148.2 0.29 1j (4-NMe2) 154.3 0.79 6 1i (4-CHO) 150.8 0.29 1h (4-Ph) 165.7 1.0 7 1h 165.7 0.28 1a 168.2 0.70 !!')!I-4-F Quantitative analysis of competition experiments between pyridine derivatives Experiments discussed earlier qualitatively display the correlation between theoretically calculated HalA values and the fraction of chlorinated pyridine observed by 1H NMR. However, these experimental results cannot be used for quantitative analysis. Quantitative HalA determination via 1H NMR analyses of previous pyridines (Figure I-8 and Table I-8) was complicated by the tendency of halopyridinium ion 1a-Cl to undergo dimerization with the free base 1a when subjected to sub-stoichiometric amounts of halenium source.37 The dimerization of halo-pyridiniums with the free base when subjected to sub-stoichiometric amounts of halenium source limits the quantitative analysis.37, 40 Moreover, the rapid exchange of chlorenium ion between the chlorinated and non-chlorinated acceptors leads to an averaged NMR signal, which does not allow for a quantitative measurement of each species via integration. Figure I-7 displays the plot for the observed 1H NMR chemical shift (average of 1a and 1a-X) for C3-H when 1a was titrated with different halenium sources (see plot). As seen from the overlay of 1H NMR spectra a-f, due to rapid exchange and possible dimerization, 1a and 1a-Cl could not be observed as individual species on the NMR timescale.  To rigorously validate HalA assessments on a quantitative scale, we resorted to equilibrium studies of sterically hindered chloropyridinium salts. We overcame this limitation by using pyridines 1b (2,6-di-tert-butyl pyridine) !'*!and 1c (4-methyl-2,6-di-tert-butyl pyridine) for equilibrium studies of 1:1 complexes with CDSC as a chlorenium source. The bulky t-butyl substituents in the ortho positions efficiently inhibit the dimerization as well as rapid intermolecular transfer of halenium ions. With this system in hand, we were able to block pyridine-halogen-pyridine dimerization and the fast exchange of halenium ion in order to observe the chlorinated and non-chlorinated species under NMR timescale. I-4-F1 1H-NMR analysis of chlorination of 4-methyl-2,6-di-tert-butyl pyridine (1c) We observed that under sub-stoichiometric amounts of the halogenating reagent, the chlorinated pyridinium (1c-Cl) and the free base (1c) can be observed as distinct species at low temperatures via 1H NMR in acetone-d6. Addition of 0.5 equiv of CDSC to 1c in acetone-d6 at room temperature led to the observation of two species (broad peaks) by 1H NMR at room temperature (Figure I-9). Lowering the temperature to -30 ¡C, resulted in two sharp peaks corresponding to 1c and chlorinated 1c-Cl in a 1:1 ratio.  !(+! This enables the integration of each individual species (free base and its chlorinated analog) such that the ratios of chlorinated and non-chlorinated counterparts could be obtained. This demonstrates that 1c has a slow exchange with its chlorinated form (1c-Cl) under the NMR timescale; thus enabling the observation of the chlorinated pyridine and its free base by 1H-NMR analysis at -30 ¡C. The bulky t-butyl substituents on the ortho positions efficiently inhibited the dimerization and the rapid intermolecular transfer of halenium ions.  Figure I-9 1H NMR spectra of 1c at different temperatures under substoichiometric amounts (0.5 equiv) of CDSC. 1c-Cl(C3-H)1c(C3-H)25 ¼C0 ¼C-15 ¼C-30 ¼CNMeNClSbCl6Meacetone-d6T ¼CSClSbCl6SCDSC(0.5 equiv)1c(1.0 equiv)1c-Cl!("!I-4-F2 Titration of pyridine 1c with various amounts of CDSC Pyridine 1c was then titrated with CDSC to measure the ratios of 1c and 1c-Cl at -30 ¡C. Figure I-10 shows the overlay of 1H NMR spectra (C3-H) with different amounts of CDSC. The resonance at 7.03 ppm corresponds to the free base, while the downfield peak at 7.96 ppm corresponds to 1c-Cl. Upon addition of 1.0 equiv of CDSC, the resonance at 7.03 ppm disappears, and only 1c-Cl is observed (7.96 ppm, Figure I-10, entry 6). This further demonstrates that the chlorenium is fully transferred to the pyridine. As expected, by adding 0.3 or 0.5 equiv of CDSC, 30% and 50% of the pyridine is chlorinated, respectively (found by integration of both peaks at 7.03 ppm (1c) and 7.96 ppm (1c-Cl)). This trend continues up to 1.0 equiv of CDSC, and remains constant after that.  !(#! I-4-F3 Titration of pyridine 1c with various halenium sources Since 1c and 1c-Cl can be observed as separate entities under the NMR timescale at -30 ¡C, we initiated similar studies with different halenium Entry CDSC (equiv) 1c (%) 1c-Cl (%) 1 0.0 100 0.0 2 0.3 69.0 30.0 3 0.5 53.0 50.0 4 0.7 31.0 70.0 5 0.9 3.0 90.0 6 1.0 0.0 100 7 1.5 0.0 100 8 2.0 0.0 100 !1c-ClNMeCDSCacetone-d6-30 ¼CNMeClSbCl61c1c-Cl1c00.30.50.70.91.01.52.0equiv CDSCFigure I-10 Titration data for chlorination of 1c with CDSC. !($!sources to observe the formation of 1c-X and validate the theoretical HalA estimates. The counter anions of DAST and TCCA have a higher HalA than 1c (Table I-9, entries 1 and 3) therefore, as anticipated, 1H NMR showed no evidence of their transferring halenium ion. Similarly, as expected from the HalA values, only CDSC, BDSB and IDSI led to a complete transfer of halenium ion to 1c forming the corresponding halo-pyridinium salts (Table I-9, entries 4-6).   Table I-9 Absolute HalA values and experimentally observed ratios of 1c and 1c-X using different halenium ion sources. Since SM8 is not compatible for elements >Kr, the gas phase HalA values are depicted for comparison of the halenium (F, Cl, Br and I) sources.   Entry Halenium source Halenium ion (X) HalA (X) of 1c gas phase (kcal/mol) HalA of Halenium source gas phase (kcal/mol) (1c-Cl)% 1 DAST F+ 287.9 432.2 0.0 2 XtF F+ 287.9 294.7 47.0 3 TCCA Cl+ 153.1 253.0 0.0 4 CDSC Cl+ 153.1 161.3 100 5 BDSB Br+ 160.4 133.2 100 6 IDSI I+ 118.4 96.7 100  !(%!I-4-G Quantitative analysis via competition experiments between 1a and 1c The optimized conditions mentioned previously were employed to study the competition for chlorenium ion capture between 1a and 1c. Since, 1a has a 15.0 kcal/mol higher chlorenium affinity than 1c, halenium ions should preferentially bind to 1a over 1c with an equilibrium constant > 1010. As shown by the 1H-NMR spectra overlay (Figure I-11), titration of the pre-formed 1c-Cl complex with 1a leads to a corresponding decrease in the concentration of 1c-Cl as the chlorenium ion is now transferred onto the stronger Lewis base 1a (intensity of the peak at 8.06 ppm for 1c-Cl decreases while the intensity of the peak at 7.06 ppm which corresponds to free 1c, increases). This is illustrated in Figure I-12 as a plot of the fraction of 1c-Cl and 1a versus the number of equivalents of 1a added. Moreover, a careful inspection of Figure I-11 indicates a downfield shift of the chlorinated species 1a-Cl and 1c-Cl until the mixture is titrated with 1.0 equiv of 1a, a Lewis base capable of undergoing dimerization (as discussed earlier). The fraction of 1c-Cl listed in Figure I-12 is derived from the integration of these two peaks corresponding to 1c and 1c-Cl. Formation of 1a-Cl is also revealed by the downfield shift of C3-H of 1a. The fraction of 1a-Cl (Figure I-12) is derived by correlating its observed chemical shift to its titration data (Figure I-7).   !(&! acetone-d6NClSbCl6NMeMeMeNNClSbCl6MeMeMe1a1c-Cl(1.0 equiv.)MeMe1c-Cl1a-Cl-30 ¼C00.50.71.01.5equiv 1a1a/1a-Cl1c1c-ClFigure I-11 Quantification of HalA assessment via competitive chlorination between 1c and 1a.  Entry 1a (equiv) (1c-Cl) % (1a-Cl) % 1 0.0 100 0.0 2 0.5 67.0 37.0 3 0.7 44.0 58.0 4 1.0 16.0 85.0 5 1.5 0.0 100 !-2002040608010012000.20.40.60.811.21.41.61c-Cl1a-ClMol Fraction (%) of 1a-Cl or 1c-ClEquiv of 1aFigure I-12 Plot for mol fraction (%) of 1a-Cl and 1c-Cl vs equiv of 1a added (Left). Table Data for titration of 1c-Cl with 1a (right). HalA (Cl)1c = 127.2 kcal/mol (SM8-acetone). HalA (Cl)1a = 148.2 kcal/mol (SM8-acetone). !('!Note: Although our NMR analysis conditions were chosen to minimize exchange and dimerization of 1c and 1c-Cl, the formation of hetero-dimers of 1c-Cl with free 1a is possible, and dimerization of 1a with 1a-Cl certainly occurs even under low temperature condition in the presence of sub-stoichiometric amounts of halenium ion source. I-4-H Quantitative analysis via competition experiments between sterically hindered pyridines The validation of theoretically calculated HalA values was performed through a competition experiment between sterically hindered pyridines 2,6-di-tert-butylpyridine (1b) and 4-methyl-2,6-di-tert-butylpyridine (1c). Steric hindrance of these pyridines removes any chances of pyridine-halogen-pyridine dimerization. A slow exchange between pyridines and their chlorinated species in 1H NMR time-scale, allow us to distinguish both pair of chlorinated 1b-Cl and 1c-Cl from non-chlorinated species 1b and 1c at -90 ¡C in acetone-d6. Figure I-13 shows the stacked 1H-NMR spectra at different equivalents of 1c. As the spectra show, addition of the stronger Lewis base 1c depletes 1b-Cl, confirming the equilibrium shift anticipated by HalA calculations. The fraction of free bases 1b and 1c was derived simply by integration of the corresponding peaks at 7.06 (1c) and 8.06 (1c-Cl) ppm, and the C3-H resonances of 1b and 1b-Cl at 7.24 and 8.16 ppm, respectively; whereas the corresponding C4-H could be observed at 7.69 and 8.73 ppm.  !((!When an equimolar mixture of 1b and 1c was treated with 1.0 equiv of CDSC, an equilibrium mixture of 1c-Cl and 1b-Cl (in a 7.3:1 ratio, Table I-10, entry 8) was observed by 1H-NMR. As anticipated, the gas phase HalA values predict 1c to have a slightly increased Lewis basicity as a result of the 4-Me acetone-d61b-Cl(1.0 equiv.)1b1c-Cl-90 ¼CNClSbCl6NNClSbCl6Me1cNMeFigure I-13 Overlay of 1H NMR spectra displaying the titration of 1b-Cl with 1c. equiv 1c1.51.00.70.50.201b-Cl(C4-H)1b-Cl(C3-H)1c-Cl(C3-H)1b(C4-H)1b(C3-H)1c(C3-H)!()!substituent (#HalA = 2.6 Kcal/mol). For a better quantitative representation, an SM8 model for simulated acetone was applied which attenuated the difference in their HalAÕs to 1.1 Kcal/mol. The experimental result is in good agreement with the theoretical HalA predictions (#HalA = 1.1 Kcal/mol; Table I-10 Data for titration of 1c-Cl with 1b. HalA (Cl)1c = 127.2 kcal/mol. HalA (Cl)1b = 126.1 kcal/mol (B3LYP/6-31G*/SM8-acetone). Entry 1c (equiv) (1b-Cl)% (1c-Cl)% 1 0.0 100 0.0 2 0.2 82.0 100.0 3 0.3 69.0 97.0 4 0.5 58.0 98.0 5 0.6 37.0 93.0 6 0.7 36.7 95.0 7 0.9 19.8 86.2 8 1.0 12.0 88.0 9 1.5 0.0 56.0 !02040608010012000.20.40.60.811.21b1cMol Fraction (%) of 1b-Cl or 1c-ClEquiv of 1cFigure I-14 Plot for mol fraction (%) of 1b-Cl and 1c-Cl vs equiv of 1c added. !(*!predicting a 7.3:1 ratio). The fraction of chlorinated 1b and 1c were plotted against the equivalents of added 1c (Figure I-14). This study not only validates quantification via HalA but also highlights its value in predicting the outcome of reactions involving subtle steric and electronic changes.  The competition reaction between 1b and 1c was repeated at different temperatures (ranging from -90 ¡C to -30 ¡C) to probe the effect on chlorenium ion transfer. Table I-11 displays the fraction of chlorinated 1b and 1c at different temperatures (listed HalA values were calculated using the SM8 model to simulate acetone). The calculated !HalA values decrease upon lowering the temperature, which is in agreement with the experimental results (fraction of 1c that is chlorinated drops from 88.0 at -30 ¡C to 83.0 % at -90 ¡C). Note that a slight excess of chlorenium donor is reflected in the >100% sum of these percentages. Table I-11 Effect of temperature on equilibrium ratios of 1b-Cl and 1c-Cl in presence of their free bases 1b and 1c.  Entry Temperature (¡C) !HalA (kcal/mol) at T ¡C (1b-Cl)% (1c-Cl)% 1 -30 1.104 17.0 88.0 2 -50 1.094 20.0 87.0 3 -70 1.091 22.0 85.0 4 -90 1.081 21.0 83.0 !!)+!I-4-I Competition study for chlorenium ion transfer from 1c-Cl to pyridines derivatives (a quantitative trend) Having qualitatively and quantitatively validated HalA calculations as a predictor for the chlorenium ion transfers, 1c was subjected to similar competition studies with a series of pyridines exhibiting different electronic and steric profiles. Pyridine derivative (A) with a lower inherent HalA than 1c was chlorinated by its reaction with CDSC. To this chloropyridinium, 1.0 equiv of 1c was added and the corresponding ratio at equilibrium was evaluated by 1H NMR.  As shown in Table I-12 (entries 1-3), the difference in HalA between 1c and the corresponding pyridine derivative 1f, 1e, and 1b correlates to the observed equilibrium ratio of 1c-Cl by 1H NMR. Thus, the fraction of 1c-Cl calculated from experimental results compliments the theoretical HalA estimates. 4-Bromopyridine (1g), 4-tert-butylpyriidine (1d), and 2,4,6-trimethylpyridine (1a), which have higher HalA values than 1c also demonstrate experimental results that comply with the theoretical estimations (entries 4-6). Reliable experimental results were not obtained upon chlorination of 1h and 1j due to instability of the chlorinated complexes; they started precipitating over time.    The stacked 1H-NMR spectra of 1c-Cl in competition with other pyridines are shown in Figure I-16. Equilibria/competitions between pyridine 1c-Cl and a series of substituted pyridines (1a-g) (Figure I-15), showed a nice trend between the relative halenium affinities (theoretical) and the amount of !)"!chlorinated pyridine 1c (experimental) as confirmed by 1H-NMR analysis. Validation of HalA computations by experimental studies demonstrates its utility as an efficient tool for quantification of the affinity of halenium ions with Lewis bases. These examples clearly demonstrate the validity of HalA as an efficient tool that allows quantitative ranking of halenium ion affinities for various Lewis bases.!  Figure I-15 Comparison of #HalA (Cl) (B3LYP/6-31G*) with experimental results of equilibrium studies between 1c-Cl (prepared in situ using 1.0 equiv CDSC) in presence of 1.0 equiv of pyridines 1b-h.  020406080100-13.5-9-4.504.59Fraction of 1c-Cl determined by 1H NMR!HalA (theoretical)NNCNN1e 1f 1g1b 1a 1d NF3CNNBracetone-d6 -90 ¼CNtButBuNRClSbCl611c-ClNRCl1-ClNtButBu1c!)#!      Figure I-16 Overlay of 1H NMR spectra displaying equilibrium ratios when chloropyridinium derivatives 1(a-f)-Cl were treated with 1.0 equiv of 1c. acetone-d6(1.0 equiv.)1c-Cl-90 ¼CSbCl6NClSbCl6Me1c(1.0 equiv.)NMeNRClNR1c(C3-H)1c-Cl(C3-H)1f1e1b1g1a1dIncreasing HalAsubstituted pyridines!)$! I-4-J Control experiments  The halo-pyridinium salts with antimony (VI) halide as the counter anion were insoluble in most of the commercially available deuterated solvents. Although THF-d6 was efficient in dissolving these salts, it was not economically viable for the entire set of planned experiments. Furthermore, use of acetonitrile-d3 led to Ritter-type reactions causing decomposition of the halo-pyridinium salts. Hence, for all the above experiments involving analyses of halo-pyridinium salts, acetone-d6 was identified as the optimum solvent. We were aware of the possibility that treatment of pyridines with halenium sources in acetone might lead to protonation (rather than chlorination) of the Table I-12 Data for observed equilibrium ratios when 1.0 equiv of 1c is added to chloropyridinium derivatives 1(a-j)-Cl. HalA values are estimated at the B3LYP/6-31G*/SM8 (acetone) level of theory.  Entry Pyridine  Derivatives (A) HalA (A) (kcal/mol)  HalA (1c) (kcal/mol)  !HalA (kcal/mol)   (1c-Cl)% 1 1f (4-CN) 138.0 127.2 +10.8 100 2 1e (4-CF3) 137.2 127.2 +10.0 97 3 1b (2,6-di-t-Bu) 126.1 127.2 -1.1 88 4 1g (4-Br) 138.8 127.2 +11.6 53 5 1d (4-t-Bu) 146.3 127.2 +19.1 4 6 1a (2,4,6-trimethyl) 148.2 127.2 +21.0 0 7 1h (4-Ph) 145.7 127.2 +18.5 32 8 1j (4-NMe2) 154.3 127.2 +27.1 30 !!)%!pyridinium nitrogen atom yielding $-chloroacetone as the end product. The protonated pyridines would exhibit a similar downfield shift of the C3-H and thus lead to erroneous results (Figure I-17). This possibility was ruled out based on our control experiments - 1.) by observing no change in chemical shift of the chloropyridiniums upon addition of K2CO3, 2.) by employing THF as a solvent and observing identical behavior as seen with acetone-d6, and, 3.) by successfully initiating a chlorolactonization of alkenoic acid using the in situ generated chloro-pyridinium 1a-Cl.!   NMeNHClMe1c-HClNClSbCl6Me1c-Cl1cFigure I-17 Overlay of 1H NMR spectra of 1c-Cl, 1c-HCl and 1c displaying their relative chemical shifts. !)&! I-4-J1 Control experiment #1 To verify whether the species under consideration were chloro-pyridinium salts, we deliberately synthesized their protonated analogs by bubbling HCl gas in the ethereal solution of 1c at 0 ¡C followed by filtration of the precipitated salt (1c-HCl). The salt was dried and suspended in 1,2-dichloroethane and treated with 1.5 equiv of SbCl5 at -40 ¡C. This yielded the protonated pyridinium-SbCl6 salt. Having the same counter anion - SbCl6%, 1H NMR spectra of 1c-H (protonated salt) and 1c-Cl (chlorinated salt) were compared in acetone-d6 at room temperature (Figure I-18). The equilibrium mixture of 1c and 1c-Cl at room temperature shows a set of poorly resolved peaks between 7.0-7.6 ppm. In contrast, the equilibrium mixture of 1c and 1c-HSbCl6 displays a set of two sharp peaks at 7.06 and 8.06 ppm corresponding to the protonated salt and the free base, respectively. The difference in their chemical shifts (ppm) and broadness of the peak clearly confirms the identity of two different species (protonated and chlorinated) and the relative rate of exchange (compared to NMR timescale) under similar conditions. Furthermore, the protonated and chlorinated species shown above were subjected to 1.0 equiv of K2CO3 and the resulting mixtures were analyzed by 1H NMR. Upon addition of K2CO3 at room temperature, the peak corresponding to 1c-HSbCl6 disappeared instantaneously with increased intensity for the peak due to free 1c. However, addition of K2CO3 to the equilibrium mixture of 1c and 1c-Cl did not lead to any immediate observable !)'!change in the intensity or ratio of the free base and its chlorinated counterpart. When this solution was left at room temperature for over 30 min, some evidence of decomposition of 1c-Cl was observed by 1H NMR. This clearly shows that under the standard optimized conditions, the addition of halenium source leads to the formation of halo-pyridinium salts rather than simple protonation.   I-4-J2 Control experiment #2 Chlorination of 1c with CDSC was performed using non-deuterated THF as a solvent (1H NMR spectrum at -90 ¡C was obtained using suppression of THF resonances). A similar behavior (when acetone-d6 was 1c(C3-H)1c-Cl(C3-H)NMeNHSbCl6MeNMeNClSbCl6Me1c1c1c-HSbCl61c-Cl1c(C3-H)1c-HSbCl6(C3-H)Figure I-18 Overlay of 1H NMR spectra displaying the protonated salt (1c-HSbCl6) and the analogous chlorinated salt (1c-Cl) in presence of the free base (1c) in acetone-d6 at room temperature. !)(!employed) of 1c and 1c-Cl was observed leading to two distinct peaks in 1H NMR at 7.06 ppm for 1c and 8.06 ppm for 1c-Cl (Figure I-19). Since there are no enolizable protons available in THF, the appearance of the downfield peak at 8.06 ppm clearly demonstrates formation of 1c-Cl.   THF-90 ¼CNClSbCl6NNClSbCl6Me1b-Cl(1.0 equiv.)NMe1c1b1c-Cl00.30.51.01.5equiv 1c1b-Cl(C4-H)1b-Cl(C3-H)1c-Cl(C3-H)1b(C4-H)1b(C3-H)1c(C3-H)Figure I-19 Competition for chlorenium ion capture between 1b and 1c at -90 ¡C in THF as a solvent. The chemical shifts (ppm) for the free bases (1b and 1c) and the corresponding chlorenium salts (1b-Cl and 1c-Cl) are identical to those observed in acetone-d6 at -90 ¡C. !))!I-4-J3 Control experiment #3 Finally, the in-situ generated complex 1a-Cl (using 1.0 equiv each, 1a and CDSC) in CDCl3 was treated with 1.0 equiv of alkenoic acid (17) at room temperature (Figure I-20). The chlorenium ion from 1a-Cl was transferred to the alkenoic acid (17), successfully initiating a chlorolactonization reaction yielding the chlorolactone (17a). !!I-5 Conclusion Qualitative reactivity ranking of potential halogen attack sites using HalA computations can be made using the HalA values listed in Tables I-1 to I-5, whereas quantitative comparison of affinities can be established by computing the full structures using optimum solvation models. Figure I-21 provides the HalA (Cl) scale for various functional groups to allow a qualitative comparison. As shown in Figure I-21, functional groups (acceptors) undergoing extended conjugation with the substituents attached, span a OHONClSbCl6MeClOOCDCl3, rt, 24h  100% conversion(1c-Cl)(1.0 equiv)1717aFigure I-20 Chlorolactonization of 17 using 1c-Cl as an active chlorenium source. !)*!larger range of HalA. For instance, alkenes, alkynes, amines, aromatic compounds etc. whose HOMO can be easily altered based on the electronics of the substituents, display a wider range of HalA values in comparison to epoxides or alcohols where the attached substituents can only exert a weaker inductive effect. A relative comparison of halenium affinities can facilitate (a) a rational approach toward choice of compatible nucleophiles (especially when the nucleophilic atom is embedded within motifs that have similar steric/electronic profiles) (b) it can account for the modulation of HalA values of alkenes by the anchimeric assistance of neighboring functionalities; this aspect underscores the importance of quantitatively evaluating HalA values on full structures rather than on truncated models. Furthermore, subtle electronic perturbations leading to modulations of HalA values are also accounted for in the calculations, and (c) accurate predictions of chemoselectivity towards development of halenium initiated cascade/Domino reactions. These studies establish that HalA values may be used as a routine design/predictive element in a field that predominantly relies on trial-and-error approaches for reaction discovery. With development of a tool such as HalA, that accurately predicts chemoselectivity in reactions, its scope will not be limited exclusively to alkene halogenation reactions. Any electrophilic species (such as sulfenium, selenium, oxenium ions) capable of activating Lewis basic functionalities (such as olefins, alkynes, allenes, amines etc.) can be !*+!efficiently parameterized on a similar scale to expedite the development of electrophilic functionalization reactions in general. These studies are ongoing and will be the subject of future disclosures. !      100124148172196220244The HalA (Cl) ScaleHalA (Cl) range for common functional groups in Kcal/molFigure I-21 The HalA (Cl) scale based on theoretical estimates of over 500 chlorenium ion acceptors.  Primary Amines Secondary Amines Tertiary Amines Phenols Aliphatic alcohols Alkenes Alkynes Pyridines Heterocycles Enones Epoxides Aromatics Phosphines !!Thiols and Sulfides !*"!          REFERENCES       !*#!REFERENCES    ",!-./.01!2,1!!"#$%&'%%(",!3456789:4;<8<!=5;>/04;.7!?@45AB!C"*((D,!#+"+E!F4G;!H078I!J!24;B1!K/<,!!#,!LG8;1!?,!.;<!2,!M.1!NO;.;/04B878>/0P8!Q.74>I>70R./04;!S8.>/04;B!T4@!/G8!2I;/G8B0B!4T!LG0@.7!LI>70>!L4UA45;<B)*!+$,(-)./0(&).1$%).23)1!!"#"1!451!)$+'9)$+),!!$,!L.B/877.;4B1!V,!.;<!2,-,!=78/>G8@1!NL5@@8;/!M8/G4<B!T4@!VBIUU8/@0>!Q.74W8;./04;!4T!X78T0;B)*!/0(&).26").7)1!!"##1!891!&(''9&((',!!%,!Y.;1!L,Z,1!K,![G451!.;<!\,\,!\85;W1!NX@W.;4>./.7I/0>!O;.;/04B878>/0P8!Q.747.>/4;0R./04;BE!2/@./8W08B!4T!Q.74W8;!V>/0P./04;)*!:;$<(%%1!!"##1!"$$&9"$$*,!!&,!38;U.@]1!2,O,1!H,O,!Z58B/8@1!.;<!M,Y,!:5@]1!NL./.7I/0>1!VBIUU8/@0>!Q.74T5;>/04;.70R./04;!4T!V7]8;8B9V!L@0/0>.7!-8@BA8>/0P8)*!+$,(-)./0(&).1$%).23)1!!"#!1!=81!"+*$)9"+*&$,!!',!Q8;;8>]81!^,1!N_8`!L./.7I/0>!VAA@4.>G8B!/4`.@<B!/G8!O;.;/04B878>/0P8!Q.74W8;./04;!4T!V7]8;8B)*!/0(&).+>?'$.7)1!!"#!1!91!%&'9%'&,!!(,!M5@.01!Z,!.;<!Q,!=5a04].1!NS8>8;/!-@4W@8BB!0;!X@W.;4>./.7I/0>!VBIUU8/@0>!Q.74>I>70R./04;)*!@(%("#A;A<(>1!!"#$1!B91!('$9)+&,!!),!@'<#,($.C#$3?$,D.!6$3'&($%'<>.'$3.+EE<?A'%?#$>1!0;!@'<#,($.C#$3?$,D.!6$3'&($%'<>.'$3.+EE<?A'%?#$>1!-,!M8/@.;W474!.;<!?,!S8B;./01!O<0/4@B,!#++)1!2A@0;W8@9b8@7.W!:8@70;E!:8@70;,!A,!"9##",!!*,!F1!L,!.;<![,!K1!NS8>8;/!-@4W@8BB!0;!/G8!VBIUU8/@0>!c;/8@U478>57.@!Q.74W8;./04;!4T!V7]8;8B)*!:;$%0(>?>1!!"#%1!4F1!&)'9&*&,!!"+,!Xa0U.1!c,1!/'%'<;%?A.+>;&&(%"?A.:;$%0(>?>,!#;<!8<,!#+++1!_8`!\4@]E!H078I9bLQ,!"9*)(,!!"",!2`88;8I1!F,:,1!NVR0@0<0;8BE!OA4d0<8Be!^W7I!L45B0;Bf*!/0(&).:#A).G(H)1!!""!1!I81!#%(9#&),!!*$!"#,!38;U.@]1!2,O,1!M,Y,!:5@]1!.;<!V,F,!Q44P8@1!NX;!/G8!V6B475/8!L4;T0W5@./04;.7!2/.6070/I!4T!:@4U4;05U!.;<!LG74@4;05U!c4;B)*!7).+&)./0(&).:#A)1!!"#"1!8IJ1!"#$#9"#$$,!!"$,!M>M.;5B1!2,-,!.;<!-,O,!-8/8@B4;1!N247P8;/!OTT8>/B!4;!Q.74;05U!c4;!L.@64;05U!c4;!Og50706@0.)*!K(%"'0(3"#$.L(%%)1!#&'(1!#(&$9#(&',!!"%,!XG/.1!:,Z,1!S,O,!Q45WG1!.;<!F,H,!2>G568@/1!NOP0<8;>8!T4@!:8/.9LG74@4>.@68;05U!.;<!:8/.9:@4U4>.@68;05U!c4;B)*!M",).L(%%)1!!""'1!51!#$"(9#$#+,!!"&,!X7.G1!?,V,!.;<!:4770;W8,FU1!N2/.678!L.@64;05U!c4;B!,&(,!Q.74;05U!c4;!=4@U./04;!b0.!_80WG64@0;W!Q.74W8;!-.@/0>0A./04;!,!Y@0U8/GI79!.;<!"1"930U8/GI78/GI78;8G.74;05U!c4;B)*!7).+&)./0(&).:#A)1!#&)*1!5N1!*%(9*&$,!!"',!X7.G1!?,V,1!F,M,!:4770;W81!.;<!F,!:@0;0>G1!N2/.678!L.@64;05U!c4;B!,(',!#1#930U8/GI7/8/@.U8/GI78;8!Q.74;05U!c4;B!.;<!.!2/5<I!4T!Q.74W8;!-.@/0>0A./04;!0;!-@4/4;./8<!M8/GI7!?.UU.9Q.74A@4AI7!Z8/4;8B!.;<!&9Q.749"9-8;/I;8B)*!7).+&)./0(&).:#A)1!#&)*1!5N1!'*))9'**#,!!"(,!X7.G1!?,V,!.;<!-,O,!-8/8@B4;1!NQ.74;05U!c4;!=4@U./04;!b0.!"1%9Q.74W8;!-.@/0>0A./04;!,!&9M8U68@8<9S0;W!Y8/@.U8/GI78;8G.74;05U!#9M8/GI7/8/@.U8/GI78;8G.74;05U!.;<!#1&930U8/GI7/8/@.U8/GI78;8G.74;05U!c4;B)*!7).+&)./0(&).:#A)1!#&)*1!5N1!%'(&9%'(),!!"),!X7.G1!?,V,1!8/!.7,1!NX;05U!c4;B!,"+,!2/@5>/5@.7!2/5<I!XT!V>I>70>!.;<!LI>70>!Q.74;05U!c4;B!6I!L9"$!_5>78.@!M.W;8/0>9S8B4;.;>8!2A8>/@4B>4AI!9!h58B/04;!4T!c;/@.U478>57.@!.;<!c;/8@U478>57.@!Og50706@./04;!4T!Q.74;05U!c4;B!`0/G!Q.74.7]I7>.@68;05U!c4;B)*!7).+&)./0(&).:#A)1!#&'%1!5F1!$&'&9$&($,!!"*,!24770;W1!Y,c,!.;<!K,!S.<4U1!NOd>G.;W8!S8.>/04;B!4T!LG74@0@.;05U!.;<!LG74@0@8;05U!c4;BE!.!?#!c;P8B/0W./04;)*!1$%).7).O'>>.>E(A%"#&)1!#&&&1!8B=1!#'$9#(+,!!#+,!X7.G1!?,V,1!:4770;W8,FU1!.;<!F,!:@0;0>G1!N2/.678!L.@64;05U!c4;B!,(',!#1#930U8/GI7/8/@.U8/GI78;8!Q.74;05U!c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d0<./04;!4T!28>4;<.@I!V7>4G47B!/4!Z8/4;8B!`0/G!Y@0>G74@40B4>I.;5@0>!V>0<)*!:;$%0)./#&&6$)1!#&&!1!JJ1!"&)*9"&*&,!!#*,!P.;!25UU8@8;1!S,-,1!8/!.7,1!NYG8!Xd0<./04;!4T!V7>4G47B!`0/G!Y@0>G74@40B4>I.;5@0>!V>0<E!-I@0<0;8!T@4U!:.B8!/4!X@W.;4>./.7IB/)*!/'%'<).:A?).K(A0$#<)1!!"#!1!J1!#+&#9#+&',!!$+,!Q.B/I1!2,F,!.;<!V,b,!38U>G8;]41!N?7I>4BI7!YG040U0<./8B!.B!b8@B./078!:507<0;W!:74>]B!T4@!X@W.;0>!2I;/G8B0B)*!/0(&).@(%("#A;A<)1!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!!"#!Chapter II: Mechanistic Investigations of Asymmetric Halocyclizations Reactions of Olefins II-1 Introduction  The complexity of multifunctional molecules with stereocenters has attracted many organic chemists to develop new organic transformations to introduce different functionalities. Functionalization of a double bond promoted by an electrophile is one the most fundamental transformations in organic chemistry and represents a promising approach toward creating these complexities. In the past century, a wealth of research has been dedicated to the development of effective methods for asymmetric functionalization of unactivated olefins with various electrophiles. The discovery of asymmetric epoxidation,1-3 aziridination,4 dihydroxylation,5 cyclopropanation,6, 7 hydrovinylation,8 hydrosilylation,9 hydroboration,10 and hydrocarbonylation,11 are important examples of these transformations (Scheme II-1). Halofunctionalization of olefins has been known for decades, but the asymmetric variants just recently begun to attract attention. It was not until recently that electrophilic halogenation of olefins in an enantioselective fashion was discovered as a process to functionalize olefins. Thanks to vigorous development of asymmetric catalytic methods, the hoary halocyclization reaction has recently entered the limelight as a powerful new tool for enantioselective synthesis.12-21 In this process, the most commonly !!"$!involved mechanism is the abstraction of a halenium ion by the olefin, followed by an intra- or intermolecular attack of a nucleophile. The final product would then contain two new functionalities, one the carbon-halenium bond, which can be further manipulated, and second the carbon-nucleophile bond. These chiral halogenated compounds are also among the most versatile building blocks in synthesis (over 4500 halogenated natural products exist in nature).22 Incorporation of a halogen in a molecule could alter the physical properties of the molecule (steric and electronic), which could change their biological activity.23, 24             PhR1PhCH3O84% eePhNTs66% eePhCH3>95% eeOBOPhCH396% ee96% eePhCH3CO2HPhOHPhOH>99% eeCO2EtPh84% eePhR1NuXX = Cl, Br or INu = NucleophileScheme II-1 Summary of asymmetric functionalization of unactivated olefins. !!""!Asymmetric introduction of halogens onto double bonds has been explored by the use of chiral auxiliaries, such as OppolzerÕs sultam,25 oxazolidines,26 and oxazolidinones27. Asymmetric olefin halogenation has also been investigated by the use of stoichiometric amounts of chiral reagents. Taguchi, Wirth, Trupp and Brown first reported reagent-controlled stereoselective iodolactonization and bromoetherification in low to moderate enantioinduction.28-32 Desymmetrization by stoichiometric chiral titanium complexes also gave promising enantioselectivities in iodolactonization and etherification reactions.30, 33-35 In 2003, Gouverneur and coworkers reported the fluorodesilylation reaction with a N-fluorocinchona alkaloid system in high enantioselectivity.36 During the next 7 years enantioselective fluoroetherification,37 iodopolycyclization,38 fluoro-semipinacol rearrangement,39 and dichlorination reactions40, 41 that employed stoichiometric catalysts were developed by Gouverneur, Ishihara, Zhang, and Snyder groups.  In the five years since the first discovery of asymmetric chlorolactonization developed by our group in 2010,42 several groups have focused on formation of stereodefined carbon-halogen bonds in an intra- or intermolecular fashion utilizing various organocatalysts. In general, control has been achieved by desymmetrizing the environment of the halenium donor with a chiral anion, or by templating the alkenoic substrate via interaction with !!%&&!a chiral catalyst, causing one face of the alkene to be preferentially halogenated.  II-2 Intramolecular organocatalytic halocyclization reactions of olefins Enantioselective halocyclization reactions can be classified based on the use of various nucleophiles and chiral organocatalysts. Since our discovery in 2010,42 many groups have explored halocyclizations with various organocatalysts such as TRIP, pyrrolidine-based, seleno-THF, ureas, thioureas, binaphthyls, squaramides, BINAP analogs, as well as benzene trimer variants, PBAM catalysts, and finally the family of cinchona alkaloid monomers and dimers. Scheme II-2 shows the sub-structures of all chiral organocatalysts used in asymmetric halofunctionalization of olefins up to this point (generalized structures which contain the important functionalities). Scheme II-3 illustrates various halogenation transformations catalyzed by these catalysts.  In 2012, Martin and coworkers utilized the bifunctional binaphthyl analogs (Family A) as chiral catalysts for the bromolactonization of 4/5-aryl- or 5-alkyl-pentenoic acids via a 5-exo-cyclization with high enantioselectivity. They proposed a mechanism based on orientation of the substrate through hydrogen bonding between the phenolic !OH and the carboxyl group in such a way that the olefin is directed away from the face of the binaphthyl scaffold to minimize torsional strain. The bromonium ion is presumably then stabilized by interaction with the amidine moiety.43 !!%&%!   Scheme II-2 Sub-structures of all organocatalysts used in asymmetric halofunctionalization of olefins. NMeONOHNNHNOMeNOHHNHONCF3BrOOiPriPriPriPriPriPrPOOHNNNNNNHHHH.NHTf2SeOOOOt-But-BuOONHNHN(C5H11)2CF3F3CHNNNHNHNNPhPhPhPhPhPhNCH3SHOHNOEtNHN(C5H11)2NHOF3CCF3PhOHNMeNMe2PPt-BuOMet-But-BuOMet-Bu22Family KCinchona Alkaloid DimersFamily JCinchona Alkaloid MonomersFamily FPBAM CatalystFamily CPyrrolidine AnalogsFamily BSeleno-THF AnalogsFamily ETRIP AnalogsFamily DBINAP AnalogsFamily IBenzene TrimersFamily HSquaramide AnalogsFamily GUrea Based CatalystsFamily ABiNaphthyl Analogs!!%&'!A C2-symmetric mannitol-derived cyclic selenium catalyst as a monofunctional Lewis base (Family B) has been explored in bromocyclization of trisubstituted olefinic amides by Yeung and coworkers. The mechanism of this selenium-catalyzed bromoamination may involve the activation of brominating agent by forming a tight selenium-coordinated bromonium intermediate species for further chiral delivery to the olefin.44 The same group also reported a bromoetherification and desymmetrization of olefinic 1,3-diols with similar seleno-THF analogs as the chiral catalyst.45  A new class of organocatalysts, based on pyrrolidine organocatalyst (Family C), were used for the asymmetric bromolactonization of 1,1-disusbtituted carboxylic acids by Yeung in 2012.46 This S-alkyl thiocarbamate catalyst could be easily synthesized from the commercially available amino acid proline and led to the formation of "Ðlactones with high enantioselectivity. A BINAP-derived organocatalyst (Family D) was developed for the bromocyclization of 1,1-disubstituted allylic amides by Hamshima in 2015.47 This is the first example of a chiral phosphine compound serving as a soft Lewis base catalyst for asymmetric synthesis of oxazolines. A number of papers have shown that phosphate catalysts (Family E) could be a promising source for chiral activation of halenium ions in various asymmetric halofunctionalization reactions. Cooperative activation of chiral phosphate catalysts and N-haloimide is reported for the enantioselective !!%&(!iodolactonization of 4-arylmethyl-4-pentenoic acids by Ishihara.48 Frohlich and coworkers showed that sodium salts of chiral phosphoric acids could be utilized for bromo- and iodo- etherification reactions via desymmetrization of in situ-generated meso-halenium ions in moderate enantioselectivities.49 This is the first report where they obtained the optically pure products from the meso-halenium ion intermediate via nucleophilic ring-closure as the stereochemistry-determining step catalyzed by chiral phosphate counter anion. Denmark and Burk discovered the bromocycloetherification of 5-arylpentenols with a binary catalyst system consisting of a chiral phosphoric acid (Bronsted acid) and an achiral Lewis base (PPh3=S).50 Shi and coworker showed that #-hydroxyl-alkenes and #-amino-alkenes can undergo efficient bromo-etherification and -amination using chiral phosphoric acid catalyst, giving substituted tetrahydrofurans and tetrahydropyrroles with good enantioselectivities.51 Asymmetric fluoro- and bromo- cyclization of unsaturated amides using a chiral phosphoric acid as an anionic phase-transfer catalyst were reported by Toste and coworkers.52, 53 In chiral anion phase-transfer catalysis, the non-selective background reaction could be removed by taking advantage of the low solubility of the halogenating source in nonpolar solvents. Via exchange of the counter anions from the reagent with lipophilic chiral phosphate anions, the active electrophile could be brought into solution as a chiral ion pair, resulting in efficient chemo- and enantioselective halocyclizations reactions.  !!%&)!Johnston and Dobish have developed a Bronsted acid and hydrogen-OOnR3XR1R2NOR2XR1R2ArNR3XR1R2PGOR3XR1R2NOR3XR1R2Haloetherification of oximesHalocyclization of amidesHaloaminationHalolactonizationONR3XR1R2CCl3Halocyclization of trichloroacetimidatesnnnnnXOOHXNORHXRNHOXOHNCCl3XHNPGHalocyclizationof dicarbonylsXHOOROR3XR1R2nROXRHalogenationsemipinacolrearrangementOHR1R3R2nOXRNHOR2XR1R2nOHalocyclization of amidesXNHOOHaloetherificationXOHt-BuR1R3R2NunScheme II-3 Intramolecular organocatalytic asymmetric halofunctionalization reactions. !!!%&*!bond-catalyzed iodolactonization reaction with employing chiral PBAM analogs (Family F).54 The reactivity of the pyrrolidine-bisamidine-based protic acid complex could be optimized easily by the change of the achiral counterion, where triflimide counterion worked best in giving high enantioinduction. Jacobsen reported a highly enantioselective iodocyclization of trichloroacetimidates by a new chiral Schiff-base urea derivative (Family G).55 They proposed that the iodinating agent could only be soluble in the reaction medium through a reversible hydrogen bonding complexation with the urea catalyst, so that the Schiff-base catalyst could promote iodocyclization by acting as a neutral phase transfer agent. The same group also developed an iodolactonization of hexenoic acids with a tertiary aminourea catalyst in high enantioselectivity.56 The squaramide-based catalysts (Scheme II-2) have been explored in a variety of asymmetric transformations 57-60 due to their efficient H-bonding ability. HansenÕs group utilized this catalyst for the first time in iodolactonization of hexenoic acids and achieved high enantioinduction for the synthesis of "-lactones.61 The structurally unique C3-symmetric trisimidazoline (benzene trimers, Family I) were developed for the bromolactonization of hexenoic acids by Fujioka.62, 63 This research group has also applied similar systems for kinetic resolution of $!substituted olefinic carboxylic acids by asymmetric !!%&+!bromolactonization.64 Complexation of chiral amine with carboxylic acid (1:3 ratio) through H-bonding activates the carboxylate in a chiral environment as a result of molecular-recognition with the trisimidazoline catalyst, which then leads to enantiopreferential attack in the ring-closing step. Another mechanism where one imidazoline moiety activates the carboxylic acid, and another activates the halenium source was not ruled out in this report. Family J (Scheme II-2) is the monomeric naturally occurring cinchona alkaloid scaffold, which include quinine, quinidine, cinchonine, and cinchonidine (Scheme II-4a).65 This family has three main categories of catalysts; the phase-transfer quaternary ammonium salts of cinchona alkaloids, the bifunctional cinchona alkaloid-based urea, and the thiourea-based organocatalysts.66 These compounds have played a pivotal role in inducing chirality in a variety of transformations.67 Recently, they have been explored in a number of asymmetric halocyclizations (Scheme II-3).20 Zhang and coworkers first applied this family of chiral quaternary ammonium salt cinchona alkaloids as a phase-transfer catalyst in asymmetric iodolactonization of pentenoic acids, where they obtained moderate enantioselectivities.68 Later, Sun developed a 5-endo chloroetherification of homoallylic alcohols by employing a quaternary ammonium salt derived from cinchonine as the phase-transfer chiral catalyst, toward the synthesis of $!chlorotetrahydrofuran.69 Mukherjee reported an enantioselective Iodoetherification of §-#-oximes for the synthesis of isoxazolines with a !!%&#!quaternary stereogenic center with the help of a bifunctional dihydrocinchonidine-derived thiourea catalyst.70 Bromolactonization of conjugated Z-enynes for the synthesis of bromoallene-lactones was achieved using a bifunctional catalyst comprised of a cinchona alkaloid bearing a urea moiety in TangÕs group.71, 72 It is believed that the quinuclidine moiety might be involved in activation of the nucleophile via deprotonation event, while the urea or thiourea groups hydrogen bond with the halenium sources. Nonetheless, the detailed mechanism has not been clarified. In 2012 Yeung reported an enantioselective bromolactonization of styrene-type carboxylic acids toward the synthesis of 3,4-dihydroisocoumarins through a quinidine-derived amino-thiocarbamate for a 6-endo cyclization.73 They revealed that switching to a cinchonine-derived amino-thiocarbamate results in better enantioselectivities for the formation of the 5-exo phthalide products. They also reported the asymmetric bromolactonization and bromoamination of disubstituted olefins, as well as bromo-enolcyclization of dicarbonyl compounds using various cinchona alkaloid-derived amino-thiocarbamate catalysts.74-80  Last group of this family is the dimeric cinchona alkaloids that have attracted much attention for asymmetric halogenation reactions (Family K, Scheme II-2).20 Prior to 2010, such catalysts provided only low enantioselectivities for asymmetric halocyclizations. Our group 42 first developed the highly enantioselective chlorolactonization of pentenoic acids !!%&$!using the dimeric hydroquinidine 1,4-phthalazinediyl ligand (DHQD)2PHAL (II-1, Scheme II-4) developed by Sharpless and coworkers81-83 for asymmetric dihydroxylation reactions. In combination with DCDPH (1,3-dichloro-5,5-diphenylhydantoin) as the chlorinating agent, (DHQD)2PHAL delivered high enantioselectivities in chlorolactonization of alkenoic acids.  We found that the use of benzoic acid as an additive enhances enantioselectivities. Similarly, Clark and coworkers reported a bromolactonization reaction under similar reaction conditions [(DHQD)2PHAL and NBS system], where they observed a significant drop in enantioselectivity in the absence of benzoic acid additive.84 In 2012, with the same catalyst and brominating agent, KanÕs group used the bromolactonization condition for catalytic desymmetrization and kinetic resolution of cyclohexadiene derivatives.85 Using the same dimeric catalyst II-1, our group also developed enantioselective chlorocyclization of unsaturated amide, where 1,1-di-, 1,2-di- and 1,1,2-trisubstituted alkenes gave high enantioselectivities to afford 5-exo and 6-endo oxazoline products.86 A similar system was used for kinetic resolution of unsaturated amides using II-1 catalyst in chlorocyclization reaction.87 Enantioselective chlorocylization of benzamides was also explored in indole derivatives with similar II-1 and DCDPH combinatorial system through a dearomatization event to form chiral indolines.88, 89 In 2011, GouverneurÕs group reported an enantioselective fluoroetherification of indoles using (DHQ)2PHAL catalyst (II-5) to induce enantiocontrol.90 This halocyclization is accompanied by a dearomatization of !!%&"!the indole ring. In 2013, we developed a solvent-dependent divergent enantioselective chlorocyclization of unsaturated carbamates with II-1 catalyst to afford both enantiomers of the synthetically useful oxazolidinones.91 These Scheme II-4 a) naturally occurring cinchona alkaloids b) dimeric cinchona alkaloids used in asymmetric halofunctionalization reactions. NMeOONOMeONNOHArNEtNEtHHNN(DHQD)2PHALII-1(DHQD)2AQNII-2OO(DHQD)2PYRII-3NNPhPhNN(DHQD)2PYDZII-4RNNRHOR = OMe, quinine (QN)R = H, cinchonidine (CD)R = OMe, quinidine (QD)R = H, cinchonine (CN)ab(DHQ)2PHALII-5NEtNMeOONOMeONNNEtHH!!%%&!family of dimeric cinchona alkaloids are also efficient catalysts for asymmetric halogenation semipinacol rearrangements (Scheme II-3). The Tian and Li groups have shown various examples of bromination and chlorination semipinacol rearrangement of reaction of alcohols to form $-haloketones (Scheme II-3) in high enantioselectivities using catalysts II-3 and II-4.92, 93 All the reports mentioned thus far have focused on intramolecular halocyclizations. Our group and others have also studied the more challenging intermolecular halofunctionalization of alkenes including dihalogenation, aminohalogenation, haloesterification, and halohydrin synthesis.16, 94-111 In all these examples after the delivery of the halenium ion, an external nucleophile such as an amine, acid, halogen, or alcohol attacks in an enantioselective manner in the presence of a chiral catalyst. II-3 Mechanistic studies on cinchona alkaloid-catalyzed halocyclizations reactions-A critical perspective As mentioned in the previous section, cinchona alkaloids and their derivatives are used to induce chirality in a number of asymmetric halocyclizations. A better understanding of the reaction mechanism is crucial,15 to further optimize these reactions, better understand the potential obstacles in controlling enantioselectivity, develop more asymmetric methodologies, and finally design and propose more efficient catalysts.  The mechanism of halocyclizations most frequently invoked, is the formation of a halonium (haliranium) intermediate, which then undergoes !!%%%!attack by an intramolecular nucleophile in a chiral environment, guided by the chiral catalyst (Scheme II-5). To better understand the asymmetric halocyclization reactions, a number of questions should to be considered. First, the detailed nature of attack on olefins by halenium ion donors with structural and electronic nature of all resulting intermediates must be understood. Second, the role of the alkaloid catalyst in inducing enantioselectivity should be explained. Third, rate- and enantio-determining steps should be elucidated.  In general, enantiocontrol in asymmetric halocyclizations has been achieved by three approaches (Scheme II-5). These include: 1) Desymmetrizing the environment of the halenium donor with a chiral catalyst to deliver halenium ion in an enantioselective manner, setting stereochemistry for a nucleophilic ring closure that is not catalyst directed (Path A). 2) Both halenium attack and nucleophilic ring-closure steps are catalytically controlled to be enantioselective (Path B). 3) Templating the alkenoic substrate via interaction of the chiral catalyst with the nucleophile, leading to a cyclization step that is enantioselective although the halenium ion is delivered to the olefin in a racemic fashion (Path C).  In the first approach (Path A, Scheme II-5) the halenium ion is engulfed in the chiral catalystÕs environment to deliver the halenium ion (X+) in an enantioselective fashion. This can be achieved by either covalent or noncovalent hydrogen-bonding of the halenium source with the chiral catalyst. !!%%'!After the asymmetric formation of the olefin-halenium % complex (II-7, Path A, Scheme II-5), three possible paths could be followed: formation of a halocarbocation intermediate (Path A1), or of a cyclic bridged haliranium intermediate (Path A2), or a concerted pathway (path A3), where the nucleophile is poised for bond formation as the olefin is halogenated. In 1937, Roberts and Kimball noted the exclusive formation of anti-products during bromination and chlorination of disubstituted alkenes, proposing the intermediacy of cyclic symmetrically bridged haliranium ions.112-114 However, studies from our group as well as those of Fahey, Sauers and others, have provided firm evidence against cyclic haliranium intermediates.115-121 The formation of both syn and anti-products from halofunctionalizations of styrylic substrates implies the existence of !-halocarbenium ions in halofunctionalization reactions.118 Furthermore, the seminal works by Fahey, Poutsma, Williams and several others have concluded that neither of these two intermediates (II-7 and II-8) is completely compatible with the observed experimental outcomes.115, 118, 122-126 As a result, Dr. Kumar AshtekarÕs studies went on to demonstrate that electrophilic addition to alkenes is not as simple as might be perceived in the classical mechanistic pathways such as A and B. He has proposed a third path (C), referred to as Nucleophilic Assisted Alkene Activation (NAAA). This concerted theory explains the importance of the nucleophile and the counter anion in activation of the olefin in reaction with halenium ions. As a class, olefins have similar HOMO energies; the !!%%(!assistance of nucleophile (in general) attenuates the HOMO-LOMO gap allowing them to react with a variety of electrophiles (with a wide range of LUMO energies). This is in accordance with the previously reported HalA values (Chapter I), where the transfer of the halenium ion to an electron-poor olefin is thermodynamically not feasible, unless it receives external aid from nucleophiles. It should be noted that Path A3 (Scheme II-5) could potentially lead to an enantioselective product II-10, since the concerted nucleophilic attack occurs in the presence of the chiral catalyst surrounding the halenium ion. A haliranium intermediate (Path A2) could also lead to the formation of asymmetric products. However, they are challenges associated with this step. After the formation of this chiral cyclic intermediate, racemization of the enantiomerically enriched haliranium ion needs to be blocked. Prior to the nucleophilic ring-closure, a process known as olefin-to-olefin transfer could erode the chirality of the haliranium ion, a phenomenon recently demonstrated by Denmark and Brown.127, 128 In an achiral environment this equilibrium may result in racemic products even if the initial halogen delivery is perfectly selective.15 This fact was confirmed by acetolysis experiments, where the bromiranium ion derived from a bromotosylate could only be captured enantioselectively in the absence of any olefin. The erosion of enantioselectivity depends on the concentrations of the olefin and the nucleophile as well as the identity of the counterion. Similar experiments with chlorenium ion did not lead to any racemization even in the presence of the !!%%)!olefin. The presence of bulky groups can retard and inhibit olefin-to-olefin racemization of chiral haliranium ions. A chiral catalyst as a bulky moiety could serve this function by staying close to the haliranium intermediate as the counterion. As shown in Path A1 (Scheme II-5) halocarbenium ion formation could also lead to loss of enantioselectivity. The only source of enantioinduction in the first path is the chiral halenium delivery; therefore going through the carbocation could lead to loss of stereochemical control at the site of nucleophilic attack.  In the second approach (Path B), the enantioselectivity of halocyclizations is controlled by both chiral delivery of the halenium and the asymmetric ring-closing step. In this mechanism, formation of a carbocation, cyclic haliranium intermediates, or a concerted mechanism could all potentially lead to high enantioinduction.  The role of the chiral catalyst in Path C (Scheme II-5) is to guide the stereoselective addition of the nucleophile after the formation of a racemic halenium intermediate. If the halenium intermediate is a carbocation (Path C1), the enantioselectivity is induced through a selective nucleophilic cyclization. A concerted reaction mechanism could also guide the nucleophilic cyclization step to occur in high enantioselectivity (Path C2). In Path C3, the influence of the chiral catalyst in the nucleophilic cyclization event could be eliminated by the necessity of an anti-opening of the bridged halenium intermediate by the nucleophile, therefore leading to Rac-II-10 product. !!%%*! Scheme II-5 Overview of three strategies to obtain high enantioinduction in halocyclization reactions. NuNuXNuXCat!Cat!XNu!II-7II-9Asym-II-10II-6Chiral delivery of the halenium to olefinChiral delivery of the halenium andAsymmetric nucleophilic ring closurePath APath BAsymmetric nucleophilic ring closurePath CII-8Cat!NuXHigh enantioselectivityXNuRac-II-10Low enantioselectivityNuXNuXNuII-6Racemizationcarbocation formationolefin to olefintransferNuXNuXNuXCat!Path A1Path A2Path A3XNuRac-II-10Low enantioselectivityRacemizationPath C1Path C2Path C3NuXCat!NuXanti cyclizationCat!Path B1-B3!!%%+!It is important to understand factors that maintain the association between halenium sources and chiral catalysts in halocyclizations. Catalysis for halocyclizations can be categorized into four classes: Bronsted acid, Lewis acid, Lewis base, and phase-transfer catalysis (Scheme II-6). Bronsted and Lewis acids increase the electrophilicity of halogen sources by covalent or non-covalent binding (Scheme II-6-a/b). Lewis bases activate halogen sources by forming a polarized species II-11 that is in equilibrium with II-12 (Scheme II-6-c). Phase-transfer catalysts could activate the halenium sources by solubilizing them in organic solvents for further reactivity (Scheme II-6-d). In this manner, the rate of background (uncatalyzed) reaction could be reduced, since the inactive halogen source can only undergo halocyclizations by being activated with the chiral catalyst. However, engineering enantioselectivity in halocyclizations is more challenging than catalysis. In order to induce chirality, four types of associative interactions have seen utility up to this point between the chiral catalyst and the halogenating sources (Scheme II-6-e-h).15 In many examples discussed earlier in Section II-2 one or multiple tactics discussed in Scheme II-6 have been used in asymmetric halocyclizations. Types e and f would explain possible mechanisms for the chiral delivery of the halenium to the olefin prior to the nucleophilic attack (Path A2) through Lewis basic complexation with haliranium, and Coulombic interactions between catalyst and haliranium, respectively (Schemes II-5 to II-6). Types g and h (Scheme II-6) represent the association of the chiral !!%%#!catalyst with the nucleophile (Path C1-2, Scheme II-5).  Scheme II-6 General catalytic and enantioselective strategies in halocyclization reactions. a) Bronsted acidb) Lewis acidc) Lewis based) Phase transferXAcidHAcidHX!"!+AcidXH!+!"XAcidAcidX!+!"XBaseXBase!+!"BaseX+"PTCXsubstrateorganicaqueous or solidX= halogenating agentCatalysis in halocyclization reactionsEnantioselective catalyst/haliranium ion associationLBX+e) chiral Lewis baseX+f) chiral counterionand anion bindingX+Y#""Yg) hydrogen bondingh) chiral Lewis acidX+NuHCat#Cat#X+NuLA!!%%$! The overall picture of the mechanism or the asymmetric induction of halocyclization reactions with dimeric cinchona alkaloid catalysts is not well understood. There is no detailed picture on how various substrates interact with the chiral catalyst, or how these interactions might change in different reaction conditions. Conformational preferences of dimeric cinchona alkaloids have not been investigated, but a few groups have focused on conformational analysis of the monomeric cinchona alkaloids, where they found protonation of the quinuclidine nitrogen, solvent, and substituents heavily influence their conformations.129, 130 In 1989, a seminal publication investigated the conformation of monomeric cinchona alkaloid in various solvents using computational chemistry and NMR studies. The rotation about the C8-C9 and C9-C4Õ bonds were found to have the most influence in the overall alkaloid conformation and four lowest energy conformations for quinidine were proposed: syn-closed, syn-open, anti-closed, anti-open (Figure II-1).67, 129 The term syn and anti refers to the relative orientation of the aromatic quinoline ring and the C9-OH bond; syn is defined if they point in the same direction. The terms open and closed refer to the conformations relating the quinuclidine nitrogen lone pair and quinoline ring. The closed conformation is when the quinuclidine nitrogen lone pair is located over the quinoline ring; while if they point away from each other, it is referred as the open conformation.129, 131   !!%%"! Further experiments revealed that substitution on the C9-oxygen has a profound effect on its conformation.129, 130 The conformations of three alkaloids II-14, II-15, and II-16 were investigated in different solvents and monitored by 1H NMR and theoretical calculations (Figure II-2). The conformation of the alkaloid II-14 with the free OH was independent of the choice of solvent, adopting 90% anti-open (C) conformation. The methylated C9-OMe alkaloid (II-15) gave a mixture of syn-closed (B) and syn-open (D) conformations. More polar solvents shifted the equilibrium toward the syn-open conformation (D). The acylated C9-OAc alkaloid (II-16) prefers mostly   Figure II-1 Four lowest energy conformations for quinidine. NHOHHNMeOC8C9C4'A anti-closedRotation about C9-C4'NHOHHC8C9C4'NOMeB syn-closedRotation about C8-C9Rotation about C9-C4'Rotation about C8-C9NHC8NHC8HOHOHHOMeNNMeOC9C4'C anti-openC9C4'D syn-open!!%'&!the syn-closed (B) conformation in all deuterated solvents, although it prefers the anti-open form (C) in methanol. The influence of protonation of the quinuclidine nitrogen on the conformation of alkaloids II-14, II-15, and II-16 was also tested in different solvents. Independent of the solvent, all alkaloids adopted the anti-open (C) conformation when protonated. These three alkaloids were stabilized only through hydrogen bonding or protonation by solvent or acid if they were in their anti-open form. The calculated stabilization energy difference between anti-open (C) and syn-closed (D) conformations for alkaloid II-14 is greater than II-15 and II-16 upon protonation (2.0, 0.9, and 0.3 kcal/mol, respectively).130 This explains why conformational preference of II-15 and II-16 is solvent dependent, since the energy barrier between forms B and C is small.  !Favors anti-open in chloroform, dichloromethane, acetone, benzene and methanol !Favors anti-open and syn-closed  !Polar solvents favoring anti-open !Nonpolar solvents favoring syn-closed !Favors syn-closed in chloroform, dichloromethane, acetone, benzene !Favors anti-open in methanol NONOHNONOMeNONOAcII-14 DHQDII-15 DHQD-MeII-16 DHQD-AcFigure II-2 Effects of oxygen alkylation and acylation on energy conformations of quinidine. !!%'%!Since our first discovery in 2010, we have developed various asymmetric halocyclizations reactions. Figure II-3 shows the (DHQD)2PHAL-catalyzed chlorolactonization (Reaction A), chlorocyclization of unsaturated amides (Reaction B) and carbamates (Reaction C/CÕ) developed by our group (1,1-disubstituted phenyl substituents was used for the comparison).42, 86, 91 Our group is working on the mechanistic understanding of these transformations, especially the role of (DHQD)2PHAL and chlorinating agents (DHQD)2PHAL (2 mol%) DCDPH (1.1 equiv)TFE, -30 ¼C, 2 h1bPhHNPhONOPhClPhNHOPhClONHOPhOCl1cPhHNOtBuOPhHNOtBuO(DHQD)2PHAL (20 mol%) DCDMH (1.2 equiv)CHCl3-Hexane (1:1), 0 ¼C, 3 h(DHQD)2PHAL (1 mol%) DCDMH (1.2 equiv)Benzoic acid, n-PrOH, -30 ¼C, 3 h2b96% yield, 90% ee1c2c83% yield, 82% eeent-2c87% yield, 80% eeReaction BReaction CReaction C'OPhOCl1aPhOHO(DHQD)2PHAL (10 mol%) DCDMH (1.1 equiv)Benzoic acid, CHCl3-Hexane (1:1)-40 ¼C, 6 h2a85% yield, 82% eeReaction A56Figure II-3 Asymmetric chlorocyclization of alkenoic acid 1a (Reaction A), unsaturated amide 1b (Reaction b), carbamate 1c under two different conditions (Reaction C and CÕ). !!%''!in chiral induction.  A number of experiments have shed light on the enantiodetermining interactions in cinchona alkaloid catalyzed halocyclizations (Reaction A). The first example reported by our group (Scheme II-7-a), demonstrates that a closed association of the hydantoin (halogenating source) and the quinuclidine residue of (DHQD)2PHAL catalyst (II-1), contributes to the high selectivity of chlorolactonization reaction.42, 132 The complex between DCH (dichlorohydantoin) and (DHQD)2PHAL has been observed by 1H NMR spectroscopy upon addition of  (1 : 1 : 2) mole ratios of DCH, (DHQD)2PHAL, and benzoic acid in CDCl3 at -40 ¡C (Scheme II-7-b). This complex can either be formed through hydrogen-bonding or Lewis base activation. The enantiotopic protons of DCH (" = 4.35 ppm, s) change to diastereotopic protons as an AB quartet at higher fields (" = 4.30 ppm, JAB = 16.5 Hz). This observation shows that the chlorinating agent must remain associated to the chiral catalyst. Further evidence for the intermediacy of this complex, was reported by Dr. Yousefi,132 who synthesized both enantiomers of the chiral hydantoin II-13 (5-isopropyl-1,3-dichlorohydantoin) to demonstrate match/mismatch behavior in reaction with both (DHQD)2PHAL and (DHQ)2PHAL (Scheme II-7-c). Chiral hydantoin (S)-II-13 in combination with (DHQD)2PHAL leads to chlorolactone (4R)-II-12 in 78% yield and (91.5:8.5) enantiomeric ratio. On the other hand, when hydantoin (R)-II-13 is used instead, both yield and er were reduced to 44% and (84.5:15.5), respectively. !!%'(!A similar trend is observed when (DHQ)2PHAL was used, where higher yield and er were obtained with hydantoin (R)-II-13. (DHQ)2PHAL is a less selective catalyst, therefore the magnitudes of the differences is reduced (see Scheme II-7). This data reconfirms the existence of an associative hydantoin/catalyst complex as demonstrated by the matched/mismatched relationship of the chiral catalyst with chiral hydantoins. This association could be either through a hydrogen-bonding complex (Scheme II-7-b), considering the requirement for the stoichiometric equivalent of benzoic acid, or through an ion-pair interaction (since the chlorocyclization of amide occurs efficiently in the absence of benzoic acid). Kinetic studies (reaction Progress Kinetic Analysis techniques-RPKA, pioneered by the Blackmond group) of the chlorolactonization reaction (Scheme II-7-a) performed by Dr. Roozbeh Yousefi have aided in determining the molecularity of the asymmetric chlorolactonization reaction. The reaction has zero-order dependence on the substrate concentration, and first order dependence on catalyst and chlorohydantoin concentrations. The zero-order dependence on the substrate demonstrates the saturation kinetics of the catalyst. The rate determining step (RDS) is either the binding of the substrate to the catalyst or the transfer of the chlorine atom to the alkene in the substrate-hydantoin-catalyst complex, since the rate of the chlorolactonization only depends on the catalyst and halogenating source. !!%')!  Scheme II-7 a) Asymmetric chlorolactonization reaction, b) proposed mode of binding in associative hydantoin/catalyst complex, c) Asymmetric chlorolactonization reaction using chiral hydantoin. NNOOClClHH!=4.35 ppm, sDHQD)2PHAL (1.0 equiv)PhCO2H (1.0 equiv)CDCl3, -40 ¡C(500 MHz 1H NMR)NEtHRHONNOClClHAHBORNEtClRHONNOClHAHB!=4.30 ppm, AB quartet (J = 16.5 Hz)OArOClArOHO(DHQD)2PHAL (10 mol%) DCDPH (1.1 equiv)Benzoic acid (1.0 equiv)CHCl3-Hexane (1:1), -40 ¼CII-12up to 99% yield, 90% eeII-11ab(DHQD)2PHAL (10 mol%)(R)- or (S)-II-13 (1.1 equiv)Benzoic acid (1.0 equiv)CHCl3-Hexane (1:1), -40 ¼C II-11Ar=(p-F-C6H5) II-12Ar=(p-F-C6H5)NNOOClClR1R2(R)- or (S)-II-13(4R)-II-12Yield [%](4S)-II-12Yield [%]e.r.(R/S)e.r.(R/S)(DHQD)2PHAL(DHQ)2PHAL (S)-II-13: R1=iPr, R2= H(R)-II-13: R1=H, R2=iPr784491.5 : 8.584.5 : 15.5306523 : 7717 : 83c!!%'*!Besides the mechanistic studies proposed for the interaction of (DHQD)2PHAL and hydantoin reagent, there are no reports about the exact role of this catalyst in halocyclizations reactions, such as the conformation and importance of various parts of this catalyst. The conformations of dimeric cinchona alkaloid (DHQD)2PHAL in different solvents and conditions are not well understood in comparison with extensive studies on the monomeric alkaloid mentioned earlier. This C2-symmetric molecule consists of two cinchona alkaloid subunits, connected together via a phthalazine linker. The electron-withdrawing linker causes the C9-oxygen to attain partial sp2 character, which in turn causes the C9-O-C=N atoms to become coplanar. In order to reduce the steric interactions with the phthalazine ring, the C9-proton adopts a coplanar rearrangement with the linker in a search for the least hindered position (Figure II-4).133, 134 It is important to realize that the proposed conformation contains a twofold rotation axis coinciding with the longitudinal axis of the central heterocycle. The existence of this axis implies that the dihydroquinuclidine subunits (A) could be mapped onto each other through 180¡ rotation. !!%'+!Dr. Sarah Marshall performed a detailed study focusing on the importance of the (DHQD)2PHAL structure on the asymmetric chlorocyclizations (Reactions A, B, C, and CÕ). She discovered that replacing the dimeric catalyst with various monomeric alkaloids result in a significant drop in enantioselectivity. Mechanistically, it is logical to think the second alkaloid unit in  (DHQD)2PHAL is required to serve as a steric wall for high asymmetric induction, or that both units have unique roles. In order to better understand the mechanism of halocyclizations reactions, Dr. Marshall synthesized a variety of (DHQD)2PHAL catalysts for structure enantioselectivity relationship (SER) studies. A summary of her SER study for Figure II-4 Co-planar atoms shown in (DHQD)2PHAL. II-1 (DHQD)2PHALNNOOHHBABAmethoxyquinoline (B)methoxyquinoline (B)dihydroquinuclidine (A)dihydroquinuclidine (A)99NONONNONNOCNOH9co-planarH-C9-O-C=N!!%'#!all four chlorocyclization reactions (Figure II-3) is shown in Figure II-5. These results show that the phthalazine nitrogen atoms play a significant role in maintaining high ee and their removal gave product in near racemic values. The linker is essential, because the nitrogen-oxygen lone pair repulsion might be responsible for locking the catalyst in an optimal conformation. It also might be involved in stabilization of the chlorenium intermediate or hydrogen bond with the substrate. The SER studies by Dr. Marshall showed that chirality about carbon attached to quinuclidine nitrogen is more significant than the one close to C9-oxygen for delivering high enantioselectivities. She also found that the changes in the catalyst effect the chlorocyclization of carbamate in n-PrOH (Reaction CÕ) similar to the chlorolactonization  (Reaction A), while in CHCl3:Hex is tolerant to nearly every change in the catalyst. This corroborates with the results obtained by Dr. Atefeh Garzan where she found that Reaction CÕ in n-PrOH was enthalpy driven, most likely via a strong interaction between catalyst and substrate in the transition state, while a weaker interaction exists in the entropy-driven CHCl3:Hex (Reaction C).91 The stronger interaction between catalyst and substrate in n-PrOH might suggest that the active site of the catalyst should be more defined, and is influenced easily with alterations surrounding the active site. The Similarity observed between SER results in Reactions A and CÕ may suggest that the substrates bind to the catalyst in a similar fashion in these two reactions.   !!%'$!        Figure II-5 Summary of SER study of chlorolactonization (Reaction A), chlorocyclization of amides (Reaction B), chlorocyclization of carbamates in CHCl3:Hex (Reaction C), and n-PrOH (Reaction CÕ) catalyzed by (DHQD)2PHAL. NONONNONNOBlocking one quinuclidinenitrogen leads to :a slight decrease in ee (Reactions A, B, C')a large decrease in ee (Reaction C)Substitution of phthalazine with pyridazine leads to: a small drop in ee (Reactions A, C, C') a small increase in ee (Reaction B)Larger groups at this position leads to: an increased ee   (Reactions A, B)Vinyl group leads to: small drop in ee(Reactions A, B)-Substitution of OMe with H leads to a decrese in ee (Reactions A, C, C')-Substitution of Me with bulky alkyl groups leads to :a decrese in ee (Reaction A)an increase in ee (Reaction B)Chirality about carbon attached to nitrogen is more significant(Reactions A, B, C, C')-Phthalazine nitrogens are essential for high enantioselectivities-Linkers without these nitrogen atoms give racemic product(Reactions A, B, C, C')!!%'"!II-4 Detailed stereochemical investigations of chlorocyclization reactions With the growing insights in halocyclizations reactions, a detailed mechanistic study is critical. The (DHQD)2PHAL-catalyzed chlorocyclizations of 1,1-disubstituted olefins have been the focus of many groups in the last few years. Nonetheless, numerous mechanistic nuances, especially the aspects that control stereochemical preferences, have not been studied in much detail. In this chapter we provide a detailed stereochemical analysis of intramolecular chlorocyclization of nucleophile tethered 1,1-disusbtituted styryl systems by using a combination of NMR, derivative and isotope labeling studies. This tool has allowed us to distinguish the selectivities of two independent stereoselective events, namely, the face-selectivities of chlorenium attack and of nucleophilic cyclization. Four related reactions (A, B, C, and CÕ) were subjected to this analysis under the established optimal conditions (Figure II-6). We sought to develop a strategy to reveal both the stereochemical outcomes of the halenium attack and of the nucleophilic closure under both non-catalyzed and catalyzed conditions to probe the influence of the catalyst in modulating the anti/syn diastereoselectivity. The first step towards mapping the role of (DHQD)2PHAL on controlling the stereochemical outcomes in these reactions begins with understanding the elements that control selectivity at each step.    !!%(&! The main aim of this study was to uncover the stereochemical relationships between the chlorenium delivery and the nucleophilic closure OPhOClPhOHO(DHQD)2PHAL,  DCDPH  CHCl3-Hex (1:1)Benzoic acid, -40 ¼C, 1 hReaction A89% ee, 2a9 other examples up to 95:5 er(DHQD)2PHAL, DCDPHTFE, -30 ¼C, 2 hPhHNPhONOPhClPhReaction B90% ee, 2b9 other examples up to 99:1 erNHOPhClONHOPhOClPhHNOtBuO82% ee, 2c8 other examples up to 91:9 er80% ee, ent-2c8 other examples up to 96:4 er1a1b1cNMeOONOMeONEtNEtHHNN(DHQD)2PHALNNOOR'R'ClClDCDMHR' = MeR' = PhDCDPH(DHQD)2PHAL (20 mol%) DCDMH (1.2 equiv)CHCl3-Hexane (1:1), 0 ¼C, 3 h(DHQD)2PHAL (1 mol%) DCDMH (1.2 equiv)Benzoic acid, n-PrOH, -30 ¼C, 3 hReaction CReaction C'PhHNOtBuO1cFigure II-6 Asymmetric chlorocyclization of alkenoic acid 1a (Reaction A), unsaturated amide 1b (Reaction B), and carbamate 1c under two different conditions (Reactions C and CÕ).  !!%(%!that yields the observed products in Figure II-6. Some key similarities and differences between the reactions of carboxylic acid 1a, and those of amides and carbamates 1b and 1c, should be noted at the outset. (a) All these reactions employ (DHQD)2PHAL as the chiral catalyst and chlorinated hydantoins as the chlorenium source. (b) The stereochemistry of the newly created quaternary carbon (C5) in the product is nucleophile dependent. (c) In the case of the carbamate substrate 1c, the C5 stereochemistry is modulated by the choice of solvent. With these diverse results in hand, we posed the following questions about the timing and mode of the catalystÕs control over the ultimate ring-closure stereochemistry: (a) Does chlorenium attack on the 1,1-disubstituted olefin have any facial preference, and if so, which face? (In the unlabeled system, after cyclization, the newly formed sp3 CH2Cl center lacks observable chirality and the face selectivity of chlorenium delivery is therefore unclear.) (b) Are variations in absolute configuration at C5 related to different olefin face selectivities in the chlorenium transfer step? What stereochemical relationships are found between the chlorine atom and the nucleophile in the final product? Net syn or anti halocyclization could shed light on the nature of the reaction path; (c) Is the overall reaction a stepwise process, via a bridged chloriranium ion or a carbocation intermediate, or is it concerted? If stepwise, the productÕs chirality may be independent of the initial chlorenium attack. Therefore, (d) what process sets the ultimate enantioselectivity? !!%('!To clarify the above ambiguities, we have employed isotopic labeling to fully characterize the stereochemistry of addition in the chlorocyclization of carboxylic acids (Reaction A),115 unsaturated amides (Reaction B) and carbamates (Reactions C and CÕ) (Figure II-6). Following our previous investigations on Reaction A,115 the presence of the deuterium in 1a-D, 1b-D, and 1c-D leads to diastereomeric products that not only reveal the chlorenium face selectivity of the olefin, but also indicate the stereochemical relationship between the delivered halogen and the captured nucleophile, i.e.; is the addition syn or anti. The results of this study, as detailed below, reveal a diversity of absolute and relative stereochemical fates in both the chlorenium attack and ring closing processes. II-5 Labeling studies The final cyclized product of the 1,1-disubstituted olefin contains only one stereocenter, since the chlorine ends upon a non-chiral carbon. To explore the stereocontrol in chlorocyclization reactions and have a sense of face selectivity of Cl+, we replaced one of the vinylic protons with deuterium. This leads to diastereomeric products with two chiral carbons, the quaternary carbon and the carbon attached to the chlorine (Scheme II-8). Having two chiral centers on the final product provides the opportunity to investigate the face selectivity in the chlorination and the subsequent attack of the internal nucleophile. If the reaction proceeds through a free halocarbonium intermediate, then the enantioselectivity of this reaction is solely controlled by !!%((!the ring-closing step; the stereochemical memory of the asymmetric delivery of the chlorine to the olefin would be lost through the formation of planar carbocation. However if the reaction proceeds through a bridged intermediate, then the enantioselectivity could be controlled by chiral delivery of the chlorenium as the nucleophile opens the intermediate through a SN2 displacement. To explore the above questions, the synthesis of the E-deuterated substrates 1b-D and 1c-D was accomplished in four steps (Scheme II-9). Propargyl phthalamide II-14 was synthesized from propargyl bromide in 61% yield. The deuterium was incorporated through palladium-catalyzed syn Open form (carbocation)PhDHNuHPhDHNuHClPhDClNuHHNuHPhDClNuHPhClDNuHPhDClNuHPhClDDiastereomer 1Diastereomer 2bridge form (halenium)PhDHNuHPhDClNuHHNuHPhDClNuHPhClDDiastereomer 1PhDClNuHHScheme II-8. Two plausible intermediates: Open form (formation of the two diastereomers), and bridged form (formation of the one diastereomer).  !!%()!hydrophenylation of II-14 with sodium tetraphenylborate in D2O/acetic acid to afford II-15.135 Hydrolysis of imide II-15 and subsequent derivatization of the deuterated amine II-16 with the appropriate acylating agent led to the formation of the desired substrates 1b-D and 1c-D with a high level of deuterium incorporation and good E/Z selectivity.   II-6 Absolute stereochemical determination The cyclization of the deuterated substrates could lead to formation of 4 possible isomers (two enantiomers, two diastereomers) across chiral carbons C-5 and C-6 (Scheme II-10). The absolute stereochemistry of the deuterated chlorocyclized product 2b-D and 2c-D at C-5 was determined by X-ray crystallography.86, 91 The absolute configuration at C-6 was confirmed via derivatization studies.  Scheme II-9 Synthesis of 1b-D and 1c-D starting from propargyl bromide.  Pd(Cl)2(PPh3)2D2O, HOAcNaBPh4PhND1. NH2NH2PhNH2DHNOOOOHPhHNDHPhO1b-D87:13 E:Z95% D-incorporation2. HCl, then KOHBzCl, Py51% yield52 ¼C, 12 h 53% yield89% yieldPhHNDHOt-BuO1c-D86:14 E:Z93% D-incorporationBoc2O, Et3N50% yieldII-14II-15II-16BrPotassium PhthalimideDMF, 80 ¼C 8h, 61% yieldPropargylbromide!!%(*!The major product of both deuterated and non-deuterated substrates was transformed to an epoxide with known stereochemistry. Hydrolysis of oxazoline 5R-2b-D (major isomer from chlorocyclization under Reaction B) with HCl afforded N-benzoyl §-amino alcohol II-17 (Scheme II-11a). The resulting halohydrin intermediate was treated with K2CO3 to afford the 1,1-disubstituted epoxide 3b-D under mild conditions. Non-deuterated epoxy amide 3b was synthesized similarly. ROESY and NOESY studies on the epoxy amide 3b established the relative stereochemistry of Ha (2.80 ppm, cis) and Hb (3.10 ppm, trans) with respect to the phenyl group. 1H NMR analysis of the epoxy amide 3b-D, obtained from the product of the chlorocyclization of 1b-D via Reaction B conditions, exhibits the peak at 3.10 ppm, suggesting that the deuterium has a cis orientation with respect to the phenyl group. This ClPhNuDH56ClChiral catalystPhNuDH56NuPhClDH564 possible productsScheme II-10 Chlorocyclization of deuterated substrates. !!%(+!leads to the assignment of R configuration for the carbon bearing the deuterium in epoxy amide 3b-D. Since the epoxy amide is formed through the SN2 closure of the corresponding chlorohydrin intermediate, the S configuration at C-6 is assigned for amide 2b-D (major product of Reaction B, Scheme II-11).   In an analogous study, the absolute stereochemistry for C-6 in products obtained from the chlorocyclization of the carbamate 1c-D under conditions noted as Reaction C and CÕ were determined (Scheme II-12). Tosyl protection of oxazolidinone 5R-2c-D and 5S-2c-D (stereochemistry of C-5 was established previously via X-ray crystallography),91 followed by cesium carbonate mediated ring opening of the resulting chlorohydrin intermediate, gave 1,1-disubstituted epoxy sulfonamide 3c-D and ent-3c-D. The non-deuterated epoxy amide ent-3c was synthesized from 5S-2c following the same protocols. ROESY analysis of epoxy amide ent-3c Scheme II-11 Absolute stereochemical assignment at the deuterated center (C-6) for substrate 2b-D. Ph(R)(R)(R)(R)OHNHD3.10 ppm in 1H-NMRNOPhClDH5R,6S-2b-D1b-DPhHND3b-D56HOPhPhOPh HCl, 1,4-dioxaneReaction BNaHCO3, 50 ¼C, 69%MeOH:H2O, 62%K2CO3, rtPhOHNHbHa3b3.10 ppm2.80 ppmNOESY-1DROESY-2DOPhPh(R)(R)OH(S)(S)ClDHHNOPhII-17!!%(#!indicated that Ha (2.75 ppm) is cis to the phenyl group, while Hb (3.20 ppm) is trans.  1H NMR data obtained for the epoxides derived from the major products of Reaction C and CÕ chlorocyclization reveal the absolute stereochemistry on the labeled C-6 center of the cyclized products 5R-2c-D and 5S-2c-D is S for both (Scheme II-12). The summary of the stereochemical assignments of the cyclized products 2c-D and ent-2c-D Scheme II-12 Absolute stereochemical assignment at the deuterated center (C-6) for substrates 2c-D (top) and ent-2c-D (bottom). Ph(S)(S)(R)(R)OHNDH2.75 ppm in 1H-NMRNHOPhClDH5S,6S-2c-D1c-DPhHNDent-3c-D56HOOtBuSOOONOPhClDH56OTsReaction C'PhOHNHbHaent-3c3.20 ppm2.75 ppmROESY-2DSOO NaH, THF/DMFTsCl, 0 ¼C to rt93%0 ¼C to rt86%Cs2CO3 MeOHPh(S)(S)O(S)(S)ClDHHNSOO1c-DPhHNDHOOtBuReaction CPhOHNHbHaent-3c3.20 ppm2.75 ppmROESY-2DSOONHOPhClDH5R,6S-2c-D56O NaH, THF/DMFTsCl, 0 ¼C to rt93%NOPhClDH56OTs0 ¼C to rt86%Cs2CO3 MeOH3c-DPh(R)(R)(R)(R)OHNHDSOO3.20 ppm in 1H-NMRPh(R)(R)O(S)(S)DHClNHSOOII-18ent-II-18!!%($!along with their 1H NMR spectra in comparison with dihydrogenated product ent-2c are shown in Figure II-7.        ',#* (,'& 3c-Danti cyclization in CHCl3:HexNHOPhClDH5R,6S-2c-D56OPh(R)(R)(R)(R)OHNHDSOOent-3c-DNHOPhClDH5S,6S-2c-D56OPh(S)(S)(R)(R)OHNDHSOOsyn cyclization in n-PrOHNHO(S)(S)PhClent-2cOPh(S)(S)OHNHHSOOent-3cFigure II-7 Summary of stereochemical assignments coupled with the NMR spectra of the epoxides. a         b         c !!%("!II-7 Stereochemical outcomes of uncatalyzed reactions To gain a better understanding on the influence of the catalyst through the course of the reactions, the intrinsic diastereoselectivity of the uncatalyzed processes was first investigated. The uncatalyzed reactions were carried out in a similar fashion as those detailed in Figures II-6 except at room temperature and in the absence of (DHQD)2PHAL. Although the products were obtained as a racemic mixture, the syn:anti ratios show the intrinsic selectivity for each reaction.  The summary of diastereomeric ratios of deuterated cyclized products is shown in Figure II-8. Carboxylic acid 1a-D reacts with DCDMH in CHCl3 to afford the cyclized product in 50:50 mixture of syn/anti ratio.115 Amidoalkene 1b-D reacts sluggishly with 1,3-dichloro-5,5-diphenylhydantoin (DCDPH) in TFE at room temperature to afford an 85:15 mixture of the two diastereomers with the anti-cyclized product as the major isomer. Similarly, predominant anti addition is found for the uncatalyzed reaction of carbamate 1c-D with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) in CHCl3-hexanes and n-PrOH solvent systems; there, anti:syn ratios were 84:16 and 97:3, respectively. Formation of significant quantities of the syn isomer serves as evidence that these reactions do not proceed exclusively through stereochemically-defined intermediates (e.g. cyclic chloriranium ions) where stereospecific cyclization to the anti isomer would ensue.   !!%)&!II-7A Calculations to determine diastereomeric ratio of labeled cyclized products via non-catalyzed pathway The synthesized deuterated starting materials (carboxylic acid, amide, and carbamates) contain di-hydrogenated and Z isomeric impurities. In order to correct for these impurities, we utilized the diastereomeric ratios obtained from 1H NMR analysis, through mathematical treatments. All the numbers obtained for all four chlorocyclizations were derived similarly. In the following the overall procedure for the correction of the uncatalyzed chlorocyclization of amides is detailed.  Nucleophilesyn/antinoncatalyzedNHOPhNHOOtBuCHCl3:Hexn-PrOHsyn/anti50/50syn/anti15/85syn/anti16/84syn/anti3/97CO2HNuPhClDHNuPhClHDNuPhClDHNuPhClHD565S 50%)5R (50%)5S,6S-2b-Dsyn5R,6S-2b-Danti5R,6R-2b-Dsyn5S,6R-2b-Dantisyn additionanti additionPhDHNuUncatalyzed ReactionsB, C, C'Figure II-8 Summary of stereochemical assignments of uncatalyzed reactions. !!%)%!The synthesized starting material 1b-D contains 5% unlabeled amide 1b, so the integral value of each diastereomeric product was calculated by subtracting the integral value of the overlapping non labeled product as depicted in Scheme II-13. Peaks a, b, c, d (AB quartet) belongs to the non-labeled substrate. The integral values of peaks a and d are equivalent (a = d = 2.47) and so are the integral values for peaks b and c (b = c = 3.10). Peaks Scheme II-13 1H NMR of labeled 2b-D, cyclized under non-catalyzed condition.  b  +  e a d  + f c !NOPhClDHNOPhClHDNOPhClDHNOPhClHD565S,6S-2b-D5R,6S-2b-D5R,6R-2b-D5S,6R-2b-DPhPhPhPhsyn additionanti additionffeeNOPhClHH5R-2b  +   5S-2bPhAB quartet = a, b, c, d non-labeled product!!%)'!e and f belong to the deuterated product and overlap with b and d, respectively. To obtain the corrected value of e, the integral value of c is subtracted from the overall integral of b and e (e = 100 Ð 3.10 = 96.90). Similarly to evaluate the integral of f, the integral value of a is subtracted from the overall integral value of d and f (f = 33.60 Ð 2.47 = 31.13). This calculation results in a 76:24 anti:syn ratio prior to the 13% correction for the presence of the Z-olefin. To correct for the E/Z isomeric mixture in starting alkene, we used the following equations II-1 and II-2. Defining the fraction of product that arises from attack of Cl+ on the olefin syn to the nucleophile as (S), and that anti to the nucleophile as (A), the following equations can be derived: After rearrangement and cross-multiplying, we get equation (III-3). Since the dihydrogen corrected amounts of syn and anti products are known (see correction discussed above), the corresponding values can be inserted in the below equation (III-3) to evaluate the ratio of anti-addition to syn-addition for the final corrected value.   D1-anti= ES(A + S)   ZA(A + S)D2-syn= ZS(A + S)   EA(A + S)II-1II-2!!%)(! Replacing the numbers would give:  Hence,  %D1 = 84.7 and %D2 = 15.29. i.e. anti-addition : syn-addition = 85:15. II-7B Effects of chlorenium sources on stereochemical outcomes of uncatalyzed reactions  In an effort to better understand factors that affect the diastereoselectivity of these transformations, numerous reaction parameters were systematically studied for the chlorocyclization of amide 1b-D. The effect of the chlorenium sources in changing the anti:syn ratio for the uncatalyzed chlorocyclization of 1b-D was investigated first (Table II-1). Most of the chlorenium sources result in diastereoselectivities in the range of 78:22 to 85:15 anti:syn cyclization except TCCA that gave 65:35 dr, nonetheless still favoring the predominant formation of the anti product (Table II-1, entries 1-8). These results suggest that the identity of the chlorenium source plays a crucial role in the stereochemistry-determining event. Noteworthy is the lack of an apparent trend with weak or strong chlorenium sources in the stereochemical outcome of the reaction.  In a concerted or near-concerted D1%D2=31.13 x 13 -96.90 x 8796.90 x 13 -31.13 x 87= 5.54D1%D2=S x Z -A x EA x Z -S x EII-3!!%))!mechanism, the simultaneous approach of both nucleophile and chlorenium source would require appropriate orientation of the two reacting species. This could explain the importance in the structure of the chlorenium sources in modulating anti:syn ratios. Additionally, the role of the byproduct anion after chlorenium ion delivery should be considered. The chlorenium ion would presumably be shared unequally between the two neutral acceptors, olefin and the donor, during the chlorenium transfer. The thermodynamic measure of the latter competition was reported previously as the halenium affinity (HalA, Chapter 1).136 The HalA parameter quantifies the strength of each acceptor and thus the relative closeness of the anionic donor or the olefin acceptor with the chlorenium. The proximity of the chlorenium to the olefin in each case could lead to various anti/syn diastereoselectivities.           !!%)*!   Entry Cl+ source Time (h) dr (A : B)[a] (syn : anti) 1 DCDPH 12  15 : 85 2 DCDMH 12  21 : 79 3 DiCh.T 12  10 : 90 4 N-Chlorosaccharin 12  14 : 86 5 TCCA 12  35 : 65 6 NCS 72  20 : 80  7[b] N-Chlorophthalamide 72  22 : 78  8[c] Ch.T 72  20 : 80 !Table II-1 Effects of chlorenium sources on syn/anti diastereomeric ratio.  1b-DPhHNDCl+ source (1.1 equiv)HOPhNOPhClDHNOPhClHDNOPhClDHNOPhClHD565S 50%)5R (50%)5S,6S-2b-Dsyn5R,6S-2b-Danti5R,6R-2b-Dsyn5S,6R-2b-Dantisyn additionanti additionPhPhPhPh(A  :  B)TFE (0.05 M), rt[a] Diastereomeric ratios were measured by 1H NMR; [b] 82% conversion after 3 days; [c] 58% conversion after 3 days. !!%)+!II-7C Effects of reaction solvent on stereochemical outcomes of uncatalyzed reactions  The effect of the reaction solvent on the anti:syn ratios was next studied (Table II-2). The dr values showed significant solvent dependence.  TFE, MeCN, and CHCl3 afforded anti:syn ratio ca. ~85:15.  When solvents with relatively lower polarity were employed, high anti:syn values were obtained. For example DCM and PhCH3 afforded anti:syn ratios of 97:3 and 98:2, respectively.  Likewise, running the reaction in a 1:1 mixture of CHCl3-hexanes gave a much higher 97:3 dr ratio as compared to the result with CHCl3 alone (86:14). In general, more polar environments seem to promote higher syn selective cyclization. These results point to the possibility that multiple mechanisms are operating under various conditions; e.g. due to the higher stability of a carbocation intermediate in polar solvents, more positively charged transition states are favored. In other words, the presence of a carbocation intermediate, which could yield higher syn products, is more probable in polar solvents. Conversely, in less polar solvents, concerted reactions, where a less ionic transition state is produced, would lead to higher ratio of anti products, !!%)#!      Entry Solvent (0.05M) Time (h) dr (A : B)[a] (syn : anti) 1 TFE 12  15 : 85 2 CHCl3 : Hex (1:1)  12  3 : 97 3 CHCl3 12   15 : 85 4 MeCN 12   14 : 86 5 DCM 12  3 : 97 6 toluene  12  2 : 98 !Table II-2 Effects of solvents on syn/anti diastereomeric ratio.  1b-DPhHNDDCDPH (1.1 equiv)HOPhNOPhClDHNOPhClHDNOPhClDHNOPhClHD565S 50%)5R (50%)5S,6S-2b-Dsyn5R,6S-2b-Danti5R,6R-2b-Dsyn5S,6R-2b-Dantisyn additionanti additionPhPhPhPh(A  :  B)Solvent (0.05 M), rt[a] Diastereomeric ratios were measured by 1H NMR !!%)$!II-7D Effects of reaction concentration on stereochemical outcomes of uncatalyzed reactions Intriguing but unexpected results were observed when the effect of reactant concentration with respect to the reaction diastereoselectivity was investigated.  Decreasing the concentration of both the substrate and DCDPH in TFE led to the formation of increasing syn product (Table II-3). This is graphically illustrated in Figure II-9, showing a steep change in anti/syn ratio at ~0.05 M. A hypothetical interpretation of this data could suggest different reactant molecularities at the transition state lead to either syn or anti products.  More succinctly stated, at high concentrations, an anti producing transition state could be composed of two molecules of DCDPH (one acting as a base, the other as the chlorenium source) and one molecule of the olefin reactant (Figure II-10).  At lower concentrations, one DCDPH molecule could function as both the base and the chlorenium source, delivering the halogen from the same face as the nucleophile. This is consistent with our subsequent studies, where the concentration of DCDPH was kept constant (0.11 M), and the concentration of substrate in TFE was decreased from 0.10 M to 0.005 M (Table II-3, entries 8-11). This led to a similar trend with an increase in the syn product. Conversely, when the concentration of substrate was kept constant at 0.01 M in TFE and concentration of DCDPH was lowered from 0.11 M (10.0 equiv) to 0.011 M (1.1 equiv), no significant changes were observed in diastereoselectivity (Table II-3, entries 12-15).  !!%)"!  Entry [Sub] M [DCDPH] M dr (A : B)[a] (syn : anti) 1 0.5  0.5  12 : 88 2 0.2  0.2  12 : 88 3 0.1  0.1  12 : 88 4 0.05  0.05  15 : 85 5 0.01  0.01  31 : 69 6 0.005  0.005  38 : 62 7 0.0025  0.0025  44 : 56 8 0.10  0.11  16 : 84 9 0.05  0.11  18 : 82 10 0.01  0.11  39 : 61 11 0.005  0.11  34 : 66 12 0.01  0.011  31 : 69 13 0.01  0.022  39 : 61 14 0.01  0.055  38 : 62 15 0.01  0.11  39 : 61 ![a] Diastereomeric ratios were measured by 1H NMR Table II-3 Effects of reactant concentrations on syn/anti diastereomeric ratio.  1b-DPhHNDDCDPH (x M)HOPhNOPhClDHNOPhClHDNOPhClDHNOPhClHD565S 50%)5R (50%)5S,6S-2b-Dsyn5R,6S-2b-Danti5R,6R-2b-Dsyn5S,6R-2b-Dantisyn additionanti additionPhPhPhPh(A  :  B)TFE (y M), rt!!%*&!This might suggest the requirement of having more than one chlorenium source that is involved in the transition state for the anti cyclization, presumably acting as the base accepting the proton from the amide moiety (Figure II-10). More detailed mechanistic studies are required to explain the trend between the syn/anti ratios and the concentration of medium.      123456780.50 0.20 0.10 0.05 0.01 0.005 0.0025 Anti/syn ratio[Sub] M!!Figure II-9 The plot of anti/syn ratios vs. concentration of 1b-D. !!%*%! II-7E Effects of the nucleophile on stereochemical outcomes of uncatalyzed reactions Lastly, we investigated the effect of modulating the electronics of the aryl group on the diastereoselectivity of the chloro amidoalkene cyclization. The largest change is seen with the 3,5-dinitro substituted aryl amide, which yields a near 1:1 anti:syn ratio of products (Table II-4).  One would assume the reduced nucleophilicity of the carbonyl group could lead to a longer-lived intermediate that is more carbocationic in nature, thus increasing the syn product ratio. Prior work by Williams and Dangat demonstrating that catalytic quantities of nucleophilic anions substantially increases reaction rates and stereoselectivities is supportive of this argument.124, 126 The totality of these studies argues against the classical hypothesis that invokes a simple cyclic PhNNOOClClOOHPhOOHNNOOClClNNOOClClsyn additionHHHHanti additionabFigure II-10 Putative models for syn (a) and anti (b) addition. The higher propensity for anti addition at high concentrations could arise from the higher molecularity of reactants at the transition state, leading to the product.  !!%*'!chloriranium ion or a pure carbocation intermediate and limits the rate determining intermediate to the interaction of a bare ÒnakedÓ halenium ion and the reacting olefin.           Entry Substrate Label Product Label dr (A : B)[a] (syn : anti) 1 1b-D, Ar = C6H5 2b-D  12 : 88 2 II-19, Ar = 4-OMe-C6H5  II-23 22 : 78 3 II-20, Ar = 4-Me-C6H5 II-24  24 : 76 4 II-21, Ar = 3,5-(NO2)2-C6H5 II-25 43 : 57 !Table II-4 Effects of nucleophile on the diastereomeric syn:anti ratios. 1b-D  Ar = C6H5II-19  Ar = 4-OMe-C6H5II-20  Ar = 4-Me-C6H5II-21  Ar = 3,5-(NO2)2-C6H5PhHNDDCDPH (1.1 equiv)HOPhNOPhClDHNOPhClHDNOPhClDHNOPhClHD565S 50%)5R (50%)5S,6S-2b-Dsyn5R,6S-2b-Danti5R,6R-2b-Dsyn5S,6R-2b-Dantisyn additionanti additionPhPhPhPh(A  :  B)TFE (0.02 M), rt[a] Diastereomeric ratios were measured by 1H NMR !!%*(!II-8 Stereochemical outcomes of asymmetric chlorocyclization reactions  Having probed the intrinsic diastereoselectivity of uncatalyzed chlorocyclization reactions discussed in Section II-7, we turned our attention to dissecting the stereochemical control elements present during the course of the (DHQD)2PHAL catalyzed asymmetric reactions. We utilized the deuterated substrates under the optimized catalytic reaction conditions shown in Figure II-6 to yield diastereotopic product at C-5 and C-6. We were able to measure the ratio of the four isomers (two enantiomers and two diasteremers across C-5 and C-6) by using a combination of chiral HPLC and 1H NMR analysis. The procedure to measure the ratios and the mathematical treatments will be explianed in full for the chlorocyclization of amide 1b-D (Reaction B, Figure II-6) in Section II-8A. II-8A Calculations to determine the quantity of the four isomeric products 2b-D obtained through (DHQD)2PHAL catalyzed chlorocyclization Reaction of the labeled substrate 1b-D under optimized asymmetric catalytic condition (Reaction B) results in products that enable analysis of olefin face selectivity for chlorenium delivery in first step by using chiral HPLC and 1H NMR spectroscopy (Scheme II-14). In order to obtain the ratio of the four isomers, two groups of products epimeric at C5 (5R versus 5S) were separated by chiral HPLC [with (93:7) er favoring R configuration at C-5 as determined by crystallography].86 Since HPLC does not separate deuterated !!%*)!from non-deuterated analogs, we obtained D1En2/D2En2 (set1) and D1En1/D2En1 (set2) after HPLC purification using OJ-H chiral column (Scheme II-14). Set1 contains two diastereomers (5R,6R) and (5R,6S), while set2 has diastereomers (5S,6S) and (5S,6R). Note that each set contains epimeric C6 compounds, reflecting the diastereomers that result from deuterium labelings. 1H NMR analysis of these two sets reveal a dr of (99:1) for set1 (obtained from chiral HPLC separation of the major enantiomer at C-5), and a dr of (73:27) for set2 (obtained from chiral HPLC separation of the minor enantiomer). These diastereomeric ratios are the finalized values after correction for the amount of non-labeled product and E/Z mixture of the starting material. The corrections are described below. Steps toward the calculation of the final corrected dr numbers are as follows. The dr ratios were calculated by subtracting the integral value of the non-labeled product from the overall integral of the diastereomers as explained earlier for the non-catalyzed chlorocyclization analysis. The 1H NMR of the starting material 1b-D shows 13% Z olefin as contaminant. For correction of the E/Z isomeric mixture, we used the following equations II-4 and II-5. Defining the fraction of product that arises from C6-Pro-S attack of Cl+ on the olefin as B (bottom face attack), and that from the C6-Pro-R attack of Cl+ as T (top face attack), 5R, 6R= EB(T + B)   ZT(T + B)5R, 6S= ZB(T + B)   ET(T + B)II-4II-5!!%**!the following equations can be derived:  After rearrangement and cross-multiplying, we get equation (II-6). Since the diastereomeric ratio is available from 1H NMR analysis, the corresponding values can be inserted in equation (II-6) to evaluate the ratio of syn-addition to anti-addition for the final corrected value.  For example, letÕs walk through the calculation of anti:syn (D1:D2) ratio of the major enantiomer (En2) using 1H NMR analysis [D1En2/D2En2 (set1), shown in Scheme II-14]. The synthesized starting material 1b-D contains 5% unlabeled amide 1b, the integral value of each diastereomer was calculated by subtracting the integral value of the overlapping non-labeled product as depicted in Scheme II-15. Peaks a, b, c, d (AB quartet) belongs to the non- labeled substrate. The integral values of peaks a and d are equivalent (a = d = 2.05) and so are the integral values for peaks b and c (b = c = 3.60). Peaks e and f belong to the deuterated product and overlap with b and d, respectively. To obtain the corrected value of e, the integral value of c is subtracted from the overall integral of b and e (e = 100 Ð 3.60 = 96.4). Similarly to evaluate the integral of f, the integral value of a is subtracted from the overall integral value of d and f (f = 16.49 Ð 2.05 = 14.44). This calculation results in 87:13 anti:syn ratio prior to 13% correction for the Z-olefin.  B%T=5R, 6Sx Z  -5R, 6Rx E5R, 6Rx Z  -5R, 6Sx E(II-6)!!%*+!Assuming similar stereoselectivity of E and Z isomers, the major diastereomer (anti) (5R,6S) product [which was found to be anti diastereomer through derivatization studies in Section II-6], results from bottom face (B) attack of Cl+ (C6-Pro-S attack) on the E olefin (major contribution) and top face (T) attack of Cl+ (C6-Pro-R attack) onto the Z olefin (minor contribution). Similarly, the minor diastereomer (syn) (5R,6R), results from top face (T) attack of Cl+ on the E olefin (major contribution) and bottom face (B) attack of Cl+ on Z olefin (minor contribution). In order to correct for 13% Z olefin impurity, we used equation (II-6):  Hence, %B = 99.96 and %T = 0.04. i.e. anti-addition : syn-addition = >99:1      B%T=14.44 x 1396.40 x 87-96.40 x 1314.44 x 87-=2662.04!!%*#!  Chiral HPLC Separation of C-5 Epimers using Chiral OJ-H column NOPhClDH2b-D1b-DPhHND(DHQD)2PHAL (2 mol%)DCDPH (1.1 equiv)TFE, -30 ¼C, 2 hHOPhPh56Scheme II-14 Face selectivity in chlorine delivery was measured by using chiral HPLC and 1H NMR.   1520253035time (min)!D1En1 D2En1 D1En2 D2En2 Major enantiomer  Minor enantiomer  NOPhClDHNOPhClHDPhPh(R)(S)(S)(S)D1En1D2En1NOPhClDHNOPhClHDPhPh(S)(R)(R)(R)D2En2D1En2NOPhClDHNOPhClHDPhPh(S)(R)(R)(R)D2En2D1En2(99 : 1)drNOPhClDHNOPhClHDPhPh(R)(S)(S)(S)D1En1D2En1dr(73 : 27)1H NMR1H NMR1H NMR Analysis for Determination of C-6  Epimeric Ratio  !!%*$! II-8B Stereochemical outcomes of asymmetric chlorolactonization reactions We previously reported on the results for the chlorolacotnization of alkenoic acid 1a (Figure 1, Reaction A), which undergoes facially selective syn addition of the carboxylate and the chlorenium ion with an overall 88:12 syn:anti preference (Figure II-11).115 The chlorolactonization of t-butyl ester was also investigated in this report; where a significant drop in enantioselectivity was observed in the nucleophilic cyclization step, yielding anti isomer as the major product. The result showed that the carboxylic acid Scheme II-15 1H NMR spectrum of the major enantiomer 5R-2b-D, cyclized under catalyzed condition.  b  +  e c d  + f a NOPhClDHNOPhClHD565R,6S-2b-D5R,6R-2b-DPhPhsyn addition product of major enantiomer(D2En2)anti addition productof major enantiomer(D1En2)feNOPhClHH5R-2bPhAB quartet = a, b, c, d non-labeled product!!%*"!moiety is important for achieving high enantioselectivity, presumably as a result of ionic interactions or hydrogen bonding within the chiral catalyst.   II-8C Stereochemical outcomes of asymmetric chloro amidoalkene cyclization Probing Reaction B, the (DHQD)2PHAL-catalyzed chlorocyclization of deuterated amide 1b-D yields four stereoisomers under the previously reported catalytic asymmetric conditions (Figure II-12).86 The chlorenium facial selectivity, investigated through 1H NMR analysis of the HPLC purified diastereomers (see Section II-8A for full detail), indicates the formation of the anti product as the major component of the mixture (94%). This finding (DHQD)2PHAL (10 mol%)DCDMH (1.1 equiv)CHCl3-hexane (1:1)PhCO2H (1 equiv), -40 ¼C85% yield, 82% eeC6-epimers distinguishable by 1H-NMRC5-epimers separable by HPLCReaction AOPhClHDOPhClHDOPhClDHOPhClDH565S (9%)5R (91%)5R,6S-2a-Danti, 3%6R (96%)6S (4%)5R,6R-2a-Dsyn, 88%5S,6R-2a-Danti, 9%5S,6S-2a-Dsyn, <0.3%6R (97%)6S (3%)OOOOPhHDOHO 1a-DFigure II-11 (DHQD)2PHAL catalyzed chlorocyclization of 1a-D (Reaction A).!!!!%+&!suggests that (DHQD)2PHAL controls the facial selectivity of the initial chlorenium attack, forming the major epimer with a 99:1 preference for 6S stereochemistry, but only moderate 6S selectivity in forming the minor product (73:27). The nucleophilic closure occurs with high selectivity (93:7 ratio) favoring the R configuration at C-5. Thus, the two bond-forming events appear to be independently controlled by the catalyst. Noteworthy is the fact that although Reactions A and B (chlorolactonization and chloroamidocyclization, respectively) lead to opposite chirality at the cyclized carbon (5S for Reaction A and 5R for Reaction B), the initial chlorenium delivery occurs from the same face of the olefin.  The overall process, therefore, is syn for chlorolactonization (Reaction A) and anti for chloroamidocyclization (Reaction B). PhHNDHPhO1b-D(DHQD)2PHAL (2 mol%)DCDPH (1.1 equiv)TFE, -30 ¼C, 2 h93% yield, 86% eeC6-epimers distinguishable by 1H-NMRC5-epimers separable by HPLCNOPhClDHNOPhClHDNOPhClDHNOPhClHD565S (7%)5R (93%)5S,6S-2b-Dsyn, 5%6R (27%)6S (73%)5R,6S-2b-Danti, 92%5R,6R-2b-Dsyn, 1%5S,6R-2b-Danti, 2%6R (1%)6S (99%)PhPhPhPhReaction BFigure II-12 (DHQD)2PHAL catalyzed chloro amidoalkene cyclization of 1b-D (Reaction B).!!!!%+%!II-8D Stereochemical outcomes of asymmetric chlorocyclization of carbamates In Reactions C and CÕ, carbamate 1c, Dr. Garzan measured a switch in the enantiopreference of (DHQD)2PHAL-catalyzed chlorocyclization depending on reaction conditions Ð primarily the reaction solvent.91 This study pointed to a strongly solvent-dependent entropy-enthalpy balance between the pro-R and pro-S pathways using Erying plot analysis. The overall stereochemistry of both these asymmetric alkene additions is now revealed via deuterated probe 1c-D. Chlorocyclization of 1c-D catalyzed with (DHQD)2PHAL in CHCl3:hexane (Reaction C, Figure II-13, top) yields the anti product 5R,6S-2c-D as the major isomer (85%).  The chlorenium delivery to yield products with 6S configuration occurs with high selectivity (93:7) for the major (5R) diastereomers. As in the above cases, although the 6S selectivity predominates for the minor diastereomer, it occurs with reduced discrimination (61:39).  The overall face selectivity for chlorenium delivery to the pro-S face of the =CHD site (i.e. 6S:6R) is 91:9. This C-6 stereoselectivity accidentally has the same numerical value as the enantioselectivity of the reaction (91:9 5R:5S).  When applied to Reaction CÕ (Figure II-13, bottom), the above analysis reveals a contrast to both the non-catalyzed reaction in n-propanol and the catalyzed Reaction C in CHCl3-hexanes where anti additions predominate (97:3 and 88:12, respectively). Instead, in a near complete switchover, the !!%+'!(DHQD)2PHAL catalyzed reaction in n-PrOH effects syn addition (net anti:syn = 10:90). However, as in all the other reactions discussed so far, chlorenium addition yields the 6S epimers in high enantioselectivity (99:1) for the major diastereomer and good selectivity (85:15) for the minor diastereomer. The net selectivity for chlorenium delivery to the C-6 pro-S face is 98:2 whereas the C-5 face selectivity is a significantly lower 90:10 pro-S preference due to greater ÔleakageÕ into the anti addition pathway.                !!%+(!  (DHQD)2PHAL (20 mol%)DCDMH (1.2 equiv)CHCl3-hexane (1:1)0 ¼C, 1h83% yield, 82% eeC6-epimers distinguishable by 1H-NMRC5-epimers separable by HPLCReaction CNHOPhClDHNHOPhClHDNHOPhClDHNHOPhClHD565S (9%)5R (91%)5S,6S-2c-Dsyn, 6%6R (39%)6S (61%)5R,6S-2c-Danti, 85%5R,6R-2c-Dsyn, 6%5S,6R-2c-Danti, 3%6R (7%)6S (93%)OOOOPhHNDHOtBuO 1c-D(DHQD)2PHAL (1 mol%)DCDMH (1.2 equiv)benzoic acid (0.5 equiv)n-PrOH, -30 ¼C, 20 min87% yield, 80% eeC6-epimers distinguishable by 1H-NMRC5-epimers separable by HPLCReaction C'PhHNDHOtBuO 1c-DNHOPhClDHNHOPhClHDNHOPhClDHNHOPhClHD565S (90%)5R (10%)5S,6S-2c-Dsyn, 89%6R (1%)6S (99%)5R,6S-2c-Danti, 9%5R,6R-2c-Dsyn, 1%5S,6R-2c-Danti, 1%6R (15%)6S (85%)OOOOFigure II-13 Chlorocyclization of carbamate 1c-D yields the anti product as the major isomer in 1:1 chloroform:hexanes (Reaction C, top), and the syn product as the major isomer in n-PrOH (Reaction CÕ, bottom).   !!%+)!II-8E Effects of chlorenium sources on stereochemical ourcomes of asymmetric chloro amidoalkene cyclization  The (DHQD)2PHAL-catalyzed chlorocyclization of deuterated amide 1b-D in TFE with DCDPH as the chlorinating source was investigated in Section II-8C. It revealed that (DHQD)2PHAL controls the facial selectivity of the initial chlorenium attack, forming the major epimer with a 99:1 preference for 6S stereochemistry, and the nucleophilic closure occurs with high selectivity (93:7 ratio) favoring the R configuration at C-5. Similar investigations in which DCDPH was replaced with dichloramineT salt (DiChT) and TCCA are summarized in Figures II-14 and II-15, respectively.   Figure II-14 Asymmetric chlorocyclization of amide 1b-D in presence of DiChT.   C6-epimers distinguishable by 1H-NMRC5-epimers separable by HPLCNOPhClDHNOPhClHDNOPhClDHNOPhClHD565S (8%)5R (92%)5S,6S-2b-Dsyn, 3%6R (57%)6S (43%)5R,6S-2b-Danti, 91%5R,6R-2b-Dsyn, 1%5S,6R-2b-Danti, 5%6R (1%)6S (99%)PhPhPhPh1b-DPhHND(DHQD)2PHAL (2 mol%)DiCh.T (1.1 equiv)TFE, -30 ¼C, 1 h91% yield, ee (84%)HOPhDiCh.TSOONClCl!!%+*!DichloramineT salt is as effective as DCDPH in chlorocyclization of unsaturated amide 1b-D yielding the anti product 5R,6S-2b-D in 91% yield and 92:8 er. The ratio of each isomer is shown in Figure II-14. (DHQD)2PHAL controls the facial selectivity of the initial chlorenium attack, forming the major epimer with a 99:1 preference for 6S stereochemistry, but low 6S selectivity in forming the minor product (43:57). The nucleophilic closure occurs with high selectivity (92:8 ratio) favoring the R configuration at C-5.  Replacing DCDPH with TCCA, however results in a significant drop in enantioselectivity apparent from loss of C-5 selectivity (Figure II-15). It led to the formation of 2b-D with the 5R isomer weakly predominant, at 38% ee. NMR analysis of the HPLC purified fractions indicates a much higher facial Figure II-15 Asymmetric chlorocyclization of amide 1b-D in presence of TCCA.   C6-epimers distinguishable by 1H-NMRC5-epimers separable by HPLC1b-DPhHNDHOPhNOPhClDHNOPhClHDNOPhClDHNOPhClHD565S (31%)5R (69%)5S,6S-2b-Dsyn, 16%6R (48%)6S (52%)5R,6S-2b-Danti, 66%5R,6R-2b-Dsyn, 3%5S,6R-2b-Danti, 15%6R (5%)6S (95%)PhPhPhPhTFE, -30 ¼C, 1 h88% yield, ee (38%)NNNClClClOOOTCCA(DHQD)2PHAL (2 mol%)TCCA (1.1 equiv)!!%++!selectivity in chlorenium transfer to the olefin than for the cyclization to the oxazoline product.  The S configuration dominates in the C-6 CHDCl group with high face selectivity of 95:5 in major epimer, but leakage into syn cyclization at C-5 at the second step is apparent from the low enantioselectivity observed in this transformation. This result hints at the importance of the chlorenium donor anion after the first enantioselective chlorenium delivery to the olefin in the syn/anti cyclization event. II-8F Structure enantioselectivity relationship studies of cinchona alkaloid dimers in stereochemical outcomes of asymmetric chloro amidoalkene cyclization  The SER studies of (DHQD)2PHAL-catalyzed chlorocyclization reactions reported by Dr. Marshall were discussed in Section II-3. Table II-5 details the effect of phthalazine linker in the final enantioselectivity of the chloro amidoalkene cyclization. Removal of the phthalazine nitrogen atoms leads to a significant drop in enantioselectivity (Table II-5, entry 1-2). Substituting the phthalazine linker with flexible acyl linkers gave only 26% ee (Table II-5, entry 1 and 3). We employed the deuterium labeled substrates to determine whether this is the result of a drop in facial selectivity of the chlorenium attack, the nucleophilic cyclization, or both events. The combined 1H NMR and HPLC technique showed a drop in enantioselectivity of both bond-forming steps for (DHQD)2NAPH-catalyzed reaction (Figure II-16). Chlorenium facial selectivity at C-6 is 51 to 49 with 81% anti cyclization. As !!%+#!noted earlier, the effect of the linker on enantioselectivity could be attributed to the conformational rigidity of the catalyst, specifically regarding the torsional angle along the alkaloid carbinol-oxygen-aryl linker bonds. The nitrogen atoms could be also involved in hydrogen-bonding interaction of the substrate with the catalyst. Catalyst (2 mol%) DCDPH (1.1 equiv)TFE, -30 ¼C, 2 hPhHNPhONOPhClPhReaction BHDDH2b-DII-1(DHQD)2PHALNONOONNOLinkerNNII-26(DHQD)2NAPHOOII-27(DHQD)2DAC1b-DEntry Catalyst  Yield[a]   ee[b] 1 II-1, (DHQD)2PHAL 93% 86% 2 II-26, (DHQD)2NAPH 94%  -4% 3 II-27, (DHQD)2DAC 90% 26% [a] Isolated yields for 2b-D; [b] ee was measured at C-5 by chiral HPLC.   Table II-5 Asymmetric chlorocyclization of amide 1b-D in the presence of cinchona alkaloids dimers.   !!%+$! We replaced the phthalazine linker with the acyl groups and tested (DHQD)2DAC for chlorocyclization of amide 1a-D (Figure II-16, bottom). DHQD)2DAC-catalyzed reaction shows a 63 to 37 facial selectivity for chlorenium attack and 78% anti cyclization. Although it is possible to imagine Figure II-16 SER studies of cinchona alkaloid dimers (DHQD)2NAPH (top) and (DHQD)2DAC (bottom)  on chloro amidoalkene cyclization of labeled amide 1b-D.   NOPhClDHNOPhClHDNOPhClDHNOPhClHD565S (37%)5R (63%)5S,6S-2a-Dsyn, 11%6R (70%)6S (30%)5R,6S-2a-Danti, 52%5R,6R-2a-Dsyn, 11%5S,6R-2a-Danti, 26%6R (18%)6S (82%)PhPhPhPh(DHQD)2DAC (2 mol%)DCDPH (1.1 equiv)TFE, -30 ¼C, 1.5 h90% yield, ee (26%)NOPhClDHNOPhClHDNOPhClDHNOPhClHD565S (52%)5R (48%)5S,6S-2a-Dsyn, 11%6R (78%)6S (22%)5R,6S-2a-Danti, 40%5R,6R-2a-Dsyn, 8%5S,6R-2a-Danti, 41%6R (17%)6S (83%)PhPhPhPh(DHQD)2NAPH (2 mol%)DCDPH (1.1 equiv)TFE, -30 ¼C, 2.5 h94% yield, ee (-4%)C6-epimers distinguishable by 1H-NMRC5-epimers separable by HPLCPhHNDHPhO1b-DReaction B(DHQD)2NAPHPhHNDHPhO1b-DReaction B(DHQD)2DACC6-epimers distinguishable by 1H-NMRC5-epimers separable by HPLC!!%+"!the ortho acyl linker in a conformation that which resemblances the phthalazine-linked catalyst in terms of electronics (where the two carbonyls mimic the two phthalazine nitrogens); the overall conformational rigidity of the catalyst might vary. This result suggests that facial selectivity of the chlorenium has the largest effect on the drop in enantioselectivity. II-9 Control experiment  Considering that the reactions discussed in Section II-8 might involve a carbocation intermediate that could undergo reversible chlorenium attachment, leading to stereo randomization of the starting olefinic geometry. Therefore, the stereochemical integrity of the recovered starting materials for Reactions B, C, and CÕ were examined (Scheme II-16). To do so, each reaction was carried out in the optimized reaction conditions (shown in Figure II-6) and quenched prior to completion.  PhDHNuHNuPhClDHClPhDHNuHClPhHDNuHReactionsB, C, C'Experimentally obtained(anti : syn) diastereomeric ratios are not derived from the isomerized starting materialScheme II-16 Possibility of the formation of the isomerized starting material.   !!%#&! Entry Substrate, Reaction[a]  Conv.[b]   E/Z ratio[c] 1 1b-D, B 0% 89.7 : 10.3 2 1b-D, B 28% 90.2 : 9.8 3 1b-D, B 30% 89.8 : 10.2 4 1b-D, B 31% 90.0 : 10.0 5 1b-D, B 49% 89.7 : 10.3 6 1b-D, B 59% 89.4 : 10.6 7 1b-D, B 76% 89.7 : 10.3 8 1c-D, C 0% 91.7 : 8.3 9 1c-D, C 42% 89.7 : 10.3 10 1c-D, C 56% 89.5 : 10.5 11 1c-D, C 68% 89.8 : 10.2 12 1c-D, C 80% 91.9 : 8.9 13 1c-D, CÕ 0% 91.7 : 8.3 14 1c-D, CÕ 8% 91.6 : 8.4 15 1c-D, CÕ 17% 91.8 : 8.2 16 1c-D, CÕ 26% 91.0 : 9.0 17 1c-D, CÕ 60% 91.0 : 9.0 [a] 1.1 equiv chlorine source was added; 2, 20, and 1 mol% catalyst loadings were used in reactions B, C, and CÕ, respectively,![b] Conversion% of 2b-D was measured by 1H NMR analysis of the crude reaction; [c] E/Z isomeric ratios of the recovered starting material was measured by 1H NMR analysis.!PhHNDHORNOPhClHDAr1b-D, R = C6H51c-D, R = O-tBu2b-D, R = C6H5NHOPhClOHD2c-D, R = O-tBuNHOPhClOHDent-2c-D, R = O-tBu(DHQD)2PHAL DCDPHTFE -30 ¼CReaction B(DHQD)2PHAL  DCDMHCHCl3-Hexane (1:1), 0 ¼C(DHQD)2PHAL  DCDMHBenzoic acidn-PrOH, -30 ¼CReaction CReaction C'Table II-6 E/Z ratios of recovered labeled starting materials at various conversions.  !!%#%!Table II-6 lists the E/Z isomeric ratios of the recovered starting materials at various conversions. The E/Z isomeric ratios of the recovered starting materials in all three reactions conditions B, C, and CÕ remained constant and identical to the starting ratios at different conversions. Lack of isomerization of the reacting olefin highlights two important points; first, it demonstrates that isomerization of the putative carbocationic intermediate is not the origin for the syn addition products, and second, the chlorenium transfer is not a reversible process.               !!%#'!II-10 Conclusion A summary of the stereochemical outcome of the various asymmetric chlorocyclization reactions disclosed here is presented in Figure II-17. Despite the use of the same catalyst and chlorine source, and similar reaction conditions, it is clear that different mechanisms are in operation. These studies further confirm that the net syn addition of halogen and nucleophile across the olefin that we had first observed in the chlorolactonization chemistry is by no means a reaction-specific phenomenon. Numerous reactions, reported by other labs,43, 46, 48, 53, 55, 56, 61-64, 70, 75, 76, 79, 84, 137, 138 might also exhibit varying degrees of syn and anti addition across 1,1-disubstituted alkenes.  The work presented above highlights one of the fundamental challenges in developing highly enantioselective halocyclizations and more generally, additions across alkenes. Here, exceptional face-selectivity in alkene halogenation still does not guarantee a similarly strong enantiopreference for the newly created quaternary stereocenter; syn and anti addition paths are in competition. Conversely, poor enantioselectivity at the newly generated quaternary carbon need not necessarily reflect poor face-selectivity in halogen-alkene bond formation.  Taken together, these results suggest one of two mechanistic possibilities: first, reaction may follow a stepwise mechanism via a carbocation intermediate, in which the catalyst independently controls the !!%#(!facial selectivity of chlorenium attack on the olefin more rigorously than the final enantiodetermining cyclization step. Second, addition of the halogen and nucleophile across the alkene may be concerted with no discrete intermediate but with extensive preorganization of the catalyst, substrate conformation and chlorenium source. The overall system must then be capable of directing either syn or anti trajectories of the nucleophile with respect to the captured chlorenium ion. Either scenario appears to rule out a bridged chlorenium ion as a stereocontrolling intermediate. In summary, we have assessed both the relative and absolute stereochemical outcomes of a family of halocyclization reactions mediated by (DHQD)2PHAL. An attribute shared by all these reactions is the fact that net stereoselectivity is independently determined at two distinct sites in the substrate. The chlorenium ion is delivered to the same side of the olefin in all four processes: carboxylic acid, amide, and carbamate chlorocyclizations. This high facial selectivity for chlorenium delivery presumably reflects catalyst-mediated pre-organization of the styrene substrate and the chlorenium source. The syn or anti nucleophilic bond closure, whether occurring in a concerted transition state or via a cationic intermediate, is governed by the nature of the nucleophile and by the solvent in a highly enantioselective manner. The resulting structural insights place boundary conditions on any mechanistic hypothesis proposed and aid in further refinement and generalization of this synthetically versatile class of !!%#)!transformations. Efforts to obtain a mechanistic understanding of binding interactions, the preferred conformations in different settings, and reaction timing are ongoing. anti50%anti85%anti84%anti97%Cl+ faceselectivityNHOPhNHOOtBupro-S97%pro-S97%pro-S91%pro-S98%syn89%anti94%anti88%syn90%anti/syncatalyzedCO2Hanti/synnoncatalyzedCHCl3:Hexn-PrOHFigure II-17. Summary of stereochemical outcomes for Reactions A, B, C, and CÕ. *Configuration designators are listed as shown in the image at left.  Nuc21DH97%89%ClNuc12DH97%94%ClNucCl12DH91%88%CHCl3:HexNuc21DH98%90%Cln-PrOHNuc = carboxylic acidNuc = amideNuc = carbamateNuc = carbamate!!%#*!II-11 Experimental results II-11A General remarks NMR spectra were obtained using a 300, 500, or 600 MHz NMR spectrometers (VARIAN INOVA). Chemical shifts are reported in parts per million (ppm) and are referenced using the residual 1H peak from the deuterated solvent. For HRMS (ESI) analysis, a Waters 2795 (Alliance HT) instrument was used and referenced against Polyethylene Glycol (PEG-400-600).  Column chromatography was performed using Silicycle 60 †, 35-75 &m silica gel. Pre-coated 0.25 mm thick silica gel 60 F254 plates were used for analytical TLC and visualized using UV light, iodine, potassium permanganate stain, p-anisaldehyde stain or phosphomolybdic acid in EtOH stain. TLC analyses were performed on silica gel plates (pre-coated on aluminum; 0.20 mm thickness with fluorescent indicator UV254). All reagents were purchased from commercial sources and used without purification unless otherwise mentioned. THF and Et2O were freshly distilled from Na-benzophenone ketyl whereas CH2Cl2 and PhCH3 were distilled over CaH2. Trifluoroethanol was purchased from Aldrich or Alfa Aesar and used without further purification. Flash silica gel (32-63 µm) was used for column chromatography. Enantiomeric excess for all products was judged by HPLC analysis using DAICEL CHIRALPAK OJ-H or AD-H columns. Diastereomeric ratios were determined by crude NMR analysis.  All known !!%#+!compounds were characterized by 1H and 13C NMR and are in complete agreement with samples reported elsewhere.  Abbreviations used: DCDMH = 1,3-dichloro-5,5-dimethylhydantoin; DCDPH = 1,3-dichloro-5,5-diphenylhydantoin; TCCA = trichloroisocyanuric acid; DiCh.T = dichloramine-T; Ch.T = Chloramine-T; NCS = N-chlorosuccinimide; TLC = Thin layer chromatography; DCM = Dichloromethane; THF = Tetrahydrofuran; EtOAc = Ethyl Acetate; Hex = Hexane; n-PrOH = n-Propanol. II-11B General procedure for the catalytic asymmetric chlorocyclization of unsaturated amide 1b  (DHQD)2PHAL (1.56 mg, 312 µL of a 5 mg/mL solution in TFE, 2 mol%) was introduced to a suspension of DCDPH (35 mg, 0.11 mmol, 1.1 equiv) in trifluoroethanol (TFE, 2.2 mL) in a screw capped vial equipped with a stir bar at -30 ¡C. After stirring vigorously for 10 min, the substrate (0.10 mmol, 1.0 equiv) was added in a single portion. The vial was capped and the stirring was continued at -30 ¡C till the reaction was complete (TLC). The reaction was quenched by the addition of 10% aq. Na2SO3 (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over NOPhClPh1bPhHN(DHQD)2PHAL (2 mol%)DCDPH (1.1 equiv)OPhTFE, -30 ¡C, 2h96% yield, 90% ee2b!!%##!Na2SO4, concentrated and purified by column chromatography on silica gel using EtOAc-Hexanes as the eluent to give product 2b in 96% yield and 90% ee. Resolution of enantiomers: CHIRALCEL OJ-H, 5% IPA-Hexane, 0.8 mL/min, 260 nm, RT1 = 18.0 min, RT2 = 34.0 min. Analytical data for 2b: 1H NMR (500 MHz, CDCl3) " 8.05 (d, J = 7.0 Hz, 2H), 7.48 Ð 7.51 (m, 1H), 7.36 Ð 7.46 (m, 6H), 7.30 Ð 7.34 (m, 1H), 4.50 (d, J = 15.0 Hz, 1H), 4.23 (d, J = 15.0 Hz, 1H), 3.92 (d, J = 12.0 Hz, 1H), 3.85 (d, J = 12.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) " 163.0, 141.5, 131.5, 128.7, 128.4, 128.3, 128.2, 127.3, 124.9, 87.56, 64.93, 51.04. HRMS (ESI) Calculated Mass for C16H14NOCl: ([M+H]+) = 271.0764, Found ([M+H]+) = 271.0765. II-11C Procedure for the synthesis of unsaturated amide substrate 1b  II-28, (3-bromoprop-1-en-2-yl)benzene NBS (8.58 g, 48.23 mmol, 1.14 equiv) was added to a solution of !-methylstyrene (5.0 g, 42.31 mmol, 1.0 equiv) in chloroform (7 mL) at room temperature. Reaction was refluxed for 15 h. After completion, the reaction !-methylstyreneBrNH2HNOII-28II-291bNBS, CHCl3, reflux60% yield, 15h1. NaN3, DMSO, 50 ¡C2. PPh3, THF, H2O, rt86% yield, 5hBzCl, Et3N, DMAPDCM, 0 ¡C to rt8h, 89% yield!!%#$!mixture was filtered and concentrated to remove chloroform. Crude sample was subjected to column chromatography using hexane (100%) to afford II-28 in 60% yield. Analytical data for II-28: 1H NMR (500 MHz, CDCl3) " 7.27-7.39 (m, 5H), 5.54 (d, J = 1.2 Hz, 1H), 5.47 (d, J = 1.2 Hz, 1H), 4.37 (s, 2H); 13C NMR (125 MHz, CDCl3) " 144.2, 137.6, 128.5, 128.3, 126.1, 117.2, 34.2. II-29, 2-phenylprop-2-en-1-amine Allyl bromide (4.5 g, 22.96 mmol, 1.0 equiv) dissolved in THF (85 mL) and H2O (21 mL), was treated with NaN3 (1.79 g, 27.53 mmol, 1.2 equiv) at room temperature. After TLC analysis revealed the complete consumption of starting material (~ 3 h), PPh3 (9.04 g, 34.46 mmol, 1.5 equiv) was added to the reaction vessel. After 2 h at ambient temperature, the reaction was concentrated to remove most of the THF. The resulting suspension was diluted with aq. HCl and extracted with ether (3x). The aqueous layer was then basified by adding solid KOH and extracted with ether (3x). The combined organics were dried (Na2SO4) and concentrated to give the crude amine, which was usually pure enough to use in the next step. Analytical data for II-29: 1H NMR (500 MHz, CDCl3) " 7.27-7.40 (m, 5H), 5.33 (d, J = 1.2 Hz, 1H), 5.20 (d, J = 1.2 Hz, 1H), 3.70 (s, 2H); 13C NMR (125 MHz, CDCl3) " 149.4, 139.5, 132.3, 131.5, 128.3, 111.0, 45.8. 1b, N-(2-phenylallyl)benzamide !!%#"!A solution of 2-phenylprop-2-en-1-amine (II-29) (1.20 g, 9.0 mmol, 1.0 equiv), triethyl amine (1.04 mL, 18.0 mmol, 2.0 equiv) and a catalytic amount of DMAP in DCM (50 mL) was cooled in an ice bath. To this solution, benzoyl chloride (1.57 mL, 13.5 mmol, 1.5 equiv) was added dropwise. After the completion of the reaction, it was allowed to warm to room temperature. It was quenched with water and extracted with DCM (3 x 25 mL). The combined organics were washed with brine (1 x 30 mL), dried over Na2SO4 and concentrated under reduced pressure to give the product as a colorless solid in 89% yield after column chromatography (10% EtOAc-Hexanes). Analytical data for 1b: MP: 123 Ð 125 ¡C.; Rf : 0.46 (30% EtOAc-Hexane)#. 1H NMR (500 MHz, CDCl3) " 7.7 (d, J = 8.5 Hz, 2H), 7.43-7.47 (m, 3H), 7.27-7.39 (m, 5H), 6.30 (br s, 1H), 5.49 (s, 1H), 5.29 (s, 1H), 4.52 (d, J = 6.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) " 167.3, 144.2, 138.3, 134.4, 131.5, 128.6, 128.5, 128.09, 126.9, 126.04, 114.0, 43.7. HRMS (ESI) Calculated Mass for C16H15NO: ([M+H]+) = 237.1154, Found ([M+H]+) = 237.1154.        !!%$&!II-11D Procedure for synthesis of labeled amide substrate 1b-D  II-30, 2-(prop-2-yn-1-yl)isoindoline-1,3-dione Potassium phthalimide (3.0 g, 16.2 mmol, 1.0 equiv) was added to a solution of 3-bromoprop-1-yne (2.8 mL of 80% wt. in toluene, 19.1 mmol, 1.18 equiv) in dry DMF (15 mL) at room temperature. After stirring the reaction at 80 ¡C for 8 h, it was poured into an ice cold water. The solid was filtered, washed with water and dried under vacuum. A white solid was obtained in 61% yield after recrystallization with DCM and Hexanes. Analytical data for II-30: 1H NMR (500 MHz, CDCl3) " 7.89-7.85 (m, 2H), 7.70-7.74 (m, 2H), 4.44 (d, J = 2.5 Hz, 2H), 2.21 (t, J = 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) " 166.9, 134.2, 131.9, 123.5, 76.7, 71.5, 27.0. II-31, Deuterated 2-(2-phenylallyl)isoindoline-1,3-dione135 A mixture of compound II-30 (800 mg, 4.33 mmol, 1.0 equiv), NaBPh4 (1.48 g, 4.33 mmol, 1.0 equiv), HOAc (247 $L, 4.33 mmol, 1.0 equiv), PdCl2(PPh3)2 BrPotassium PhthalimideDMF, 80 ¡C 8h, 61% yieldNaBPh4, D2O HOAc, Pd(Cl)2(PPh3)252 ¼C, 12h, 53% yieldPhND1. NH2NH2.H2OMeOH, rt, 12h2. HCl (conc.)  then KOH  89% yieldPhNH2DHNOOOOHBzCl, Py, DCM0 ¼C to rt, 3h51% yieldPhHNDPhO1b-D87:13 E:Z95% D-incorporationII-30II-31II-29-D3-bromoprop-1-yneH!!%$%!(91 mg, 0.13 mmol, 0.03 equiv), and D2O (8.7 mL) was heated in a sealed tube under nitrogen at 50 ¡C for 12 h. After that, the solvents and volatiles were removed under reduced pressure and the mixture was subjected to column chromatography to afford compound II-31 as a pale yellow powder in 53% yield. Analytical data for II-31: 1H NMR (600 MHz, CDCl3): "7.82 (d, J = 6.0, 3.0 Hz, 2H), 7.68 (dd, J = 6.0, 3.0 Hz, 2H), 7.48 (dd, J = 7.8 Hz, 2H), 7.32 (m, 2H), 7.26 (t, J = 7.2 Hz, 1H), 5.12 (t, J = 1.8 Hz, 1H), 4.69 (d, J = 1.8 Hz, 2H), 13C NMR (150 MHz, CDCl3): " 167.9, 142.3, 138.5, 133.9, 132.0, 128.4, 128.0, 126.4, 123.3, 113.6 (t, J = 23.7 Hz), 41.4. IR (cm-1, NaCl plate): 2918, 2495, 1704; HRMS (C17H12DNO2): Calc. [M+H]+: 265.1088, Found [M+H]+: 265.1086.  II-29-D, Deuterated 2-phenylprop-2-en-1-amine Compound II-31 (3.7 g, 18.9 mmol, 1.0 equiv) was dissolved in MeOH (40 mL). NH2NH2.H2O (1.7 mL) was introduced into the reaction vessel and the resulting suspension was stirred at room temperature over night. The reaction was then diluted with water (100 mL) and most of MeOH was removed by rotary evaporation. Concentrated HCl (19 mL) was added and the resulting suspension was stirred for a further 60 min at ambient temperature. The precipitated solids were filtered and the filter cake was washed with water. The combined filtrates were basified with solid NaOH and extracted with EtOAc and concentrated to give deuterated 2-phenylprop-2-en-1-amine II-29-!!%$'!D, which was used in the next step without any purification. Analytical data for II-29-D: 1H NMR (600 MHz, CDCl3): " 7.26-7.4 (1H, 5H), 5.19 (t, J = 1.8 Hz, 1H), 3.69 (s, 2H), 1.39 (br s, 2H); 13C NMR (150 MHz, CDCl3): " 149.7, 139.7, 128.4, 127.6, 126.1, 110.9 (t, J = 24 Hz), 46.1. HRMS (ESI) Calculated Mass for C9H10DN: ([M+H]+) = 135.1033, Found ([M+H]+) = 135.1034. 1b-D, Deuterated N-(2-phenylallyl)benzamide A solution of labeled 2-phenylprop-2-en-1-amine II-29-D (50 mg, 0.37 mmol, 1.0 equiv) and pyridine (63 mg, 0.74 mmol, 2.0 equiv) in DCM (2.5 mL) was cooled in an ice bath. To this, benzoyl chloride (80 mg, 0.57 mmol, 1.5 equiv.) was added drop wise. After the addition was complete, the reaction was allowed to warm to room temperature. After 3 h, the reaction was diluted with an equal amount of water and extracted with DCM (3 x 5 mL). The combined organics were washed with brine (1 x 3 mL), dried over Na2SO4 and concentrated under reduced pressure to give the product as a yellow solid. It was recrystallized from MeOH to obtain the pure product as a colorless solid in 51% yield [95% D-incorporated, (87:13) E:Z ratio of isomers]. Analytical data for 1b-D: 1H NMR (600 MHz, CDCl3): " 7.69 (d J = 8.4 Hz, 2H), 7.47 (m, 3H), 7.38 (t, J = 7.8 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 6.15 (br s, 1H), 5.3 (t, J = 1.8 Hz, 1H), 4.52 (d, J = 5.4 Hz, 2H); 13C NMR (150 MHz, CDCl3): " 167.3, 144.1, 138.2, 134.4, 131.4, 128.6, 128.5, 128.1, 126.8, 126.0, 113.7 (t, J = 24.0 Hz), 43.6; IR (cm-1, NaCl plate): 3340, 2345, 1647. !!%$(!HRMS (C16H14DNO): Calc. [M+H]+: 239.1294, Found [M+H]+: 239.1297.  II-11E Procedure for the non-asymmetric chlorocyclization of labeled unsaturated amide 1b-D Substrate 1b-D (24 mg, 0.10 mmol, 1.0 equiv) was added to a solution of DCDPH (35 mg, 0.11 mmol, 1.1 equiv) in TFE or CHCl3 (2.2 mL) in a screw-capped vial equipped with a stir bar. After stirring vigorously for 10 h, the reaction was quenched by the addition of 10% aq. Na2SO3 (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over anhydrous Na2SO4. Pure products were isolated by column chromatography on silica gel using EtOAc-Hexanes (1:19) as the eluent to give the desired product 2b-D in 87% yield as a mixture of two diastereomers (85:15 dr) (analyzed by 1HNMR). Analytical data for 2b-D: 1H NMR (500 MHz, CDCl3): " 8.05 (dd, J = 1.5, 11.5 Hz, 2H), 7.32-7.50 (m, 8H), 4.49 (d, J = 15.0 Hz, 1H), 4.22 (d, J = 15.0 Hz, 1H), 3.91 (s, 1H); 1H NMR (500 MHz, C6D6): " 8.23 (m, 2H), 7.0-7.15 (m, 8H), 4.23 (d, J = 15.0 Hz, 1H), 3.98 (d, J = 15.0 Hz, 1H), 3.41 (s, 1H); 13C NMR (125 MHz, CDCl3): " 163.0, 141.5, 131.6, 128.7, 128.4, 128.3, 128.2, 127.4, 124.9, 87.5, 64.9, 50.8 (t, J = 23.7 Hz). HRMS (ESI) NOPhClHDPh1b-DPhHNDDCDPH (1.1 equiv), RTHOPhTFE, 87% yield, 10 h2b-D!!%$)!Calculated Mass for C16H14ONClD: ([M+H]+) = 273.0905, Found ([M+H]+) = 273.0900.  II-11F General procedure for the synthesis of labeled substrates 9b-D to 11b-D  Substrates II-19 to II-21 were synthesized in a similar manner to that described for substrate 1b-D with the only difference being the choice of the amine protecting groups. II-19, Deuterated 4-methoxy-N-(2-phenylallyl)benzamide Analytical data for II-19: 1H NMR (500 MHz, CDCl3) " 7.66 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 7.0 Hz, 2H), 7.34 (t, J = 7.0 Hz, 2H), 7.29 (d, J = 7.5 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 6.07 (br s, 1H), 5.28 (s, 1H), 4.50 (d, J = 5.5 Hz, 2H), 3.81 (s, 3H); 13C NMR (125 MHz, CDCl3) " 166.8, 162.2, 144.3, 138.3, 128.7, 128.6, 128.1, 126.7, 126.1, 113.75, 113.70 (t, J = 22.0 Hz), 55.4, 43.7.  II-20, Deuterated 4-methyl-N-(2-phenylallyl)benzamide PhHNDHOOMePhHNDDCDPH (1.1 equiv)HOArNOPhClHDArTFE (0.02 M), rtPhNH2DHBzCl, Py DCM0 ¼C to rt1b-D  Ar = C6H5II-19  Ar = 4-OMe-C6H5II-20  Ar = 4-Me-C6H5II-21  Ar = 3,5-(NO2)2-C6H51b-D  Ar = C6H5II-23  Ar = 4-OMe-C6H5II-24  Ar = 4-Me-C6H5II-25  Ar = 3,5-(NO2)2-C6H5II-29-D!!%$*!Analytical data for II-20: 1H NMR (500 MHz, CDCl3) " 7.59 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 7.0 Hz, 2H), 7.33 (t, J = 6.5 Hz, 2H), 7.28 (d, J = 7.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.17 (br s, 1H), 5.28 (s, 1H), 4.51 (dd, J = 5.5 Hz, J = 1.0 Hz, 2H), 2.35 (s, 3H); 13C NMR (125 MHz, CDCl3) " 167.2, 144.25, 141.9, 138.3, 131.6, 129.2, 128.6, 128.1, 126.9, 126.0, 113.7 (t, J = 24.0 Hz), 43.6, 21.4.  HRMS (ESI) Calculated Mass for C17H16DNO: ([M+H]+) = 253.1451, Found ([M+H]+) = 253.1450.  II-21, Deuterated 3,5-dinitro-N-(2-phenylallyl)benzamide Analytical data for II-21: 1H NMR (500 MHz, CDCl3) " 9.10 (s, 1H), 8.86 (s, 2H), 7.42 (d, J = 7.5 Hz, 2H), 7.26-7.36 (m, 3H), 6.69 (br s, 1H), 5.31 (s, 1H), 4.57 (d, J = 5.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) " 162.7, 148.6, 143.2, 137.7, 137.6, 128.7, 128.4, 127.2, 126.0, 121.0, 114.8 (t, J = 24.0 Hz), 44.3.  II-11G General procedure for the non-asymmetric chlorocyclization of labeled II-23 to II-25:  Substrates II-23 to II-25 were synthesized similarly to that described for substrate 2b-D. PhHNDHOMePhHNDHONO2NO2!!%$+!II-23, Deuterated 5-(chloromethyl)-2-(4-methoxyphenyl)-5-phenyl-4,5-dihydrooxazole Analytical data for II-23: 1H NMR (500 MHz, C6D6) " 8.20 (d, J = 8.5 Hz, 2H), 6.90-7.10 (m, 5H), 6.68 (d, J = 9.0 Hz, 2H), 4.22 (d, J = 15 Hz, 1H), 3.99 (d, J = 15 Hz, 1H), 3.42 (s, 1H), 314 (s, 3H); HRMS (ESI) Calculated Mass for C17H15DNO2Cl: ([M+H]+) = 303.1010, Found ([M+H]+) = 303.1004. II-24, Deuterated 5-(chloromethyl)-5-phenyl-2-(p-tolyl)-4,5-dihydrooxazole Analytical data for II-24: 1H NMR (500 MHz, CDCl3) " 7.94-7.97 (m, 2H), 7.39-7.45 (m, 3H), 7.34-7.37 (m, 1H), 7.26-7.28 (m, 3H), 4.51 (d, J = 14.5 Hz, 1H), 4.24 (d, J = 14.5 Hz, 1H), 3.93 (s, 1H), 2.42 (s, 3H); HRMS (ESI) Calculated Mass for C17H15DNOCl: ([M+H]+) = 287.1061, Found ([M+H]+) = 287.1057. II-25, Deuterated 5-(chloromethyl)-2-(3,5-dinitrophenyl)-5-phenyl-4,5-dihydrooxazole NOPhClHDOMeNOPhClHDMeNOPhClHDNO2NO2!!%$#!Analytical data for II-25: 1H NMR (500 MHz, CDCl3) " 9.20 (s, 3H), 7.37-7.45 (m, 5H), 4.63 (d, J = 15.5 Hz, 1H), 4.35 (d, J = 15.5 Hz, 1H), 3.96 (s, 1H). II-11H Procedure for the catalytic asymmetric chlorocyclization of labeled unsaturated amide 1b-D DCDPH (35 mg, 0.11 mmol, 1.1 equiv) was suspended in trifluoroethanol (TFE, 2.2 mL) in a screw-capped vial equipped with a stir bar. The resulting suspension was cooled to -30 ¡C in an immersion cooler. (DHQD)2PHAL (1.56 mg, 312 mL of a 5 mg/mL solution in TFE, 2 mol%) was then introduced. After stirring vigorously for 10 min, unsaturated amide 1b-D (24 mg, 0.10 mmol, 1.0 equiv) was added in a single portion. The vial was capped and the stirring was continued at -30 ¡C till the reaction was complete (TLC). The reaction was quenched by the addition of 10% aq. Na2SO3 (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over anhydrous Na2SO4. The pure product was isolated by column chromatography on silica gel using EtOAc-Hexanes (1:19) as the eluent in 93% yield. The resulting two enantiomers (ignoring the chiral center on the labeled carbon (C-6) as it is not distinguishable by chiral HPLC) were NOPhClDH2b-D1b-DPhHND(DHQD)2PHAL (2 mol%)DCDPH (1.1 equiv)TFE, -30 ¼C, 2hmajor product isolated (5R)5HOPhPh!!%$$!separated using a chiral pack OJ-H column (5% IPA in hexanes; 0.8 mL/min; 265 nm; RT1 = 17.9 (S enantiomer) and RT2 = 34.3 (R enantiomer)) and an R to S ratio of 93:7 was obtained. Analytical data for 2b-D: 1H NMR (500 MHz, CDCl3): " 8.05 (dd, J = 1.5, 11.5 Hz, 2H), 7.32-7.50 (m, 8H), 4.49 (d, J = 15.0 Hz, 1H), 4.22 (d, J = 15.0 Hz, 1H), 3.91 (s, 1H); 1H NMR (500 MHz, C6D6): " 8.23 (m, 2H), 7.0-7.15 (m, 8H), 4.23 (d, J = 15.0 Hz, 1H), 3.98 (d, J = 15.0 Hz, 1H), 3.41 (s, 1H); 13C NMR (125 MHz, CDCl3): " 163.0, 141.5, 131.6, 128.7, 128.4, 128.3, 128.2, 127.4, 124.9, 87.5, 64.9, 50.8 (t, J = 24.0 Hz). HRMS (ESI) Calculated Mass for C16H14ONClD: ([M+H]+) = 273.0905, Found ([M+H]+) = 273.0900. II-11I General Procedure for synthesis of labeled epoxy alcohol 3b and 3b-D139  NOPhCl5R-2b5Ph HCl, 1,4-dioxaneNaHCO3, 50 ¼C, 69%MeOH:H2O, 62%K2CO3, rtPhOHNHbHa3b3.10 ppm2.80 ppmOPhPh(R)(R)OHClHNOPhII-26Ph(R)(R)(R)(R)OHNHDNOPhClDH5R,6S-2b-D3b-D56PhOPh HCl, 1,4-dioxaneNaHCO3, 50 ¼C, 69%MeOH:H2O, 62%K2CO3, rtPh(R)(R)OH(S)(S)ClDHHNOPhII-17!!%$"! Oxazoline 2b or 2b-D (127 mg, 0.47 mmol, 1.0 equiv, 93:7 er after chiral chromatographic separation) was placed in a pre-dried flask. 1,4-dioxane (10 mL) and 1N hydrochloric acid (10 mL) were added to the flask subsequently. The resulting mixture was stirred for 4 h at 50 ¡C. After it was cooled to room temperature, the reaction mixture was neutralized with saturated NaHCO3 aq and then extracted six times with EtOAc. The combined organic layers was dried over Na2SO4 and evaporated under reduced pressure. Column chromatography gave the product II-26 or II-17 in 69% yield. Analytical data for II-26: 1H NMR (500 MHz, CDCl3) " 7.63 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 7.5 Hz, 2H), 7.46 (t, J = 7.0 Hz, 1H), 7.34-7.35 (m, 4H), 7.30 (t, J = 7.0 Hz, 1H), 6.50 (br s, 1H), 4.11 (dd, J = 14.5 Hz, J = 7.0 Hz, 1H), 3.92 (d, J = 11.5 Hz, 1H), 3.85 (d, J = 11.5 Hz, 1H), 3.75 (dd, J = 14.0 Hz, J = 5.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) " 168.8, 141.0, 133.8, 131.8, 128.6, 128.0, 126.9, 125.5, 76.7, 52.0, 48.0.  HRMS (ESI) Calculated Mass for C16H16NO2Cl: ([M+H]+) = 290.0948, Found ([M+H]+) = 290.0948. Analytical data for II-17: 1H NMR (500 MHz, CDCl3) " 7.64 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 7.0 Hz, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.35-7.39 (m, 4H), 7.30 (t, J = 7.0 Hz, Ph(R)(R)OHClHNOPhII-26Ph(R)(R)OH(S)(S)ClDHHNOPhII-17or!!%"&!1H), 6.51 (br s, 1H), 4.12 (dd, J = 14.5 Hz, J = 6.5 Hz, 1H), 3.91 (s, 1H), 3.74 (dd, J = 14.0 Hz, J = 5.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) " 168.8, 141.0, 133.7, 131.8, 128.5, 128.0, 126.9, 125.5, 76.7, 51.8 (t, J = 23.0 Hz), 48.0.  HRMS (ESI) Calculated Mass for C16H15DClNO2: ([M+H]+) = 291.1010, Found ([M+H]+) = 291.1011. K2CO3 (7.2 mg, 0.052 mmol, 1.5 equiv) was added to a solution of II-17 or II-26 (10 mg, 0.035 mmol, 1.0 equiv) in MeOH:H2O (10:1) (1.0 mL) at 0 ¡C and then warmed to room temperature. After completion of the reaction by TLC, MeOH was removed under reduced pressure; then it was extracted with EtOAc and H2O. The organics were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified with column chromatography to yield 3b or 3b-D in 62% yield. Analytical data for 3b: 1H NMR (500 MHz, CDCl3) " 7.71 (d, J = 7.0 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.25-7.44 (m, 7H), 6.29 (br s, 1H), 4.22 (dd, J = 14.5 Hz, J = 7.0 Hz, 1H), 4.01 (dd, J = 14.5 Hz, J = 4.5 Hz, 1H), 3.11 (d, J = 5.0 Hz, 1H), 2.81 (d, J = 5.0 Hz, 1H). HRMS (ESI) Calculated Mass for C16H15NO2: ([M+H]+) = 254.1181, Found ([M+H]+) = 254.1178. Analytical data for 3b-D: 1H NMR (500 MHz, CDCl3) " 7.75 (d, J = 7.5 Hz, 2H), 7.22-7.56 (m, 8H), 6.39 (br s, 1H), 4.27 (dd, J = 14.5 Hz, J = 7.0 Hz, 1H), 4.06 (dd, J = 14.5 Hz, J = 5.0 Hz, 1H), PhOHN3bOPhPhOHNHD3b-DPhOor!!%"%!3.14 (s, 1H). HRMS (ESI) Calculated Mass for C16H14DNO2: ([M+H]+) = 255.1244, Found ([M+H]+) = 255.1252. II-11J General prodecure for the synthesis of carbamate substrate 1c A solution of di-tert-butyl dicarbonate (0.71 g, 3.14 mmol, 1.1 equiv) in dry DCM (1 mL) was added under nitrogen at 0 ¡C to a solution of amine II-29 (0.5 g, 2.85 mmol, 1.0 equiv) and triethylamine (0.87 mL, 6.27 mmol, 2.2 equiv) in dry DCM (2 mL). The reaction mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo, and the residue was dissolved with DCM (6 mL) and water (4 mL). The aqueous layer was extracted with DCM (3 % 5 mL). The combined organic extracts were washed with water (5 mL), dried with MgSO4, filtered, and concentrated. The resulting mixture was purified by flash chromatography on silica gel using 10% EtOAc-hexane to give carbamate 1c (tert-butyl (2-phenylallyl)carbamate) in 89% yield. Analytical data for 1c: 1H NMR (500 MHz, CDCl3) " 7.40 (d, J = 7.5 Hz, 2H), 7.30-7.38 (m, 2H), 7.25-7.29 (m, 1H), 5.41 (s, 1H), 5.21 (s, 1H), 4.61 (br s, 1H), 4.17 (d, J = 5.0 Hz, 2H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) "  155.7, 144.8, 138.6, 128.4, 127.9, 126.1, 112.9, 79.4, 44.3, 28.4. HRMS NH2HNOOII-291c(Boc)2O, Et3N DCM, 0 ¡C to rt8h, 89% yield!!%"'!(ESI) Calculated Mass for C14H19NO2: ([M+Na]+) = 256.1313, Found ([M+Na]+) = 256.1322.  II-11K Genaral procedure for the catalytic asymmetric chlorocyclization of carbamates in n-PrOH A screw-capped vial equipped with a stir bar was charged with 1.3 mL of a 0.21 mg/mL stock solution of (DHQD)2PHAL in n-PrOH [0.30 mg (DHQD)2PHAL, 1 mol%]. After cooling to -30 ¡C in an immersion cooler, DCDMH (9.5 mg, 0.041 mmol, 1.3 equiv) and benzoic acid (2.3 mg, 0.019 mmol, 0.5 equiv) were added sequentially. After stirring vigorously for 10 min, the substrate (0.037 mmol, 1.0 equiv) in n-PrOH (0.2 mL, pre-cooled to reaction temperature) was added in a single portion. The vial was capped and the stirring was continued at -30 ¡C until the reaction was complete as judged by TLC. The reaction was quenched by the addition of 2% aq. NaOH (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in the presence of a small quantity of silica gel. Pure product ent-2c (5-(chloromethyl)-5-phenyloxazolidin-2-one) was isolated by column chromatography on a short silica gel column using NHOPhOCl 1cPhHNOtBuO(DHQD)2PHAL (1 mol%) DCDMH (1.2 equiv)Benzoic acid, n-PrOH, -30 ¼C, 3h 87% yield, -80% eeent-2c!!%"(!EtOAc-hexane as the eluent (87% yield). The resulting two enantiomers were separated using a chiral pack AD-H column (10% IPA in hexanes; 1.0 mL/min. Analytical data for ent-2c: 1H NMR (500 MHz, CDCl3) " 7.33-7.42 (m, 5H), 5.77 (br s, 1H), 4.11 (d, J = 9.0 Hz, 1H), 3.84 (d, J = 12.0 Hz, 1H), 3.79 (d, J = 8.5 Hz, 1H), 3.75 (d, J = 12.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) " 158.1, 139.8, 128.9, 128.8, 124.7, 83.8, 50.7, 49.4. HRMS (ESI) Calculated Mass for C10H10ClNO2 :([M+H]+) = 212.0478, Found ([M+H]+) = 212.0479.  II-11L Genaral procedure for the catalytic asymmetric chlorocyclization of carbamates in CHCl3-Hexane (DHQD)2PHAL (6 mg, 20 mol%) was introduced to a suspension of DCDMH (9.5 mg, 0.041 mmol, 1.3 equiv) in CHCl3-hexane (1:1 mixture, 1.3 mL) in a screw-capped vial equipped with a stir bar. The resulting suspension was cooled to 0 ¡C in an immersion cooler. After stirring vigorously for 10 min, the substrate (0.037 mmol, 1.0 equiv) in CHCl3-hexane (1:1 mixture, 0.2 mL, pre-cooled to reaction temperature) was added in a single portion. The vial was capped and the stirring was continued at 0 ¡C until the reaction was complete (TLC). The reaction was quenched by the addition of 2% aq. NaOH (3 mL) and diluted with DCM (3 mL). The organics were separated and the NHOPhClOPhHNOtBuO(DHQD)2PHAL (20 mol%) DCDMH (1.2 equiv)CHCl3-Hexane (1:1), 0 ¼C, 3h 83% yield, +82% ee1c2c!!%")!aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in the presence of a small quantity of silica gel. Pure products were isolated by column chromatography on a short silica gel column using EtOAc-hexane (20-50%) as the eluent. Analytical data is similar to the section II-11K. II-11M Procedure for synthesis of labeled carbamate substrate 1c-D  Synthesis of compound II-29-D was shown previously in Section II-11D. Boc-protection of the primary amine (II-29-D) to provide 1c-D was carried out similar to the procedure for synthesis of non-labeled carbamate 1c discussed in Section II-11J. The desired compound 1c-D was synthesized in 50% yield with 86:14 E:Z ratio and 93% deuterium incorporation. Analytical data for 1c-D: 1H NMR (500 MHz, CDCl3) " 7.40 (d, J = 7.0 Hz, 2H), 7.25-7.34 (m, 3H), 5.2 (t, J = 1.5 Hz, 1H), 4.61 (br s, 1H), 4.17 (d, J = 5.0 Hz, 2H), 1.42 (s, 9H); 1H NMR (500 MHz, C6D6) " 7.30 (d, J = 7.0 Hz, 2H), 7.01-7.20 86:14 E:Z93% D-incorporationPhHNDHOtBuO1c-DEt3N, (Boc)2O DCM, rt, 24h50% yieldBrPotassium PhthalimideDMF, 80 ¡C 8h, 61% yieldNaBPh4, D2O HOAc, Pd(Cl)2(PPh3)252 ¼C, 12h, 53% yieldPhND1. NH2NH2.H2OMeOH, rt, 12h2. HCl (conc.)  then KOH  89% yieldPhNH2DHNOOOOHII-30II-31II-29-D3-bromoprop-1-yne!!%"*!(m, 3H), 5.00 (s, 1H), 4.18 (br s, 1H), 4.07 (d, J = 5.5 Hz, 2H), 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3) " 155.7, 144.9, 138.7, 128.5, 127.9, 126.1, 112.9 (t, J = 25.0 Hz), 79.4, 44.4, 28.4. HRMS (ESI) Calculated Mass for C14H18DNO2: ([M+Na]+) = 257.1376, Found ([M+Na]+) = 257.1380.  II-11N Procedure for the racemic chlorocyclization of labeled unsaturated carbamate 1c-D Substrate 1c-D (15 mg, 0.064 mmol, 1.0 equiv) was added to a solution of DCDMH (15 mg, 0.072 mmol, 1.2 equiv) in CHCl3:Hexane (1:1) (2.5 mL) or n-PrOH (2.5 mL) in a screw-capped vial equipped with a stir bar. After stirring vigorously for 12 h, the reaction was quenched by the addition of 2% aq. NaOH (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL).  The combined organics were dried over Na2SO4 and the solvent was removed under reduced pressure. Pure products were isolated by column chromatography on silica gel using EtOAc-Hexanes as the eluent to give the desired product 2c-D as a mixture of two diastereomers (97:3 dr) and (84:16) for reactions carried out in n-PrOH and CHCl3/Hexane, respectively (as PhHNDHOtBuO 1c-DNHOPhClDH2c-DODCDMH (1.2 equiv, rt)n-PrOH or CHCl3-hexane (1:1)!!%"+!analyzed by 1H NMR). The resulting two enantiomers were separated using a chiral pack AD-H column (10% IPA in hexanes; 1.0 mL/min. Analytical data for 2c-D: 1H NMR (500 MHz, CDCl3) " 7.35-7.43 (m, 5H), 5.29 (br s, 1H), 4.11 (dd, J = 8.5 Hz, J = 1.0 Hz, 1H), 3.83 (s, 1H), 3.79 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) " 157.8, 139.8, 128.93, 128.90, 124.7, 83.7, 50.4 (t, J = 22.0 Hz), 49.3. HRMS (ESI) Calculated Mass for C10H9DNO2Cl: ([M+H]+) = 213.0541, Found ([M+H]+) = 213.0541.  II-11O Procedure for the catalytic asymmetric chlorocyclization of labeled unsaturated carbamate 1c-D  Procedure for the synthesis of carbamates 2c-D and ent-2c-D is identical to the one reported for the non-labeled 2c and ent-2c (Section II-11K and II-11L).   PhHNDHOtBuO 1c-D(DHQD)2PHAL (20 mol%)DCDMH (1.2 equiv)CHCl3-hexane (1:1)0 ¼C, 1h83% yield, 82% eeNHOPhClDH2c-DO(DHQD)2PHAL (1 mol%)DCDMH (1.2 equiv)benzoic acid (0.5 equiv)n-PrOH, -30 ¼C, 20 min87% yield, 80% eeNHOPhClDHent-2c-DO!!%"#!II-11P Absolute stereochemical assignment at the deuterated center of substrate 2c-D and ent-2c-D    NHO(S)(S)PhClPh(S)(S)OHNent-3cent-2cOSOONHOPhClDH5R,6S-2c-D56O NaH, THF/DMFTsCl, 0 ¼C to rt93%NOPhClDHOTsII-180 ¼C to rt86%Cs2CO3 MeOH3c-DPh(R)(R)(R)(R)OHNHDSOONHOPhClDH5S,6S-2c-D56ONOPhClDHOTs NaH, THF/DMFTsCl, 0 ¼C to rt93%ent-II-18Ph(S)(S)(R)(R)OHNDHent-3c-DSOO0 ¼C to rt86%Cs2CO3 MeOH NaH, THF/DMFTsCl, 0 ¼C to rt93%NOPhClOTsII-320 ¼C to rt86%Cs2CO3 MeOHNOPhClOTsII-32NOPhClDHOTsII-18NOPhClDHOTsent-II-18ororFigure II-18 The X-ray structure of II-32. !!%"$!To a stirred suspension of NaH (60% wt., 12 mg, 0.28 mmol, 2.0 equiv) in a mixture of THF (0.8 mL) and DMF (0.5 mL) at 0 ¡C were added successively substrate 5R,6S-2c-D, 5S,6S-2c-D or ent-2c (30 mg, 0.14 mmol, 1.0 equiv) in THF (1.0 mL) and p-TsCl (35.2 mg, 0.18 mmol, 1.3 equiv). Stirring was continued for 18 h at room temperature, at which time the reaction was quenched by the addition of a saturated solution of NH4Cl (2.0 mL) at -78 ¡C with vigorous stirring. The mixture was extracted with Et2O, and the extract was washed successively with HCl (3 mL), NaHCO3 (3 mL), H2O (3 mL). The combined organics were dried over MgSO4 and the solvent was removed under reduced pressure. Purification by column chromatography on silica gel afforded the N-tosyl oxazolidinone  (5-(chloromethyl)-5-phenyl-3-tosyloxazolidin-2-one) II-32, II-18, or ent-II-18 in 93% yield. Analytical data for II-32: 1H NMR (500 MHz, CDCl3) " 7.90 (d, J = 8.0 Hz, 2H), 7.34-7.41 (m, 3H), 7.29-7.33 (m, 4H), 4.52 (d, J = 9.5 Hz, 1H), 4.22 (d, J = 9.5 Hz, 1H), 3.72 (dd, J = 17.5 Hz, J = 12.5 Hz, 2H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) " 150.3, 145.8, 138.1, 133.9, 129.8, 129.4, 129.1, 128.2, 124.4, 81.3, 52.8, 50.6, 21.7. HRMS (ESI) Calculated Mass for C17H16NO4SCl: ([M+H]+) = 366.0567, Found ([M+H]+) = 366.0559. Absolute stereochemistry of 5S-II-32  (CCDC 1416555 is the corresponding Cambridge Structural Database deposition number) was determined by singe crystal X-ray diffraction (XRD). !!%""!Crystals for XRD were obtained by crystallization from CHCl3 layered with hexanes in a silicone-coated vial. Two diastereomers could be obtained from the deuterated substrate depending on the reaction condition. Analytical data for deuterated 5R,6S-II-18 (diastereomer B obtained from chlorocyclization in CHCl3-Hex): 1H NMR (500 MHz, CDCl3) " 7.91 (d, J = 8.5 Hz, 2H), 7.36-7.41 (m, 3H), 7.29-7.33 (m, 4H), 4.51 (d, J = 9.5 Hz, 1H), 4.22 (d, J = 9.0 Hz, 1H), 3.73 (s, 1H), 2.43 (s, 3H). HRMS (ESI) Calculated Mass for C17H15DClNO4S: ([M+H]+) = 367.0630, Found ([M+H]+) = 367.0626. Analytical data for deuterated 5S,6S-ent-II-18 (diastereomer A obtained from chlorocyclization in n-PrOH): 1H NMR (500 MHz, CDCl3) " 7.90 (d, J = 8.5 Hz, 2H), 7.35-7.41 (m, 3H), 7.29-7.33 (m, 4H), 4.51 (d, J = 9.0 Hz, 1H), 4.21 (d, J = 9.5 Hz, 1H), 3.69 (s, 1H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) " 150.3, 145.9, 138.1, 134.0, 129.9, 129.4, 129.2, 128.3, 124.5, 81.2, 52.8, 50.4 (t, J = 23.0 Hz), 21.7. HRMS (ESI) Calculated Mass for C17H15DClNO4S: ([M+H]+) = 367.0630, Found ([M+H]+) = 367.0626.   A catalytic amount of cesium carbonate (2 mg, 0.03 g.mmol-1) was added to a solution of N-tosyl oxazolidinone II-32, II-18, or ent-II-18 (20 mg, Ph(S)(S)OHNent-3cSOO3c-DPh(R)(R)(R)(R)OHNHDSOOPh(S)(S)(R)(R)OHNDHent-3c-DSOOoror!!'&&!0.55 mmol) in methanol (1 mL). The reaction was stirred at room temperature for 12 h and was then concentrated in vacuum. The residue was purified by chromatography on a silica-gel column using a mixture of hexanes and ethyl acetate as the eluent to give the product in 86% yield (87% conversion). Analytical data for ent-3c: 1H NMR (500 MHz, CDCl3) " 7.68 (d, J = 8.5 Hz, 2H), 7.25-7.33 (m, 7H), 4.51 (t, J = 4.0 Hz, 1H), 3.58 (dd, J = 8.5 Hz, J = 13.5 Hz, 1H), 3.46 (dd, J = 4.5 Hz, J = 13.5 Hz, 1H), 3.20 (d, J = 5.0 Hz, 1H), 2.74 (d, J = 5.0 Hz, 1H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) " 143.7, 137.0, 136.6, 129.8, 128.6, 128.3, 127.0, 125.7, 58.6, 53.0, 45.6, 21.5. HRMS (ESI) Calculated Mass for C16H17NO3S: ([M+H]+) = 304.1007, Found ([M+H]+) = 304.1003.  Analytical data for 2S,3R-ent-3c-D (diastereomer A obtained from chlorocyclization in n-PrOH): 1H NMR (500 MHz, CDCl3) " 7.68 (d, J = 8.0 Hz, 2H), 7.25-7.33 (m, 7H), 4.51 (dd, J = 4.5 Hz, J = 8.0 Hz, 1H), 3.59 (dd, J = 8.5 Hz, J = 13.5 Hz, 1H), 3.46 (dd, J = 4.0 Hz, J = 13.5 Hz, 1H), 2.74 (s, 1H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) " 143.6, 137.0, 136.5, 129.7, 128.6, 128.3, 127.0, 125.7, 58.5, 52.7 (t, J = 26.8 Hz), 45.6, 21.5. HRMS (ESI) Calculated Mass for C16H16DNO3S: ([M+Na]+) = 327.0890, Found ([M+Na]+) = 327.0886.  Analytical data for 2R,3R-ent-3c-D (diastereomer B obtained from chlorocyclization in CHCl3:Hex): 1H NMR (500 MHz, CDCl3) " 7.69 (d, J = 8.5 !!'&%!Hz, 2H), 7.25-7.32 (m, 7H), 4.51 (t, J = 4.0 Hz, 1H), 3.59 (dd, J = 8.0 Hz, J = 13.5 Hz, 1H), 3.46 (dd, J = 4.5 Hz, J = 13.5 Hz, 1H), 3.19 (s, 1H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) " 143.6, 137.0, 136.6, 129.8, 128.6, 128.3, 127.0, 125.7, 58.5, 52.7 (t, J = 28.0 Hz), 45.7, 21.5.  HRMS (ESI) Calculated Mass for C16H16DNO3S: ([M+Na]+) = 327.0890, Found ([M+Na]+) = 327.0886.                  !!'&'!          REFERENCES        !!'&(!REFERENCES    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!!!!"#$!Chapter III: Organocatalytic Asymmetric Halofunctionalization of Alleneamides III-1 Introduction  Asymmetric halofunctionalization of a C-C unsaturated bond represents one of the most effective and powerful transformations for formation of stereodefined carbon-halogen linkages in organic synthesis, as was discussed in Chapter II. Numerous approaches toward the synthesis of halogenated molecules exist due to their significance in production of both pharmaceuticals and agrochemicals.  Since our first discovery in asymmetric chlorolactonization of unsaturated carboxylic acids,1 tremendous progress has been reported on the asymmetric halofunctionalization of olefins. Some of the reviews published in this field point toward the importance of these transformations in the synthesis of high-valued chiral products.2-11 The halofunctionalizations of olefins involve the chlorenium delivery to the olefin, followed by a nucleophilic opening of an ill-defined halenium intermediate to afford halo-heterocycles (Figure III-1a). The question we had posed was whether we could extend the same reactivity observed for olefins to allenes (Figure III-1b). Despite numerous reports on halofunctionalization of alkenes, the corresponding halofunctionalization of allenes is relatively unexplored and few enantioselective variants in asymmetric halofunctionalization of allenes have been described to date. The halofunctionalization of allenes could open !!!!"#%!a new avenue toward the synthesis of vinyl halide products with great potential to partake in cross-coupling reactions.   Different groups have reported racemic halofunctionalizations of allenes using electrophilic halenium sources. Zhu and coworkers have reported a fluorocyclization of carboxylic acids and tosylamides toward the synthesis of fluorovinyl lactones and pyrrolidines in moderate to high yields using Selectfluor under mild conditions.12 Ma and coworkers have reported a bromocyclization of amides toward the racemic synthesis of oxazolines in 2014.13 Highly diastereoselective iodoetherification of 4,5-alkadienols by MaÕs group has led to the development of a new methodology for the synthesis of iodovinyl tetrahydrofurans in high regio- and stereoselectivity.14 They have Figure III-1 Comparison of halocyclizations for olefins (a) versus allenes (b). NuXNuXNu!!XChiral catalystChiral catalystNuXNuXNu!!XChiral catalystChiral catalyst.AlkenesAllenesa) Halocyclization of olefinsb) Halocyclization of allenesX = Cl, Br, F, I!!!!"#&!also developed an iodolactonization of allenoic acids, where the intrinsic axial chirality of allenes could be efficiently transferred through an anti-cyclization mode to deliver chiral lactones in a highly diastereoselective manner.15 Similar transfer of planar chirality upon halocyclizations, was observed in boromoamination of allenes to afford pyrrolidines in high optical purity by Backvall and coworkers.16 Racemic synthesis of bicyclic ethers was achieved by KrauseÕs group through a sequence of gold-catalyzed iodoetherefication, palladium cross coupling, and second gold-catalyzed iodoetherification processes in high yield and diastereoselectivity.17 Less often used IPy2BF4 has shown to be an efficient iodonium donor in iodoarylation of allenes in both intra- and intermolecular pathways, as discovered by Gonzalez group.18 Silver-catalyzed chloroamination of allenes by using a 1,10-phenanthroline-ligated cationic silver complex through a 5-endo-trig manner has been reported by Matsubara group toward the synthesis of pyrroline and pyrrole derivatives.19  Few groups have investigated the asymmetric halofunctionalization of allenes. The enantioselectivity induced in this transformation has been achieved by the use of chiral organocatalysts or metal catalysis. Hennecke and co-workers reported the asymmetric, reagent-controlled bromolactonization of allenoic acids using (DHQD)2PHAL catalyst; however only moderate enantioselectivities were achieved (Figure III-2).20 In 2014, Fujioka- and coworkers reported an iodocyclization of allenoic acids using a !!!!"#'!trisimidazoline catalyst and I2 in moderate enantioinduction as shown in Figure III-2.21 They have proposed a !-allyl cation intermediate in the enantiodetermining step based on mechanistic studies of trisubstituted allenoic acids where a mixture of 1:1 allene stereoisomers gave a major Z isomer upon cyclization. Asymmetric semipinacol rearrangement of 2,3-allenols was achieved by MaÕs group using quinidine as a catalyst and BINOL-dervied phosphoric acid as a cocatalyst (Figure III-4).22 The real identity of the catalyst was not clarified in their report, but it yields 3-bromo-3-enal derivatives in moderate enantioselectivities of up to 78% ee. Recently TosteÕs group have shown the highly enantioselective bromocyclization of allenes in a 5-exo-manner, through the use of an achiral dinuclear gold OHOR'R'RR.OOR'R'BrRRHDBDMH (1.2 equiv)(DHQD)2PHAL (10 mol%)PhCO2H (1.0 equiv)orNBS (1.2 equiv)(DHQD)2PHAL (10 mol%)CHCl3:Hex (1:1), -30 ¡C5 examples45-86% yield12-66% eeNMeOONOMeONEtNEtHHNN(DHQD)2PHALFigure III-2 Asymmetric bromolactonization of allenoic acids developed by Hennecke group. !!!!""(!complex (Figure III-5).23 The reaction was proposed to proceed through a vinyl gold intermediate followed by bromodeauration in the presence of an N-bromolactam as the bromine source in a stepwise halogenation fashion. The presence of a suitable electrophilic source was crucial to outcompete the protodeauration pathway. N-halolactams generate a stronger internal base than succinimide anions and can furnish enantioenriched pyrrolidines without formation of protodeaurated products in combination with a chiral gold complex. This report has been the only example for highly enantioselective halofunctionalization of allenes to date, however the requirement of using gold metal is crucial for achieving high enantioinduction. All the examples discussed so far were showing the electrophilic halogenation of allenes in both diastereo- and enantioselective manners. However, a practical method for halocyclizations of allenes in an asymmetric organocatalytic fashion to achieve highly enantioselective halo-vinyl hetereocycles has not been reported until now. In this chapter, we are presenting the first asymmetric organocatalytic halofunctionalization of allenes using a combination of hydantoins and dimeric cinchona alkaloid catalyst (DHQD)2PHAL. This methodology would give access to the formation of vinyl halide products with an allylic tertiary or quaternary stereocenter in high yield and moderate to excellent enantioselectivity under operationally simple conditions without any requirement for the use of metals.!!!!!""#!!Recently we published an asymmetric chlorocyclization of unsaturated amides for the formation of oxazolines as well as kinetic resolution under similar reaction conditions.24-26 We planned to expand this methodology to alleneamides. With the discovery that cinchona alkaloids based ligands were effective in halocyclizations reactions, we expected to achieve high enantioinduction for our system. We had postulated before that non-covalent interaction between (DHQD)2PHAL and amide substrates, most probably through hydrogen binding, is required for the ultimate high enantioinduction. !!!!!!I2 (2.5 equiv)III-1 (10 mol%)DTBP (2.5 equiv)toluene, 0 ¡CROHO.OORINNNNNNArArArArArArIII-1  Ar = DMP-tris11 examples35-89% yield2-82% eeFigure III-3 Asymmetric iodolactonization of allenoic acids developed by Fujioka group. DTBP = 2,6-di-tert-butyl-pyridine. !!!!"""!!!!!!!Ar.quinidine (15 mol%)III-2 (5 mol%), III-3 (1.2 equiv)MeOH (10 mol%), toluene, 24 ¡C17 examples54-98% yield8-78% eeRHOBrRArCHONOOBrIII-3OOPOOHPhPhIII-2Figure III-4 Asymmetric semipinacol rearrangement of allenols developed by Ma group. Figure III-5 Asymmetric amino bromination of allenes developed by Toste group. PNB = p-nitrobenzoate. .dinuclear gold complexes:(R)-DM-BINAP(AuPNB)2 (5 mol%)or (S)-BINAP(AuPNB)2 (5 mol%)or (R)-Cl-MeO-BIPHEP(AuPNB)2 (5 mol%)NBL (1.5-2.0 equiv), MeNO2 (0.2 M), 24 ¡C13 examples74-93% yield26-99% eeRRXNHPGR'R'BrXPGNRRR'R'PG = Ns, Ts, BocX = O, NNOBrnNBLn = 1, 3, 4PPArAr22Ar = Ph             BINAPAr = 3,5-diMe   DM-BINAPH3COH3COPPPhPh22ClClCl-MeO-BIPHEP!!!!"")!III-2 Solvent Screen for asymmetric chlorocyclization of alleneamides For the initial investigation, we chose to test compound III-4 as our model substrate. We first focused on screening different solvents to generate oxazoline III-5 in high yield and enantioselectivity (Table III-1). A comprehensive solvent screen in combination with (DHQD)2PHAL (chiral catalyst), DCDMH (chlorine source) and various additives was undertaken to maximize the enantioselectivity of the reaction. Dichloromethane (DCM), chloroform (CHCl3), and dichloroethane (DCE) gave the cyclized product III-5 in 38, 44 and 56% ee, respectively. These aprotic solvents showed a slow rate for the chlorocyclization of amide III-4 (up to 39% conversion after 1 day). Addition of benzoic acid as an acidic additive did not improve the conversion and enantioselectivity of the reaction (Table III-1, entry 2). Protic solvents such as n-PrOH gave a faster reaction rate but lower selectivity of only 10% ee (Table III-1, entry 5). The presence of fluorinated solvents such as TFE (trifluoroethanol) was crucial for obtaining high enantioinduction of 82% and 84% ee at room temperature and -30 ¡C, respectively. However, intermolecular incorporation of TFE led to the formation of chloroether product III-6 (35-40%), and this by-product was observed in high regio- and enantioselectivity, 74% and 86% ee at room temperature and -30 ¡C, respectively (Table III-1, entries 6 and 9). Addition of benzoic acid and HFIP (hexafluoroisopropanol) additives did not help to increase the enantioselectivity and reduce the amount of the side product (Table III-1, !!!!""*!entries 7-8). Using HFIP exclusively as the solvent led to the formation of III-5 NHPhOIII-4III-5ClHNOPhOIII-6(DHQD)2PHAl (10 mol%)DCDMH (1.1 Equiv).ClONPhSolvent (0.025M), T ¡C, 3-20 hNNOOMeMeClClDCDMH(DHQD)2PHALNMeONOHNNHNOMeNOHHF3CH2C[a] All reactions were run on a 0.12 mmol scale. The ee% was determined by HPLC on a chiral stationary phase. [b] Benzoic acid (1.0 equiv) and HFIP (20 equiv) were used as additives. [c] Conversion and ratios were measured by NMR analysis of the crude product after 5h; except entries 1-3 were measured after 1day.   Table III-1 Solvent and additive screening for chlorocyclization of alleneamides.  Entry[a] Solvent, Temp ¡C Additive[b] Conv. (%)[c] Ratio[c] (III-5:III-6) ee (%) (III-5) ee (%) (III-6) 1 DCM, rt - 38 100 : 0 38 - 2 DCM, rt BA 39 100 : 0 30 - 3 CHCl3, rt - 37 100 : 0 44 - 4 DCE, rt - 39 100 : 0 56 - 5 n-PrOH, rt - 100 100 : 0 10 - 6 TFE, rt - 100 60 : 40 82 74 7 TFE, rt BA 100 63 : 37 74 76 8 TFE, rt  HFIP 100 65 : 35 80 74 9 TFE, -30 - 100 52 : 48 84 86 10 HFIP, rt - 100 100 : 0 62 - 11 HFIP, 0 - 100 100 : 0 54 - !!!!!""+!as the sole product but in 62% ee at room temperature and 54% ee at 0 ¡C (entries 10-11).!Next, various co-solvents were tested to maintain high enantioselectivity and reduce the formation of by-product III-6 (Table III-2). These results show the importance of fluorinated solvents for achieving high enantioinduction, for example use of CHCl3 and hexanes led to a dramatic drop in the enantioselectivity (Table III-2, entry 1). The combination of CHCl3, DCM, and MeCN with HFIP led to 100% formation of III-5 in 76-78% ee (Table III-2, entries 2-4). We found that the presence of TFE is crucial for obtaining high enantioinduction, thus we screened MeCN, DCM, DCE, and HFIP as co-solvents with TFE to maintain the high enantioselectivity while reducing the formation of III-6 side product (Table III-2, entries 5-8). Further experimentation revealed that employing HFIP in TFE (1:1) could not only improve on the ratio of III-5:III-6  (92:8), but also maintain high enantioselectivity (88% ee). HFIP is similar in nature to TFE, both being fluorinated protic solvents with a relatively acidic hydroxyl proton [pKa (HFIP) = 9.3, pKa (TFE) = 12.4, pKa (EtOH) = 15]. However, HFIP is bulky and cannot incorporate into the allene in an intermolecular fashion. Addition of benzoic acid additive to this solvent mixture led to a drop in enantioselectivity and the ratio of III-5 to III-6 (Table III-2, entry 9).!!!!!!!!!""$!!!!!!!!!Entry[a] Solvent (1:1) Conv. (%)[b] Ratio[b] (III-5:III-6) ee (%) (III-5) ee (%) (III-6) 1 CHCl3:Hex 50 100 : 0 36 - 2 DCM:HFIP 100 100 : 0 78 - 3 MeCN:HFIP 100 100 : 0 76 - 4 CHCl3:HFIP 100 100 : 0 78 -   5[c] MeCN:TFE 100 67 : 33 72 - 6 DCM:TFE 100 63 : 37 76 70 7 DCE:TFE 100 90 : 10 76 66 8 HFIP:TFE 100 92 : 8 88 -   9[d] HFIP:TFE 100 80 : 20 72 72 ![a] All reactions were run on a 0.12 mmol scale. The ee% was determined by HPLC on a chiral stationary phase. All entries were run for 3h, except entry 1 for 1 day. [b] Conversion and ratios were measured by NMR analysis of the crude product. [c] Temperature of -30 ¡C was used. [d] Benzoic acid (1.0 equiv) was used as an additive.  NHPhOIII-4III-5ClHNOPhOIII-6(DHQD)2PHAl (10 mol%)DCDMH (1.1 Equiv).ClONPhSolvent (0.025M), rt, 3 hF3CH2CTable III-2 Co-solvent screening for chlorocyclization of alleneamides. !!!!""%!III-3 Halogen source and catalyst screen for asymmetric chlorocyclization of alleneamides  In addition to screening different protic and aprotic solvents and co-solvents for chlorocyclization of allemande III-4, we were intrigued to investigate various halogen sources and cinchona alkaloid catalysts (Table III-3). In TFE:HFIP (1:1) solvent mixture, going from DCDMH (88% ee, entry 1) to chloramineT (Ch.T) (54% ee, entry 2), selectivity dropped by 35%. Slower reaction rate (lower conversion) and lower ratio of III-5:III-6 was also observed when we switched to Ch.T. Similarly dichloramineT (DiCh.T) produced an inferior result (24% ee, entry 3), but similar reaction rate in comparison to DCDMH. We next investigated different cinchona alkaloid catalysts, such as hydroquinidine, (DHQD)2PYR, and (DHQ)2AQN; they all led to the formation of racemic product (Table III-3, entries 4-6). All further attempts at tweaking the reaction parameters to increase stereoselectivity (order of addition, slow addition, catalyst aging, etc.) were infructuous.  The results highlights the importance of the C2-symmetric dimeric cinchona alkaloid ((DHQD)2PHAL) over monomeric hydroquinidine in inducing chirality. Entries 4-6 also explain the importance of the phthalazine nitrogen atoms of (DHQD)2PHAL in obtaining high enantioselectivity.!!!!!!!!""&!!Entry[a] Catalyst Cl+ source Conv. (%)[b] Ratio[b] (III-5:III-6) ee (%) (III-5) 1 (DHQD)2PHAL DCDMH 100 92 : 8 88 2 (DHQD)2PHAL Ch.T 31 77 : 23 54 3 (DHQD)2PHAL DiCh.T 100 79 :21 26 4 Hydroquinidine DCDMH 100 90 : 10 0 5 (DHQD)2PYR DCDMH 100 91 : 9 4 6 (DHQD)2AQN DCDMH 100 92 : 8 2 ![a] All reactions were run on a 0.12 mmol scale. The ee% was determined by HPLC on a chiral stationary phase. [b] Conversion and ratios were measured by NMR analysis of the crude product.   Table III-3 Halogen source/catalyst screening for chlorocyclization of alleneamides.  NMeOONOMeOArNEtNEtHHNN(DHQD)2PHALOONNPhPhNHydroquinidineH3CHNH3COHOH(DHQD)2AQN(DHQD)2PYRNHPhOIII-4III-5ClHNOPhOIII-6Catalyst (10 mol%)Cl+ source (1.1 Equiv).ClONPhTFE:HFIP (1:1) (0.025M), rt, 3 hF3CH2CSOONClNaH3CCh.TSOONClH3CDiCh.TCl!!!!""'!III-4 Effect of concentration and catalyst loadings for asymmetric chlorocyclization of alleneamides  The concentration of substrate III-4 in (1:1) TFE:HFIP were changed from 0.025 M to 1.6 M (Table III-4, entries 1-4). The data show a 2% increase in enantioselectivity when the concentration is increased from 0.025 M to 0.32 M. However, more concentrated reaction condition of 1.6 M led to lower enantioselectivity of 82%. The loading of the catalyst could also be reduced from 10 mol % to 2 mol % with only 6% drop in ee (entries 3 and 5). Further lowering the catalyst loading to 0.5 mol% gave the cyclized product III-5 in only 50% ee, which shows a 40% drop from the optimized condition (entries 3 and 6). This data shows that higher concentrations could improve the enantioinduction up to a certain point (0.32 M), but increasing the concentration further would result in a drop in selectivity due to the catalyst aggregation.  Finally, we discovered that (DHQD)2PHAL (hydroquinidine 1,4-phthalazinediyl diether, 10 mol%) in combination with DCDMH in a 1:1 solvent mixture of TFE and HFIP (0.025 M) was the most selective condition for this transformation at room temperature (lower concentration of 0.025 M was chosen as the optimized condition for better solubility).!!!!!!!!")(!!III-5 Substrate scope for asymmetric chlorocyclization of alleneamides  Having discovered the optimized condition for the enantioselective organocatalytic chlorocyclization of alleneamides, a number of analogues were prepared and evaluated. In order to probe the substrate scope for this reaction, a series of mono- and disubstituted terminal alleneamides were synthesized and examined with the optimized reaction conditions (Scheme III-1).!!Entry[a] Catalyst loading [Substrate] Yield (%)[b] ee (%) (III-5) 1 10 0.025 M 92% 88% 2 10 0.10 M 81% 86% 3 10 0.32 M 75% 90% 4 10 1.6 M 85% 82% 5 2 0.32 M 71% 84% 6 0.5 0.32 M 70% 50% ![a] All reactions were run on a 0.12 mmol scale. The ee% was determined by HPLC on a chiral stationary phase. [b] Isolated Yield%.   Table III-4 Concentration and catalyst loading screening for chlorocyclization of alleneamides.  NHPhOIII-4III-5(DHQD)2PHAL (x mol%)DCDMH (1.1 Equiv).ClONPhTFE:HFIP (1:1), rt, 3 h!!!!")#!!Scheme III-1 Substrate scope for the intramolecular chlorocyclization of alleneamides. [a] Reaction concentration of 0.32 M was used. [b] 93% yield, 70% ee by switching TFE:HFIP to only HFIP. [c] Reaction temperature of -20 ¡C was used. [d] MeCN:TFE (4:1) at -30 ¡C was used.  !ClONIII-5[a]92% yield, 90% eeClONIII-1095% yield, 94% eeClONBrIII-775% yield, 94% eeClONNO2NO2ClONIII-15[d]89% yield, 86% eePhClONMeClONIII-1190% yield, 94% eeEtBrIII-1382% yield, 92% eeClON III-8[b]62% yield, 94% eeClONIII-1496% yield, 92% eeBnBr III-16 72% yield, 92% eeIII-1896% yield, 4% eeClONBrClONClON(DHQD)2PHAL (10 mol%)DCDMH (1.1 equiv)R'RTFE:HFIP (1:1) (0.025 M) rt, 1-5 hNHR'O.RIII-2177% yield, 18% eeClON III-966% yield, 94% eeNO2NO2ClON III-12[c]   67% yield, 92% eeOMeOMeClONMeBrIII-1791% yield, 98% eeClONMeNO2III-1997% yield, 98% eeClON III-2061% yield, 12% eeNO2!!!!")"!As depicted in Scheme III-1, four factors were tested to reveal the generality and practicality of chlorocyclization reaction of alleneamides (Note: few alterations to the optimized conditions of some substrates were carried out to enhance their selectivity). 1) We looked at varying the R group to see the influence of steric and electronics of the nucleophilic benzoyl derivatives on the scope of this transformation. The strongly electron-withdrawing NO2 group on the benzoyl group (Scheme III-1, III-7 to III-9) showed a higher enantioselectivity of 94% ee as compared to III-5 (90% ee). However, the desired products were isolated in lower yields due to the formation of TFE-incorporated by-products (62-75% yield). Presumably, the electron-withdrawing NO2 group lowered the nucleophilicity of the amide moiety and increased the level of intermolecular attack by the solvent TFE. Further optimization to improve the yield of these substrates will be discussed later in this chapter. The m/p-OMeC6H4 and the 4-BrC6H4 substituted products (III-10, III-12 and III-13) were both formed in slightly enhanced enantioselectivity in comparison to the test substrate. This shows that the electronic properties of the benzoyl-protecting group do not change the stereoselectivity of chlorocyclization reactions significantly. 2) We looked at varying RÕ group to see the influence of substitution on the alleneamide substrate on the scope of this transformation.  We were delighted to discover that the same reaction condition could be extended to the disubstituted alleneamides and much higher selectivities were obtained for alkyl disubstituted allenes. Almost all of !!!!"))!the RÕ substituted products evaluated gave 86% to 98% ee. For the phenyl-substituted product III-15, lower temperature was required to obtain high stereoinduction, due to the high background reaction. Benzyl disubstituted oxazoline III-14 gave slightly higher enantioselectivity (92% ee) than the test substrate (90% ee). However, for alkyl-disubstituted substrates such as methyl-, and ethyl-substituted products, III-11, III-16, III-17, and III-19, high enantioselectivity of 92-98% ee were observed. The effect of substituents on the benzoyl group of disubstituted alleneamides also followed the same trend as the monosubstituted ones; where replacing the para-H with -Br and -NO2 led to an enhancement in enantioselectivity. The alkyl-disubstituted alleneamides with electron-withdrawing aryl groups were the most stereoselective compounds and returned the corresponding product with a quaternary stereocenter in high yield and excellent enantioselectivity. 3) We also looked at the effect of substitution on the methylene group next to nitrogen. The gem-dimethyl substituted substrate III-18a undergoes cyclization to afford product III-18 in excellent yield (96%) but no stereoinduction (4% ee). Either the steric interactions or the change in substrate conformation perturb its interaction with the catalyst and results in low ee. This is in agreement with low observed stereoselectivity, in our effort toward a kinetic resolution of racemic alleneamides (vida infra). 4) Extending the distance between the nucleophilic site and the allene with one extra carbon resulted in the formation of the six-membered ring products, III-20 and !!!!")*!III-21, in moderate yields and low enantioselectivities (12-18% ee). This emphasizes the importance of the proximity between the nucleophile and electrophilic site for a better substrate-catalyst interaction.!III-5A Further investigation of the optimized reaction condition for chlorocyclization of alleneamides  The optimized reaction condition was further investigated for the following substrates, III-7, III-8, III-15, III-20, and IIII-21. As mentioned in Section IIII-5, the NO2-substituted substrates III-7 and III-8, underwent chlorocyclization in moderate yields of 75% and 62%, respectively. The attenuated yields are due to intermolecular incorporation of TFE solvent into the allene, since the electron-withdrawing NO2 group increases the chance of intermolecular attack in comparison to the intramolecular cyclization. We demonstrated that replacing the 1:1 solvent mixtures from TFE:HFIP to exclusively HFIP led to an improvement in yield but a decrease in enantioselectivity (Table III-5). This change was much more clear for substrate III-8, where removing the TFE solvent led to a reduced formation of the by-product.  This led to an increase in the yield from 62% to 93%, however the selectivity dropped form 94% to 70 % ee.  Next, we looked at improving the enantioselectivity for chlorocyclization of extended alleneamides. As shown in Scheme III-1, under the optimized condition, the cyclized products III-20 and III-21 were formed in (61% yield, 12% ee) and (77% yield, 18% ee), respectively. We repeated the reaction !!!!")+!under similar condition except at lower temperatures (Table III-6). Lowering the temperature to -60 ¡C was accomplished by the use of MeCN as a co-solvent, since TFE freezes below -35 ¡C. However, the reaction was sluggish and only gave 10% conversion after 1 day. Furthermore, no change in selectivity was observed when we switched from room temperature to -30 ¡C, enantioselectivity remained the same 18%, but yield increase from 77% to !86% (Table III-6, entries 3-4). !!Entry[a] Substrate Solvent Yield (%)[b] ee (%) 1 Ar = 3,5-diNO2, III-7 TFE:HFIP (1:1) 75% 94% 2 Ar = 3,5-diNO2, III-7 HFIP 79% 92% 3 Ar = p-NO2, III-8 TFE:HFIP (1:1) 62% 94% 4 Ar = p-NO2, III-8 HFIP 93% 70% ![a] All reactions were run on a 0.12 mmol scale. The ee% was determined by HPLC on a chiral stationary phase. [b] Isolated Yield%.   Table III-5 Optimizing the conditions for substrates III-7 and III-8.  NHArO(DHQD)2PHAL (10 mol%)DCDMH (1.1 Equiv).ClONArsolvent (0.025 M), rt!!!!")$! As discussed in the previous section, the alkyl disubstituted alleneamides showed the best enantioselectivities for the chlorocyclization of alleneamides (Scheme III-1). However, the aryl-disubstituted alleneamides underwent chlorocyclization with lower selectivity as compared with alkyl-disubstituted ones. Further optimization of the reaction conditions for formation of oxazoline III-15 was performed (Table III-7). The chosen optimized condition gave III-15 in only 62% yield and 36% ee. The low enantioselectivity obtained for chlorocyclization of III-15a was due to the high background reaction outcompeting the catalyzed pathway. To overcome this Entry[a] Substrate Solvent Temp ¼C Yield (%)[b] ee (%) 1 Ar = p-NO2, III-20 TFE:HFIP (1:1) rt 59% 12%   2[c] Ar = p-NO2, III-20 TFE:MeCN (4:1) -60  - - 3 Ar = Ph, III-21 TFE:HFIP (1:1) rt 77% 18% 4 Ar = Ph, III-21 TFE:HFIP (1:1) -30 86% 18% ![a] All reactions were run on a 0.12 mmol scale. The ee% was determined by HPLC on a chiral stationary phase. [b] Isolated Yield%. [c] 10% conversion after 1 day.  Table III-6 Optimizing the condition for substrates III-20 and III-21.  HN(DHQD)2PHAL (10 mol%)DCDMH (1.1 Equiv).solvent (0.025 M), temp ¡CClONArOAr!!!!")%!problem we tested the influence of higher catalyst loading (Table III-7, entry 2), which gave slightly higher yield and enantioselectivity (66% and 42%, respectively). Surprisingly, lowering the temperature to -30 ¡C did not improve the selectivity (30% ee, entry 3). Pure TFE solvent led to the formation of the desired product in 63% yield and 52% ee (entry 4). This shows that the lower enantioselectivity is obtained when HFIP is used a co-solvent, which could be due to faster background reaction under these conditions. Replacing the co-solvent from HFIP to DCE (dichloroethane) only gave 38% ee (entry 5). Switching to MeCN (acetonitrile) as a co-solvent (4:1 TFE:MeCN) led to a much higher enantioselectivity for this reaction (71% yield and 78% ee, entry 6). Lowering the temperature further to -60 ¡C or use of higher catalyst loading (20 mol%) did not help in improving the enantioselectivity (74% ee, entries 7-8). Finally the use of TFE:MeCN in a 1:4 ratio at -30 ¡C yielded III-115 in 89% yield and 86% ee (entry 9). The data suggests that MeCN helps in reducing the competing background reaction and improving the selectivity. Kinetic studies are on the way to further confirm this hypothesis.!!!!!!!!!!!")&!!III-5B Practicality of asymmetric intramolecular chlorocyclization of alleneamides! Due to the high enantioselectivity observed specially for the alkyl-disubstituted alleneamides, we varied the catalyst loading for substrate III-17 (Table III-8). It was observed that the stereoselectivity of this reaction was not Entry[a] Solvent Catalyst  (mol%) Temp ¼C Yield (%)[b] ee (%) 1 TFE:HFIP (1:1) 10% rt 62% 36% 2 TFE:HFIP (1:1) 20% rt 66% 42% 3 TFE:HFIP (1:1) 10% -30 60% 30% 4 TFE 10% -30 63% 52% 5 TFE:DCE (1:1) 10% -30 64% 38% 6 TFE:MeCN (4:1) 10% -30 71% 78% 7 TFE:MeCN (4:1) 10% -60 70% 74% 8 TFE:MeCN (4:1) 20% -60 70% 74% 9 TFE:MeCN (1:4) 10% -30 89% 86% ![a] All reactions were run on a 0.12 mmol scale. The ee% was determined by HPLC on a chiral stationary phase. [b] Isolated Yield%.   Table III-7 Optimizing the conditions for substrates III-15.  NHPhO(DHQD)2PHAL (x mol%)DCDMH (1.1 Equiv).ClONPhsolvent (0.025 M), rtPhPhIII-15III-15a!!!!")'!significantly diminished, even at a catalyst loading of 1 mol% (94% ee, entry 4).  As shown in Scheme III-1, III-19 is formed in 97% yield and 98% ee under optimized condition. We have demonstrated this reaction on preparative scale by synthesizing chlorovinyl-2,3-substituted oxazoline III-19 on a Ògram scaleÓ, where it gave quantitative yield and 96% ee by employing just 2 mol% of the catalyst and lower amount of solvent (0.1 M).!!!!Entry[a] Catalyst (mol%) Yield (%)[b] ee (%) 1 10% 91% 98% 2 5% 91% 96% 3 2% 98% 94% 4 1% 99% 94% ![a] All reactions were run on a 0.12 mmol scale. The ee% was determined by HPLC on a chiral stationary phase. [b] Isolated Yield%.   Table III-8 Lowering the catalyst loading for III-17. (DHQD)2PHAL (x mol%)DCDMH (1.1 Equiv)TFE:HFIP (1:1) (0.025 M), rtNHMeO.BrClONMeBrIII-17aIII-17!!!!"*(!III-6 Asymmetric intramolecular organocatalytic chlorocyclization of dialleneamides  The reaction may also be extended to the synthesis of bisoxazolines in good yields and high enantioselectivities via double chlorocyclization of dialleneamides (Scheme III-2). The synthesis of the C2 symmetric bis(oxazoline) compounds have potential as chiral ligands in asymmetric transition-metal catalysis, as they resemble BOX ligand.27 The para-dialleneamide undergoes the chlorocyclization at both ends to form product III-23 in 80% yield and 94% enantioselectivity. The meta-dialleneamide is easily converted to the monocylized III-24 with 1.1 equiv of DCDMH. The mono-oxazoline III-24 was formed in 51% yield and 96% ee. The low yield was due to the intermolecular incorporation of TFE after the first cyclization event, and also the formation of double-cyclized by-product. Double cyclization of meta-dialleneamide was possible with 2.2 equiv of DCDMH, providing III-22 in 70% yield and 98% ee. Unfortunately, we observed the formation of 18% meso compound (Scheme III-2, dashed box); which was separable by HPLC only. Screen of different solvents and temperatures did not reduce the formation of the meso isomer (Table III-9). We also formed the meta-bis(oxazoline) III-22 from an isolated mono-cyclized III-24 under the same conditions (Table III-9, entry 2), which only gave the product in 27% yield (96% ee) with formation of 14% meso-III-22. Lowering the temperature to -30 ¡C or increasing to +50 ¡C, did not help in improving the diastereomeric !!!!"*#!ratios, and yet 20-21% meso products were formed (entries 3-4). Removal of TFE solvent gave the worst result (39% meso-III-22, entry 5). Nonetheless, under all the reaction conditions the enantioselectivity of the desired product III-22 remained higher than 95% ee. Compound III-22 can be synthesized in overall three steps from a commercially available isophthaloyl dichloride, with high yields and enantioselectivity; the meso-by-product could be easily separated by chiral HPLC. This methodology could be an innovative and practical way for synthesis of this family of compounds in short steps, great yields, and excellent enantioselectivities. We were also intrigued to see how a meta-bioxazoline pyridine complex would react with our methodology to afford bis(oxazoline) pyridines. We screened the effect of chlorine sources, co-solvents, additives, and temperature on the formation of double-cyclized product for the pyridine dialleneamide. Most conditions led to sluggish reactions. We were able to form product III-25 in TFE:DCE (1:1) at -30 ¡C with 58% yield and 98% ee (Scheme III-2). This suggests that after the first cyclization, the second alleneamide undergoes an intermolecular chloroetherification by TFE solvent. We could isolate trace amount of mono-cyclized product in some cases, but the second allene did not undergo cyclization under any circumstances. Further work is ongoing to block the nitrogen lone pair through oxidation and see its effect on the double cyclization reaction.!!!!!!"*"!!!!Scheme III-2 Substrate scope for the intramolecular chlorocyclization of dialleneamides. [a] Reaction was carried out in TFE:DCE (1:1) at -30 ¡C. !(DHQD)2PHAL (10 mol%)DCDMH (1.1-2.2 equiv)TFE:HFIP (1:1) (0.025 M) rt, 1-5 hXONCl..XONHNHONOClONClOHN.NOClONClNOClIII-2380%, 94% eeIII-2451%, 96% eeIII-2270%, 98% ee, (82:18) drX = C, NNOHNNOClOClF3CIII-25[a]58%, 94% eeNOClONClmeso-III-22NOCl!!!!"*)!!!III-6A Stereochemical determination of III-22 isomers  Identification of the meso-bis(oxazoline)-III-22 (Scheme III-2, dashed box) in the chlorocyclization of III-22a was confirmed through combinatorial 1H NMR, chiral HPLC, and optical rotation measurements in four different conditions (A-D, Table III-10).!Entry[a] Solvent Temp (¡C) Ratio (dr)[b] (III-22:meso) Yield (%)[c] (III-22) ee (%) (III-22) 1 TFE:HFIP (1:1) rt 82 : 18 83% 98%   2[d] TFE:HFIP (1:1) rt 86 : 14 27% 96% 3 TFE:HFIP (1:1) -30 80 : 20 70% 98% 4 TFE:HFIP (1:1) +50 79 : 21 72% 99% 5 HFIP rt 61 : 39 77% 95% ![a] All reactions were run on a 0.06 mmol scale. The ee% was determined by HPLC on a chiral stationary phase. [b] The diastereomeric ratios were measure by chiral HPLC. [b] Isolated Yield%.[d] The second chlorocyclization was performed from the isolated monocyclized product (III-24).  Table III-9 Optimization of the reaction conditions for III-22 to reduce the formation of meso-bisoxazoline-III-22. (DHQD)2PHAL (10 mol%)DCDMH (2.2 equiv)solvent (0.025 M)Temp ¡CNOClONClIII-22OHN.OHN.III-22a!!!!"**!!A Table III-10 HPLC traces and integration of III-22 isomers in conditions A-D. B C D Entry[a] Condition Peak 1 (15.0 min) Peak 2  (16.5 min) Peak 3 (22.0 min) 1 A 27.0 55.0 18.0 2 B 0.5 18.0 81.5 3 C 0.5 13.5 86.0 4 D 1.0 49.5 49.5 !NOClONClent-III-22peak 1NOClONClmeso-III-22peak 2NOClONClIII-22peak 3!!!!"*+!Condition A shows the double chlorocyclization of dialleneamide III-22a in the absence of any catalyst (Table III-10, entry 1). HPLC trace of products from condition A show the existence of three peaks 1, 2, and 3 with 27%, 55%, 18% ratios, respectively. To identify each peak (enantiomeric or diastereomeric pairs), the following experiments were carried out. In condition B, dialleneamide was cyclized under the optimized condition in the presence of 10 mol% (DHQD)2PHAL with 2.2 equiv DCDMH to afford the double-cyclized III-22 in one pot. This experiment showed a 0.5:18:81.5 ratios for peaks 1:2:3 (entry 2). At this point we could not confirm whether the 18% isomer is the minor enantiomer or the meso diastereomer. We carried out the chlorocyclization under condition C. In the first step we isolated the mono-cyclized product III-24 in the presence of 10 mol% (DHQD)2PHAL with 1.0 equiv DCDMH. In the second step we cyclized III-24 in the presence of 10 mol% (DHQD)2PHAL with 1.1 equiv DCDMH to form III-22. We formed similar isomeric ratios of 0.5:13.5:86 for peaks 1:2:3 (entry 3). Conditions B and C are similar except for the number of steps to products. Cyclization of both allenes occurs in the presence of chiral catalyst in one pot (condition B) and two steps (condition C). To reveal the real identity of peak 2, we performed the reaction under condition D in a two-step manner. In the first step we formed the mono-chlorocyclized III-24 in the presence of 10 mol% (DHQD)2PHAL with 1.0 equiv DCDMH (96% ee). In the second step, the chiral monocyclized oxazoline was transformed to double cyclized III-22 in a !!!!"*$!racemic fashion with 1.1 equiv DCDMH in the absence of any catalyst. This would confirm that peaks 2 and 3 formed under condition D (with 1:1 ratio) are diastereomeric pairs, therefore peaks 1 and 3 are enantiomeric pairs. Finally, were able to assign peaks 1-3 to the structures drawn in Table III-10, where integration of peak 1 and 3 disclose the enantioselectivity and integration of peak 2 and 3 shows the diastereomeric ratio, due to the formation of, meso-III-22 (peak 2). This results were further reconfirmed by measuring optical rotations of each isomers isolated from chiral HPLC.!As evident from conditions B and C, the enantioselectivities for the double cyclizations are high, however up to 18% meso-by-product was formed. Comparing catalyzed conditions B and C reveal that the reason for the formation of the meso-isomer is due to the low selectivity of the second cyclization after the first chlorocyclization, most probably due to a mismatched chirality between the substrate and the catalyst.!III-7 Intermolecular asymmetric halofunctionalization of alleneamides Despite the catalytic, enantioselective reactions evolved from intramolecular capture of (putative) haliranium intermediates by a tethered nucleophiles including allene- amines, acids, alcohols (mentioned in section III-1), much less attention has been paid to the development of intermolecular functionalization of allenes. As mentioned in Section III-2 and III-3, the intermolecular incorporation of TFE solvent into the alleneamide to form III-6 as a side product was observed in high regio- and enantioselectivity (up to !!!!"*%!86% ee). This provided a good starting point to develop a general method, which uses an external nucleophile in order to outcompete the intramolecular cyclization (Scheme III-3). !!The intermolecular reactions were divided into three categories: intermolecular dichlorination, haloetherification, and halo-hydrin formation reactions. We started looking at developing a methodology for asymmetric dichlorination reaction of mono- and di-substituted alleneamides, first.  Despite the growing number of halogenated natural products,28-30 little attention has been paid on the asymmetric dihalogenation31-36 of alkenes. However, to the best of our knowledge no reports of enantioselective dihalogenation of allenes have been reported. For the first time, we were able to demonstrate that dichlorination of alleneamide can occur in moderate chiral catalystCl+ sourceNu-H solventNHONuXRIntermolecularNHR'O.RClONchiral catalystCl+ sourceR'RsolventIntramolecularNHR'ORClNuNHR'ORClScheme III-3 General scheme for intermolecular and intramolecular halofunctionalization of alleneamides. !!!!"*&!enantioselectivities. Table III-11 shows the optimization of reaction conditions for the asymmetric dichlorination of III-8a. We first tested the effect of utilizing different external nucleophiles (Cl- source) for the formation of III-26. Ammonium chloride (NH4Cl) and cesium chloride (CsCl) failed to yield the desired product (entries 1-2). Only trace amounts of III-26 was observed by crude 1H NMR, and mainly TFE-incorporated product was isolated in these reactions. 100 equivalents of LiCl in 0.02 M TFE afforded the product in 70% yield and 52% ee at room temperature (entry 3). Lower yield obtained in this condition was due to the formation of 14% cyclized oxazoline (III-8) and 15% TFE-incorporated by-products. In entry 4, 100 equivalent of LiCl was dissolved in 0.06 M TFE and only the soluble solution was added to the reaction mixture, which gave higher yields of 91% yield and 66% ee. We finally found that lowering the temperature to -30 ¡C was critical on achieving higher enantioselectivity (76% ee, 92% yield, 0.02 M TFE with 10 mol% (DHQD)2PHAL and 1.1 equiv DCDMH, entry 5).  We chose this as our optimized reaction condition, since playing with the catalyst loading and concentration did not improve the enantioselectivity of III-26 (entries 6-11). Switching the solvent from TFE to TFE:MeCN (4:1) to obtain lower reaction temperature of -60 ¡C was unsuccessful in pushing the ee higher (entry 12). Using 100 equivalent of LiCl is important, since 50 equivalent LiCl only gave 50% ee for this transformation (entries 5 and 13).!!!!!!"*'!!NHOCl.NHO(DHQD)2PHAl (x mol%)DCDMH (2.0 equiv)NuH, Solvent, 1-8 hClNO2NO2III-26III-8aTable III-11 Optimization of intermolecular asymmetric dichlorination of III-8a. Entry[a] Catalyst (mol %) External Nu (Equiv) Solvent (M) Temp (¡C) Yield (%) ee (%) 1 10 NH4Cl (100 eq) TFE (0.02) -30 trace - 2 10 CsCl (20 eq) TFE (0.02) -30 trace -   3[b] 10 LiCl (100 eq) TFE (0.02) rt 70% 52%   4[c] 10 LiCl (100 eq)(s) TFE (0.06) rt 91% 66%   5[d] 10 LiCl (100 eq) TFE (0.02) -30 92% 76% 6 2 LiCl (100 eq) TFE (0.05) -30 98% 38% 7 20 LiCl (100 eq) TFE (0.02) -30 89% 40% 8 2 LiCl (100 eq) TFE (0.02) -30 90% 40% 9 10 LiCl (100 eq) TFE (0.01) -30 86% 62% 10 10 LiCl (100 eq) TFE (0.1) -30 78% 54% 11 2 LiCl (100 eq) TFE (0.1) -30 94% 66%   12[e] 10 LiCl (100 eq) TFE:MeCN  (0.02) -60 87% 70% 13 10 LiCl (50 eq) TFE (0.02) -30 93% 50% [a] Isolated yield and % ee measured for III-26. [b] Ratio of (cyclized product, III-8) : (III-26) : (TFE-incorporated) was measured as (14 : 71 : 15); [c] 100 equiv LiCl was dissolved in TFE and only the soluble solution was added to the reaction mixture. [d] Background reaction (7% conversion after 8 hours). [e] TFE:MeCN (4:1) was used. !!!!!"+(!Despite the numerous attempts on asymmetric intermolecular haloetherification of olefins,3, 37 no reports on allene variants are presented. We next moved our attention towards optimizing the reaction condition for chloroetherification of alleneamides (Table III-12). We looked into chloroetherification of III-8a using MeOH as both the solvent and the nucleophile, however the reaction proceeded with little conversion even in the presence of the catalyst in MeOH after 2 days (entry 1). Acetic acid (20 equiv) as an additive was helpful in achieving higher conversions and moderate enantioselectivity (70% ee, entry 2). Further experiments were carried out to achieve higher conversions, ee, and lower the amount of cyclized by-product (P). We realized that the reaction in MeCN as a co-solvent was not only slow but also furnished III-27 in 30% ee (entry 3). Replacing MeCN with the slightly acidic HFIP co-solvent led to faster reaction rates (78% conversion after 12 hours) and 62% ee (entry 3-4). To push the reaction even further 2 equivalents of DCDMH was used, which led to 100% conversion after 7 days (56% ee, entry 5). Besides the formation of 15% cyclized by-product (P, III-8), we observed a side-product, which was formed from 3 equivalents of MeOH being incorporated into the allene (detected by LC-MS and 1H NMR, Scheme III-11). We believe that after the first chloroetherification, the resulting vinyl chloride, undergoes the second chloroetherification, and finally the third MeOH replaces the terminal chlorine.!!!!!!"+#!!Entry Sub Solvent Temp ¡C Time Ratio[a] (C:P:S) Conv.% ee% (P) 1 III-8a MeOH rt 24h - low -   2[b] III-8a MeOH rt 24h 15:75:10 90% 70% 3 III-8a MeOH:MeCN(1:1) rt 12h 19:32:49 51% 30%   4[c] III-8a MeOH:HFIP (5:1) rt 12h 17:61:22 78% 62%   5[d] III-8a MeOH:HFIP (5:1) rt 7d 15:75:0 100% 56% 6 III-8a MeOH:HFIP (5:1) -30  12h 4:20:76 24% 80% 7 III-8a MeOH:HFIP (1:1) -30  12h 15:85:0 100% 66% 8 III-8a MeOH:HFIP (5:1) -30  10d 8:92:0 100% 82% 9 III-8a MeOH:HFIP (5:1) +60 3d 0:90:10 90% 48% 10 III-7a MeOH:HFIP (5:1) rt 1d 9:91:0 100% 70% 11 III-7a MeOH:HFIP (5:1) -30 10d 5:95:0 100% 74% 12[e] III-7a MeOH:TFE (5:1) rt 12h 0:100:0 100% 66% 13 III-7a MeOH:HFIP (5:1) rt 12h Messy - - 14 III-7a MeOH:HFIP (5:1) +80 12h 0:100:0 100% 50% [a] Ratios were measure by crude 1H NMR analysis. [b] 20 equiv Acetic acid was added as an additive. [c] Cyclized product (C) was formed in 70% ee. [c] 2 equiv DCDMH was added. [e] TFE-incorporated was formed as a side product. !Table III-12 Optimization of intermolecular asymmetric haloetherification. NHOOMeNHOClAr = p-NO2         III-8aAr = 3,5-diNO2   III-7a.Ar = p-NO2         III-27Ar = 3,5-diNO2   III-28(DHQD)2PHAL (10 mol%)DCDMH (1.1 equiv)Solvent (0.025M), Additive TemperatureClONNO2NHOOMeClNO2NHO.NO2Cyclized (C)Product (P)Substrate (S)NO2NO2!!!!"+"!Lowering the temperature to -30 ¡C was helpful in increasing the enantioselectivity from 62% to 80% (entries 4 and 6), however the reaction was slow and gave 24% conversion after 12 h. To improve the conversion, 1:1 ratio of MeOH and HFIP was used (entry 7), since we knew acidic additives and solvents play an important role in rate of the reaction. This led to 100% conversion under the same time interval, but with lower selectivity (66% ee, entries 6-7). Extending the reaction time to 10 days at -30 ¡C, provided the product with 100% conversion and 82% ee (entry 8). The chloroetherification of alleneamides were found to be faster at high temperatures (60-80 ¡C), but with lower selectivities (entries 9 and 14). Similar observations were also made for III-7a (3,5-diNO2-substituted substrate, entries 10-14). Much less of the cyclized by-product (III-7) was formed in this transformation, since having two electron-withdrawing groups would deactivate the tethered nucleophile. Lower temperatures gave better selectivities (entry 11), and the use of the base additive NaHCO3 led to a sluggish reaction (entry 13).   Lastly we looked at optimizing conditions for the formation of halovinyl hydrins from alleneamides. MeOH (which we used as both solvent and external nucleophile) was replaced with H2O for the chloro- and bromo- hydroxylation of alleneamide III-29 and III-30. Table III-13 shows the parameters varied for attaining high enantioselectivities and yields of the products. We found that chlorohydrin III-29 could be formed in 65% yield and !!!!"+)!76% ee in H2O:TFE (5:1) with DCDMH and (DHQD)2PHAL system (Table III-13, entry 1). Use of DBDMH provided bromohydrin III-30 in 68% yield and 76% ee in 1:9 H2O:MeCN at -10 ¡C (entry 5). Having other brominating agents and co-solvents did not give promising results for this transformation (entries 2-4). With these optimization results in hand (Tables III-11 to III-13), we moved our attention to the substrate scope for chloroetherification, dichlorination, and halohydroxylation of monosubstituted alleneamides. Scheme III-4 shows the finalized optimized conditions for chloroetherification (Condition A), chlorohydrin formation (Condition B), bromohydrin formation (Condition BÕ), and dichlorination (Condition C). These conditions were applied to various mono- and di-substituted allenes (Scheme III-5). Chloroethers III-27 and III-28 were obtained in great yields and moderate enantioselectivities (88% yield, 82% ee and 85% yield, 74% ee, respectively). Chloro- and bromo-hydrins III-29 and III-30 were formed under conditions B and BÕ in 65-68% yield and 76% ee. Dichlorination of NO2-substituted allenes gave better enantioselelctivities than bromo-substituted ones (76% ee for III-26, 70% ee for III-33, 46% ee for III-32), but all in excellent yields. Extending the distance between the allene moiety and the amide group led to the formation of dichlorinated amide III-34 in only 16% ee but excellent yield (99%), similar to low selectivity observed in intramolecular cyclization (Scheme III-1).!!!!!"+*!!Besides monosubstituted allenes, disubstituted amides were used under similar conditions A and C (Scheme III-5). We were not able to observe the formation of III-35 to III-37 in any trace amounts. Methyl-substituted alleneamides gave the cyclized products III-19 in 76% yield and 99% ee (higher than the normal optimized condition shown in Scheme III-1) under Entry[a] X+ source Solvent (0.025 M) Temp ¡C Yield% (C) ee% (C) Yield% (P) ee% (P) 1 DCDMH H2O:TFE (5:1) rt - - 65% 76%   2[b] NBS H2O:TFE (3:1) rt - - 14% - 3 DBDMH H2O:TFE (4:1) rt 46% 0% 25% 62% 4 DBDMH H2O:HFIP (3:1) rt 26% 46% 45% 50% 5 DBDMH H2O:MeCN(1:9) -10 30% 44% 68% 76% [a] Isolated yields for both C (III-8 or III-31) and P (III-29 or III-31). [b] 15% conversion. !NHOOHNHOX     III-8a.X = Cl    III-29X = Br    III-30(DHQD)2PHAL (10 mol%)X+ source (1.1 equiv)Solvent (0.025M), 24 h TemperatureXONNO2NO2NO2X = Cl    III-8X = Br    III-31CPTable III-13 Optimization of intermolecular asymmetric halohydroxylation. !!!!"++!chloroetherification condition (A) and 80% yield and 90% ee under dichlorination condition (C). Phenyl-substituted allenes also formed the cyclized III-15 in 55% yield and 34% ee under dichlorination condition (C). These results illustrate that the rate of intramolecular cyclization reaction is Scheme III-4 Optimized conditions for asymmetric chloroetherification (A), dichlorination (C), chlorohydroxylation (B), and bromohydroxylation (BÕ). NHOOMeClRR'NHOClClRR'NHOOHClRR'NHR'O.RCondition A(DHQD)2PHAL (10 mol%) DCDMH (2.0 equiv)MeOH:HFIP (5:1)(0.025M)-30 ¡C, 10 daysCondition B(DHQD)2PHAL (10 mol%) DCDMH (1.1 equiv)H2O:TFE (5:1)(0.025M) rt, 1-2 daysCondition C(DHQD)2PHAL (10 mol%)DCDMH (2.0 equiv)LiCl (100 equiv), TFE (0.02 M)-30 ¡C, 1-2 hNHOOHBrRR'Condition B'(DHQD)2PHAL (10 mol%)DBDMH (1.1 equiv)H2O:MeCN (1:9)(0.025M)-10 ¡C, 1-2 days!!!!"+$!much higher than the intermolecular path under these conditions for disubstituted allenes.!It also demonstrates the high tolerance of substrate III-19a to afford the cyclization product III-19 in high asymmetric induction under various conditions. The absolute configuration of the cyclized products III-10 (mono-substituted), III-19 (di-substituted) and intermolecularly functionalized III-26 were verified by the X-ray crystal structure and were inferred by analogy to other substrates in Scheme III-1 and III-5.              !!!!"+%!III-8 Synthesis of alleneamides and elaboration of cyclized chlorovinyl oxazolines  Mono- and di-substituted alleneamide were synthesized through different paths. Scheme III-6 shows the general scheme for the preparation of monosubstituted alleneamides in two steps in great yields from the commercially available propargyl amines. In the first step, propargyl amides are synthesized from propargyl amines and the appropriate choice of acid chlorides in high yields. Next the terminal alleneamides are synthesized through the Crabbe allene synthesis38 via Cu-catalyzed homologation of acetylene precursors in the presence of diisopropylamine and formaldehyde. The di-alleneamides were synthesized in a similar manner. Commercially available tetraphthaloyl or isophthaloyl dichlorides were converted into di-propargyl amides with excess propargyl amine, followed by Crabbe allene synthesis to convert both alkyne moieties to allenes as shown in Scheme III-7.!!!!!"+&!!Scheme III-5 Substrate scope for asymmetric chloroetherification (condition A), dichlorination (condition C), chlorohydroxylation (condition B), and bromohydroxylation (condition BÕ) of mono- and disubstituted alleneamides. NHOOMeClNO2III-2788% yield, 82% eeCondition ANHOOMeClIII-2885% yield, 74% eeCondition ANO2NO2NHOOHClNO2III-2965% yield, 76% eeCondition BNHOOHBrNO2III-3068% yield, 76% eeCondition B'NHOClClNO2III-2692% yield, 76% eeCondition CNHOClClIII-3391% yield, 70% eeCondition CNO2NO2NHOClClBrIII-3295% yield, 46% eeCondition CMonosubstituted alleneamidesClClIII-3499% yield, 16% eeCondition CHNONO2NHOClClPhDisubstituted alleneamidesNHOClClNO2MeIII-360% yieldCondition CIII-370% yieldCondition CIII-1980% yield, 90% eeIII-1555% yield, 34% eeIII-1976% yield, 99% eeNHOOMeClNO2MeIII-350% yieldCondition A!!!!"+'!!Disubstituted alleneamides were synthesized in 5-8 steps (Scheme III-8). The commercially available disubstituted propargyl alcohols were purchased and used to synthesize the final products. The non-commercially available propargyl alcohols were synthesized from terminal propargyl alcohol through protection of alcohol with THP, followed by alkylation of alkyne with the appropriate alkyl bromide under basic condition. Lastly, deprotection of alcohol under mild acidic conditions gave the disubstituted propargyl alcohol in overall three steps in high yields. In the forth step, bromination of the alcohol with PBr3 under basic condition with pyridine provided the desired propargyl bromide. In the next step the allenylic alcohols were synthesized under mild conditions through an indium-mediated coupling reaction in an aqueous media in the presence of formaldehyde.39, 40 Mitsunobu 41 reaction of the primary alcohol delivers the phthalimido-substituted allenes using a suitable nitrogen nucleophile such as phthalamide in the presence of PPh3, and DIAD (diisopropyl azodicarboxylate). The amine group was then liberated from the phthalamide moiety through basic hydrolysis (Gabriel reaction 42). Scheme III-6 General scheme for synthesis of mono-substituted alleneamides. NH2Et3N, ArCl, DCM0 ¡C to rt, 2-5 hHNOArCuI, CH2O, i-Pr2NHDioxane, 110 ¡C, 12hRRRR.NHArORR!!!!"$(!Allene amines were then converted to the desired di-substituted alleneamides with the appropriate choice of acid chlorides in high yields.!!The obtained cyclized 2,5-substituted oxazolines are of a great interest, not only in their own right, but also as useful building blocks. In collaboration with Xin Liang Ding, we demonstrated that the cyclized chlorovinyl oxazolines could be further manipulated to a variety of chiral heterocycles (Scheme III-9). Compound III-5 was easily converted into the chiral amino-alcohol III-38 through a simple acid hydrolysis. Under various cross-coupling conditions, chlorovinyl oxazoline III-5 undergoes ring opening as shown in the dashed box in Scheme III-9a. The vinyl chloride moiety successfully undergoes cross-coupling with the phenyl group, however due to the formation of !-allyl carbocation, the second phenyl group incorporates through SN2 and SN2Õ pathways to afford III-41 and III-42, respectively. To avoid ring-opening, Boc-protected oxazoline III-39 was synthesized from Scheme III-7 General scheme for synthesis of di-alleneamides. CuI, CH2Oi-Pr2NHDioxane110 ¡C1-5 h.XOHNOHNEt3N, PA DCM0 ¡C to rt 2-5 hXOHNOHN.XClOOClX = C or NPropargyl amine=PA!!!!"$#!amino-alcohol III-38 in two steps through a simple protecting group exchange protocol. Suzuki protocol applied to III-39 provided III-40 in 54% yield and 82% ee (Scheme III-9a).!!The vinyl chloride functionality in compound III-5 was further elaborated via the Sonogashira cross-coupling reaction (Scheme III-9b). The elimination of HCl from III-5 produced III-43 by treatment with LDA under kinetic conditions. This intermediate afforded compound III-44 under Sonogashira cross-coupling condition in 86% yield with complete stereochemical fidelity (86% ee).  PBr3, pyridine, Et2O0 to 35 ¡C, 2-5 hIn, CH2O, H2Ort, 10-14 hPhthalamide, PPh3 DIAD, THF 0 ¡C to rt, 2-4 hE3N, ArCOClDCM, 0 ¡C to rtNHR'O.RR'.OHR'.NH2NH2NH2, MeOHrt, 12-20 hOHDHP, p-TsOHEt2O, rt, 5 hOTHPnBuLi, THF, R'-Br-78 ¡C to rt3-5 hp-TsOH, MeOHrt, 1hR'.NOOOTHPR'OHR'BrR'Scheme III-8 General scheme for synthesis of di-substituted alleneamides. !!!!"$"! Scheme III-9 Elaboration of chlorovinyl oxazolines through Suzuki coupling (a), Sonogashira coupling (b), and hydrogenation reactions (c). ClOHNH2HClClNOBocPhB(OH)2, Pd(OAc)2S-Phos, K3PO4ClONIII-590% ee48 h, 70% yieldToluene:H2O (100:1)120 ¡C, Microwave2 h, 54% yield1.5 N aq. HCl110 ¡C, sealed tubeIII-38III-39III-40[!]D20 = +25¡ 82% eeNOBocprotecting groupexchangeLDA, THF, -78 ¡C1 h, 35% yieldIII-43ONClONIII-590% eePhI, Pd(OAc)2, PPh3CuI, i-Pr2NHrt, 12 h, 50% yieldONIII-44[!]D20 = +128¡ 86% eeClONIII-596% eeMeNO2H2, Pd/C, MeOH2 h, 98% yieldMeHNONH2III-4736% eeClONPd2(dba)3, P(tBu)3 PhB(OH)2,KF, THF60 ¡C, 12h 68% conv.PhPhHNPhOHNPhOPhPhRac-III-5III-415% yieldIII-4216%yieldabcONONTBAF, DMF, 100 ¡C21 h, 100% conv.ClONRac-III-5III-4534% yieldIII-4641% yield!!!!"$)!Note: using TBAF in this elimination reaction forms the aromatic vinyloxazole III-45 as a side product in 34% yield (Scheme III-9b, dashed box); probably through deprotonation of chiral allylic proton to form an allene intermediate followed by a double bond migration/aromatization events.!Lastly, hydrogenation of III-5 using H2, palladium on carbon in MeOH led to a complete reduction of oxazoline ring and the terminal double bond groups to afford amide III-47 in 98% yield and 36% ee (Scheme III-9c). Formation of palladium !-allyl carbocation results in 62% loss in enantioselectivity. Further optimizations are needed to compensate for this loss.!III-9 Computational calculation of chlorenium affinities (HalA (Cl)) for allene substrates  We investigated how easily does a given allene capture a chlorenium ion. More specifically, we were interested in quantifying the propensity of various allenes to react with chlorenium sources using a reliable and predictable mean, the halenium affinity (HalA). This term was discussed fully in Chapter I. Similar theoretical means were applied to calculate HalA (Cl) for allenes containing various functionalities.      !!!!"$*! Table III-14 Calculated HalA (Cl) values for various allenes. (*frozen structure) Entry Substrate Binding site Stabilization HalA (Cl) Kcal/mol 1  C3 C2 C1 C2  C2* O N H shift O O N - - - 187.7 212.6 213.6 183.2 164.4 141.1 145.4 2  C2 C2 - O 167.0 202.5 3  C2 C2 C2 Ph O N 196.3 218.0 182.8 4  C2 C2 N O 180.8 203.5 5  C2 C2 Ph N 188.7 198.9 6  C2 C2 - Ph 175.1 186.5 7  C2 C2 - O 167.9 188.3 8  C2 C2 - O 163.8 187.8 9  C2 C2 - O 146.6 181.3  !!!!"$+!Table III-14 represents the final numbers using DFT calculations with [B3LYP/6-31G*] basic sets. These theoretical measurements predict the propensity for the halofunctionalization of allenes with different tethered nucleophiles other than amides discussed in this chapter. Table III-14 shows the tendency of allenes to undergo chlorination at different sites (C1, C2, and C3 of allene, N and O of the nucleophilic site). Each substrate shows the possibility of chlorination for chloro- lactonization, etherification, as well as chlorocyclization of amides, carbamates, and aryl compounds.!The allene with tethered benzamide group shows various HalA (Cl) values depending on the site, where Cl+ attacks (Table III-14, entry 1). The geometry optimized structures with different binding modes and stabilization effects are shown in Figure III-6. We found that C3 undergoes chlorination only if H+ migrates to the carbonyl oxygen (187.7 Kcal/mol). Higher chlorenium affinities were obtained upon chlorination of C1 and C2 under the stabilization by oxygen (212.6 Kcal/mol (C2), 213.6 Kcal/mol (C3)). The calculated HalA values of C2 with no stabilization (*constraint was used during geometry optimization) or anchimeric assistance of N or O atoms were found to be 164.4, 183.2 and 212.6 Kcal/mol. This suggests the influence of neighboring groups!on increasing the affinity of allene toward electrophilic chlorenium ion. The oxygen and nitrogen atoms of the benzamide group showed much lower HalA values of 141.1 and 145.4 Kcal/mol. In order to remove the anchimeric assistance of the neighboring groups, we had to !!!!"$$!constrain or freeze the chlorinated structure. The stabilized and non-stabilized HalA (Cl) values for C2 of the p-NO2-substituted benzamide are 167.0 and 202.5 Kcal/mol, respectively. Anchimeric assistance of neighboring functionalities extends delocalization of allylic carbocation formed upon chlorenium attack!and lead to an increase in the halogen affinities for allenes. Anchimeric influence of p-OMe substituted benzamide is higher than benzamide and that is higher than p-NO2 substituted systems. This correlates well with the calculated HalA values of 218.0, 212.6, and 202.5 Kcal/mol. (entries 1-3). Allene carbamates also show similar halogen affinities of 203.5 Kcal/mol (entry 4). However, allenes lacking the neighboring carbonyl oxygen moiety showed lower halogen affinities, similar to a halogen affinity observed for olefins (entries 5-9).!!!!!!!!!!!!!"$%!!!!C3 attacks Cl+ H shift HalA (Cl) = 187.7 Kcal/mol  C2 attacks Cl+ Stabilization of C1 by N  HalA (Cl) = 183.2 Kcal/mol  C1 attacks Cl+ Stabilization of C2 by O  HalA (Cl) = 213.6 Kcal/mol   C2 attacks Cl+ Stabilization of C1 by O  HalA (Cl) = 212.6 Kcal/mol   Figure III-6 Geometry minimized structures with calculated HalA (Cl) (B3LYP/6-31G*) with anchimeric assistance of neighboring groups. !!!!"$&!III-10 Kinetic analysis of chlorocyclization of alleneamides Kinetic investigations of organic reactions provide critical information towards understanding the reaction mechanism by revealing the order of each reaction component and determining the rate-determining step (RDS). Classical kinetic measurements rely on initial data points, which can be obtained by using excess amount of one component in order to establish pseudo first order conditions in a multi component reaction. Blackmond and co-workers have developed the Reaction Progress Kinetic Analysis (RPKA), to study the mechanism of complex reactions.43, 44 This new methodology enables the extraction of kinetic information out of fewer experiments using Òdifferent excessÓ protocol. A better mechanistic understanding is achieved by monitoring the reaction kinetics from beginning to end. In addition, RPKA provides a new tool to address the role of side products, catalyst deactivation, and product inhibition using Òsame excessÓ protocol.45, 46 We applied the Òdifferent excessÓ protocol to chlorocyclization of III-5a to afford III-5 under the optimized reaction condition (Table III-15). The progress of the reaction was monitored by ReactIR. Different concentrations of DCDMH and substrate with 5 mol% (DHQD)2PHAL (to slow down the reaction) were used in 1:1 TFE:HFIP (1 mL). Different excesses (DE = 0.0, 0.020, and 0.048) were chosen with DCDMH as the limiting reagent. After collecting the data points at 15 sec time intervals, we used iC Kinetics software to process the data. We found an overlay between the rate/[allene]-!!!!"$'!0.45 and [DCMDH]2.18 (Figure III-7). Based on these rate studies we surmised that the reaction is inversely proportional with respect to the alleneamide with an order of 0.45 and directly proportional to DCDMH with an order of 2.18. At this point the rate for the asymmetric chlorocyclization of alleneamides can be expressed as rate = k [DCDMH]2.18/[allene]0.45. This data suggests the inhibitory effect of substrate on the rate of the reaction. Catalyst might get deactivated in presence of higher amounts of substrate through a different catalytic pathway. However, DCDMH enhances the rate of the reaction and is involved during or before the RDS.!!Entry [Sub]  M [DCDMH] M Solvent mL Excess 1 0.320 M 0.320 M 1 mL 0.000 2 0.320 M 0.300 M 1 mL 0.020 3 0.320 M 0.272 M 1 mL 0.048 !ClON(DHQD)2PHAl (5 mol%)TFE:HFIP (1:1)  DCDMH, rtNHO.III-5aIII-5Table III-15 ÒDifferent excessÓ protocol for asymmetric chlorocyzliation of alleneamide III-5a. !!!!"%(!!!!III-11 Future directions  We have shown the feasibility of the asymmetric chlorocyclization of alleneamides in high yields and excellent enantioselectivities with (DHQD)2PHAL and DCDMH (Sections III-4 and III-5). We then moved our attention toward bromocyclization of alleneamides, since brominated products are amenable to various transformations. For example, vinyl bromides undergo various cross-coupling reactions much easier than vinyl chlorides. Figure III-7 Linear correlation between rate/[allene]-0.45 versus [DCMDH]2.18 for asymmetric chlorocyclization of alleneamides at different excesses (DE) of 0.0, 0.020, and 0.048. 00.00050.0010.001500.0050.010.0150.020.025DE=0.020DE=0.048DE=0.000Rate/[Allene]^-0.45[DCDMH]^2.18!!!!"%#!Table III-16 shows the initial optimizations toward improving the selectivity of these reactions. We observed slow reaction rates at lower temperatures (-30 to -50 ¡C) in TFE:MeCN for bromocyclization of alleneamides (Table III-16, entries 1 and 6). However, reactions were faster in TFE:HFIP (1:1), leading to 10% and 30% ee for (DHQD)2PHAL-catalyzed reaction of III-10a at -10 and -30 ¡C, respectively (entries 2-3). NO2-substituted alleneamide III-8a showed similar selectivity (32% ee) under these conditions but at room temperature (entry 4). Interestingly, use of MeCN as a co-solvent improved the selectivity to 40% ee at room temperature and 56% ee at -30 ¡C (entries 5-6). We believe that MeCN could be involved in lowering the rate of background reaction. Conversely, we think HFIP might increase the rate of uncatalyzed reaction that leads to the low observed enantioselectivity (8% ee, entry 7). More optimizations are necessary to improve enantioselectivity. As shown in Table III-16, change of catalyst from (DHQD)2PHAL to other dimeric or monomeric cinchona alkaloids led to racemic products (entries 8-10). Other family of catalysts, bromenium sources, solvents, and temperatures should be screened. Furthermore, kinetic studies could help to understand the role of MeCN, TFE, and HFIP in the rate of catalyzed/uncatalyzed reactions in correlation with observed stereoselectivities.!!!!!!!!"%"!!!The chemistry of electrophilic functionalization of alleneamides with halenium sources could be further expanded to allenes with different tethered nucleophiles. This chemistry could be tested on allene alcohols, allenoic acids, allene amines, and allene carbamates to provide various chlorovinyl-Entry Substrate  Catalyst Solvent T (¡C) Yield% ee%   1[a] III-10a (DHQD)2PHAL TFE:MeCN(4:1) -50 trace - 2 III-10a (DHQD)2PHAL TFE:HFIP (1:1) -10 72% 10% 3 III-10a (DHQD)2PHAL TFE:HFIP (1:1) -30 70% 30% 4 III-8a (DHQD)2PHAL TFE:HFIP (1:1) rt 62% 32% 5 III-8a (DHQD)2PHAL TFE:MeCN(1:4) rt 60% 40%   6[a] III-8a (DHQD)2PHAL TFE:MeCN(1:4) -30 21% 56% 7 III-8a (DHQD)2PHAL HFIP rt 62% 8% 8 III-8a (DHQD)2PYR TFE:MeCN(1:4) rt 73% 2% 9 III-8a (DHQ)2AQN TFE:MeCN(1:4) rt 80% 2% 10 III-8a Hydroquinidine TFE:MeCN(1:4) rt 56% 2%      [a] Low conversion low temperatures.!BrONNHO.RRR = NO2   III-8aR = Br      III-10aR = NO2   III-48R = Br      III-49Catalyst (10 mol%)DBDMH (1.1 equiv)Solvent (0.025M), Temp ¡CTable III-16 Optimization of asymmetric bromocyclization of alleneamides. !!!!"%)!substituted heterocycles such as tetrahydro-furans, -pyrans, lactones, pyrrolidines, piperidines, and oxazolidinones in an asymmetric fashion. We have examined the chlorocyclization of allene carbamate III-50. We have been able to form III-51 in 95% yield and 38% ee under similar conditions to chlorocyclization of alleneamides (Scheme III-10). The enantioselectivity of this transformation could be further optimized in the future.!!!During the intermolecular chloroetherification of alleneamides, we observed the formation of a side product upon using of 2 equivalents of DCDMH after 7 days (Scheme III-11).  We obtained chloroether III-52 in 12% yield as a single diastereomer (ee has not been determined at this point). The remaining material was the mono-chloroetherified product III-27 (Scheme III-5). This methodology could be further investigated. We believe that after the second chloroetherification of the vinyl chloride, the terminal chlorine is again Scheme III-10 Asymmetric chlorocyclization of allene carbamates.  ClOHNONHO.O(DHQD)2PHAL (10 mol%)DCDMH (1.1 equiv)TFE:HFIP (1:1) (0.025M), rt95% yield, 38% eeIII-50III-51!!!!"%*!displaced with third molecule of MeOH. This transformation would functionalize all three allene carbons in one pot. !!!Kinetic resolution in organic chemistry, a concept similar to molecular recognition observed in enzyme catalysis, is a practical mean for synthesis of enantioenriched molecules.47 Jacobsen and co-workers have elegantly shown the requirement and criteria for an ideal kinetic resolution.48 We were interested on exploiting the strong substrate-catalyst interaction observed in asymmetric chlorocyclization of alleneamides, in developing a kinetic resolution of racemic substituted alleneamides. The initial optimization results are shown in Table III-17. We observed the influence of chlorine sources, solvents, and temperature on the diastereomeric ratios of III-54 and enantioselectivity of the each diastereomers (D1 and D2). Unfortunately, we observed moderate diastereoselectivities and higher enantioselectivity of the minor isomer. Efforts to further improve the selectivity of this chemistry will be intriguing for preparation of chlorovinyl oxazolines bearing two chiral centers.!NHO.NO2III-8a(DHQD)2PHAL (10 mol%)DCDMH (2.0 equiv)MeOH:HFIP (5:1) (0.025M)rt, 7 days, 12% yield, >99:1 drMeOClOMeOMeNHONO2III-52Scheme III-11 Chloroetherification of alleneamides with 3 MeOH incorporation.  !!!!"%+!!We have shown the first asymmetric organocatalytic chlorocyclization of mono- and di-substituted alleneamide in high yield and excellent enantioselectivities (Sections III-4 and III-5). Our results reinforces the idea that this methodology could be expanded to tri- or tetra-substituted alleneamides. Various synthetic paths were investigated to synthesize tetra- or tri-substituted alleneamides but failed or gave low yields. These efforts will be described briefly in this section. In the future different approaches should be pursued towards the synthesis of tri- or tetra-substituted alleneamides.!NHO.III-53(DHQD)2PHAL (10 mol%)Cl+ source (0.40-0.55 equiv)Solvent (0.025M), T ¡CIII-54ClONMeMeDiastereomers D1 or D2Entry Cl+ source Solvent T (¡C) Conv. (%) Ratio[a]  (dr) (D1/D2) ee% (D1) ee% (D2) ee% (III-53) 1 DCDMH TFE:HFIP (1:1) rt 43% 42:58 58% 32% 32% 2 DCDMH TFE -30 18% 12:88 50% 2% 14% 3 NCP TFE rt 37% 16:84 58% 24% 22%      [a] Diatereomeric ratios were measured by 1H NMR analysis of crude mixture.!Table III-17 Kinetic resolution of alleneamide III-53. !!!!"%$!!We started our effort for preparation of tri-substituted alleneamides with two phenyl groups on the terminal allene carbon (Scheme III-12). Intermediate III-57 was synthesized from commercially available benzophenone in three steps with excellent yields. However, LiAlH4 reduction of propargyl alcohol III-57 did not afford the desired allene alcohol III-50. Scheme III-12 Efforts toward the synthesis of tri-substituted alleneamide with terminal diphenyl group.  OTMS1. nBuLi, THF, -10 ¡C2. NaOH, MeOH, 0 ¡C    4h, 79% yieldOHDHP, pTsOH, DCM-20 ¡C to rt, 3 h98% yieldOTHPn-BuLi, Et2O, CH2O-78 ¡C to rt, 10 h98% yieldLiAlH4, Et2O0 ¡C to rt, 5 hHNOR.III-55benzophenoneOTHPHOOH.III-56III-57III-58tri-substituted alleneOTHPHOIII-57LiAlH4, Et2O0 ¡C to rt, 5 h72% yieldIII-59!!!!"%%!Instead highly conjugated III-59 was produced. Lowering the temperature to -78 ¡C could only help in forming the desired III-50 in 10% yield.!To avoid the problem observed in the elimination of allene alcohol III-56, we decided on switching from the highly conjugated system to the gem-dimethyl substituted alleneamides (Scheme III-13). Allene alcohol III-62 was synthesized in three steps successfully in great yields, however the Mitsunobu reaction for conversion of III-62 to III-63 was not successful and gave only 3% yield. Similar problem of low yields (8%) in Mitsunobu reaction of allene alcohols to amines was observed for the cyclic allenol III-67 Scheme III-13 Efforts toward the synthesis of tri-substituted alleneamide with terminal dimethyl group. DHP, pTsOH, DCM-20 ¡C to rt, 3 h98% yieldn-BuLi, Et2O, CH2O-78 ¡C to rt, 10 h78% yieldLiAlH4, Et2O0 ¡C to rt, 5 h70% yieldIII-60MeMeOH1. PhthH, DIAD, PPh3    THF, 0 ¡C to rt, 2 h2. NH2NH2, MeOH3% yield2-methylbut-3-yn-2-olMeMeOTHPMeMeOTHPHOOH.MeMeIII-61III-62NH2.MeMeIII-63HNOR.MeMetri-substituted allene!!!!"%&!(Scheme III-14). For both, full conversions were observed; however, low yields were due to the decomposition of starting materials and the products.!!!We then focused our attention on synthesizing 1,3-disubstituted alleneamides (Scheme III-15). Similar to trisubstituted allenols mentioned above, the Mitsunobu reaction gave poor yield (5%) for the synthesis of 1,3-disubstituted alleneamides III-74. We then decided on synthesizing III-72 through the Crabbe synthesis by substituting acetaldehyde in place of formaldehyde. As shown in Scheme III-15, the propargyl amide III-73 does not form the 1,3-disubstituted alleneamide III-74 using Crabbe allene protocol; DHP, pTsOH, DCM-20 ¡C to rt, 3 h65% yieldn-BuLi, Et2O, CH2O-78 ¡C to rt, 10 h75% yieldLiAlH4, Et2O0 ¡C to rt, 5 h86% yield1. PhthH, DIAD, PPh3    THF, 0 ¡C to rt, 2 h2. NH2NH2, MeOH8% yieldOH.III-64HNOR.tri-substituted alleneTHPOOHO              , THFMgBr-15 ¡C to rt, 5 h61% yieldHOTHPONH2.cyclohexanoneIII-65III-66III-67III-68Scheme III-14 Efforts toward the synthesis of tri-substituted alleneamide with terminal cyclohexyl group. !!!!"%'!instead III-76 is formed without any incorporation of acetaldehyde. We then decided on using a new protocol recently reported by Ma and coworkers, where 1,3-disubstituted allenes could be synthesized through a one-pot synthesis in presence of appropriate alkyne, aldehydes, zinc iodide, and morpholine.49 This method is a modification of Crabbe allene synthesis, where it is not only limited to paraformaldehyde and works for a variety of aldehydes. Although the scope of this methodology does not include propargyl amide substrates, we did test similar reaction conditions for substrate III-77. The reaction failed to provide the desired III-78; instead it furnished III-79 and III-80 in 33% and 4% yields, respectively. It undergoes an intermolecular incorporation of benzaldehyde and then it is trapped by intramolecular nucleophilic amide moiety. This transformation could be further expanded and optimized for synthesis of styryloxazole chromophores.!We were able to synthesize trisubstituted alleneamide III-82 in three steps in 35% yield (Scheme III-16). Intramolecular nucleophilic incorporation of amide moieties led to the formations of E/Z isomeric III-83 in 31% and 19% yields, respectively. Based on the methods discussed so far we have come to a conclusion that the amide group should be protected prior to allene formation. This led us to a different path shown in Scheme III-17. We planned on double protecting the propargyl amine to yield III-84, to remove the chance of intramolecular cyclization. However functionalization of alkyne encountered a problem by formation of III-88 side product in 35% yield.!!!!!"&(!!HN.PhNH2Et3N, BzCl, DCM0 ¡C to rt,10h87% yieldHNOPhZnI2, PhCHO Morpholinetoluene, 130 ¡CPhNOPhPhNOPhOHPhOPropargylamineIII-77III-78HNOPhIII-77ZnI2, PhCHO Morpholinetoluene, 130 ¡CIII-7933% yieldIII-804% yieldHNOCuI, MeCHO, i-Pr2NHDioxane, 110 ¡C , 12hOMeONOMeovertimertONOMeIII-73III-75HNOOMeNH2Et3N, BzCl DCM, 10 h0 ¡C to rt77% yieldPropargylamineHN.MeZnI2, MeCHO Morpholinetoluene, 130 ¡CArOAr = p-OMe   III-74III-73III-76MeOHMeOTHPDHP, p-TsOHDCM, 0 ¡C to rt60% yield, 5 hdr (58:42)n-BuLi, Et2OCH2O, -78 ¡C to rt41% yield, 10 hMeOTHPOHdr (90:10)LiAlH4, Et2O0 ¡C to rt, 5 h42% yieldphthalamide, PPh3DIAD, THF, 0 ¡C to rt5% yield, 2hN.MeOO.MeOHIII-69but-3-yn-2-olIII-70III-71III-72Scheme III-15 Efforts for the synthesis of 1,3-di-substituted alleneamide. !!!!"&#!!!Scheme III-16 Synthesis of tri-substituted alleneamide III-82. HN.PhNH2Et3N, BzCl, DCM0 ¡C to rt,10h87% yieldHNOPhn-BuLi, THFPhCHO-78 ¡C to rt, 5 h45% conv.30% yieldPhOPropargylamineIII-77III-81HNOPhHOPh1) Et3N, MsCl    THF, 0 ¡C2) MeLi, CuCN    THF, -78 to 0 ¡CMePhNOPhNOPhPhIII-8236% yieldE-III-8331% yieldZ-III-8319% yieldN.PhNH2(Boc)2O, ACNDMAP, rt,16 h86% yieldNBocBocPropargylamineIII-84III-85NBocHOPh1) Et3N, MsCl    THF, 0 ¡C2) MeLi, CuCN    THF, -78 to 0 ¡CMeIII-86Boc i-Pr2NH, n-BuLi HMPA, PhCHOTHF, 0 to -78 ¡CBocBocHN.PhMeIII-87ArONBocBocNBocBoci-Pr2NH, n-BuLi, THF HMPA, PhCHO0 to -78 ¡CIII-84HOPhPhOHIII-8835% yieldScheme III-17 Synthesis of tri-substituted alleneamide III-87. !!!!"&"!III-12 Conclusion  In summary, we have reported the first asymmetric halofunctionalization of mono- and di-substituted alleneamides in both intra- and inter-molecular fashion to give access to chiral chlorovinyl oxazoline hetereocycles. This transformation is mediated by (1-10 mol%) of commercially available (DHQD)2PHAL as the chiral catalyst and hydantoins (DCDMH or DBDMH) as halogenating agents. These results demonstrate the feasibility of functionalization of alleneamides in high regioselectivity, yields and enantioselectivities. High selectivities, however, are highly dependent on the right choice of solvent and appropriate temperature. We noted the importance of fluorinated solvents (TFE) in gaining high enantioinduction.  Expansions of this methodology to tri- or tetra-substituted alleneamides or to other allenes with different nucleophiles, as well as the mechanistic underpinnings of this transformation will be the future directions of this project.!!!!!!!!!!!!"&)!III-13 Experimentals NMR spectra were obtained using a 300, 500, or 600 MHz NMR spectrometers (VARIAN INOVA). Chemical shifts are reported in parts per million (ppm) and are referenced using the residual 1H peak from the deuterated solvent. For HRMS (ESI) analysis, a Waters 2795 (Alliance HT) instrument was used and referenced against Polyethylene Glycol (PEG-400-600).  Column chromatography was performed using Silicycle 60 †, 35-75 !m silica gel. Pre-coated 0.25 mm thick silica gel 60 F254 plates were used for analytical TLC and visualized using UV light, iodine, potassium permanganate stain, p-anisaldehyde stain or phosphomolybdic acid in EtOH stain. TLC analyses were performed on silica gel plates (pre-coated on aluminum; 0.20 mm thickness with fluorescent indicator UV254). All reagents were purchased from commercial sources and used without purification unless otherwise mentioned. THF and Et2O were freshly distilled from Na-benzophenone ketyl whereas CH2Cl2 and PhCH3 were distilled over CaH2. Trifluoroethanol was purchased from Aldrich or Alfa Aesar and used without further purification. Flash silica gel (32-63 µm, Silicycle 60 †) was used for column chromatography. Enantiomeric excess for all products was judged by HPLC analysis using DAICEL CHIRALCEL¨ OJ-H and OD-H or DAICEL CHIRALPAK¨ IA-H, AS-H, and AD-H columns. Optical rotations of all products were measured in chloroform. Diastereomeric ratios !!!!"&*!were determined by crude NMR analysis.  All known compounds were characterized by 1H and 13C NMR and are in complete agreement with samples reported elsewhere. III-13-A General procedures for the preparation of products III-13-A1 General procedure for catalytic asymmetric intramolecular chloro- or bromocyclization of alleneamides A screw-capped vial, equipped with a magnetic stir bar, was charged with the substrate (0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (7.8 mg, 10 mol%). To the following vial TFE:HFIP (1:1) (4.0 mL) solvent mixture was added. The vial was capped and the resulting suspension was stirred at ambient temperature till all the solids had completely dissolved. DCDMH (21.6 mg, 0.11 mmol, 1.1 equiv) or DBDMH (31.2 mg, 0.11 mmol, 1.1 equiv) was then introduced in a single portion. The stirring was continued till the reaction was complete (TLC). The reaction was then quenched with saturated aqueous Na2SO3 solution (3.0 mL) and extracted with CH2Cl2 (3 x 2 mL). The combined organics were washed with brine and then dried over anhydrous Na2SO4 and filtered. Column chromatography (SiO2/EtOAc Ð Hexanes gradient elution) gave the desired product. Some modifications were used for some of the substrates including the change of solvent to TFE:MeCN (1:4), lower temperature of -20 ¡C to -30 ¡C, and higher concentration of substrate !!!!"&+!(0.32M). For double cyclization of dialleneamides 2.2 equiv of DCDMH was utilized. III-13-A2 Analytical data for the chlorocyclized oxazoline products!III-5: (R)-5-(1-chlorovinyl)-2-phenyl-4,5-dihydrooxazole    1H NMR (500 MHz, CDCl3) " 7.95 (d, J = 7.5 Hz, 2H), 7.40-7.50 (m, 3H), 5.55 (d, J = 2.0 Hz, 1H), 5.37 (d, J = 2.0 Hz, 1H), 5.19 (dd, J = 9.5 Hz, J = 7.0 Hz, 1H), 4.24 (dd, J = 15.5 Hz, J = 10.0 Hz, 1H), 4.05 (dd, J = 15.0 Hz, J = 7.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 163.5, 139.6, 131.6, 128.4, 128.2, 127.1, 113.6, 80.2, 59.8. HRMS (ESI) Calculated Mass for C11H10NOCl: ([M+H]+) = 208.0529, Found ([M+H]+) = 208.0535. Resolution of enantiomers: DAICEL Chiralcel¨ IA-H column, 1% IPA-Hexanes, 0.7 mL/min, 254 nm, RT1 (minor) = 16.6 min, RT2 (major) = 19.9 min . [#]D20 = +96.7 (c = 1.11, CHCl3, er = 95:5)    ClON!!!!"&$!  III-7: (R)-5-(1-chlorovinyl)-2-(3,5-dinitrophenyl)-4,5-dihydrooxazole    1H NMR (500 MHz, CDCl3) " 9.2 (t, J = 2.0 Hz, 1H), 9.09 (d, J = 2.0 Hz, 2H), 5.60 (d, J = 2.0 Hz, 1H), 5.46 (d, J = 2.0 Hz, 1H), 5.35 (dd, J = 10.5 Hz, J = 7.5 Hz, 1H), 4.34 (dd, J = 15.5 Hz, J = 10.5 Hz, 1H), 4.05 (dd, J = 15.5 Hz, J = 7.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 159.9, 148.6, 138.7, 130.1, 128.2, 121.0, 115.5, 81.7, 59.9. HRMS (ESI) Calculated Mass for C11H8N3O5Cl: ([M+H]+) = 298.0231, Found ([M+H]+) = 298.0232. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 10% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 13.5 min, RT2 (minor) = 16.4 min . [#]D20 = +69.0 (c = 0.14, CHCl3, er = 97:3)  III-8: (R)-5-(1-chlorovinyl)-2-(4-nitrophenyl)-4,5-dihydrooxazole    ClONNO2NO2ClONNO2!!!!"&%!1H NMR (500 MHz, CDCl3) " 8.26 (d, J = 9.0 Hz, 2H), 8.12 (d, J = 8.5 Hz, 2H), 5.56 (d, J = 2.0 Hz, 1H), 5.41 (d, J = 2.0 Hz, 1H), 5.26 (dd, J = 10.5 Hz, J = 7.5 Hz, 1H), 4.29 (dd, J = 15.5 Hz, J = 10.5 Hz, 1H), 4.10 (dd, J = 15.5 Hz, J = 7.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 161.9, 149.6, 139.1, 132.8, 129.3, 123.6, 114.6, 80.9, 59.8. HRMS (ESI) Calculated Mass for C11H9N2O3Cl: ([M+H]+) = 253.0380, Found ([M+H]+) = 253.0389. Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 10% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 17.5 min, RT2 (minor) = 20.3 min . [#]D20 = +20.0 (c = 0.187, CHCl3, er = 97:3)  III-9: (R)-5-(1-chlorovinyl)-2-(3-nitrophenyl)-4,5-dihydrooxazole    1H NMR (500 MHz, CDCl3) " 8.78 (s, 1H), 8.32 (dd, J = 23.0 Hz, J = 8.0 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 5.57 (s, 1H), 5.42 (s, 1H), 5.27 (t, J = 8.0 Hz, 1H), 4.29 (dd, J = 15.0 Hz, J = 10.5 Hz, 1H), 4.10 (dd, J = 15.0 Hz, J = 7.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 161.6, 139.1, 134.0, 129.6, 128.9, 126.1, 123.3, 114.6, 80.9, 59.7. ClONNO2!!!!"&&!HRMS (ESI) Calculated Mass for C11H9N2O3Cl: ([M+H]+) = 253.0380, Found ([M+H]+) = 253.0380. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 1% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 19.0 min, RT2 (minor) = 20.5 min . [#]D20 = +55.1 (c = 0.45, CHCl3, er = 97:3)  III-10: (R)-2-(4-bromophenyl)-5-(1-chlorovinyl)-4,5-dihydrooxazole     1H NMR (500 MHz, CDCl3) " 7.82 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 5.53 (dd, J = 2.0 Hz, J = 1.0 Hz, 1H), 5.38 (d, J = 2.0 Hz, 1H), 5.2 (dd, J = 10.5 Hz, J = 7.0 Hz, 1H), 4.23 (dd, J = 15.0 Hz, J = 10.5 Hz, 1H), 4.03 (dd, J = 15.0 Hz, J = 7.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 162.9, 139.3, 131.8, 129.8, 126.5, 125.9, 114.0, 80.5, 59.6. HRMS (ESI) Calculated Mass for C11H9NOClBr: ([M+H]+) = 285.9634, Found ([M+H]+) = 285.9638. Resolution of enantiomers: DAICEL Chiralcel¨ IA-H column, 1% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 14.7 min, RT2 (major) = 18.2 min . ClONBr!!!!"&'![#]D20 = +47.0 (c = 0.575, CHCl3, er = 97:3)  III-11: (R)-2-(4-bromophenyl)-5-(1-chlorovinyl)-5-ethyl-4,5-dihydrooxazole    1H NMR (500 MHz, CDCl3) " 7.80 (d, J = 9.0 Hz, 2H), " 7.54 (d, J = 8.0 Hz, 2H), 5.55 (d, J = 2.0 Hz, 1H), 5.35 (d, J = 2.0 Hz, 1H), 4.16 (d, J = 15.5 Hz, 1H), 3.82 (d, J = 15.5 Hz, 1H), 2.06 (ddd, J = 7.5 Hz, J = 7.5 Hz, J = 7.5 Hz, 1H), 1.86 (ddd, J = 7.0 Hz, J = 7.0 Hz, J = 7.0 Hz, 1H), 0.97 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) " 162.0, 141.3, 131.7, 129.6, 126.5, 126.2, 112.3, 89.8, 64.7, 30.2, 7.8. HRMS (ESI) Calculated Mass for C13H13NOClBr: ([M+H]+) = 313.9947, Found ([M+H]+) = 313.9959. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 1% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 10.1 min, RT2 (minor) = 11.4 min . [#]D20 = +147.1 (c = 0.633, CHCl3, er = 97:3)  III-12: (R)-5-(1-chlorovinyl)-2-(4-methoxyphenyl)-4,5-dihydrooxazole  ClONEtBrClONOMe!!!!"'(!1H NMR (500 MHz, CDCl3) " 7.89 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 5.53 (s, 1H), 5.36 (s, 1H), 5.15 (dd, J = 10.0 Hz, J = 7.0 Hz, 1H), 4.21 (dd, J = 15.0 Hz, J = 10.0 Hz, 1H), 4.02 (dd, J = 15.0 Hz, J = 7.0 Hz, 1H), 3.83 (s, 3H). 13C NMR (125 MHz, CDCl3) " 163.4, 162.3, 139.7, 130.0, 119.5, 113.8, 113.4, 80.1, 59.6, 55.4. HRMS (ESI) Calculated Mass for C12H12NO2Cl: ([M+H]+) = 238.0635, Found ([M+H]+) = 238.0643. Resolution of enantiomers: DAICEL Chiralcel¨ IA-H column, 5% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 11.2 min, RT2 (minor) = 12.9 min . [#]D20 = +57.0 (c = 0.3, CHCl3, er = 95:5)  III-13: (R)-5-(1-chlorovinyl)-2-(3-methoxyphenyl)-4,5-dihydrooxazole    1H NMR (500 MHz, CDCl3) " 7.54 (d, J = 7.5 Hz, 1H), 7.49 (s, 1H), 7.32 (t, J = 2.0 Hz, 1H), 7.03 (dd, J = 8.0 Hz, J = 2.5 Hz, 1H), 5.55 (s, 1H), 5.38 (s, 1H), 5.19 (dd, J = 7.0 Hz, J = 10.0 Hz, 1H), 4.24 (dd, J = 15.0 Hz, J = 10.0 Hz, 1H), 4.04 (dd, J = 15.0 Hz, J = 6.5 Hz, 1H), 3.83 (s, 3H). 13C NMR (125 MHz, CDCl3) " 163.6, 159.5, 139.5, 129.5, 128.2, 120.7, 118.4, 113.7, 112.5, 80.3, 59.6, 55.4. ClONOMe!!!!"'#!HRMS (ESI) Calculated Mass for C12H12NO2Cl: ([M+H]+) = 238.0635, Found ([M+H]+) = 238.0646. Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 8% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 10.6 min, RT2 (major) = 11.3 min . [#]D20 = +63.2 (c = 1.10, CHCl3, er = 96:4)  III-14: (R)-5-benzyl-2-(4-bromophenyl)-5-(1-chlorovinyl)-4,5-dihydrooxazole    1H NMR (500 MHz, CDCl3) " 7.76 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.20-7.29 (m, 5H), 5.36 (d, J = 1.5 Hz, 1H), 5.24 (d, J = 1.5 Hz, 1H), 4.21 (d, J = 15.5 Hz, 1H), 3.95 (d, J = 15.5 Hz, 1H), 3.32 (d, J = 14.0 Hz, 1H), 3.13 (d, J = 14.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 161.8, 140.6, 134.9, 131.8, 130.3, 129.6, 128.1, 127.0, 126.3, 126.2, 113.0, 89.4, 64.6, 42.9. HRMS (ESI) Calculated Mass for C18H15NOClBr: ([M+H]+) = 376.0104, Found ([M+H]+) = 376.0118. Resolution of enantiomers: DAICEL Chiralcel¨ AS-H column, 1% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 6.5 min, RT2 (minor) = 8.3 min . [#]D20 = +76.0 (c = 0.2, CHCl3, er = 96:4)  ClONBnBr!!!!"'"!III-15: (R)-5-(1-chlorovinyl)-2,5-diphenyl-4,5-dihydrooxazole   1H NMR (500 MHz, CDCl3) " 8.01 (d, J = 8.5 Hz, 2H), 7.32-7.52 (m, 8H), 5.50 (d, J = 2.0 Hz, 1H), 5.44 (d, J = 2.0 Hz, 1H), 4.65 (d, J = 15.0 Hz, 1H), 4.44 (d, J = 15.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 162.5, 142.9, 140.2, 131.6, 128.5, 128.2, 127.4, 126.2, 114.6, 89.8, 65.8. HRMS (ESI) Calculated Mass for C17H14NOCl: ([M+H]+) = 284.0842, Found ([M+H]+) = 284.0854. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 10% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 7.0 min, RT2 (minor) = 10.0 min . [#]D20 = +18.1 (c = 0.613, CHCl3, er = 93:7)  III-16: (R)-5-(1-chlorovinyl)-5-methyl-2-phenyl-4,5-dihydrooxazole    1H NMR (500 MHz, CDCl3) " 7.94 (d, J = 7.5 Hz, 2H), 7.39-7.49 (m, 3H), 5.58 (d, J = 1.5 Hz, 1H), 5.31 (d, J = 1.5 Hz, 1H), 4.22 (d, J = 15.0 Hz, 1H), 3.83 (d, J = 14.5 Hz, 1H), 1.69 (s, 3H). ClONPhClONMe!!!!"')!13C NMR (125 MHz, CDCl3) " 162.7, 143.2, 131.5, 128.4, 128.1, 127.6, 111.7, 86.4, 65.8, 24.9. HRMS (ESI) Calculated Mass for C12H12NOCl: ([M+H]+) = 222.0686, Found ([M+H]+) = 222.0697. Resolution of enantiomers: DAICEL Chiralcel¨ OD-H column, 1% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 6.2 min, RT2 (minor) = 13.4 min . [#]D20 = +82.0 (c = 0.293, CHCl3, er = 96:4)  III-17: (R)-2-(4-bromophenyl)-5-(1-chlorovinyl)-5-methyl-4,5-dihydrooxazole   1H NMR (500 MHz, CDCl3) " 7.80 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 5.55 (d, J = 2.0 Hz, 1H), 5.32 (d, J = 1.0 Hz, 1H), 4.20 (d, J = 15.0 Hz, 1H), 3.81 (d, J = 15.5 Hz, 1H), 1.68 (s, 3H). 13C NMR (125 MHz, CDCl3) " 162.0, 143.0, 131.7, 129.6, 126.5, 126.2, 111.8, 86.7, 65.9, 24.9. HRMS (ESI) Calculated Mass for C12H11NOClBr: ([M+H]+) = 299.9791, Found ([M+H]+) = 299.9806. Resolution of enantiomers: DAICEL Chiralcel¨ OD-H column, 1% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 6.1 min, RT2 (minor) = 11.9 min . ClONMeBr!!!!"'*![#]D20 = +99.9 (c = 0.505, CHCl3, er = 98:2)  III-18: (R)-2-(4-bromophenyl)-5-(1-chlorovinyl)-4,4-dimethyl-4,5-dihydrooxazole   1H NMR (500 MHz, CDCl3) " 7.79 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 5.55 (t, J = 1.0 Hz, 1H), 5.44 (d, J = 1.0 Hz, 1H), 4.73 (s, 1H), 1.51 (s, 3H), 1.29 (s, 3H). 13C NMR (125 MHz, CDCl3) " 159.6, 136.6, 131.7, 129.7, 126.4, 126.1, 113.1, 89.0, 70.6, 30.3, 23.2. HRMS (ESI) Calculated Mass for C13H13NOClBr: ([M+H]+) = 313.9947, Found ([M+H]+) = 313.9961. Resolution of enantiomers: DAICEL Chiralcel¨ AS-H column, 1% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 6.0 min, RT2 (minor) = 12.0 min . III-19: (R)-5-(1-chlorovinyl)-5-methyl-2-(4-nitrophenyl)-4,5-dihydrooxazole      ClONBrClONMeNO2!!!!"'+!1H NMR (500 MHz, CDCl3) " 8.26 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.5 Hz, 2H), 5.57 (d, J = 2.0 Hz, 1H), 5.36 (d, J = 2.0 Hz, 1H), 4.26 (d, J = 16.0 Hz, 1H), 3.88 (d, J = 15.0 Hz, 1H), 1.71 (s, 3H). 13C NMR (125 MHz, CDCl3) " 161.0, 149.6, 142.7, 133.3, 129.2, 123.6, 112.2, 87.2, 66.1, 25.0. HRMS (ESI) Calculated Mass for C12H11N2O3Cl: ([M+H]+) = 267.0536, Found ([M+H]+) = 267.0547. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 3% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 9.9 min, RT2 (minor) = 11.9 min . [#]D20 = +104.0 (c = 0.495, CHCl3, er = 99:1)  III-20: (R)-6-(1-chlorovinyl)-2-(4-nitrophenyl)-5,6-dihydro-4H-1,3-oxazine    1H NMR (500 MHz, CDCl3) " 8.21 (d, J = 9.5 Hz, 2H), 8.09 (d, J = 8.5 Hz, 2H), 5.51 (t, J = 1.5 Hz, 1H), 5.48 (d, J = 1.5 Hz, 1H), 4.84 (dd, J = 9.0 Hz, J = 4.0 Hz, 1H), 3.67 (m, 2H), 2.18 (m, 1H), 2.04 (dddd, J = 5.5 Hz, J = 9.0 Hz, J = 9.0 Hz, J = 14.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 152.8, 149.2, 139.1, 138.9, 128.0, 123.3, 113.9, 76.3, 41.9, 24.9. ClONNO2!!!!"'$!HRMS (ESI) Calculated Mass for C12H11N2O3Cl: ([M+H]+) = 267.0536, Found ([M+H]+) = 267.0547. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 5% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 9.9 min, RT2 (major) = 11.0 min . [#]D20 = +0.4 (c = 1.275, CHCl3, er = 56:44) III-21: (R)-6-(1-chlorovinyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazine   1H NMR (500 MHz, CDCl3) " 7.91 (d, J = 8.5 Hz, 2H), 7.35-7.45 (m, 3H), 5.53 (t, J = 1.5 Hz, 1H), 5.45 (d, J = 2.0 Hz, 1H), 4.81 (dd, J = 8.5 Hz, J = 3.5 Hz, 1H), 3.63 (m, 2H), 2.16 (m, 1H), 2.01 (dddd, J = 5.0 Hz, J = 8.0 Hz, J = 8.0 Hz, J = 13.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 154.4, 139.2, 133.3, 130.6, 128.1, 127.0, 113.3, 75.8, 41.5, 25.0. HRMS (ESI) Calculated Mass for C12H12NOCl: ([M+H]+) = 222.0686, Found ([M+H]+) = 222.0697. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 10% IPA-Hexanes, 0.5 mL/min, 254 nm, RT1 (major) = 9.7 min, RT2 (minor) = 10.7 min . [#]D20 = +0.9 (c = 0.373, CHCl3, er = 59:41)   ClON!!!!"'%!III-13-A3 Analytical data for the mono- and double cyclized bis-oxazoline products III-22: 1,3-bis((R)-5-(1-chlorovinyl)-4,5-dihydrooxazol-2-yl)benzene    1H NMR (500 MHz, CDCl3) " 8.51 (d, J = 2.0 Hz, 1H), 8.10 (m, 2H), 7.49 (t, J = 8.0 Hz, 1H), 5.55 (d, J = 1.0 Hz, 2H), 5.38 (s, 2H), 5.20 (dd, J = 10.0 Hz, J = 7.0 Hz, 2H), 4.25 (dd, J = 15.0 Hz, J = 10.0 Hz, 2H), 4.06 (dd, J = 15.0 Hz, J = 7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) " 162.9, 162.8, 139.4, 131.3, 131.2, 128.7, 128.0, 127.9, 127.6, 113.9, 80.5, 80.4, 59.8. HRMS (ESI) Calculated Mass for C16H14N2O2Cl2: ([M+H]+) = 337.0511, Found ([M+H]+) = 337.0526. Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 5% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 [minor(S,S)] = 15.1 min, RT2 [meso(R,S)/(S,R)] = 16.5 min , RT3 [major(R,R)] = 22.0 min. [#]D20 = +57.0 (c = 0.173, CHCl3, er = 98:2, 14% meso)   III-23: 1,4-bis((R)-5-(1-chlorovinyl)-4,5-dihydrooxazol-2-yl)benzene  NOClONClONClNOCl!!!!"'&!1H NMR (500 MHz, CDCl3) " 8.00 (s, 4H), 5.55 (d, J = 1.0 Hz, 2H), 5.38 (d, J = 2.0 Hz, 2H), 5.21 (dd, J = 10.0 Hz, J = 7.0 Hz, 2H), 4.26 (dd, J = 15.0 Hz, J = 10.0 Hz, 2H), 4.07 (dd, J = 15.0 Hz, J = 7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) " 162.9, 139.4, 129.9, 128.3, 113.9, 80.4, 59.9. HRMS (ESI) Calculated Mass for C16H14N2O2Cl2: ([M+H]+) = 337.0511, Found ([M+H]+) = 337.0522. Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 5% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 19.7 min, RT2 (major) = 21.7 min .  [#]D20 = +98.4 (c = 0.475, CHCl3, er = 97:3)  III-24: (R)-N-(buta-2,3-dien-1-yl)-3-(5-(1-chlorovinyl)-4,5-dihydrooxazol-2-yl)benzamide    1H NMR (500 MHz, CDCl3) " 8.29 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 6.41 (br s, 1H), 5.56 (s, 1H), 5.39 (d, J = 2.0 Hz, 1H), 5.30 (ddd, J = 6.0 Hz, J = 6.0 Hz, J = 12.0 Hz, 1H), 5.22 (dd, J = 7.0 Hz, J = 10.0 Hz, 1H), 4.86 (ddd, J = 3.0 Hz, J = 3.0 Hz, J = 6.5 Hz, 2H), 4.25 (dd, J = 15.0 Hz, J = 10.5 Hz, 1H), 4.03-4.09 (m, 3H). 13C NMR (125 MHz, CDCl3) " 208.2, 166.3, 162.9, 139.3, 134.8, 131.1, 130.7, 129.0, 127.4, 126.0, 114.1, 87.8, 80.5, 77.8, 59.6, 38.1. OHN.NOCl!!!!"''!HRMS (ESI) Calculated Mass for C16H15N2O2Cl: ([M+H]+) = 303.0900, Found ([M+H]+) = 303.0907. Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 7% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 23.8 min, RT2 (minor) = 27.1 min . [#]D20 = +52.0 (c = 0.40, CHCl3, er = 98:2)  III-25: N-((R)-3-chloro-2-(2,2,2-trifluoroethoxy)but-3-en-1-yl)-6-((R)-5-(1-chlorovinyl)-4,5-dihydrooxazol-2-yl)picolinamide    1H NMR (500 MHz, CDCl3) " 8.36 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.07 (br s, 1H), 8.03 (t, J = 7.5 Hz, 1H), 7.84 (br s, 1H), 5.58 (d, J = 4.0 Hz, 2H), 5.32 (dddd, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, J = 12.5 Hz, 1H), 4.88 (m, 2H), 4.26 (dd, J = 9.0 Hz, J = 4.0 Hz, 1H), 4.06-4.11 (m, 4H), 3.94-4.01 (m, 1H), 3.76 (dddd, J = 8.5 Hz, J = 8.5 Hz, J = 8.5 Hz, J = 12.5 Hz, 1H), 3.48-3.54 (ddd, J = 4.5 Hz, J = 8.5 Hz, J = 13.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 163.6, 163.1, 148.8, 148.3, 139.1, 137.5, 125.3, 125.0, 117.2, 87.6, 82.4, 77.5, 66.1 (q, J = 34.0), 42.0, 37.7. HRMS (ESI) Calculated Mass for C17H16N3O3Cl2F3: ([M+H]+) = 438.0599, Found ([M+H]+) = 438.0610. NOHNNOClOClF3C!!!!)((!Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 10% IPA-Hexanes, 0.6 mL/min, 254 nm, RT1 (minor) = 18.5 min, RT2 (major) = 20.0 min.  [#]D20 = +9.0 (c = 0.287, CHCl3, er = 97:3)  III-13-A4 Analytical data for the bromocyclized oxazoline products III-48: (R)-5-(1-bromovinyl)-2-(4-nitrophenyl)-4,5-dihydrooxazole   1H NMR (500 MHz, CDCl3) " 8.27 (d, J = 9.0 Hz, 2H), 8.14 (d, J = 9.0 Hz, 2H), 6.01 (dd, J = 2.5 Hz, J = 1.0 Hz, 1H), 4.24 (d, J = 2.5 Hz, 1H), 5.24 (dd, J = 7.5 Hz, J = 10.0 Hz, 1H), 4.29 (dd, J = 15.5 Hz, J = 10.0 Hz, 1H), 4.07 (dd, J = 15.5 Hz, J = 7.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 161.7, 149.6, 132.9, 131.0, 129.3, 123.6, 118.7, 82.0, 60.7. HRMS (ESI) Calculated Mass for C11H9N2O3Br: ([M+H]+) = 296.9875, Found ([M+H]+) = 296.9886. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 10% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 9.0 min, RT2 (minor) = 11.0 min . [#]D20 = +9.0 (c = 0.253, CHCl3, er = 70:30)  BrONNO2!!!!)(#!III-49: (R)-2-(4-bromophenyl)-5-(1-bromovinyl)-4,5-dihydrooxazole    1H NMR (500 MHz, CDCl3) " 7.81 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 5.97 (dd, J = 2.5 Hz, J = 1.0 Hz, 1H), 5.61 (d, J = 2.5 Hz, 1H), 5.17 (dd, J = 10.0 Hz, J = 7.0 Hz, 1H), 4.21 (dd, J = 15.0 Hz, J = 10.0 Hz, 1H), 4.00 (dd, J = 15.0 Hz, J = 7.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 162.7, 131.7, 131.3, 129.7, 126.3, 126.1, 118.1, 81.6, 60.5. HRMS (ESI) Calculated Mass for C11H9NOBr2: ([M+H]+) = 329.9129, Found ([M+H]+) = 329.9143. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 4% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 8.3 min, RT2 (minor) = 9.5 min . [#]D20 = +6.0 (c = 0.185, CHCl3, er = 65:35)  III-13-A5 Analytical data for the cyclized oxazolidinone products III-51: (R)-5-(1-chlorovinyl)-5-ethyloxazolidin-2-one    BrONBrClOHNO!!!!)("!1H NMR (500 MHz, CDCl3) " 5.71 (d, J = 2.0 Hz, 1H), 5.43 (d, J = 2.0 Hz, 2H), 3.71 (d, J = 9.5 Hz, 1H), 3.37 (d, J = 9.5 Hz, 1H), 2.03 (dddd, J = 7.5 Hz, J = 7.5 Hz, J = 7.5 Hz, J = 15.0 Hz, 1H), 1.90 (dddd, J = 7.0 Hz, J = 7.0 Hz, J = 7.0 Hz, J = 14.0 Hz, 1H), 0.96 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) " 158.4, 139.1, 113.9, 85.9, 49.4, 30.2, 7.4. HRMS (ESI) Calculated Mass for C7H10NO2Cl: ([M+H]+) = 176.0478, Found ([M+H]+) = 176.0481. III-89: (R)-5-(1-chlorovinyl)-5-ethyl-3-tosyloxazolidin-2-one    1H NMR (500 MHz, CDCl3) " 7.89 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 7.5 Hz, 2H), 5.56 (d, J = 2.5 Hz, 1H), 5.40 (d, J = 2.5 Hz, 1H), 4.13 (d, J = 10.0 Hz, 1H), 3.76 (d, J = 10.0 Hz, 1H), 2.44 (s, 3H), 2.00 (dddd, J = 7.0 Hz, J = 7.0 Hz, J = 7.0 Hz, J = 14.0 Hz, 1H), 1.80 (dddd, J = 7.0 Hz, J = 7.0 Hz, J = 7.0 Hz, J = 14.0 Hz, 1H), 0.88 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) " 150.5, 145.9, 137.4, 133.9, 129.9, 128.2, 115.1, 83.5, 53.0, 29.8, 21.7, 7.2. HRMS (ESI) Calculated Mass for C14H16NO4ClS: ([M+H]+) = 330.0567, Found ([M+H]+) = 330.0581. ClONOTs!!!!)()!Resolution of enantiomers: DAICEL Chiralcel¨ AS-H column, 5% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 17.0 min, RT2 (major) = 21.0 min . [#]D20 = +13.9 (c = 1.06, CHCl3, er = 69:31)  III-13-A6 General procedure for catalytic asymmetric intermolecular dichlorination of unsaturated terminal alleneamides    A screw-capped vial, equipped with a magnetic stir bar, was charged with the substrate (0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (7.8 mg, 10 mol%). To the following vial LiCl (424 mg, 100 equiv), and TFE (5.0 mL) were added. The vial was capped and the resulting suspension was stirred at -30 ¡C for 10 min. DCDMH (39.2 mg, 0.20 mmol, 2.0 equiv) was then introduced in a single portion at -30 ¡C. The stirring was continued till the reaction was complete (TLC). The reaction was then quenched with saturated aqueous Na2SO3 solution (3.0 mL) and extracted with CH2Cl2 (3 x 2 mL). The combined organics were washed with brine and then dried over anhydrous Na2SO4 and filtered. Column chromatography (SiO2/EtOAc Ð Hexanes gradient elution) gave the desired product.     !!!!)(*!III-13-A7 Analytical data for the dichlorinated products III-26: (R)-N-(2,3-dichlorobut-3-en-1-yl)-4-nitrobenzamide      1H NMR (500 MHz, CDCl3) " 8.28 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 6.56 (br s, 1H), 5.63 (d, J = 2.0 Hz, 1H), 5.48 (d, J = 2.0 Hz, 1H), 4.84 (dd, J = 7.0 Hz, J = 6.5 Hz, 1H), 3.97 (ddd, J = 6.5 Hz, J = 6.5 Hz, J = 14.5 Hz, 1H), 3.82 (ddd, J = 5.5 Hz, J = 7.5 Hz, J = 13.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 165.7, 149.8, 139.3, 138.3, 128.2, 124.0, 117.9, 61.0, 44.6. HRMS (ESI) Calculated Mass for C11H10N2O3Cl2: ([M+H]+) = 289.0147, Found ([M+H]+) = 289.0144. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 10% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 15.0 min, RT2 (minor) = 17.0 min . [#]D20 = +3.0 (c = 0.88, CHCl3, er = 88:12)  III-32: (R)-4-bromo-N-(2,3-dichlorobut-3-en-1-yl)benzamide    !NHOClClNO2NHOClClBr!!!!)(+!1H NMR (500 MHz, CDCl3) " 7.61 (d, J = 9.0 Hz, 2H), 7.57 (d, J = 9.0 Hz, 2H), 6.40 (br s, 1H), 5.60 (d, J = 2.0 Hz, 1H), 5.46 (d, J = 2.0 Hz, 1H), 4.83 (dd, J = 7.5 Hz, J = 6.0 Hz, 1H), 3.92 (ddd, J = 6.5 Hz, J = 6.5 Hz, J = 14.0 Hz, 1H), 3.79 (ddd, J = 6.0 Hz, J = 8.0 Hz, J = 13.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 166.7, 138.5, 132.5, 131.9, 128.5, 126.7, 117.8, 61.2, 44.4. HRMS (ESI) Calculated Mass for C11H10NOCl2Br: ([M+H]+) = 321.9401, Found ([M+H]+) = 321.9397. Resolution of enantiomers: DAICEL Chiralcel¨ AD-H column, 10% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 11.3 min, RT2 (minor) = 13.7 min . [#]D20 = +0.6 (c = 0.34, CHCl3, er = 73:27)  III-33: (R)-N-(2,3-dichlorobut-3-en-1-yl)-3,5-dinitrobenzamide    1H NMR (500 MHz, CDCl3) " 9.18 (t, J = 2.0 Hz, 1H), 8.93 (d, J = 2.0 Hz, 2H), 6.76 (br s, 1H), 5.66 (d, J = 2.0 Hz, 1H), 5.51 (d, J = 2.0 Hz, 1H), 4.86 (dd, J = 7.5 Hz, J = 5.0 Hz, 1H), 4.03 (ddd, J = 6.0 Hz, J = 6.0 Hz, J = 14.0 Hz, 1H), 3.87 (ddd, J = 6.0 Hz, J = 8.0 Hz, J = 14.5 Hz, 1H). NHOClClNO2NO2!!!!)($!13C NMR (125 MHz, CDCl3) " 163.2, 148.7, 138.0, 137.1, 127.2, 121.5, 118.1, 60.9, 44.9. HRMS (ESI) Calculated Mass for C11H9N3O5Cl2: ([M+H]+) = 333.9998, Found ([M+H]+) = 333.9996. Resolution of enantiomers: DAICEL Chiralcel¨ OD-H column, 20% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 25.0 min, RT2 (minor) = 30.0 min . [#]D20 = +1.60 (c = 0.873, CHCl3, er = 85:15)  III-13-A8 General procedure for catalytic asymmetric intermolecular haloetherification/halohydrin formation of unsaturated terminal alleneamides A screw-capped vial, equipped with a magnetic stir bar, was charged with the substrate (0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (7.8 mg, 10 mol%). To the following vial MeOH:HFIP (5:1) (4.0 mL) for haloetherification or H2O:TFE (5:1) (4.0 mL) solvent mixture for halohydrin formation reaction, were added. The vial was capped and the resulting suspension was stirred at ambient temperature till all the solids had completely dissolved. DCDMH (21.6 mg, 0.11 mmol, 1.1 equiv) or DBDMH (31.2 mg, 0.11 mmol, 1.1 equiv) was then introduced in a single portion. The stirring was continued till the reaction was complete (TLC). The reaction was then quenched with saturated aqueous Na2SO3 solution (3.0 mL) and extracted with CH2Cl2 (3 x 2 mL). The !!!!)(%!combined organics were washed with brine and then dried over anhydrous Na2SO4 and filtered. Column chromatography (SiO2/EtOAc Ð Hexanes gradient elution) gave the desired product. Some modifications were used for some of the substrates including the change of solvent to H2O:MeCN (1:9), and lower temperature of -10 ¡C or -30 ¡C. III-13-A9 Analytical data for the halohydrin or haloether products III-27: (R)-N-(3-chloro-2-methoxybut-3-en-1-yl)-4-nitrobenzamide    1H NMR (500 MHz, CDCl3) " 8.28 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 7.5 Hz, 2H), 6.47 (br s, 1H), 5.52 (d, J = 2.5 Hz, 2H), 3.98 (dd, J = 7.5 Hz, J = 4.5 Hz, 1H), 3.88 (ddd, J = 4.5 Hz, J = 6.5 Hz, J = 13.0 Hz, 1H), 3.55 (ddd, J = 5.0 Hz, J = 7.5 Hz, J = 13.5 Hz, 1H), 3.35 (d, J = 1.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) " 165.5, 149.7, 139.8, 138.7, 128.2, 123.9, 116.3, 81.9, 57.0, 42.6. HRMS (ESI) Calculated Mass for C12H13N2O4Cl: ([M+H]+) = 285.0642, Found ([M+H]+) = 285.0646. Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 10% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 23.0 min, RT2 (major) = 26.7 min . [#]D20 = +5.0 (c = 0.2, CHCl3, er = 83:17)  CHCl3 NHOOMeClNO2!!!!)(&!III-28: (R)-N-(3-chloro-2-methoxybut-3-en-1-yl)-3,5-dinitrobenzamide     1H NMR (500 MHz, CDCl3) " 9.16 (s, 1H), 8.93 (s, 2H), 6.68 (br s, 1H), 5.55 (d, J = 5.0 Hz, 2H), 4.00 (dd, J = 7.5 Hz, J = 4.0 Hz, 1H), 3.92 (ddd, J = 4.5 Hz, J = 6.5 Hz, J = 13.0 Hz, 1H), 3.60 (ddd, J = 4.0 Hz, J = 7.0 Hz, J = 13.0 Hz, 1H), 3.37 (s, 3H).  13C NMR (125 MHz, CDCl3) " 162.9, 148.7, 138.4, 137.7, 127.2, 121.2, 116.5, 81.7, 57.0, 43.0. HRMS (ESI) Calculated Mass for C12H12N3O6Cl: ([M+H]+) = 330.0493, Found ([M+H]+) = 330.0493. Resolution of enantiomers: CP-Chirasil-DEX-CB, 120 ¡C to 220 ¡C ramp (1 ¡C/min), 220 ¡C for 60 min RT1 = 111.7 min, RT2 = 112.6 min . III-29: (R)-N-(3-chloro-2-hydroxybut-3-en-1-yl)-4-nitrobenzamide   1H NMR (500 MHz, CDCl3) " 8.28 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H), 6.66 (br s, 1H), 5.64 (s, 1H), 5.42 (s, 1H), 4.44 (br s, 1H), 3.92 (ddd, J = NHOOMeClNO2NO2NHOOHClNO2!!!!)('!3.0 Hz, J = 6.5 Hz, J = 14.0 Hz, 1H), 3.76 (br s, 1H), 3.65 (ddd, J = 6.0 Hz, J = 6.0 Hz, J = 14.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 167.2, 149.8, 140.5, 139.2, 128.3, 123.9, 114.0, 74.1, 44.4. HRMS (ESI) Calculated Mass for C11H11N2O4Cl: ([M+H]+) = 271.0486, Found ([M+H]+) = 271.0491. Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 15% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 12.0 min, RT2 (major) = 13.0 min . [#]D20 = +25.0 (c = 0.533, CHCl3, er = 88:12)  III-30: (R)-N-(3-bromo-2-hydroxybut-3-en-1-yl)-4-nitrobenzamide    1H NMR (500 MHz, CDCl3) " 8.29 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 6.57 (br s, 1H), 6.09 (s, 1H), 5.67 (d, J = 1.0 Hz, 1H), 4.45 (br s, 1H), 3.93 (ddd, J = 3.0 Hz, J = 6.5 Hz, J = 14.0 Hz, 1H), 3.68 (ddd, J = 6.5 Hz, J = 6.5 Hz, J = 14.5 Hz, 1H), 3.60 (br d, J = 4.0 Hz, 1H).  13C NMR (125 MHz, CDCl3) " 167.1, 149.8, 139.2, 132.5, 128.2, 124.0, 118.5, 75.2, 44.8. HRMS (ESI) Calculated Mass for C11H11N2O4Br: ([M+H]+) = 314.9980, Found ([M+H]+) = 314.9967. NHOOHBrNO2!!!!)#(!Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 10% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 20.5 min, RT2 (major) = 23.5 min . [#]D20 = +10.2 (c = 0.387, CHCl3, er = 88:12)  III-6: (R)-N-(3-chloro-2-(2,2,2-trifluoroethoxy)but-3-en-1-yl)benzamide    1H NMR (500 MHz, CDCl3) " 7.74 (d, J = 8.5 Hz, 2H), 7.41-7.52 (m, 3H), 6.46 (br s 1H), 5.55 (dd, J = 5.5 Hz, J = 1.5 Hz, 2H), 4.29 (dd, J = 8.5 Hz, J = 4.0 Hz, 1H), 3.91-3.98 (m, 2H), 3.74 (dddd, J = 8.5 Hz, J = 8.5 Hz, J = 8.5 Hz, J = 20.5 Hz, 1H), 3.49-3.54 (ddd, J = 5.0 Hz, J = 8.5 Hz, J = 14.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) " 167.7, 137.7, 134.0, 131.7, 128.7, 126.9, 124.8, 117.3, 81.9, 66.0 (q, J = 34.5 Hz), 42.2. HRMS (ESI) Calculated Mass for C13H13NO2ClF3: ([M+H]+) = 308.0665, Found ([M+H]+) = 308.0670. Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 5% IPA-Hexanes, 0.8 mL/min, 254 nm, RT1 (minor) = 15.5 min, RT2 (major) = 17.6 min . [#]D20 = +25.1 (c = 0.327, CHCl3, er = 93:7)  NHOOClCH2CF3!!!!)##!III-90: (R)-N-(3-chloro-2-(2,2,2-trifluoroethoxy)but-3-en-1-yl)-4-methoxybenzamide    1H NMR (500 MHz, CDCl3) " 7.70 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 6.36 (br s, 1H), 5.55 (d, J = 2.0 Hz, 1H), 5.54 (d, J = 1.5 Hz, 1H), 4.27 (d, J = 8.0 Hz, J = 4.0 Hz, 1H), 3.90-3.98 (m, 2H), 3.84 (s, 3H), 3.73 (dddd, J = 8.0 Hz, J = 8.0 Hz, J = 8.0 Hz, J = 12.0 Hz, 1H), 3.48 (ddd, J = 5.0 Hz, J = 8.5 Hz, J = 14.5 Hz, 1H).  13C NMR (125 MHz, CDCl3) " 167.1, 162.4, 137.8, 128.7, 126.3, 122.5, 117.3, 113.8, 82.1, 66.0 (q, J = 34.5 Hz), 55.4, 42.2. HRMS (ESI) Calculated Mass for C14H15NO3ClF3: ([M+H]+) = 338.0771, Found ([M+H]+) = 338.0778. Resolution of enantiomers: DAICEL Chiralcel¨ OJ-H column, 5% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 26.9 min, RT2 (major) = 33.7 min . [#]D20 = +22.1 (c = 0.2, CHCl3, er = 94:6)     NHOOClCH2CF3OMe!!!!)#"!III-13-B General procedures for the preparation of starting materials III-13-B1 General procedure for synthesis of monosubstituted alleneamide starting materials   A solution of the commercially available propargyl amine (1.0 equiv) and triethyl amine (3.0 equiv) in CH2Cl2 (5 mL per mmol of amine) was cooled in an ice bath. To it was added acid chloride derivatives (1.1 equiv) drop wise under N2 and the reaction was warmed to ambient temperature. After 8 h, the reaction was diluted with an equal amount of water and extracted with DCM (3x). The combined organics were washed with brine (1x), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. Purification was achieved by column chromatography on silica gel and EtOAc-Hexanes gradient as eluent to afford propargyl amide in 70-95% yield.  To an oven-dried reaction flask were added propargyl amide (1 mmol, 1.0 equiv), anhydrous 1,4-dioxane (2 mL), CuI (19 mg, 0.1 mmol, 0.1 equiv), paraformaldehyde (48 mg, 1.6 mmol, 1.6 equiv), and diisopropylamine (0.20 mL, 1.4 mmol, 1.4 equiv) sequentially under an argon atmosphere. The resulting mixture was then submerged in an oil bath preheated to 110 ¡C. NH2Et3N, ArCl, DCM0 ¡C to rt, 2-5 hHNOArCuI, CH2O, i-Pr2NHDioxane, 110 ¡C, 12hRRRR.NHArORR!!!!)#)!When the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Column chromatography on silica gel EtOAc-Hexanes as eluent afforded alleneamides in 65-92% yields. III-13-B2 Analytical data for monosubstituted alleneamide starting materials III-5a: N-(buta-2,3-dien-1-yl)benzamide     White solid; M.P.: 46-48 ¡C 1H NMR (500 MHz, CDCl3) " 7.75 (d, J = 8.0 Hz, 2H), 7.46-7.49 (m, 1H), 7.39-7.43 (m, 2H), 6.3 (br s, 1H), 5.34 (dddd, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, 1H), 4.88 (ddd, J = 3.5 Hz, J = 3.5 Hz, J = 7.0 Hz, 2H), 4.04 (ddddd, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 6.0 Hz, J = 6.0 Hz, 2H) 13C NMR (125 MHz, CDCl3) " 208.0, 167.3, 134.4, 131.5, 128.6, 126.9, 88.0, 78.0, 37.8.  HRMS (ESI) Calculated Mass for C11H11NO: ([M+H]+) = 174.0919, Found ([M+H]+) = 174.0925.    NHO.!!!!)#*!III-7a: N-(buta-2,3-dien-1-yl)-3,5-dinitrobenzamide    White solid; M.P.: 109-110 ¡C 1H NMR (500 MHz, CDCl3) " 9.15 (s, 1H), 8.94 (s, 2H), 6.65 (br s, 1H), 5.34 (dddd, J = 6.5 Hz, J = 6.5 Hz, J = 6.5 Hz, J = 6.5 Hz, 1H), 4.93 (ddd, J = 3.5 Hz, J = 3.5 Hz, J = 7.0 Hz, 2H), 4.11 (ddddd, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 6.0 Hz, J = 6.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) " 208.2, 162.6, 148.6, 137.8, 127.2, 121.2, 87.2, 78.5, 38.4.  HRMS (ESI) Calculated Mass for C12H13NO2: ([M+H]+) = 204.1025, Found ([M+H]+) = 204.1028. III-8a: N-(buta-2,3-dien-1-yl)-4-nitrobenzamide    White solid; M.P.: 121-122 ¡C 1H NMR (500 MHz, CDCl3) " 7.83 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H), 6.51 (br s, 1H), 5.31 (dddd, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, 1H), 4.88 (ddd, J = 3.5 Hz, J = 3.5 Hz, J = 7.0 Hz, 2H), 4.04 (ddddd, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 6.0 Hz, J = 6.0 Hz, 2H). NHO.NO2NO2NHO.NO2!!!!)#+!13C NMR (125 MHz, CDCl3) " 208.0, 165.3, 149.5, 140.0, 128.1, 123.8, 87.6, 78.2, 38.1.  HRMS (ESI) Calculated Mass for C11H10N2O3: ([M+H]+) = 219.0770, Found ([M+H]+) = 219.0769. III-9a: N-(buta-2,3-dien-1-yl)-3-nitrobenzamide    White solid; M.P.: 78-79 ¡C 1H NMR (500 MHz, CDCl3) " 8.58 (t, J = 1.5 Hz, 1H), 8.32 (d, J = 9.5 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 6.67 (br s, 1H), 5.31 (dddd, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, 1H), 4.87 (ddd, J = 3.5 Hz, J = 3.5 Hz, J = 7.0 Hz, 2H), 4.06 (ddddd, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 6.0 Hz, J = 6.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) " 208.1, 164.9, 148.1, 136.0, 133.2, 129.9, 126.1, 121.8, 87.6, 78.1, 38.2. HRMS (ESI) Calculated Mass for C11H10N2O3: ([M+H]+) = 219.0770, Found ([M+H]+) = 219.0773. III-10a: 4-bromo-N-(buta-2,3-dien-1-yl)benzamide   NHO.NO2NHO.Br!!!!)#$!White solid; M.P.: 78-80 ¡C 1H NMR (500 MHz, CDCl3) " 7.60 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 6.78 (br s, 1H), 5.25 (dddd, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, 1H), 4.81 (br m, 2H), 3.96 (br m, 2H). 13C NMR (125 MHz, CDCl3) " 207.9, 166.4, 133.1, 131.6, 128.5, 126.0, 87.8, 77.7, 37.8.  HRMS (ESI) Calculated Mass for C11H10NOBr: ([M+H]+) = 252.0024, Found ([M+H]+) = 252.0029. III-12a: N-(buta-2,3-dien-1-yl)-4-methoxybenzamide    White solid; M.P.: 84-86 ¡C 1H NMR (500 MHz, CDCl3) " 7.72 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.6 (br s, 1H), 5.26 (dddd, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, 1H), 4.80 (ddd, J = 3.5 Hz, J = 3.5 Hz, J = 6.5 Hz, 2H), 3.97 (ddddd, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 6.0 Hz, J = 6.0 Hz, 2H), 3.78 (s, 3H).  13C NMR (125 MHz, CDCl3) " 207.9, 166.8, 162.0, 128.7, 126.6, 113.6, 88.08, 77.5, 55.3, 37.8.  HRMS (ESI) Calculated Mass for C12H13NO2: ([M+H]+) = 204.1025, Found ([M+H]+) = 204.1033.  NHO.OMe!!!!)#%!III-13a: N-(buta-2,3-dien-1-yl)-3-methoxybenzamide    1H NMR (500 MHz, CDCl3) " 7.27-7.37 (m, 3H), 7.04 (d, J = 8.5 Hz, 1H), 6.3 (br s, 1H), 5.34 (dddd, J = 6.5 Hz, J = 6.5 Hz, J = 6.5 Hz, J = 6.5 Hz, 1H), 4.91 (ddd, J = 3.5 Hz, J = 3.5 Hz, J = 7.0 Hz, 2H), 4.06 (ddddd, J = 4.0 Hz, J = 4.0 Hz, J = 4.0 Hz, J = 5.5 Hz, J = 5.5 Hz, 2H), 3.85 (s, 3H). 13C NMR (125 MHz, CDCl3) " 208.0, 167.1, 159.8, 135.9, 129.5, 118.6, 117.7, 112.3, 87.9, 77.9, 55.4, 37.8.  HRMS (ESI) Calculated Mass for C12H13NO2: ([M+H]+) = 204.1025, Found ([M+H]+) = 204.1035. III-18a: 4-bromo-N-(2-methylpenta-3,4-dien-2-yl)benzamide   White solid; M.P.: 88-89 ¡C 1H NMR (500 MHz, CDCl3) " 7.55 (d, J = 9.0 Hz, 2H), 4.49 (d, J = 8.5 Hz, 2H), 6.25 (br s, 1H), 5.56 (t, J = 6.5 Hz, 1H), 4.91 (d, J = 6.5 Hz, 2H), 1.55 (s, 6H). 13C NMR (125 MHz, CDCl3) " 205.3, 165.6, 134.3, 131.6, 128.4, 125.7, 98.7, 79.1, 52.5, 27.6.  NHO.OMeNHO.Br!!!!)#&!HRMS (ESI) Calculated Mass for C13H14NOBr: ([M+H]+) = 280.0337, Found ([M+H]+) = 280.0341. III-13-B3 General procedure for synthesis of elongated monosubstituted alleneamide starting materials  p-Toluenesulfonylchloride (12.2 g, 63.5 mmol, 1.5 equiv) was added portion wise to a solution of but-3-yn-1-ol (2.93 g, 42.5 mmol, 1.0 equiv) in pyridine (10 mL) at 0¡ C, followed by addition of DMAP (5 mg). The mixture was allowed to stand for 15 h, then poured into water (50 mL) and extracted with ether (50 mL). The ether extract was washed with 1N HCl (50 mL), water (50 mL) and brine (30 mL), dried over Na2SO4 and evaporated to afford a yellow oil. To a stirred solution of this tosylate in DMSO (100 mL) at 35¡ C, was added sodium azide (5.5 g, 85 mmol, 2.0 equiv). After stirring for 3 h, the OHbut-3-yn-1-olN3p-TsCl, PyridineDMAP (cat)then  NaN3, DMSO0 ¡C to 35 ¡C, 20 hNH3ClPPh3, H2OEt2O, 0 ¡C to rtthen 1N HCl, 22 hCuI, CH2O i-Pr2NHDioxane110 ¡C, 12 hNHArOHN.O4-azidobut-1-yneArCOCl, Et3N, DCM0 ¡C to rt, 12 hbut-3-yn-1-aminium chlorideIII-91R = NO2    III-20aR = Ph       III-21aR!!!!)#'!mixture was poured into ether (40 mL), washed with water (3x50 mL), dried over Na2SO4 and evaporated at 0¡ C. (water aspirator). Cautious distillation into a flask cooled to -78¡ C yielded the pure azide (4-azidobut-1-yne) as a colorless, volatile liquid in 53% yield. Triphenylphosphine (8.7 g, 33.2 mmol, 1.5 equiv) was added to a solution of azide (2.1 g, 22.1 mmol, 1.0 equiv) in Et2O (100 mL) at 0¡ C and stirred for 2 h. Water (4.0 mL) was added and the resulting mixture was stirred for an additional 20 h at room temperature. The resulting mixture was poured into HCl (1 N, 24 mL) and the aqueous layer extracted with Et2O (3x10 mL). The remaining aqueous layer was concentrated under reduced pressure rotary evaporation to give the desired salt (but-3-yn-1-ammonium chloride) in 62% yield. A solution of but-3-yn-1-ammonium chloride (200 mg, 1.91 mmol, 1.0 equiv) and triethyl amine (1.3 mL, 9.5 mmol, 5.0 equiv) in CH2Cl2 (30 mL) was cooled in an ice bath. To it was added appropriate acid chloride derivatives (1.0 equiv) drop wise under N2 and the reaction was warmed to ambient temperature. After 8 h, the reaction was diluted with an equal amount of water and extracted with DCM (3x). The combined organics were washed with brine (1x), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. Purification was achieved by column chromatography on silica gel and EtOAc-Hexanes gradient as eluent to afford intermediate III-91 in 81-89% yield.  !!!!)"(!To an oven-dried reaction flask were added substrate III-91 (204 mg, 1 mmol, 1 equiv), anhydrous 1,4-dioxane (2 mL), CuI (19 mg, 0.1 mmol, 0.1 equiv), paraformaldehyde (48 mg, 1.6 mmol, 1.6 equiv), and diisopropylamine (0.20 mL, 1.4 mmol, 1.4 equiv) sequentially under an argon atmosphere. The resulting mixture was then submerged in an oil bath preheated to 110 ¡C. When the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Column chromatography on silica gel EtOAc-Hexanes as eluent afforded alleneamides III-20a and III-21a in 52-76% yield. III-13-B4 Analytical data for elongated monosubstituted alleneamide starting materials III-20a: 4-nitro-N-(penta-3,4-dien-1-yl)benzamide     White solid; M.P.: 100-103 ¡C 1H NMR (500 MHz, CDCl3) " 8.26 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.5 Hz, 2H), 6.42 (br s, 1H), 5.14 (dddd, J = 6.5 Hz, J = 6.5 Hz, J = 6.5 Hz, J = 6.5 Hz, 1H), 4.74 (ddd, J = 2.5 Hz, J = 2.5 Hz, J = 6.0 Hz, 2H), 3.57 (dd, J = 6.5 Hz, J = 12.5 Hz, 2H), 2.33 (ddddd, J = 3.0 Hz, J = 3.0 Hz, J = 6.5 Hz, J = 6.5 Hz, J = 6.5 Hz, 2H). HN.ONO2!!!!)"#!13C NMR (125 MHz, CDCl3) " 208.9, 165.4, 149.5, 140.3, 128.0, 123.8, 87.0, 75.9, 39.3, 28.1.  HRMS (ESI) Calculated Mass for C12H12N2O3: ([M+H]+) = 233.0926, Found ([M+H]+) = 233.0937. III-21a: N-(penta-3,4-dien-1-yl)benzamide    White solid; M.P.: 41-42 ¡C 1H NMR (500 MHz, CDCl3) " 7.73 (d, J = 8.0 Hz, 2H), 7.39-7.49 (m, 3H), 6.33 (br s, 1H), 5.14 (dddd, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, 1H), 4.73 (ddd, J = 3.0 Hz, J = 3.0 Hz, J = 5.0 Hz, 2H), 3.55 (ddd, J = 2.0 Hz, J = 8.5 Hz, J = 8.5 Hz, 2H), 2.31 (ddddd, J = 3.5 Hz, J = 3.5 Hz, J = 7.0 Hz, J = 7.0 Hz, J = 7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) " 208.9, 167.4, 134.7, 131.4, 128.6, 126.8, 87.2, 75.7, 39.0, 28.3.  HRMS (ESI) Calculated Mass for C12H13NO: ([M+H]+) = 188.1075, Found ([M+H]+) = 188.1083.    HN.O!!!!)""!III-13-B5 General procedure for synthesis of disubstituted alleneamide starting materials  To a solution of 3,4- dihydro-2H-pyran (9.4 g, 111.6 mmol) in 60 mL of anhydrous ether was added p-toluenesulfonic acid (0.04 g) and propargyl alcohol (1.56 g, 27.6 mmol) at 0 ¡C. The resulting mixture was stirred at room temperature for 5 h, followed by the addition of concentrated ammonium hydroxide (0.3 mL) and methanol (5 mL). The solvent was evaporated, and ether was added. This mixture was filtered to remove precipitated ammonium p-toluenesulfate. The filtrate was concentrated, and the crude product was PBr3, pyridine, Et2O0 to 35 ¡C, 2-5 hIn, CH2O, H2Ort, 10-14 hPhthalamide, PPh3 DIAD, THF 0 ¡C to rt, 2-4 hE3N, ArCOClDCM, 0 ¡C to rtNHR'O.RR'.OHR'.NH2NH2NH2, MeOHrt, 12-20 hOHDHP, p-TsOHEt2O, rt, 5 hOTHPnBuLi, THF, R'-Br-78 ¡C to rt3-5 hp-TsOH, MeOHrt, 1hR'.NOOOTHPR'OHR'BrR'prop-2-yn-1-ol2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyranIII-92III-93III-94III-95III-96III-97di-substitutedalleneamide!!!!)")!purified by flash column chromatography (5% ethyl acetate in hexanes) to give pure THP-protected propargyl alcohol in 92% yield.50  To a solution of 2-(prop-2-ynyloxy)tetrahydro-2H-pyran (5.0 mmol) in 5.0 mL THF at -78 ¡C was added n-BuLi (2.50 M, 2.20 mL) under Ar atmosphere, the resulting mixture was stirred for 1 h at this temperature and RÕ-Br (5.5 mmol) was added, then the reaction was allowed to warm to room temperature for 2 h. After the reaction completed, the reaction was quenched by addition of saturated NH4Cl solution, extracted with Et2O, dried over anhydrous Na2SO4. The solvent was concentrated under reduced pressure and the residue was further purified by silica gel column chromatography to give the target product III-92 (55-72% yield).51  To a solution of III-92 (2.5 mmol) in MeOH (5 mL) was added p-TSA (0.25 mmol, 10 mol%) at room temperature and the mixture was stirred overnight. Then, the solution was diluted in Et2O and a saturated aqueous solution of NaHCO3 was added. The aqueous phase was extracted with Et2O. Combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by flash chromatography to give III-93 in quantitative yields.52 Phosphorous tribromide (2.4 mL, 25 mmol, 1.0 equiv) was added to a solution of substrate III-93 (2.84 equiv), dried diethyl ether (50 mL) and pyridine (1 mL) under nitrogen atmosphere at -30 ¡C over 30 min, and then the reaction was allowed to warm to room temperature over 1 h. The reaction !!!!)"*!was refluxed for 1 h. After the completion of the reaction, it was poured onto a saturated solution of NaCl (50 mL) at 0 ¡C. Then the aqueous layer was further extracted with diethyl ether (30 mL). The combined organic extracts were dried over Na2SO4, and removed under atmospheric pressure. The residues were distilled under reduced pressure to afford the product III-94 in 71-85% yield. Formaldehyde (2.6 mL) was added to a solution of substrate III-94 (1.0 equiv) and water (44 mL) at room temperature, followed by addition of Indium (4.0 g, 34.8 mmol, 1.53 equiv). Reaction mixture was stirred vigorously for 12 h. After completion of the reaction mixture, it was extracted with DCM (2x), dried over Na2SO4 and concentrated. Column chromatography gave product allene alcohol III-95 in 72-89% yield as a yellow oil.  To a stirred solution of the crude allenyl alcohol III-95 (3.56 mmol, 1.0 equiv) in dry THF (0.1 M) was added triphenylphosphine (1.0 g, 3.84 mmol, 1.5 equiv) under N2 at ambient temperature. The solution was cooled to 0 ¡C phthalimide (0.57 g, 3.84 mmol, 1.5 equiv) were added subsequently. To the reaction mixture was added DIAD (0.76 mL, 3.84 mmol, 1.5 equiv) dropwise over an hour. The reaction mixture was allowed to stir for 1 h, slowly warming to ambient temperature. After 2 h, the solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography to afford allene III-96 as a white crystalline solid.  To a solution of III-96 (51.1 mmol) in MeOH (220 mL) was added !!!!)"+!NH2NH2.H2O (9 mL) at room temperature. The reaction was stirred for 12 h to completion (this reaction could be refluxed also in EtOH for 3 h to complete). To non-volatile compounds water was added, and MeOH was removed under reduced pressure. Then concentrated HCl (11 mL) was added at 0 ¡C and it was stirred for 1 h. It was then filtered, and the filtrate was basified by NeOH (1N) to pH=10. The aqueous layer was extracted with EtOAc and combined organic layers were removed under reduced pressure. The crude amine III-97 was then used for the next step without further purification. To volatile compounds water (5 mL) and concentrated HCl (11 mL) was added, and after filtration the solvents were removed to provide the HCl salt of III-97. To a solution of III-97 or III-97-HCl/salt (1.91 mmol, 1.0 equiv) in CH2Cl2 (30 mL) was added triethyl amine (3.82 mmol, 2.0 equiv) or (9.55 mmol, 5.0 equiv), respectively in an ice bath. To it was added appropriate acid chloride derivatives (1.0 equiv) drop wise under N2 and the reaction was warmed to ambient temperature. After 8 h, the reaction was diluted with an equal amount of water and extracted with DCM (3x). The combined organics were washed with brine (1x), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. Purification was achieved by column chromatography on silica gel and EtOAc-Hexanes gradient as eluent to afford desired di-substituted alleneamides in 81-89% yield.    !!!!)"$!III-13-B6 Analytical data for disubstituted alleneamide starting materials III-11a: 4-bromo-N-(2-ethylbuta-2,3-dien-1-yl)benzamide    White solid; M.P.: 64-65 ¡C 1H NMR (500 MHz, CDCl3) " 7.62 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 6.23 (br s, 1H), 4.92 (ddddd, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, 2H), 3.94 (dd, J = 3.5 Hz, J = 9.0 Hz, 2H), 2.01 (ddddd, J = 3.5 Hz, J = 3.5 Hz, J = 7.0 Hz, J = 7.0 Hz, J = 7.0 Hz, 2H), 1.05 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) " 204.0, 166.2, 133.4, 131.8, 128.5, 126.1, 103.6, 79.7, 40.5, 23.2, 12.0. HRMS (ESI) Calculated Mass for C13H14NOBr: ([M+H]+) = 280.0337, Found ([M+H]+) = 280.0350. III-14a: N-(2-benzylbuta-2,3-dien-1-yl)-4-bromobenzamide    White solid; M.P.: 99-100 ¡C NHO.EtBrNHO.BnBr!!!!)"%!1H NMR (500 MHz, CDCl3) " 7.52 (s, 4H), 7.21-7.31 (m, 5H), 6.17 (br s, 1H), 4.91 (ddddd, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, 2H), 3.94 (dd, J = 3.5 Hz, J = 9.0 Hz, 2H), 3.39 (t, J = 2.5 Hz, 2H).  13C NMR (125 MHz, CDCl3) " 205.5, 166.1, 138.6, 133.2, 131.7, 128.8, 128.5, 128.4, 126.6, 126.1, 100.9, 78.6, 40.5, 37.7.  HRMS (ESI) Calculated Mass for C18H16NOBr: ([M+H]+) = 342.0494, Found ([M+H]+) = 342.0508. III-15a: N-(2-phenylbuta-2,3-dien-1-yl)benzamide    White solid; M.P.: 96-98 ¡C 1H NMR (500 MHz, CDCl3) " 7.77 (d, J = 9.0 Hz, 2H), 7.22-7.52 (m, 8H), 6.32 (br s, 1H), 5.32 (t, J = 3.0 Hz, 2H), 4.52 (ddd, J = 3.5 Hz, J = 3.5 Hz, J = 5.5 Hz, 2H). 13C NMR (125 MHz, CDCl3) " 207.6, 167.3, 134.5, 133.6, 131.6, 128.7, 128.6, 127.4, 126.9, 126.0, 103.3, 81.1, 39.0. HRMS (ESI) Calculated Mass for C17H15NO: ([M+H]+) = 250.1232, Found ([M+H]+) = 250.1241.   NHO.Ph!!!!)"&!III-16a: N-(2-methylbuta-2,3-dien-1-yl)benzamide    White solid; M.P.: 44-47 ¡C 1H NMR (500 MHz, CDCl3) " 7.75 (d, J = 8.0 Hz, 2H), 7.39-7.50 (m, 3H), 6.28 (br s, 1H), 4.83 (br m, 2H), 3.94 (br m, 2H), 1.75 (s, 3H). 13C NMR (125 MHz, CDCl3) " 204.8, 167.2, 134.5, 131.4, 128.6, 126.8, 97.0, 77.7, 41.5, 16.5.  HRMS (ESI) Calculated Mass for C12H13NO: ([M+H]+) = 188.1075, Found ([M+H]+) = 188.1084. III-17a: 4-bromo-N-(2-methylbuta-2,3-dien-1-yl)benzamide    White solid; M.P.: 67-68 ¡C 1H NMR (500 MHz, CDCl3) " 7.62 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 9.0 Hz, 2H), 6.22 (br s, 1H), 4.83 (ddddd, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, 2H), 3.92 (dd, J = 3.5 Hz, J = 8.5 Hz, 2H), 1.74 (t, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) " 204.7, 166.2, 133.5, 131.8, 128.5, 126.1, 96.9, 77.9, 41.5, 16.5. NHO.MeNHO.BrMe!!!!)"'!HRMS (ESI) Calculated Mass for C12H12NOBr: ([M+H]+) = 266.0181, Found ([M+H]+) = 266.0191. III-19a: N-(2-methylbuta-2,3-dien-1-yl)-4-nitrobenzamide    White solid; M.P.: 83-84 ¡C 1H NMR (500 MHz, CDCl3) " 8.28 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H), 6.28 (br s, 1H), 4.86 (ddddd, J = 3.0 Hz, J = 3.0 Hz, J = 3.0 Hz, J = 3.0 Hz, J = 3.0 Hz, 2H), 3.95 (dd, J = 4.5 Hz, J = 9.0 Hz, 2H), 1.77 (t, J = 3.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) " 204.7, 165.2, 140.1, 128.1, 123.9, 96.7, 78.3, 41.6, 21.9, 16.5.  HRMS (ESI) Calculated Mass for C12H12N2O3: ([M+H]+) = 233.0926, Found ([M+H]+) = 233.0929. III-13-B7 General procedure for synthesis of monosubstituted dialleneamide starting materials NHO.MeNO2CuI, CH2Oi-Pr2NHDioxane110 ¡C1-5 h.XOHNOHNEt3N, PA DCM0 ¡C to rt 2-5 hXOHNOHN.XClOOClX = C or NPropargyl amine=PAIII-98di-allenamidesdi-acid chlorides!!!!))(! To a solution of propargyl amine (4.6 mL, 3.0 equiv) in CH2Cl2 (300 mL) was added Et3N (10 mL) and di-acid chlorides (1.53 mmol, 1.0 equiv), respectively in an ice bath. After 8 h, the reaction was diluted with an equal amount of water and extracted with DCM (3x). The combined organics were washed with brine (1x), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. Purification was achieved by column chromatography on silica gel with EtOAc-Hexanes gradient (20-50%) to afford desired III-98 in 79-88% yield. To an oven-dried reaction flask were added substrate III-98 (8.33 mmol, 1 equiv), anhydrous 1,4-dioxane (30 mL), CuI (0.8 g, 4.2 mmol, 0.5 equiv), paraformaldehyde (0.8 g, 26.7 mmol, 3.2 equiv), and diisopropylamine (3.5 mL, 25.0 mmol, 3.0 equiv) sequentially under an argon atmosphere. The resulting mixture was then submerged in an oil bath preheated to 110 ¡C. When the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Column chromatography on silica gel with EtOAc-Hexanes afforded di-alleneamides in 52-86% yield.     !!!!))#!III-13-B8 Analytical data for monosubstituted dialleneamide starting materials III-22a: N1,N3-di(buta-2,3-dien-1-yl)isophthalamide    White solid; M.P.: 84-86 ¡C 1H NMR (500 MHz, CDCl3) " 8.18 (t, J = 1.5 Hz, 1H), 7.89 (dd, J = 1.5 Hz, J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 6.49 (br s, 2H), 5.29 (dddd, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, 2H), 4.87 (ddd, J = 3.5 Hz, J = 3.5 Hz, J = 3.5 Hz, 4H), 4.03 (dddd, J = 3.0 Hz, J = 3.0 Hz, J = 6.0 Hz, J = 9.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) " 208.1, 166.3, 134.8, 129.9, 129.0, 125.4, 87.7, 78.0, 38.0. HRMS (ESI) Calculated Mass for C16H16N2O2: ([M+H]+) = 269.1290, Found ([M+H]+) = 269.1303. III-23a: N1,N4-di(buta-2,3-dien-1-yl)terephthalamide    White solid; M.P.: 183-185 ¡C OHN.OHN.OHN.NHO.!!!!))"!1H NMR (500 MHz, CDCl3) " 7.81 (s, 4H), 6.26 (br s, 2H), 5.33 (dddd, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, J = 6.0 Hz, 2H), 4.90 (ddd, J = 3.5 Hz, J = 3.5 Hz, J = 6.5 Hz, 4H), 4.05 (dddd, J = 3.5 Hz, J = 3.5 Hz, J = 5.5 Hz, J = 5.5 Hz, 4H). 13C NMR (125 MHz, CDCl3) " 208.0, 166.3, 137.1, 127.2, 87.8, 78.2, 37.9.  HRMS (ESI) Calculated Mass for C16H16N2O2: ([M+H]+) = 269.1290, Found ([M+H]+) = 269.1302. III-25a: N2,N6-di(buta-2,3-dien-1-yl)pyridine-2,6-dicarboxamide    White solid; M.P.: 85-86 ¡C 1H NMR (500 MHz, CD3COCD3) " 9.02 (br, s, 2H), 8.35 (d, J = 7.5 Hz, 2H), 8.24 (t, J = 8.0 Hz, 1H), 5.32 (dddd, J = 6.5 Hz, J = 6.5 Hz, J = 6.5 Hz, J = 6.5 Hz, 2H), 4.83 (ddd, J = 3.0 Hz, J = 3.0 Hz, J = 6.5 Hz, 4H), 4.05 (dddd, J = 3.0 Hz, J = 3.0 Hz, J = 6.0 Hz, J = 6.0 Hz, 4H). 13C NMR (125 MHz, CD3COCD3) " 209.1, 164.0, 150.1, 140.1, 125.4, 89.1, 77.0, 38.5.  HRMS (ESI) Calculated Mass for C15H15N3O2: ([M+Na]+) = 292.1062, Found ([M+Na]+) = 292.1072.  NOHN.OHN.!!!!)))!III-13-B9 General procedure for synthesis of disubstituted allenecarbamte starting materials  Allene amine III-99 was synthesized according to the procedure explained in Section III-13-B5. Et3N (2.8 mL, 5.0 equiv) was added to a solution of the protonated amine III-99 (1.0 g, 7.5 mmol, 1.0 equiv) in DCM (110 mL). (Boc)2O (1.64 g, 7.5 mmol, 1.0 equiv) was added to the reaction mixture at 0 ¡C. After completion of the reaction, it was quenched with water, extracted with EtOAc, and the solvent was removed under reduced pressure. Column chromatography on silica gel with EtOAc-Hexanes afforded III-50 in 56% yield. III-13-B10 Analytical data for disubstituted diallenecarbamate starting materials 28a: tert-butyl (2-ethylbuta-2,3-dien-1-yl)carbamate    1H NMR (500 MHz, CDCl3) " 4.83 (dddd, J = 4.0 Hz, J = 4.0 Hz, J = 4.0 Hz, J = 4.0 Hz, 2H), 4.62 (br s, 1H), 3.64 (s, 2H), 1.94 (ddddd, J = 3.5 Hz, J = 3.5 NHO.O.NH2OHprop-2-yn-1-olIII-99StepsNHO.OIII-50Et3N, (BOC)2ODCM, 0 ¡C to rt8-12 h!!!!))*!Hz, J = 7.0 Hz, J = 7.0 Hz, J = 7.0 Hz, 2H), 1.42 (s, 9H), 1.00 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) " 204.2, 155.8, 103.8, 79.2, 78.9, 41.8, 28.4, 22.8, 11.9. HRMS (ESI) Calculated Mass for C11H19NO2: ([M+H]+) = 198.1494, Found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`!DR2?0>:1A!2:3!T@<<>7/3/:1!51</J20/J1A!J/2!Z71?0<>[./7/?!W7H></:20/>:!>M!9771:>/?!9?/3A!2:3!9B/31A!"!'(71!$#!$'()&$!!!""'4!/>4!#&'D#'*,!!#),!-2:=4!P,4!L,!6.1:4!2:3!K,X,!X24!8K0H3/1A!>:!Z71?0<>[./7/?!6@?7/C20/>:!>M!PDaLH02D"4)D3/1:@7b2B/31A!]/0.!PDL<>B>AH??/:/B/31!2:3!/0A!9[[7/?20/>:A!"!%AG!$*415(!$':5:B!4!!"#%4!.C<4!*&+D*'",!!#*,!RH4!L,4!10!27,4!8V/=.7@!I1=/>D!2:3!K01<1>A171?0/J1!6@?7/?!U>3>10.1</M/?20/>:!>M!*4+D97N23/1:>7A,!9:!ZMM/?/1:0!T<1[2<20/>:!>M!"Da#caSbDU>3>27N1:@7bE10<2.@3<>MH<2:A!"!#!$E;9!$'()&!4!!""'4!>24!*)&D**#,!!#+,!S.2:=4!d,4!10!27,4!8K01<1>A171?0/J1!U>3>72?0>:/C20/>:!>M!*D9771:>/?!9?/3A!]/0.!ZMM/?/1:0!6./<27/0@!E<2:AM1<^!51J17>[B1:0!>M!9!P1]!Z71?0<>[./7/?!U>3/:20/>:!I12=1:0!"!'()&765;44!!"#!4!-H4!#)+(#D#)+(',!!#$,!V><J20.4!9,4!Q,!L1::1<4!2:3!Q,Z,!L2?NJ2774!8Z:2:0/>?>:0<>7713!K@:0.1A/A!>M!)DT@<<>7/:1A!M<>B!97[.2D9B/:>!9771:1A!"!=0;!$#!$E;9!$'()&!4!!""%4!)"*(D)"*),!!#%,!Y>?N174!L,!2:3!P,!F<2HA14!8K@:0.1A/A!>M!L/?@?7/?!Z0.1<A!e@!2!Y>73fT27723/HBfY>73D62027@C13!6@?7/C20/>:f6<>AA!6>H[7/:=!K1gH1:?1!"!=0;!$#!$E;9!$'()&!4!!"#"4!)##D)#$,!!#&,!L2<7H1:=24!Q,4!10!27,4!8U>3>2<@720/>:!I12?0/>:A!>M!9771:1A^!U:01<D!2:3!U:0<2B>71?H72<!T<>?1AA1A!"!'()&!$=0;!$#!4!!""'4!-C4!&'*$D&'+(,!!#',!K2/4!X,!2:3!K,!X20AHe2<24!8K/7J1<D62027@C13!U:0<2B>71?H72<!6.7><>2B/:20/>:!>M!9771:1A^!Z2A@!9??1AA!0>!WH:?0/>:27/C13!)DT@<<>7/:1!2:3!T@<<>71!51</J20/J1A!"!E;9!$I)55!4!!"##4!-.4!*$%$D*$%',!!"(,!-/7N/:=4!X,4!6,Y,!52:/7/H?4!2:3!O,!V1::1?N14!89A@BB10</?4!;<=2:>?2027@0/?!L<>B>72?0>:/C20/>:!>M!9771:>/?!9?/3A!"!*41B)554!!"#%4!/C4!#%(#D#%(*,!!"#,!XH<2/4!F,4!P,!K./B/CH4!2:3!V,!WHh/>N24!8Z:2:0/>A171?0/J1!U>3>72?0>:/C20/>:!>M!9771:>/?!9?/3A!"!'()&!$'+&&01!4!!"#%4!CD4!#"+)(D#"+)),!!"",!YH>4!L,Q,4!6,R,!WH4!2:3!K,X,!X24!89A@BB10</?!K1B/[/:2?>7!I12<<2:=1B1:0!>M!"4)D9771:>7A!]/0.!PDL<>B>D#4&DP2[.0.27/B/31!"!'()&!$'+&&01!4!!"#%4!CD4!***+D***%,!!!!!!))&!"),!X/71A4!5,V,4!X,!i1=H/772A4!2:3!W,5,!E>A014!8Y>73aUbD62027@C13!Z:2:0/>A171?0/J1!L<>B>?@?7/C20/>:!I12?0/>:A!>M!9771:1A!"!'()&!$*,7!4!!"#$4!24!)*"%D)*)#,!!"*,!Q2=2:20.2:4!9,4!10!27,4!89!62027@0/?!9A@BB10</?!6.7><>?@?7/C20/>:!>M!O:A20H<2013!9B/31A!"!%19)?!$'()&!$@15!$=A!4!!"##4!CD4!"+')D"+'$,!!"+,!Q2=2:20.2:4!9,4!I,Q,!K02[71A4!2:3!L,!L><.2:4!8F/:10/?!I1A>7H0/>:!>M!O:A20H<2013!9B/31A!/:!2!6.7><>?@?7/C20/>:!I12?0/>:^!6>:?>B/02:0!Z:2:0/>B1<!5/MM1<1:0/20/>:!2:3!W2?1!K171?0/J1!97N1:1!6.7></:20/>:!e@!2!K/:=71!62027@A0!"!#!$%&!$'()&!$*+,!4!!"#$4!-.C4!#*&($D#*&#),!!"$,!Q2=2:20.2:4!9,!2:3!L,!L><.2:4!86.7><>AH7M>:2B/31!K270A!2<1!KH[1</><!Z71?0<>[./7/?!6.7></:1!T<1?H<A><A!M><!0.1!;<=2:>?2027@0/?!9A@BB10</?!6.7><>?@?7/C20/>:!>M!O:A20H<2013!9B/31A!"!E;9!$I)55!4!!"#%4!-<4!)$#$D)$#',!!"%,!51A/B>:/4!Y,4!Y,!W2/024!2:3!F,9,!Q><=1:A1:4!86D"DK@BB10</?!6./<27!L/Aa;j2C>7/:1b!R/=2:3A!/:!9A@BB10</?!62027@A/A!"!'()&!$F)G!4!!""(4!-D<4!)+$#D)$+#,!"&,!F723/4!X,4!6,!i2=/2A4!2:3!i,!I>HAA/A4!8i>720/71!V27>=1:2013!X102e>7/01A!M<>B!X2</:1!I13!97=21!"!J(45+,()&$F)G4!!""%4!.4!))%D)$$,!!"',!Y</ee714!Y,-,4!8E.1!5/J1<A/0@!>M!P20H<277@!T<>3H?13!;<=2:>.27>=1:A!"!'()&+6K();)4!!""$4!C/4!"&'D"'%,!!)(,!Y</ee714!Y,-,4!8P20H<277@!;??H<</:=!;<=2:>.27>=1:!6>B[>H:3A!"!%,,!$'()&!$F)6!4!#'')4!.-4!#*#D#+",!!)#,!VH4!5,d,4!10!27,4!862027@0/?!6.1B>D4!I1=/>D4!2:3!Z:2:0/>A171?0/J1!L<>B>?.7></:20/>:!>M!977@7/?!97?>.>7A!"!#!$%&!$'()&!$*+,!4!!"#&4!-.>4!)%'+D)%'&,!!)",!K:@31<4!K,9,4!S,DG,!E2:=4!2:3!I,!YH[024!8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IV: Elaboration of Aziridinols Toward Pyrrolidines And Piperidine Compounds  IV-1 Introduction Polyhydroxylated alkaloids such as piperidines and pyrrolidines constitute the skeletal framework of several important iminosugars and several biologically important natural products.1-3 They mimic the structures of monosaccharides, and their exceptional biological activity as glycosidase inhibitors make them as one of the most attractive classes of carbohydrate mimics reported so far in the literature.4, 5 In the past couple of years, these heterocycles have made their way to several clinical and pre-clinical studies.6, 7 Biological activity of iminosugars span the inhibition of a variety of enzymes of medicinal interest such as glycosyltransferases,8 glycogen phopshorylases,9 nucleoside-processing enzymes,10 a sugar nucleotide mutase and metalloproteins.11, 12 Beside their biological properties, enantiomerically pure pyrrolidines have been used as chiral auxiliaries in a variety of organic transformations.13-20 Synthetic challenges, and thus the development costs associated with higher functionalization, however, might limit the scope of further substituted analogs in pharmaceutical research.  A great deal of research has focused on the diastereo- and enantioselective access to piperidines3, 6, 21-23 and pyrrolidines.24-28 In our group, we have focused on the diastereoselective assembly of heterocycles that possess the pyrrolidine and piperidine structural motifs, motivated by !"#%!both their biological significance and our synthetic interests.29, 30 In our synthetic approaches, we have developed new methodologies where the stereochemistry of the simple starting materials can be easily translated to complex products with complete fidelity.  Dr. Jennifer Schomaker has developed a highly efficient transformation of aziridinols to pyrrolidines through a ylide-base aza-Payne rearrangement in the presence of excess dimethyl sulfoxonium methylide (Scheme IV-1).29 Through an aza-Payne rearrangement of aziridinols under basic conditions, epoxy amines are formed, favorably. Subsequent nucleophilic attack of epoxide by the ylide affords a bis-anion, which upon a 5-exo-tet ring closure yields the desired pyrrolidines. OHR1R2NTsNTsR1OR2SONTsR1OHR2SOSOrt80 ¡CNTsR1R2OH2,3-substituted pyrrolidinesScheme IV-1 One-pot conversion of 2,3-aziridin-1-ols to 2,3-substituted pyrrolidines! !"#"!The yilde-based aza-Payne rearrangement methodology was further revised to incorporate the use of alkynes to act as an electron sink to obtain highly functionalized pyrrolidines by a one-pot tandem aza-Payne/hydroamination process (Scheme IV-2). Dr. Schomaker and Dr. Aman Kulshrestha have recently developed a selective methodology for addition reactions of Grignard reagents to aziridine-2-carboxaldehydes.30, 31 Excellent diastereoselectivity was realized for the synthesis of aziridine alcohols IV-1 during the addition of Grignard reagents to N-protected aziridine-2-carboxaldehydes. They found that a high diastereoselectivity is obtained in the addition of propargyl magnesium bromide to 2,2,3-trisubstituted aziridines with a tosyl-protecting group where only syn-aziridinols were obtained as the sole detectable product. The deprotonation of this stereo-defined aziridine alcohol IV-1 could lead to an ylide-based aza-Payne rearrangement yielding an epoxy N-Ts amide intermediate IV-3;29 only the syn diastereomer undergoes hydroamination, as the aza-Payne rearrangement orients the anionic nitrogen and the alkyne on the same side of the epoxide (Scheme IV-2). The hydroamination proceeds through a 5-exo-dig ring closure to yield tetrasubstituted pyrrolidines in the form of strained enamides in a metal free condition.  Our own efforts have focused on synthetic elaborations of the latter methodology towards complex and advanced level intermediates. Our interest in further exploiting the aza-Payne/hydroamination pathway in a manner to !"##!increase diversity in structure, particularly in light of our interest in gaining access to polyhydroxylated motifs led us to explore a different reaction manifold.32, 33  IV-2 3,4-Dihydroxypyrrolidines via modified tandem aza-Payne/hydroamination pathway In a collaboration with Dr. Kulshrestha, we began our investigation with the plan of intercepting the aza-Payne intermediate IV-2 (Scheme IV-2) with a latent nucleophile to alter the outcome of the subsequent hydroamination reaction.34 Aziridine ring opening with a modified nucleophile would lead to enamide compounds embellished with different functionalities. Scheme IV-3 illustrates our proposal that relies on the use of CO2 as a latent nucleophile. Scheme IV-2 High syn diastereoselectivity for the "#$%&'(#)*#"*&+($(,()#-./!"#--#01,*23*&*#)145#'*'&),1%*&+&46&3)1783,$#&%()&'(#)*$1&9'(#)! OHR1R2NTsNaH, Me3SOIDMSOR1R2NTsOR1R2NTsONTsR1R2OOR1R2NTsHMgXR3R3R3R3SOHR3aziridine aldehydesIV-1substituted pyrrolidinesIV-2IV-3!"#&!We anticipated that CO2 would initially serve as an electrophile to affect the acylation of the alkoxide intermediate, thereby introducing instead a carbonate nucleophile to carry out the aziridine ring opening. Ensuing 5-exo-ring closure would then deliver the functionalized enamide carbonate product containing the masked dihydroxylated unit.35  Scheme IV-3 Modification of t&),1%*&+&46&3)1783,$#&%()&'(#)*$1&9'(#)*23*&*-&'1)'*):9-1#58(-1*;<=! R1OR2NTsNTsR1R2OTsNOR1R2TsNR1R2OR1NR2OHTsMe3SOI/NaHDMSOR1NR2TsOMgBrNTsR1R2OOOCO2R1R2NTsOOOTsNOOR1R2Ok-2TsNR1R2OOOk2H+H+Path APath B!"#'! The aza-Payne process is an efficient intramolecular pathway, thus interjecting an external nucleophile would pose a kinetic challenge.36, 37 Two points were critical in our assessment that led us to believe a longer-lived alkoxide species could participate in an intermolecular pathway prior to intramolecular ring-opening of the aziridine. First, evidence for an altered pathway that did not immediately engage in an aza-Payne rearrangement of alkoxide came from a desilylation experiment. The TBS ether IV-4 (Figure IV-1) participated in a semi-Pinacol rearrangement38, 39 affording an unexpected aldehyde product IV-6; the transformation entails migration of an alkyl group and insinuates the higher stability of the alkoxide IV-5 generated under the specific reaction conditions. Second, a handful of reports have shown the feasibility of 2,3-epoxy-1-ols to trap CO2 in the form of a carbonate,35 which further proceed to open the epoxide in a Payne-like reaction. Armed with the observations discussed above, we subjected TBS ether IV-4 to a reaction condition that contains excess of NaHCO3 as a source of CO2 dissolved in a polar solvent. The reaction in DMF at 0 ¼C for 2 h led to a mixture of four products (Table IV-1). As anticipated, the desilylated product IV-7 was observed. Along with that, the aza-Payne rearrangement led to significant amounts of IV-8, and the previously reported pyrrolidine IV-9. Nonetheless, a substantial amount of the enamide carbonate IV-10 was isolated, suggesting that the alkoxide intermediate must have trapped a molecule of CO2, which subsequently initiated a downstream hydroamination !"#(!to yield the stated molecule. Table IV-1 demonstrates various conditions that were examined to optimize the reaction in order to maximize the production of the desired carbonate compound. Warming the reaction to room temperature led to the first significant improvement (entry 2) by completely eliminating compounds IV-7 and IV-8. Inclusion of molecular sieves furnished the enamide epoxide IV-9 only, suggesting that the presence of water is necessary to carry the reaction toward the desired molecule (entry 4). The source of CO2 is critical as can be seen from the comparison of entries 2 with 7-10 (Table IV-1). The best results were obtained with bubbling CO2 in the presence of NaHCO3. Curiously, greater amount of TBAF was also necessary to yield the desired product IV-10, exclusively (entry 10).  Figure IV-1 The alkoxide intermediate leads to a semipinacol rearranged aldehyde product without any evidence of an aza-Payne rearranged process under the reaction conditions.! IV-4BnONCH3OTBSTsTBAF/THF0 ¼C, 89% yieldBnONCH3OTsONHTsH3CBnOIV-6BnONCH3OHTs+IV-7IV-565:35!"#)!  Table IV-1 Optimization of reaction conditions for the synthesis of N-Ts enamide carbonate IV-10.! +IV-10IV-9IV-7IV-8IV-4TBAF NaHCO3BnONCH3OTBSTsDMF (0.08 M)T ¼C, addtitivesBnONCH3OHTsBnOTsHNOTsNBnOOTsNBnOOOOEntry TBAF (equiv) NaHCO3 (equiv) Time (h) Temp (¡C) Additives Ratios IV- (7:8:9:10) 1 5 10 2 0 - 18:22:26:34 2 5 10 6 0 to rt - 0:0:20:80 3 2.5 10 12 0 to rt - 0:0:38:62 4   5[a] 10 12 rt 4† ms 0:0:100:0 5 2 20 8 -10 to rt - 0:0:18:82 6 2 20   12[b] -30 to 60 - 0:0:30:70   7[c] 2 20 6 0 to rt CsCO3 0:0:62:38   8[e] 2 20 5 0 to rt CsCO3 0:0:90:10 9 2 20 5 0 to rt CO2  0:0:5:95[d] 10 11 20 8 0 to rt CO2 0:0:0:100 [a] TBAF was stirred over 4 † ms for 1 h before its was added to the reaction. [b] Polar and unidentified impurities were observed, as analyzed by NMR of crude mixture, at elevated temperature. [c] TBAF was added at 0 ¼C then reaction was warmed to RT followed by sonication. [d] Only 38% conversion was observed by NMR analysis of crude reaction mixture. [e] Products IV-9 and IV-10 in separate experiments, when subjected to the reaction conditions, did not interconvert. !"#*! Scheme IV-4 illustrates the scope of the TBS-protected 2,2,3-trisubstituted aziridine alcohols that successfully participated in the modified tandem aza-Payne/hydroamination reaction, utilizing the optimized conditions, yielding the desired enamine carbonate products IV-10, IV-11, and IV-12 in 70%, 61%, and 65% yields, respectively. The stereochemistry of the products was verified via NMR analysis and in the case of IV-12, a crystal structure provided unequivocal confirmation.  The perceived mechanism for the transformation would suggest no need for requisite silyl protected alcohol as the starting material. As such, we TsNRH3COOORNCH3OTBSTsTsNH3COOOBnOIV-1070% yieldTsNH3COOOIV-1161% yieldTsNPhH3COOOIV-1265% yieldTBAF (11 equiv)NaHCO3 (20 equiv.)CO2, DMF (0.08 M)0 ¼C to rtScheme IV-4 Substrate scope for the synthesis of N-Ts enamide carbonates from silyl aziridine alcohols.  !"&+!next explored the use of unprotected aziridine alcohol IV-11a as the starting material for the conversion into the enamide carbonate product IV-11. Surprisingly, our first attempts met with failure and led to the isolation of the unreacted aziridine alcohol under conditions that otherwise should have delivered the product (Table IV-2, entry 1). Inclusion of NaHCO3 made no change, neither did the use of trimethylsulfoxonium iodide, the preferred proton source for the hydroamination step, as was reported previously (Table IV-2, entries 2-5).30 Solubility of the sodium alkoxide was also probed via changing the solvent and also the use of TBAI as a phase transfer catalyst, but those also did not resolve the issue. Surprisingly, addition of TBAF did yield the desired enamine carbonate IV-11 as the sole isolable product (entry 6), thus illustrating the importance of TBAF in promoting the reaction. The latter data suggest the fortuitous nature of our initial reaction conditions, in which TBAF was used to promote the desilylation of the TBS-protected alcohol. Nonetheless, it seems that the presence of TBAF is required for further reactivity after the alkoxide is revealed. This is also in agreement with our initial observation that an increased equivalence of TBAF was necessary to achieve full conversion to the product (Table IV-1, entry 10).    !"&$!  Scheme IV-5 illustrates the scope of di- and tri-substituted aziridine alcohols that successfully participated in the modified tandem aza-Payne/hydroamination reaction using the optimized reaction conditions found in Table IV-2. All these result suggests the importance of TBAF and NaHCO3 reagents for the synthesis of the desired enamide carbonate products, starting from TBS-protected or Ðnonprotected aziridine alcohols.    Entry Condition Product (IV-11) 1 NaH (4.0 equiv), DMF n.r. 2 NaH (2.5 equiv), NaHCO3 (20 equiv), THF n.r. 3 NaH (4.0 equiv), TMSOI (4 equiv), DMSO n.r. 4 NaH (2.5 equiv), TBAI (11 equiv), NaHCO3 (20 equiv), DMF n.r. 5 NaH (2.5 equiv), TBAF (12 equiv), NaHCO3 (30 equiv), DMF 69%  Table IV-2 Optimization of reaction conditions for the synthesis of N-Ts enamide carbonate IV-11 from aziridine alcohol IV-11a.  IV-11aIV-11TsNH3COOONCH3OHTsConditionCO2 bubbling, 0 ¼C to rt, 12 h!"&%! To get a better understanding on the mechanism of the reaction, especially the role of TBAF and NaHCO3 we carried out various experiments. We further investigated the role of TBAF by running the reaction under identical conditions with the exception of substituting TBAF with CsF, KF, and CsF/TBAI (Table IV-3, entries 1-4). In all cases staring material was recovered quantitatively. Interestingly, the use of TBAOMe did lead to the isolation of the product in the same yield but in a shorter reaction time (entries 6-7). It is also important to note that NaH could be replaced with a cheaper base, Na2CO3, to afford the desired product in 45% yield.   Scheme IV-5 Substrate scope for the synthesis of N-Ts enamide carbonates from aziridine alcohols.  TsNR1R2OOOR1NR2OHTsTsNOOOIV-1362% yieldTsNH3COOOIV-1169% yieldTsNPhH3COOOIV-1255% yieldNaHCO3 (20-30 equiv.)CO2, DMF (0.08 M)0 ¼C to rtNaH (2.5 equiv.)TBAF (11-12 equiv)!"&"! A few reports might suggest the role for fluoride in the generation of a fluorocarbonate species (fluoride reacting with CO2).40, 41 Based on DFT analysis by Dr. Ashtekar,34 this fluorocarbonate is an appropriate candidate as a potential electrophile in comparison to CO2. This insinuates its role in increasing the soluble CO2 concentration, and as a result of its reversible TsNRH3COOONaHCO3 (20 equiv.)CO2, DMF (0.08 M)0 ¼C to rtNaH (2.5 equiv.)Catalyst (11-13 equiv)OHRCH3NTsR = Et     IV-11R = Ph    IV-12R = Et     IV-11aR = Ph    IV-12aEntry Substrate Catalyst Product (IV-11) 1 IV-11a TBAI n.r.   2[a] IV-12a CsF n.r. 3 IV-12a KF n.r. 4 IV-12a CsF/TBAI n.r. 5 IV-12a CsI/TBAF 52%, 1.5 h 6 IV-12a TBAOMe 55%, 1 h 7 IV-12a TBAF 55%, 6 h [a] Addition of water (0.3 M) formed the product in small traces.  Table IV-3 Examining the role of catalyst.  !"&#!nature, it promotes the carboxylation reaction. This is also in agreement with our initial observation that an increased equivalence of TBAF was necessary to achieve full conversion to the product (Table IV-1, entry 10). TBAOMe used as an additive (Table IV-3, entry 6), increases soluble CO2 levels by producing methoxycarbonate in situ, which also leads to shorter reaction time observed for the formation of IV-12. Scheme IV-6 provides anecdotal evidence for the need of TBAF as a necessary reagent in promoting the carboxylation of the intermediate alkoxide. Primary alcohol IV-14a successfully traps CO2 and, via the aza-Payne like ring opening of the adjacent aziridine, yields IV-14 with or without TBAF (conditions B and A, respectively, Scheme IV-6). It should be noted that the reaction was completed in a slightly faster time course in the presence of TBAF. The secondary alcohol IV-15a reacted only in the presence of TBAF as an additive (condition B) to furnish the CO2 trapped aza-Payne-like product IV-15 in high yield. This clearly suggests the crucial role of TBAF in enabling the participation of sluggish nucleophiles in carboxylation reactions.  Besides the importance of a fluoride ion in presumably increasing the concentration of ÔdissolvedÕ CO2, NaHCO3 also plays an important role in this transformation. We have found that the role of NaHCO3 is not solely limited as a CO2 supply reagent. Illustrated in Scheme IV-7, exclusion of NaHCO3 from the reaction, in the presence of saturating CO2 and TBAF, leads to a mixture of products dominated by the nonhydroaminated compound IV-16. !"&&!The same is observed if rigorously anhydrous reaction conditions are used. Presumably, this is due to the lack of a sufficient proton source in the reaction medium for the final protonation of the vinyl anion. So both moisture and NaHCO3 play a role in the final protonation step for moving the reaction forward toward the formation of the desired enamide carbonate product and avoid the !-elimination to the non-hydroaminated products.     Scheme IV-6 Alkoxide trap of CO2 and subsequent aziridine ring opening of primary and secondary alcohols.  R = H      IV-14aR = CH3  IV-15aRNTsPhCondition ANaH (2.5 equiv), DMF0 ¡C to rt, CO2 bubblingCH3PhOOH3COTsHNCondition BNaH (2.5 equiv),  DMFTBAF (11 equiv)0 ¡C to rt, CO2 bubblingOHRR = H      IV-14; 89% (1.3 h)R = CH3  IV-15; n.r. (1 d)PhOOH3COTsHNRR = H      IV-14; 88% (1 h)R = CH3  IV-15; 72% (1 h)!"&'! Based on ab initio calculations at the B3LYP/6-31G* level by Dr. Ashtekar,34 Scheme IV-8 illustrates a detailed mechanistic outline proposed for the reaction that could proceed to yield either the epoxy enamine IV-21 (Path A) or the carbonate enamine IV-25 (Path B). We have assumed the irreversible nature of the first desilylation step and the protonation of the penultimate vinyl anion. With those considerations in mind, the remaining steps are assumed to be reversible and thus could siphon the reaction path toward the thermodynamically more stable cis-fused 5-5 ring system in comparison to the kinetically accessed cis-fused 3-5 ring system, given the correct conditions. Desilylation of aziridinol IV-17 generates the alkoxide intermediate IV-18, which in the absence of CO2, would exist in equilibrium with the aza-Payne intermediate IV-19. Noticeably, the equilibrium favors species IV-19 by 25 kcal/mol where the anionic nitrogen is stabilized by an electron-withdrawing group.36  Scheme IV-7 Role of NaHCO3 in the formation of IV-11.  NOTBSTsTsNOOO+NHTsOOOTBAF (11 equiv)CO2, DMF0 ¼C to rt70% yieldIV-11eIV-11IV-16IV-11 : IV-16(1 : 2)!"&(! 5-Exo-dig ring closure of IV-19 yields the vinyl anion intermediate IV-20, which upon rapid protonation provides the epoxy N-Ts enamide IV-21. The rate constant k-1 governs the extent of the reversibility of the N-Ts enamide vinyl anion back to the ring opened amide intermediate IV-19 in the reaction as calculated by Dr. Ashtekar. On the other hand in the presence of R1OR2NR1R2NOOONTsR1R2OCO2 + FNTsR1R2OOO!1!2TsNTsNOOOR1R2R1R2Ok-1k-2!1 > !2k-1 > k-2TsNR1R2OTsNR1R2OOOIV-17IV-18IV-22IV-19IV-23IV-20IV-21IV-24IV-25k1k2R1NR2OH/TBSTsNaH/TBAFFCO2H+H+Path APath BTsTs"H (IV-20+CO2)>"H (IV-24)Scheme IV-8 Mechanistic rationale for the synthesis of enamide epoxide and carbonate products.  !"&)!soluble CO2 the alkoxide intermediate IV-18 could trap the electrophile leading to the formation of the carbonate intermediate IV-22. This seems to be further facilitated by the presence of fluoride ions, presumably increasing the solubility of dissolved CO2 or its carbonate equivalent. The latter would execute the intramolecular aziridine ring opening to generate IV-23, poised for a similar ring-closing event that would yield vinyl anion IV-24.  Although Path A to the epoxy enamine IV-21 does not depend on an intermolecular event that should hasten its production in comparison to the carbonate enamine product IV-25, two points are key to understand why the equilibrium can be completely shifted toward the more stable fused ring system. First, the !-elimination of vinyl anions IV-20 and IV-24, defined by k-1 and k-2, respectively, would depend on the magnitude of each rate constant. As a result of the larger anticipated strain of the 5-3 fused ring system, we assume that k-1 is larger than k-2, thus shifting the population of the reaction intermediates toward the production of the observed carbonate enamine product IV-25. Second, B3LYP/6-31G*/SM8 (DMF) analysis reveals that the formation of IV-22 via trapping of CO2 by the oxyanion IV-18 is downhill by 29 kcal/mol. Furthermore, the dihedral angle "1, which defines the bite angle for intramolecular attack in epoxy amide IV-19, is larger (120.0¡) than "2 (113.3¡) in the carbonate amide IV-23. The smaller "2 confines a closer proximity of the reactive nitrogen anion and the acetylene carbon by 0.7 † (Scheme IV-8), thus leading to a more facile reaction (presumably k2 would be larger than k1). !"&*!This geometrical disposition helps to lower the relative transition state energy barrier for the hydroamination of IV-23 as compared to that for IV-19 by 2.3 kcal/mol. The critical element is the availability of CO2 and its reactivity with alkoxide IV-18 since the carbonate pathway is rate limited by its bimolecular nature. Bubbling of CO2 greatly increases the yield of IV-25. The presence of a fluoride ion is also essential to presumably increase the concentration of ÔdissolvedÕ CO2. Although the level of ÔdissolvedÕ CO2 seems to have a strong influence on the fate of the reaction, NaHCO3 is required as a proton source as well as being a source of CO2 in the reaction medium; which rapidly protonates intermediate IV-24, and thus avoids the !-elimination to IV-23.  This transformation utilizes CO2 as a latent nucleophile, by intercepting a reactive alkoxide, to deliver a set of alternate products. The modified nucleophiles enable access to pyrrolidines with different functionalities at the C-3 and C-4 positions. The final carbonate enamine product can be further transformed through reductive ozonolysis to yield lactams, which upon hydrolysis to furnish the 3,4-dihydroxylactams.  The outcome of the aza-Payne/hydroamination reaction could be modified by other latent nucleophiles. Various reaction conditions have been examined for trapping of CS2, RNCO, RNCS, CCl3CN, and DCC reagents, although none have been successful as of yet. !"'+!IV-3 Diastereoselective Baylis-Hillman/Aza-payne/Conjugate Addition Reaction Next, we moved our attention to modifying the aza-Payne/hydroamination reaction, paving the way for the synthesis of 6-member ring piperidines. As discussed in Section IV-1 and IV-2, facile aza-Payne rearrangement of diastereomerically pure aziridinol, followed by metal free hydroamination provides structurally interesting tetra substituted pyrrolidines (Scheme IV-9, Path A). The success of our one-pot aza-Payne/hydroamination approach relies on the choice of a suitable latent electrophile.30 The alkyne moiety serves as a nucleophile during the addition of the Grignard reagents to the aziridine-2-carboxaldehyde, and later reveals its electrophilicity under the appropriate conditions allowing for the cyclization.  Notice, under these conditions, electrophilicity at C-1 (IV-27) results into the 5-exo-dig cyclization, yielding 5-member rings exclusively. We aimed to exploit a similar concept that would modify this route and thus would enable the formation of 6-member rings. Notice, this new route would require the use of a latent electrophile, with altered electronics that provides higher electrophilicity at C-2 (IV-26). Olefins tethered to electron withdrawing groups are considered to exhibit higher electrophilicity at the C-2 position (! with respect to the carbonyl or other electron withdrawing substituents) and therefore, would fulfill such a requirement.  Scheme IV-9 illustrates our proposed plan for such a strategy (Path C).  Notice this plan incorporates !"'$!aziridinols tethered with an ",!-unsaturated carbonyl group (or other electron withdrawing groups). This would hopefully lead to an epoxy amide intermediate via the base-induced aza-Payne rearrangement. Ensuing 6-endo-dig ring closure would then permit access to piperidine compounds. We were aware of the prerequisite for diastereomeric purity of aziridinols, since only the syn isomer places both the electrophile and the nucleophile in exact orientation to aid in the cyclization.31 Thus initial focus of our investigation was the assembly of syn-aziridinol compounds substituted with ",!-unsaturated carbonyl or other electron withdrawing groups. Synthesis of such aziridinols was envisioned via addition of suitable nucleophiles to aziridine-2-carboxaldehydes via a Baylis-Hillman reaction to allow a C-C bond formation between an activated olefin and electrophile. Syn-selectivity was also anticipated during these reactions, based on the predominance of a stable bisected exo conformer, observed previously in the case of Grignard addition to aziridine-2-carboxaldehydes.31 Since chelation does not play any role during such additions; replacement of the Grignard nucleophile with a carbon enolate, in theory, should not affect the resulting stereochemical outcome. Thus, as shown in Scheme IV-10, we planned to carry out Baylis-Hillman addition reactions on aziridine-2-carboxaldehydes.  !"'%! Scheme IV-9 Modification of t&),1%*&+&46&3)1783,$#&%()&'(#)*$1&9'(#)*'#0&$,*'81*.3)'81.(.*#"*5(51$(,()1.! CO2MebaseR1NR2OHTsCO2MeR1OR2NPath CTsNTsCO2MeR1R2OHNTsR1R2OCO2MeNTsR1R2OOMeOOMeOR1OR2NTsNTsR1R2OTsNOR1R2TsNR1R2OR1NR2OHTsH+Path AMe3SOI/NaHDMSOR1NR2TsOMgBrR1OR2NEWGTsElelctrophilic center : C-212R1OR2NTsElelctrophilic center : C-121H+IV-26IV-27!"'"!Utility of N-Tr protected monosubstituted aziridine-2-carboxaldehydes has been reported by Zwanenburg and coworkers in a facile Baylis-Hillman reaction using a variety of activated olefins.42 Catalytic amount of DABCO was used as the base to obtain an almost equimolar mixture of syn/anti adducts.  Although, reaction times were long (8-10 days), moderate yield of the adducts was obtained. Among various nucleophiles used for the reaction, best reactivity and selectivity was demonstrated by acrylonitrile (syn/anti: 67/33). Recently, Yudin et al. reported the synthesis of Baylis-Hillman type adducts via the aza-Michael/Aldol pathway to furnish aminohydroxy products in greats yields and diastereoselectivities of 20/1 (syn/anti).43  Our initial investigations focused on at the Baylis-Hillman reaction of various tri- and di-substituted aziridine carboxaldehydes (Scheme IV-10). Methyl acrylate and acrylonitrile were investigated as the appropriate electrophiles in this transformation. Indeed when the reaction was carried out without solvent at room temperature, in the presence of catalytic amount of DABCO, while using excess amounts of the electrophile, starting material was completely consumed in 1 to 2 days to yield syn Baylis-Hillman adduct in excellent to moderate yields and diastereoselectivities. Structural information of compound IV-34 was further confirmed by X-ray crystallography. Several other tri-substituted aziridine-2-carboxaldehydes were subjected to the Baylis-Hillman reaction and gratifyingly afforded exclusively the syn products (IV-28 to IV-34). Both alkyl ethers and non-ether substituents participated in the !"'#!reactions successfully in high yield, leading to the product with excellent selectivity. We were encouraged by the observed expected diastereoselectivity, since this further validates our hypothesis in achieving high syn diastereoselectivity in the addition of Grignard reagents to aziridine carboxaldehydes.31 Both the substitution pattern and the protecting group on nitrogen played an important role in determining the stereochemical outcome observed for addition of Grignard reagents to aziridine-2-carboxaldehydes. The same is observed here. The pattern also holds for the Baylis-Hillman reaction of disubstituted aziridine carboxaldehydes; the desired products were obtained in low yields and moderate to good selectivities in parallel to results obtained previously for addition of Grignards (IV-35 to IV-41).31 Various optimizations attempted to improve the yield for the Baylis-Hillman reaction of disubstituted aziridine carboxaldehydes, such as increasing the equivalents of DABCO. This led to an improved yield but a slight drop in diastereoselectivity. Replacing DABCO with PPh3 did not improve the yields for disubstituted Baylis-Hillman adducts, but led to the formation of side-products (aziridine ring opening and elimination after Baylis-Hillman reaction). To our disappointment when N-Boc disubstituted aziridine-2-carboxaldehydes were subjected to the Baylis-Hillman reaction conditions, low yields were obtained.  !"'&! Scheme IV-10 Substrate scope for Baylis-Hillman reaction of aziridine carboxaldehydes. (5.0 equiv)DABCO (0.5-0.7 equiv)1-2 days, rtEWGR1R2ONTsR1R2NTsEWGOHNTsCO2MeOHTBSOIV-3485%, dr (99/1)NTsCO2MeOHTBSOIV-3624%, dr (95/5)MeNTsCO2MeOHIV-3537%, dr (60/40)NTsCO2MeOH IV-28 60%, dr (99/1)PhNTsCO2MeOH IV-3070%, dr (83/16)NTsCO2MeOHBnOIV-32 82%, dr (97/3)NTsCO2MeOHOIV-3379%, dr (97/3)BzNTsCNOH IV-2985%, dr (99/1)PhNTsCNOHIV-3195%, dr (99/1)NTsCNOHTBSOIV-3720%, dr (60/40)NTsCNOHBnOIV-3816%, dr (95/5)NTsCO2MeOHBnOIV-3910%, dr (95/5)NTsCO2MeOHIV-4018%, dr (95/5)NTsCNOHIV-4131%, dr (95/5)!"''!Efforts were made to perform the cyclization of the Baylis-Hillman adducts under the conditions that were optimized for tandem aza-Payne/hydroamination reaction (Scheme IV-2).30 Treatment of syn aziridinol compound with dimethylsulfoxonium methylide in DMSO only led to degradation of the starting material, perhaps due to the harsh conditions.  At this point we decided first to probe the appropriate conditions to execute the aza-Payne rearrangement. Previously it was shown that the aza-Payne rearrangement could be carried out in the presence of NaH and DMSO. Thus, we attempted the rearrangement by subjecting the Baylis-Hillman adducts to NaH (2 equivalents) and DMSO. Unfortunately the reaction was marred by the presence of several undesired products as evident by crude NMR analysis. However, treatment with catalytic amount of NaH at cooler temperatures successfully afforded the unexpected dehydropiperidine compound in high yield. The mechanism of this transformation is shown in IV-9 (Path C). Treatment of the Baylis-Hillman adduct under basic conditions instigates the formation of the epoxy amide intermediate via the aza-Payne rearrangement of aziridinol. The resulting anionic nitrogen undergoes an intramolecular conjugate addition reaction to form 6-member ring piperidines. However, at this stage concomitant opening of the epoxide is likely to result via the enolate, which leads to the formation of dehydropiperidine compounds. Unfortunately, epoxide opening could not be avoided even upon lowering the temperature to -78 ¡C.  Notably, epoxide opening was observed !"'(!(TLC monitoring) along with the presence of starting material even at -78 ¡C.  Thus epoxide opening seems unavoidable and favored perhaps due to the thermodynamic stability gained via ring strain release. Nevertheless, we were delighted by the access to the highly stereodefined 6-membered ring, which can be easily obtained via aza-Payne/conjugate addition reaction in one step (Scheme IV-11).     R1R2NTsEWGOHNaH (0.3-0.5 equiv)NTsEWGR1R2OHDMF, -30 ¡C to 0 ¡C30-60 minNTsMeO2COHIV-43 91% yieldNTsMeO2CPhOHIV-4477% yieldNTsMeO2COHIV-4282% yieldOTBSNTsMeO2COHIV-4780% yieldOBnNTsNCOHIV-4585% yieldOTBSNTsNCOHIV-4674% yieldScheme IV-11 Substrate scope for aza-Payne/Conjugate addition reaction of Baylis-Hillman adducts. !"')!The scope of this transformation was investigated next (Scheme IV-11). All the Baylis-Hillman adducts yielded the cyclized product in good yields and excellent syn selectivity. We also observed that in the case of methyl acrylonitrile, double bond migration occurs. This could be explained by the lower pKa of the hydrogen atoms next to the cyanide group as compared to the ester group. Structural identity of the cyclized products was confirmed by X-ray crystallography. We were, therefore able to access highly stereodefined dehydropiperidine adducts via the aza-Payne/conjugate addition reaction in good yields and good syn selectivity in one step starting from the Baylis-Hillman aziridinol adducts.  One-pot syntheses are advantageous since they avoid lengthy separations, and are operationally simpler and less time consuming.  This makes the tandem aza-Payne/conjugate addition protocol an attractive route for the synthesis of piperidine compounds. We turned our attention towards performing all the three steps in one pot. The one-pot protocol for telescoping the Baylis-Hillman, aza-Payne, and conjugate addition reactions efficiently afforded the desired dehydropiperidine compounds in high yields and as a single diastereomer (Scheme IV-12). N-Ts protected dehydropiperidines were further elaborated to unprotected piperidines with powdered Mg and methanol under sonication. !"'*! Thus, dehydropiperidine compounds, with high complexity can be obtained in one pot starting from simple starting materials such as aziridine-2-carboxaldehydes.  Solvent-free condition for the Baylis-Hillman reaction and operation of three steps in one pot also makes this reaction environmentally benign and efficient.       Scheme IV-12 One-pot synthesis of dehydropiperidines via Baylis-Hillman/aza-Payne/conjugate addition reactions. 2.  NaH (0.3-0.5 equiv)     DMF, -30 ¡C to 0 ¡C     1-2 daysR1R2ONTsEWG, DABCO, rt1.NTsEWGR1R2OHNTsMeO2COHIV-4265% yieldOTBSNTsNCOHIV-4590% yieldOTBSNTsMeO2COHIV-43 51% yield!"(+!IV-4 Conclusion and future direction  In summary, we were able to modify the tandem aza-Payne/hydroamination reaction towards the synthesis of more complex pyrrolidines. The current transformation used carbon dioxide as a latent nucleophile, by intercepting a reactive alkoxide, to deliver a set of alternate products. This methodology enables access to enamide carbonates with different functionalities at the C-3 and C-4 positions. Future goal in this field is to investigate trapping of other latent nucleophiles in this transformation, so that other heteroatoms other than oxygen could be functionalized at C-3 and C-4. We were also able to modify the aza-Payne/hydroamination reaction by altering the electrophilicity of the alkyne group. Switching the electrophilicity from C-1 to C-2 by replacing an alkyne with a vinyl group containing an electron-withdrawing group led us to 6-membered ring piperidine compounds through a 6-endo-dig cyclization. Dehydropiperidine compounds can be obtained with high complexity starting from simple aziridine-2-carboxaldehyde as staring material in moderate to excellent yields and diastereoselectivities. Future direction would focus on elaboration of dehydropiperidines to advanced intermediates and other targets such as iminosugars.   !"($!IV-5 Experimental All the glassware was dried in an oven at 150 ¡C prior to use. Air/moisture sensitive experiments were performed under an inert atmosphere of dry Nitrogen unless indicated otherwise. Commercially available starting materials were obtained from Aldrich, Alfa Aesar, or Acros Organics and were used without further purification. Trimethylsulfoxonium iodide was dried under high vacuum at 30 ¡C overnight prior to use. Chloramine-T was dried at 60 ¡C under vacuum overnight prior to use. N-Bromosuccinimide was re-crystallized from hot water and dried over P2O5 under vacuum.  Unless otherwise mentioned, solvents were purified as follows: tetrahydrofuran (THF) and diethyl ether (Et2O) were freshly distilled from sodium/benzophenone ketyl. Dichloromethane (CH2Cl2), acetonitrile (CH3CN), and toluene (PhCH3) were dried over CaH2 and freshly distilled prior to use. Dimethylsulfoxide (DMSO), dimethylformamide (DMF), triethylamine (Et3N), and 2,6-lutidine were distilled from CaH2 and stored over properly activated molecular sieves. Trimethylsulfoxonium iodide was dried under high vaccum at 30 ¡C overnight prior to use and stored in a desiccator. 1H NMR spectra were measured at a 500 MHz on a Varian VXR-500 or 600 MHz Inova NMR spectrometer. Chemical shifts are reported relative to residual solvent peaks (# 7.24, 2.04, and 1.94 ppm for CDCl3, (CD3)2CO, and CD3CN respectively). 13C NMR spectra were measured were measured on 125 MHz Varian or 150 MHz Inova NMR spectrometer and referenced using deuterated chloroform, unless !"(%!otherwise mentioned. Chemical shifts are reported relative to residual solvent peaks (# 77.0, 29.8, and 118.3 ppm for CDCl3, (CD3)2CO, CD3CN respectively). Analytical thin layer chromatography (TLC) was performed using pre-coated silica gel 60 F254 plates. Compounds were visualized with UV light, various staining techniques including p-anisaldehyde, potassium permanganate, phosphomolybdic acid in ethanol. Silica gel flash column chromatography was performed using Silicycle  40-60 † ( 30-75 µm) silica gel. Infrared spectra were taken on a Nicolet IR/42 spectrometer using thin neat film deposition on NaCl plates and peaks are reported in wave numbers (cm-1). High-resolution mass spectra (HRMS) were taken on a Micromass Q-TOF Ultima. Ultra sonic reactions were performed using FS30 Fisher Scientific ultrasonicator.         !"("!Preparation of aziridine alcohol IV-11a.  The aziridine-2-carboxaldehyde IV-11c (0.296 g, 1.11 mmole, 1.0 equiv) was dissolved in 41 mL of dry dichloromethane and cooled to -78 ¡C. Ethynyl magnesium bromide (11.12 mL of 0.5 M solution in THF, 5.56 mmole, 5.0 equiv) was added drop wise over 15 min and the reaction was stirred for 2 h and quenched with saturated ammonium chloride (15 mL). Aqueous phase was extracted three times with dichloromethane. Combined organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the IV-11a-C2H syn in 89% yield with >99:1 dr (ratios for all syn vs anti diastereomers were determined by analyzing the integrations of crude NMR).  IV-11a-C2H syn: 3-ethyl-2-methyl-1-tosylaziridin-2-yl)prop-2-yn-1-ol Melting point: 79.5-82.5 ¡C. 1H NMR (500 MHz, CDCl3) # 7.79 (d, 2H, J = 8.0 Hz), # 7.30 (d, 2H, J = 8.0 Hz), # 4.83 (dd, 1H, J = 2.5 Hz, J = 3.3 Hz), # 3.54 (d, 1H, J = 3.5 Hz), # 2.96 (dd, 1H, J = 6 Hz, J = 7.5 Hz), # 2.50 (d, 1H, J = 2.5 Hz), # 2.42 (s, 3H), # 1.49 (s, 3H), # 1.43 (m, 2H), # 0.84 (t, 3H, J = 7.5 Hz). OHNTsIV-11a-C2H synONTsIV-11cHMgBr, CH2Cl2- 78 ¡C, 2 h, 89 %!"(#!13C NMR (125 MHz, CDCl3), # 144.2, 137.3, 129.6, 127.2, 80.6, 74.2, 65.5, 59.4, 52.17, 21.6, 20.5, 12.6, 11.4.  HRMS (ESI) (m/z): [M+H]+ calculated for [C15H20NO3S]+ 294.1164; Found [M+H]+ 294.1158. *Preparation of TBS-ether IV-11e.  The alcohol IV-11a-C2H syn (1.49 g, 5.10 mmole, 1.0 equiv) was dissolved in dry dichloromethane (51 mL) and cooled to 0 ¡C. TBSOTf (2.38 mL, 10.40 mmole, 2.04 equiv) and dry 2,6-lutidine (1.2 mL, 10.2 mmole, 2.0 equiv) were added under nitrogen at 0 ¡C. After completion of reaction by TLC, it was quenched with saturated sodium bicarbonate (20 mL). The aqueous phase was extracted three times with dichloromethane (3x100 mL). The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (9:1 hexanes/ethyl acetate) to yield TBS ether IV-11e as a colorless oil in 58% yield.  IV-11e-C2H syn: ((tert-butyldimethylsilyl)oxy)prop-2-yn-1-yl)-3-ethyl-2-methyl-1-tosylaziridine IV-11a-C2H synOTBSNTsOHNTsTBSOTf, 2,6-lutidine, DCM0 ¡C to rt, 4 h, 58 %IV-11e-C2H syn!"(&!1H NMR (500 MHz, CDCl3) # 7.80 (d, 2H, J = 9.0 Hz), # 7.25 (d, 2H, J = 8.0 Hz), # 5.0 (d, 1H, J = 2.0 Hz), # 2.68 (t, 1H, J = 7.0 Hz), # 2.41 (d, 1H, J = 2 Hz), # 2.39 (s, 3H), # 1.47 (s, 3H), # 1.45 (m, 2H), # 0.93 (s, 9H), # 0.75 (t, 3H, J = 7.5 Hz), # 0.15 (s, 3H), # 0.12 (s, 3H). 13C NMR (125 MHz, CDCl3) # 143.6, 138.0, 129.3, 127.3, 83.0, 73.5, 64.4, 49.7, 25.7, 25.5, 21.5, 20.2, 12.3, 11.2, -4.5, -4.8. IR (neat, cm-1) 3309, 3267, 2954, 2929, 2884, 2856, 1646, 1599, 1494, 1252, 1096.  HRMS (ESI) (m/z): [M+H]+ calculated for [C21H34NO3SSi]+ 408.2029; Found [M+H]+ 408.2020. Preparation of N-Ts enamide carbonate IV-11.   Condition A: Dry ice was placed in an Erlenmeyer flask at room temperature and the generated CO2 was bubbled though a needle into the solution of TBS ether IV-11e (100 mg, 0.246 mmole, 1.0 equiv) and NaHCO3 (413 mg, 4.91 mmole, 20 equiv) in DMF (2.7 mL). While bubbling CO2, a 1.0 IV-11a-C2H synNTsOOOTBAF, NaHCO3, DMF rt, CO2 bubbling, 10 h, 61 %OTBSNTsOHNTsNaH, TBAF, NaHCO3, DMF0 ¡C to rt, CO2 bubbling, 5 h, 69 %Condition ACondition BIV-11e-C2H synIV-11!"('!M solution of TBAF (3.19 mL of 1M solution in THF, 3.19 mmole, 13 equiv) was added drop wise within 15 min to the above solution. After stirring for 10 h, TLC analysis revealed complete conversion. Reaction was quenched with water (8.0 mL). The aqueous phase was extracted with ethyl acetate (3 X 10 mL). The combined organics were dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product in 61% yield.  Condition B: To a solution of NaH (9.8 mg, 0.409 mmole, 2.5 equiv, 60% dispersion in oil) and NaHCO3 (258 mg, 3.07 mmole, 30 equiv) in DMF (0.8 mL) was added TBAF (1.22 mL of 1M solution in THF, 1.22 mmole, 12 equiv) solution. While bubbling CO2, the aziridinol IV-11a (30 mg, 0.1024 mmole, 1.0 equiv) in DMF (0.2 mL) was added drop wise within 10 min at 0 ¡C. The reaction was warmed to room temperature and stirred for 5 h, after which was quenched with saturated NH4Cl (3 mL). The aqueous phase was extracted with ethyl acetate (3 X 4 mL) and the combined organics were dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product in 69% yield.  IV-11: 4-ethyl-3a-methyl-6-methylene-5-tosyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrol-2-one Melting point: 112-114 ¡C. 1H NMR (500 MHz, CDCl3) # 7.66 (d, 2H, J = 8.0 Hz), # 7.28 (d, 2H, J = 8.0 Hz), # 5.57 (dd, 1H, J = 1.7 Hz, J = 1.0 Hz), # 4.88 (dd, 1H, J =1.5 Hz, J =1 !"((!Hz), # 4.75 (t, 1H, J = 1 Hz), # 4.36 (dd, 1H, J = 4.5 Hz, J = 8.5 Hz), # 2.39 (s, 3H), # 1.81 (m, 1H), # 1.46 (s, 3H), # 1.40 (m, 1H), # 1.07 (t, 3H, J = 4 Hz); 13C NMR (125 MHz, CDCl3), # 151.8, 145.0, 139.8, 134.2, 129.7, 127.3, 103.1, 88.3, 85.1, 69.9, 25.4, 21.6, 18.9, 9.9.  HRMS (ESI) (m/z): [M+H]+ calculated for [C16H20NO5S]+ 338.1059; Found [M+H]+ 338.1062.  Preparation of N-Ts carbonate IV-16.  Dry ice was placed in an Erlenmeyer flask at room temperature and the generated CO2 was bubbled though a needle into the solution of TBS ether IV-11e (100 mg, 0.246 mmole, 1.0 equiv) in DMF (2.7 mL). While bubbling CO2, a 1.0 M solution of TBAF (2.7 mL of 1M solution in THF, 2.70 mmole, 11 equiv) was added drop wise within 15 min to the above solution. After stirring for 8 h, TLC analysis revealed complete conversion. The eaction was quenched with water (6.0 mL). The aqueous phase was extracted with ethyl acetate (3 X 10 mL). The combined organics were dried over sodium sulfate. The crude product was purified via column chromatography (8:2 IV-11e-C2H synIV-11NTsOOOTBAF, DMFrt, CO2 bubbling, 8 h, 70 %OTBSNTsNHTsOOOIV-16IV-11 : IV-161 : 2!"()!hexanes/ethyl acetate) to give mixture of IV-11 and IV-16 in 70% yield with 33:66 ratio.  IV-16: 5-ethynyl-4-methyl-2-oxo-1,3-dioxolan-4-yl)propyl)-4-methylbenzenesulfonamide 1H NMR (500 MHz, CDCl3) # 7.72 (d, 2H, J = 8.0 Hz), # 7.28 (d, 2H, J = 8.0 Hz), # 5.05 (d, 1H, J = 2.5 Hz), # 4.51 (d, 1H, J = 10 Hz), # 3.66 (m, 1H), # 2.90 (d, 1H, J = 2.5 Hz), # 2.40 (s, 3H), # 1.95 (m, 1H), # 1.55 (s, 3H), # 1.40 (m, 1H), # 0.70 (t, 3H, J = 7.5 Hz). X-ray crystal structure of IV-16 is included at the end of this section. Preparation of epoxide enamide IV-46.  To a solution of NaH (27.3 mg, 0.684 mmole, 4.0 equiv, 60% dispersion in oil) in DMSO (2 mL) was added trimethylsulfoxonium iodide (150 mg, 0.682 mmole, 4.0 equiv) at room temperature. Once the addition was complete the milky solution was stirred for 30 min. A solution of alcohol IV-11a (50 mg, 0.171 mmole, 1.0 equiv) in DMSO (1 mL) was added to the flask and stirred overnight at room temperature under nitrogen. After completion of reaction by TLC, it was quenched with saturated NH4Cl (2 mL). The aqueous phase was extracted three times with ethyl acetate (3 x 3 mL). The combined NTsONaH, TMSOI, DMSOOHNTsIV-11a-C2H synIV-46rt, 12 h, 62%!"(*!organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (9:1 hexanes/ethyl acetate) to give the epoxide IV-46 in 62% yield.  IV-46: 2-ethyl-1-methyl-4-methylene-3-tosyl-6-oxa-3-azabicyclo[3.1.0]hexane 1H NMR (500 MHz, CDCl3) # 7.63 (d, 2H, J = 8.5 Hz), # 7.26 (d, 2H, J = 8.0 Hz), # 5.41 (d, 1H, J = 1.0 Hz), # 4.89 (s, 1H), # 4.0 (t, 1H, J = 5.0 Hz), # 3.42 (d, 1H, J = 0.5 Hz), # 2.40 (s, 3H), # 2.05 (m, 1H), # 1.65 (m, 1H), # 1.43 (s, 3H), # 1.01 (t, 3H, J = 7.5 Hz). Preparation of compound IV-47.  To a solution of NaH (16.3 mg, 0.682 mmole, 1.2 equiv, 60% dispersion in oil) in THF (0.8 mL) was added CS2 (1.0 mL, 0.33M) and tert-butyl ammonium iodide (126 mg, 0.3412, 1.0 equiv). After cooling to -30 ¡C, alcohol IV-11a (100 mg, 0.341 mmole, 1.0 equiv) in THF (0.5 mL) was added drop wise to the flask. 1 drop of methanol was added to the mixture and flask was warmed to 0 ¡C in 15 min. After completion of the reaction (analyzed by TLC), it was quenched with saturated NH4Cl (2 mL). The aqueous phase was extracted with ethyl acetate (3 X 2 mL). The combined organics were washed IV-11a-C2H synIV-47NaH, THF, MeOH (1 drop)OHNTsCS2, TBAI, -30 ¡C to rtSONHTsS!")+!with brine and dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the unstable compound IV-47.  IV-47: (Z)-4-methyl-N-(2-(4-methylene-2-thioxo-1,3-oxathiolan-5-ylidene)pentan-3-yl)benzenesulfonamide 1H NMR (500 MHz, CDCl3) # 7.63 (d, 2H, J = 8.5 Hz), # 7.23 (d, 2H, J = 8.0 Hz), # 5.55 (d, 1H, J = 3.0 Hz), # 5.38 (d, 1H, J = 3 Hz), # 4.69 (d, 1H, J = 7.0 Hz), # 4.47 (dd, 1H, J = 7.0 Hz, J = 15 Hz), # 2.40 (s, 3H), # 1.70 (m, 1H), # 1.58 (m, 1H), # 1.43 (s, 3H), # 0.93 (t, 3H, J = 10.0 Hz).  1H NMR (500 MHz, D2O) # 7.63 (d, 2H, J = 8.5 Hz), # 7.24 (d, 2H, J = 8.0 Hz), # 5.55 (d, 1H, J = 3.0 Hz), # 5.83 (d, 1H, J = 3 Hz), # 4.42 (t, 1H, J = 10.0 Hz), # 2.40 (s, 3H), # 1.73 (m, 1H), # 1.57 (m, 1H), # 1.43 (s, 3H), # 0.94 (t, 3H, J = 10.0 Hz).  13C NMR (125 MHz, CDCl3), # 201.7, 160.8, 149.5, 144.7, 129.5, 127.0, 122.3, 109.9, 82.0, 53.2, 31.6, 26.9, 11.9, 10.0. gCOSY and HMQC spectra are included at the end of this section.       !")$!Preparation of compound IV-49.  Preparation of compound IV-48.  To a solution of ethyl "-bromo propionate (0.72 mL, 5.52 mmole, 1.0 equiv) in THF (5.5 mL) was added triphenyl phosphine (1.37 mL, 5.52 mmole, 1.0 equiv) drop wise at 0 ¡C. After 5 min benzaldehyde (0.61 mL, 6.076 mmole, 1.1 equiv) was added followed by tetrabutyl ammonium fluoride (1.95 mL of 1M solution in THF, 6.63 mmole, 1.2 equiv). After completion of reaction by TLC, solvent was removed under reduced pressure. The crude product was purified via column chromatography to afford compound IV-48 as yellow oil in 30% yield.  PhMeOHPhMeOHNaBH4, EtOHrt, 40 min 99% yieldOEtOBr1) PhCHO, PBu3      THF, 0 ¡C2) TBAF, 20 h     30% yieldPhMeOOEt LiAlH4, THF, 6h 73% yieldIV-49IV-48(E)-2-methyl-3-phenylacrylaldehydeethyl 2-bromo-propanoateOEtOBr1) PhCHO, PBu3      THF, 0 ¡C2) TBAF, 20 h     30% yieldPhMeOOEtIV-48ethyl 2-bromo-propanoate!")%!IV-48: ethyl (E)-2-methyl-3-phenylacrylate 1H NMR (500 MHz, CDCl3) # 7.66 (d, 1H, J = 1.5 Hz), # 7.28-7.43 (m, 5H), # 4.28 (q, 2H, J = 7.0 Hz), # 2.09 (s, 3H), 1.33 (t, 3H, J = 7.0 Hz). Preparation of compound IV-49.  Compound IV-48 (250 mg, 1.31 mmole, 1.0 equiv) in THF (6.0 mL) was added to a solution of LiAlH4 (109.9 mg, 2.89 mmole, 2.2 equiv) in THF (7.0 mL) at -78 ¡C. After stirring at room temperature for 6 h, the reaction was quenched with NaOH (5%) solution. The aqueous phase was extracted with diethyl ether (3 X 20 mL). The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give IV-49 in 73% yield.  IV-49: (E)-2-methyl-3-phenylprop-2-en-1-ol 1H NMR (500 MHz, CDCl3) # 7.16-7.23 (m, 3H), # 7.28-7.30 (m, 2H), # 6.44 (s, 1H), # 4.26 (d, 2H, J = 5.5 Hz), # 1.99 (d, 3H, J = 2.5 Hz), # 1.49 (s, 1H, broad).    PhMeOOEtIV-48PhMeOHIV-49 LiAlH4, THF, 6h 73% yield!")"! A solution of "-methyl cinnamaldehyde (predominantly E) (10 g, 68.5 mmole, 1.0 equiv) in ethanol (138 mL) was added to NaBH4 (3.1 g, 82.2 mmole, 1.2 equiv) in an ice-bath over 20 min. After completion of reaction (40 min), reaction was quenched with saturated NH4Cl (38 mL) and water (38 mL); and was stirred for additional 60 min. The aqueous phase was extracted with diethyl ether (3 X 150 mL). The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give IV-49 in 99% yield.  IV-49: (E)-2-methyl-3-phenylprop-2-en-1-ol 1H NMR (500 MHz, CDCl3) # 7.16-7.23 (m, 3H), # 7.28-7.30 (m, 2H), # 6.44 (s, 1H), # 4.26 (d, 2H, J = 5.5 Hz), # 1.99 (d, 3H, J = 2.5 Hz), # 1.49 (s, 1H, broad).      PhMeOHPhMeOHNaBH4, EtOHrt, 40 min 99% yieldIV-49(E)-2-methyl-3-phenylacrylaldehyde!")#!Preparation of aziridine alcohol IV-12a.  Preparation of aziridine alcohol IV-14a. Allylic alcohol IV-49 (4.4 g, 29.7 mmole, 1.0 equiv) was placed in dry acetonitrile (140 mL). Anhydrous Chloramine-T (6.7 g, 29.7 mmole, 1.0 equiv) and N-bromosuccinimide (1.0 g, 5.9 mmole, 0.2 equiv) were added successively and the light yellow slurry was allowed for 10 h. The reaction was quenched with water and aqueous phase was extracted 3x with portions of ethyl acetate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give aziridinol IV-14a in 94% yield.  OHMeNTsPhIV-12a-C2H synPhMeOHChloramine-T, NBSCH3CN, 10h, 94%PhMeOHNTsIV-14aPhMeHNTsODMP, NaHCO3, CH2Cl2 0 ¡C to rt, 3h, 68% -78 ¡C, 2h, 84%MgBr, CH2Cl2IV-49IV-14cPhMeOHChloramine-T, NBSCH3CN, 10h, 94%PhMeOHNTsIV-14aIV-49!")&!IV-14a: 2-methyl-3-phenyl-1-tosylaziridin-2-yl)methanol 1H NMR (500 MHz, CDCl3) # 7.84 (d, 2H, J = 8.5 Hz), # 7.32 (d, 2H, J = 8.0 Hz), # 7.23 (m, 3H), # 7.01 (m, 2H), # 4.21 (s, 1H), # 4.16 (s, 2H), # 3.10 (s, 1H, broad), # 2.43 (s, 3H), # 1.16 (s, 3H).  13C NMR (125 MHz, CDCl3) # 144.1, 137.3, 132.9, 129.6, 128.2, 127.7, 127.0, 126.9, 65.4, 59.0, 51.2, 21.5, 15.9. Preparation of aziridine carboxaldehyde IV-14c.  Synthesized DMP reagent (2.68 g, 6.31 mmole, 4.0 equiv) and sodium bicarbonate (531 mg, 6.32 mmole, 4.0 equiv) were added to a solution of alcohol IV-14a (500 mg, 1.58 mmole, 1.0 equiv) in dichloromethane (17 mL) at 0 ¡C. After 3 h, aqueous phase was extracted 3x with portions of dichloromethane. The combined organics were washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give aldehyde IV-14c in 68% yield as a white solid.  IV-14c: 2-methyl-3-phenyl-1-tosylaziridine-2-carbaldehyde Melting point: 101-103 ¡C. 1H NMR (500 MHz, CDCl3) # 9.69 (s, 1H), # 7.87 (d, 2H, J = 8.5 Hz), # 7.33 PhMeOHNTsIV-14aDMP, NaHCO3, CH2Cl2 0 ¡C to rt, 3h, 68%PhMeHNTsOIV-14c!")'!(d, 2H, J = 8.5 Hz), # 7.21-7.23 (m, 3H), # 7.04-7.06 (m, 2H), # 4.66 (s, 1H), # 2.44 (s, 3H), # 1.14 (s, 3H). 13C NMR (125 MHz, CDCl3), # 194.2, 144.8, 136.2, 131.1, 129.8, 128.68, 128.62, 127.4, 127.1, 59.8, 52.1, 21.6, 11.3.  Preparation of aziridine alcohol IV-12a.  The aldehyde IV-12a (100 mg, 0.317 mmole, 1.0 equiv) was dissolved in dry dichloromethane (12 mL) and cooled to -78 ¡C. Ethynyl magnesium bromide (3.0 mL of 0.5 M solution in THF, 1.57 mmole, 5.0 equiv) was added drop wise over 15 min and the reaction was stirred for 2 h and quenched with saturated NH4Cl (2 mL). Aqueous phase was extracted with dichloromethane (3 X 15 mL) and the combined organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the aziridinol as a white solid in 84% yield with >99:1 dr (Ratios for all syn vs anti diastereomers were determined by analyzing the integrations of crude NMR).  IV-12a: 2-methyl-3-phenyl-1-tosylaziridin-2-yl)prop-2-yn-1-ol Melting point: 119-120 ¡C. OHMeNTsPhIV-12a-C2H synPhMeHNTsO -78 ¡C, 2h, 84%MgBr, CH2Cl2IV-14c!")(!1H NMR (500 MHz, CDCl3) # 7.85 (d, 2H, J = 8.0 Hz), # 7.33 (d, 2H, J = 8.0 Hz), # 7.24 (m, 3H), # 7.00 (m, 2H), # 5.06 (t, 1H, J = 2.5 Hz), # 4.20 (s, 1H), # 3.56 (d, 1H, J = 3.5 Hz), # 2.59 (d, 1H, J = 2 Hz), # 2.44 (s, 3H), # 1.24 (s, 3H).  13C NMR (125 MHz, CDCl3) # 144.5, 136.9, 132.4, 129.6, 128.3, 127.9, 127.1, 126.7, 80.3, 74.5, 65.2, 60.4, 51.6, 21.5, 12.6.  HRMS (ESI) (m/z): [M+H]+ calculated for [C19H20NO3S]+ 342.1164; Found [M+H]+ 342.1160.  Preparation of aziridine alcohol IV-12a.  The alcohol IV-12a (1.0 g, 2.93 mmole, 1.0 equiv) was dissolved in dry dichloromethane (30 mL) and cooled to 0 ¡C. TBSOTf (1.4 mL, 5.98 mmole, 2.04 equiv) and dry 2,6-lutidine (0.7 mL, 5.95 mmole, 2.0 equiv) were added under nitrogen at 0 ¡C. After completion of reaction by TLC, the reaction was quenched with saturated NaHCO3 (20 mL). The aqueous phase was extracted three times with dichloromethane (3 X 50 mL). The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (9:1 hexanes/ethyl acetate) to give the TBS ether IV-12e as a white solid in 97% yield.  OHMeNTsPhOTBSMeNTsPhTBSOTf, 2,6-lutidine, DCM0 ¡C to rt, 4 h, 97 %IV-12a-C2H synIV-12e-C2H syn!"))!IV-12e: 1-((tert-butyldimethylsilyl)oxy)prop-2-yn-1-yl)-2-methyl-3-phenyl-1-tosylaziridine Melting point: 102-105 ¡C. 1H NMR (500 MHz, CDCl3) # 7.86 (d, 2H, J = 8.5 Hz), # 7.26 (d, 2H, J = 8.0 Hz), # 7.19 (m, 3H), # 6.97 (m, 2H), # 5.31 (d, 1H, J = 2 Hz), # 3.98 (s, 1H), # 2.53 (d, 1H, J = 2 Hz), # 2.39 (s, 3H), # 1.5 (s, 1H), # 1.18 (s, 3H), # 0.93 (s, 9H), # 0.22 (d, 6H, J = 1 Hz).  13C NMR (125 MHz, CDCl3), # 144.2, 137.6, 132.9, 129.7, 128.4, 127.6, 127.4, 126.8, 83.1, 74.1, 64.2, 61.2, 49.9, 26.0, 25.9, 21.8, 13.1, -4.1, -4.9. HRMS (ESI) (m/z): [M+H]+ calculated for [C25H34NO3SSi]+ 456.2029; Found [M+H]+ 456.2020.  Preparation of N-Ts enamide carbonate IV-12.  Condition A: The protected alcohol IV-12e (100 mg, 0.219 mmole, 1.0 equiv) was dissolved in DMF (2.5 mL). After addition of NaHCO3 (369 mg, IV-12a-C2H synNTsPhMeOOOTBAF, NaHCO3, DMF rt, CO2 bubbling, 9 h, 65 %OTBSMeNTsPhOHMeNTsPhNaH, TBAF, NaHCO3, DMF0 ¡C to rt, CO2 bubbling, 6 h, 55 %Condition ACondition BIV-12e-C2H synIV-12!")*!4.39 mmole, 20.0 equiv), while bubbling CO2, TBAF (2.42 mL of 1M solution in THF, 2.42 mmole, 13 equiv) was added drop wise within 15 min. The reaction was stirred for 9 h, after which it was quenched with saturated ammonium chloride. The aqueous phase was extracted 3x with portions of ethyl acetate and the combined organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product in 65% yield.  Condition B: To a solution of NaH (28.2 mg, 1.17 mmole, 2.5 equiv, 60% dispersion in oil) and NaHCO3 (493 mg, 5.86 mmole, 20 equiv) in DMF (2.5 mL) was added TBAF (3.2 mL of 1M solution IV-12a (100 mg, 0.2932 mmole, 1.0 equiv) in DMF (1.0 mL) was added drop wise within 10 min at 0 ¡C.  The reaction was warmed to room temperature and stirred for 6 h. The reaction was quenched with saturated ammonium chloride. The aqueous phase was extracted with portions of ethyl acetate (3 X 5 mL) and the combined organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product in 55% yield.  IV-12: 3a-methyl-6-methylene-4-phenyl-5-tosyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrol-2-one Melting point: 123-126 ¡C. 1H NMR (500 MHz, CDCl3) # 7.69 (d, 2H, J = 8.5 Hz), # 7.37 (m, 3H), # 7.31 (d, 2H, J = 8.0 Hz), # 7.23 (m, 2H), # 5.62 (dd, 1H, J = 1.0 Hz, J = 2 Hz), # !"*+!5.35 (s, 1H), # 4.93 (dd, 1H, J = 1.0 Hz, J = 1.25 Hz), # 4.92 (s, 1H), # 2.42 (s, 3H), # 1.11 (s, 3H). 13C NMR (125 MHz, CDCl3), # 152.2, 145.4, 141.1, 137.5, 134.5, 130.1, 129.4, 129.2, 127.5, 126.8, 100.7, 88.8, 85.5, 73.4, 21.8, 20.9.  HRMS (ESI) (m/z): [M+H]+ calculated for [C20H20NO5S]+: 386.1062; Found [M+H]+: 386.1065. gCOSY and gHMQC spectra, and X-ray structure of compound IV-12 are available and included at the end of this section.  Preparation of carbonate IV-14. *Condition A: The aziridinol IV-14a (50 mg, 0.1577 mmole, 1.0 equiv) in DMF (0.5 mL) was added to a solution of NaH (15.2 mg, 0.631 mmole, 2.5 equiv, 60% dispersion in oil) in dry DMF (0.5 mL) at 0 ¡C while bubbling CO2 into the solution. The reaction was warmed to room temperature and stirred till completion (1.3h). The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x with portions of ethyl acetate and the combined organics were washed with brine and dried over sodium sulfate. IV-14aOHNTsPhCondition ANaH (2.5 equiv), DMF0 ¡C to rt, CO2 bubbling1.3 h, 89% yieldCH3PhOOH3COTsHNCondition BNaH (2.5 equiv),  DMFTBAF (11 equiv)0 ¡C to rt, CO2 bubbling1 h, 88% yieldRIV-14!"*$!The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product in 89% yield.   Condition B: To a solution of NaH (15.2 mg, 0.631 mmole, 2.5 equiv, 60% dispersion in oil) in dry DMF (0.5 mL), TBAF (1.7 mL of 1M solution in THF, 1.7 mmole, 11 equiv) was added drop wise within 5 min. CO2 was bubbled into the solution. Aziridinol IV-14a (50 mg, 0.1577 mmole, 1.0 equiv) in DMF (0.5 mL) was added drop wise at 0 ¡C within 5 min. The reaction was warmed to room temperature and stirred till completion (1 h). The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x with portions of ethyl acetate and the combined organics were washed with brine and dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product in 88% yield.  IV-14: 4-methyl-N-((R)-((R)-4-methyl-2-oxo-1,3-dioxolan-4-yl)(phenyl)methyl)benzenesulfonamide Melting point: 162-164 ¡C. 1H NMR (500 MHz, (CD3)2CO, 1 drop D2O) # 7.42 (d, 2H, J = 8.0 Hz), # 7.22 (m, 2H), # 7.10 (m, 3H), # 7.03 (d, 2H, J = 9.0 Hz), # 4.62 (s, 1H), # 4.46 (d, 1H, J = 9.0 Hz), # 4.24 (d, 1H, J = 9 Hz), # 3.30 (s, 1H, broad), # 2.22 (s, 3H), # 1.53 (s, 3H). !"*%!1H NMR (500 MHz, CDCl3) # 7.41 (d, 2H, J = 8.0 Hz), # 7.07-7.14 (m, 23H), # 6.94-6.98 (m, 4H), # 6.12 (d, 1H, J =10.5 Hz), # 4.41 (dd, 2H, J = 10.5 Hz, J = 8.5 Hz), # 4.08 (d, 1H, J = 9 Hz), # 2.24 (s, 3H), # 1.53 (s, 3H). 13C NMR (125 MHz, (CD3)2CO), # 153.8, 142.9, 138.3, 135.4, 129.8, 129.2, 128.8, 128.5, 127.6, 84.8, 72.8, 59.9, 22.3, 21.1.  13C NMR (125 MHz, CDCl3), # 153.9, 143.4, 136.4, 133.8, 129.2, 128.6, 128.4, 127.7, 126.9, 84.2, 72.3, 62.7, 22.3, 21.1. gCOSY spectrum is attached to the end of this section.  Preparation of aziridine alcohol IV-15a.  The aldehyde IV-15c (1.05 g, 3.33 mmole, 1.0 equiv) was dissolved in dry dichloromethane (120 mL) and cooled to -78 ¡C. Methyl magnesium bromide (16.7 mL of 1.0 M solution in THF, 16.7 mmole, 5.0 equiv) was added drop wise over 15 min and the reaction was stirred for 4 h and quenched with saturated NH4Cl (10 mL). The aqueous phase was extracted with dichloromethane (3 X 130 mL) and the combined organics were dried over sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the aziridinol IV-15a in MeOHMeNTsPhIV-14cPhMeHNTsOIV-15a-C2H syn -78 ¡C, 4h, 30%MeMgBr, CH2Cl2!"*"!30% yield with >93:7 dr (ratios for all syn vs anti diastereomers were determined by analyzing the integrations of crude NMR).  IV-15a: 2-methyl-3-phenyl-1-tosylaziridin-2-yl)ethan-1-ol 1H NMR (500 MHz, CDCl3) # 7.85 (d, 2H, J = 8.0 Hz), # 7.30 (d, 2H, J = 8.5 Hz), # 7.22 (m, 3H), # 6.96 (m, 2H), # 4.35 (m, 1H), # 4.10 (s, 1H), # 3.53 (d, 1H, J = 2.5 Hz), # 2.43 (s, 3H), # 1.38 (d, 3H, J = 6.5 Hz), # 1.08 (s, 3H). HRMS (ESI) (m/z): [M+H]+ calculated for [C18H22NO3S]+: 332.1320; Found [M+H]+: 332.1332. Preparation of N-Ts enamide carbonate IV-15.  To a solution of NaH (26.1 mg, 1.087 mmole, 2.5 equiv, 60% dispersion in oil) in dry DMF (1.5 mL), TBAF (2.9 mL of 1M solution in THF, 2.9 mmole, 11 equiv) was added drop wise within 5 min. CO2 was bubbled into the solution. Aziridinol IV-15a (90 mg, 0.272 mmole, 1.0 equiv) in DMF (0.5 mL) was added drop wise at 0 ¡C within 5 min. The reaction was warmed to room temperature and stirred till completion (1 h). The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x with portions of ethyl acetate and the combined organics were dried over IV-15aMeNTsPhCH3PhOOH3COTsHNNaH (2.5 equiv),  DMFTBAF (11 equiv)0 ¡C to rt, CO2 bubbling1 h, 72% yieldMeIV-15OH!"*#!anhydrous sodium sulfate. The crude product was purified via column chromatography (7:3 hexanes/ethyl acetate) to give the product IV-15 in 72% yield.  IV-15: 4,5-dimethyl-2-oxo-1,3-dioxolan-4-yl)(phenyl)methyl)-4-methylbenzenesulfonamide 1H NMR (500 MHz, CD3CN) # 7.30 (d, 2H, J = 8.0 Hz), # 6.94-7.02 (m, 7H), # 6.22 (d, 1H, J = 11.5 Hz), # 4.81 (d, 1H, J = 11 Hz), # 4.70 (q, 1H, J = 6.5 Hz), # 2.24 (s, 3H), # 1.60 (d, 3H, J = 7 Hz), # 1.37 (s, 3H). 13C NMR (125 MHz, CD3CN), # 154.1, 144.2, 138.3, 135.9, 129.9, 129.6, 128.6, 128.0, 127.7, 82.6, 69.9, 59.9, 21.3, 21.1, 15.0.  HRMS (ESI) (m/z): [M+NH4]+ calculated for [C19H25N2O5S]+: 393.1484; Found [M+NH4]+: 393.1467. Preparation of epoxide enamide IV-50.  To a solution of NaH (14.1 mg, 0.586 mmole, 2.5 equiv, 60% dispersion in mineral oil) in DMSO (2 mL) was added trimethylsulfoxonium iodide (130 mg, 0.586 mmole, 4.0 equiv) and DCC (206.3 mg, 2.94 mmole, 20 equiv) at room temperature. Once the addition was complete the milky solution was stirred for 30 min. A solution of alcohol IV-12a (50 mg, 0.147 IV-12a-C2H synOHMeNTsPhNaH, TMSOI, DCC  DMSO, rt, 2h, 70%NTsPhMeOIV-50!"*&!mmole, 1.0 equiv) in DMSO (1 mL) was added to the flask and stirred for 2 h at room temperature under nitrogen. After completion of reaction by TLC, it was quenched with water. The aqueous phase was extracted 3x with portions of ethyl acetate and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (9:1 hexanes/ethyl acetate) to give the corresponding product in 70% yield.  IV-50: 1-methyl-4-methylene-2-phenyl-3-tosyl-6-oxa-3-azabicyclo[3.1.0]hexane Melting point: 84-86 ¡C. 1H NMR (500 MHz, CDCl3) # 7.69 (d, 2H, J = 8.5 Hz), # 7.27-7.39 (m, 7H), # 5.47 (s, 1H), # 4.97 (s, 1H), # 4.90 (s, 1H), # 3.61 (s, 1H), # 2.42 (s, 3H), # 1.13 (s, 3H).  Preparation of epoxide IV-51.  NaH (15.2 mg, 0.631 mmole, 2.5 equiv, 60% dispersion in oil) was suspended in dry DMF (0.5 mL) and DCC (652 mg, 3.16 mmole, 20.0 equiv) was added to the flask. The aziridinol IV-14a (50 mg, 0.158 mmole, 1.0 equiv) NaH, DCC, DMFrt, 3h, 80%OHMeNTsPhIV-14aOMeNHTsPhIV-51!"*'!in dry DMF (0.5 mL) was added to a solution drop wise at 0 ¡C. The reaction was stirred for 3 h at room temperature. After completion, the reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x with portions of ethyl acetate and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (9:1 hexanes/ethyl acetate) to give the epoxide IV-51 in 80% yield.  IV-51: 4-methyl-N-((R)-((R)-2-methyloxiran-2-yl)(phenyl)methyl)benzenesulfonamide 1H NMR (500 MHz, CDCl3) # 7.47 (d, 2H, J = 8.5 Hz), # 7.11-7.16 (m, 3H), # 7.04-7.08 (m, 4H), # 5.33 (d, 1H, J = 5.5 Hz), # 4.33 (d, 1H, J = 5.5 Hz), # 2.60 (d, 1H, J = 5.0 Hz), # 2.59 (d, 1H, J = 4.5 Hz), # 2.31 (s, 3H), # 1.24 (s, 3H). Preparation of compounds IV-52 and IV-53.  NaH (15.1 mg, 0.631 mmole, 2.5 equiv, 60% dispersion in oil) was suspended in dry DMF (0.5 mL) and CS2 (240 mg, 3.16 mmole, 20.0 equiv) was added to the flask. The aziridinol IV-14a (50 mg, 0.158 mmole, 1.0 equiv) in DMF (0.5 mL) was added drop wise at 0 ¡C. After completion, the reaction NaH, DMF, CS20 ¡C to rtPhNHOMeSSTsOHMeNTsPhIV-14aPhNHOMeSSTsIV-52IV-53!"*(!was quenched with saturated ammonium chloride. The aqueous phase was extracted 3x with portions of ethyl acetate and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (7:3 hexanes/ethyl acetate) to give IV-52 and IV-53 with a 43:57 diastereomeric ratio.  IV-52/IV-53 mixture: 4-methyl-N-((4-methyl-2-thioxo-1,3-oxathiolan-4-yl)(phenyl)methyl)benzenesulfonamide 1H NMR (500 MHz, CDCl3) # 7.44-7.46 (m, 4H), # 6.92-7.16 (m, 14H), # 5.84 (s, 1H, broad), # 5.78 (s, 1H, broad), # 4.95 (d, 1H, J = 10.5 Hz), # 4.73 (d, 1H, J = 10 Hz), # 4.53 (d, 1H, J = 10 Hz), # 4.49 (d, 1H, J = 10.5 Hz), # 4.23 (d, 1H, J = 12.5 Hz), # 3.5 (d, 1H, J = 12.0 Hz), # 2.26 (s, 3H), # 2.26 (s, 3H), # 1.58 (s, 3H), # 1.56 (s, 3H). 13C NMR (125 MHz, CDCl3), # 144.1, 144.0, 136.0, 135.3, 129.6, 129.7, 128.8, 128.7, 128.6, 128.5, 127.9, 127.5, 127.3, 127.2, 85.0, 72.5, 65.4, 63.1, 62.4, 52.3, 21.6, 21.6, 21.1, 21.1, 14.3. gCOSY spectra is included at the end of this section. Preparation of aziridine alcohols IV-54 and IV-55.  IV-54-C2H synMgBr, CH2Cl2-78 ¡C, 3 h, 77 %MeHNTsOMeNTsOHMeNTsOHIV-55-C2H antiIV-35c!"*)!The aldehyde IV-35c (0.5 g, 2.092 mmole, 1.0 equiv) was dissolved in dry dichloromethane (75 mL) and cooled to -78 ¡C. Ethynyl magnesium bromide (21 mL of 0.5 M solution in THF, 10.46 mmole, 5.0 equiv) was added drop wise over 15 min and the reaction was stirred for 3 h. It was quenched with saturated NH4Cl. The aqueous phase was extracted with dichloromethane (3 X 70 mL) and the combined organics were washed with brine and dried over dry sodium sulfate. The crude product was purified via column chromatography (5:5 hexanes/ethyl acetate) to give a mixture of diastereomers with a ratio of 62:38 in 77% yield. Diastereomers were separated with proper concentration of diethylether/hexane solutions and a very long column to afford IV-54 and IV-55.  IV-54: 3-methyl-1-tosylaziridin-2-yl)prop-2-yn-1-ol 1H NMR (500 MHz, CDCl3) # 7.81 (d, 2H, J = 8.5 Hz), # 7.27 (d, 2H, J = 8.0 Hz), # 4.s0 (s, 1H), # 3.06 (t, 1H, J = 4.5 Hz), # 2.91 (m, 1H), # 2.90 (s, 1H, broad), # 2.36 (s, 3H), # 2.36 (d, 1H, J = 2.5 Hz), # 1.54 (d, 3H, J = 6 Hz). 13C NMR (125 MHz, CDCl3), # 144.2, 136.9, 129.4, 127.4, 80.7, 74.2, 60.5, 51.8, 42,7, 21.5, 13.8.  HRMS (ESI) (m/z): [M+H]+ calculated for [C13H16NO3S]+: 266.0851; Found [M+H]+: 266.0846.  IV-55: 3-methyl-1-tosylaziridin-2-yl)prop-2-yn-1-ol !"**!1H NMR (500 MHz, CDCl3) # 7.81 (d, 2H, J = 8.0 Hz), # 7.30 (d, 2H, J = 7.0 Hz), # 4.38 (t, 1H, J = 2 Hz), # 3.10 (m, 1H), # 2.97 (m, 1H), # 2.38 (s, 3H), # 2.35 (d, 1H, J = 2.5 Hz), # 1.6 (d, 3H, J = 6 Hz). 13C NMR (125 MHz, CDCl3), # 144.3, 137.1, 129.4, 127.5, 80.2, 74.6, 60.7, 49.8, 43.9, 21.5, 13.2.  HRMS (ESI) (m/z): [M+H]+ calculated for [C13H16NO3S]+: 266.0851; Found [M+H]+: 266.0848.   Preparation of carbonate IV-56.  TBAF (1.4 mL of 1M solution in THF, 1.4 mmole, 12.0 equiv) solution was added to a solution of NaH (10.8 mg, 0.4509 mmole, 2.5 equiv, 60% dispersion in oil) and NaHCO3 (285 mg, 3.38 mmole, 30 equiv) in DMF (0.9 mL).  While bubbling CO2, the aziridinol IV-54 (30 mg, 0.1128 mmole, 1.0 equiv) in DMF (0.4 mL) was added drop wise within 10 min at 0 ¡C. The reaction was warmed to room temperature and stirred for 5 h. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted with ethyl acetate (3 X 3 mL) and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via IV-54-C2H syn0 ¡C to rt, 5 h, 65 %MeNTsOHMeNHTsOOONaH, NaHCO3, TBAF, DMFIV-56!#++!column chromatography (7:3 hexanes/ethyl acetate) to give the product in 65% yield.  IV-56:  5-ethynyl-2-oxo-1,3-dioxolan-4-yl)ethyl)-4-methylbenzenesulfonamide Melting point: 130-132 ¡C. 1H NMR (500 MHz, CDCl3) # 7.74 (d, 2H, J = 8.5 Hz), # 7.31 (d, 2H, J = 8 Hz), # 5.37 (dd, 1H, J = 8.0 Hz, J = 2 Hz), # 5.06 (d, 1H, J = 9 Hz), # 4.81 (dd, 1H, J = 8.0 Hz, J = 3.5), # 3.85 (m, 1H), # 2.83 (d, 1H, J = 2.5 Hz), # 2.41 (s, 3H), # 1.19 (d, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3), # 152.7, 144.0, 137.5, 129.9, 126.9, 81.1, 80.1, 73.7, 68.0, 50.3, 21.5, 15.2. IR (neat, cm-1) 3272, 2923, 2853, 1810, 1327, 1161, 1088, 1050.  HRMS (ESI) (m/z): [M+Na]+ calculated for [C14H15NO5SNa]+: 332.0569; Found [M+Na]+: 332.0570.  Preparation of carbonate IV-57.  TBAF (1.4 mL of 1M solution in THF, 1.4 mmole, 12.0 equiv) was added to a solution of NaH (10.8 mg, 0.4509 mmole, 2.5 equiv, 60% dispersion in oil) and NaHCO3 (285 mg, 3.38 mmole, 30 equiv) in DMF (0.9 mL).  While bubbling CO2, the aziridinol IV-55 (30 mg, 0.1128 mmole, 1.0 IV-55-C2H anti0 ¡C to rt, 5 h, 43 %MeNTsOHMeNHTsOOONaH, NaHCO3, TBAF, DMFIV-57!#+$!equiv) in DMF (0.4 mL) was added drop wise within 10 min at 0 ¡C. The reaction was warmed to room temperature and stirred for 5 h. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted with portions of ethyl acetate and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (7:3 hexanes/ethyl acetate) to give the product in 43% yield.  IV-57:  5-ethynyl-2-oxo-1,3-dioxolan-4-yl)ethyl)-4-methylbenzenesulfonamide 1H NMR (500 MHz, CDCl3) # 7.75 (d, 2H, J = 8.5 Hz), # 7.32 (d, 2H, J = 8 Hz), # 5.24 (dd, 1H, J = 5.5 Hz, J = 2 Hz), # 5.03 (d, 1H, J = 9 Hz), # 4.33 (dd, 1H, J = 7.5 Hz, J = 5.5), # 3.46 (m, 1H), # 2.77 (d, 1H, J = 2.5 Hz), # 2.41 (s, 3H), # 1.01 (d, 3H, J = 7 Hz). 13C NMR (125 MHz, CDCl3), # 152.8, 144.4, 136.7, 130.1, 127.0, 83.5, 78.4, 77.2, 68.2, 51.0, 21.5, 16.8. IR (neat, cm-1) 3439, 3295, 2927, 2132, 1810, 1645, 1163, 913.  HRMS (ESI) (m/z): [M+H]+ calculated for [C14H16NO5S]+: 310.0749; Found [M+H]+: 310.0775. X-ray crystal structure is available attached at the end of this section. Preparation of aziridine carboxaldehyde IV-13c. IV-58OHNTsHNTsODMP, NaHCO3, CH2Cl20 ¡C, 3h, 60%IV-13c!#+%!DMP reagent (4.7 g, 11.011 mmole, 1.4 equiv) and sodium bicarbonate (0.99 g, 11.79 mmole, 1.5 equiv) were added to a solution of compound IV-58 (2.12 g, 7.86 mmole, 1.0 equiv) in dichloromethane (88 mL) at 0 ¡C. After 3 h, aqueous phase was extracted with dichloromethane (3 X 90 mL). The combined organics were washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give aziridinal IV-13c in 60 % yield.  IV-13c: 3-propyl-1-tosylaziridine-2-carbaldehyde 1H NMR (500 MHz, CDCl3) # 9.41 (d, 1H, J = 7 Hz), # 7.83 (d, 2H, J = 8.5 Hz), # 7.34 (d, 2H, J = 8.5 Hz), # 3.35 (m, 1H), # 3.06 (dd, 1H, J = 4 Hz, J = 7 Hz), # 2.41 (s, 3H), # 1.61-1.69 (m, 2H), # 1.34 (m, 2H), # 0.88 (t, 3H, J = 7 Hz). 13C NMR (125 MHz, CDCl3), # 194.2, 144.7, 135.5, 129.5, 127.4, 25.0, 46.4, 31.5, 21.4, 20.1, 13.2.  HRMS (ESI) (m/z): [M+H]+ calculated for [C13H18NO3S]+: 268.1007; Found [M+H]+: 268.1013. Preparation of aziridine carboxaldehyde IV-13a.  HNTsOIV-13cNTsOHNTsOHIV-13a-C2H synMgBr, CH2Cl2-78 ¡C, 5 h, 65 %IV-13a-C2H anti!#+"!The aldehyde IV-13c (1.0 g, 3.74 mmole, 1.0 equiv) was dissolved in dry dichloromethane (135 mL) and cooled to -78 ¡C. Ethynyl magnesium bromide (38.0 mL of 0.5 M solution in THF, 18.72 mmole, 5.0 equiv) was added drop wise over 15 min and the reaction was stirred for 5.0 h and quenched with saturated NH4Cl. The aqueous phase was extracted with dichloromethane (3 X 100 mL) and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (7:3 hexanes/ethyl acetate) to give a mixture of diastereomers with a ratio of 66:33 in 65% yield.  IV-13a-C2H syn: 3-propyl-1-tosylaziridin-2-yl)prop-2-yn-1-ol 1H NMR (500 MHz, CDCl3) # 7.96 (d, 2H, J = 8.0 Hz), # 7.25 (d, 2H, J = 8.5 Hz), # 4.46 (m, 1H), # 3.00 (dd, 2H, 3 Hz, J = 4.5 Hz, J = 7 Hz), # 2.85 (m, 1H), # 2.42 (d, 1H, J = 2.5), # 2.36 (s, 3H), # 1.76 (m, 1H), # 1.65 (m, 1H), # 1.35 (m, 2H), # 0.89 (t, 3H, J = 7 Hz). 13C NMR (125 MHz, CDCl3), # 144.2, 136.7, 129.5, 127.4, 80.5, 74.4, 61.0, 52.4, 46.7, 30.9, 21.4, 20.4, 13.4.  IV-13a-C2H anti: 1-hydroxyprop-2-yn-1-yl)-1-tosylaziridin-2-yl)propan-1-ylium 1H NMR (500 MHz, CDCl3) # 7.81 (d, 2H, J = 9.0 Hz), # 7.27 (d, 2H, J = 8.0 Hz), # 4.40 (s, 1H), # 3.07 (m, 1H), # 2.88 (m, 1H), # 2.56 (s, 1H, broad), # 2.39 (s, 3H), # 2.38 (d, 1H, J = 1 Hz), # 2.00 (m, 1H), # 1.82 (m, 1H), # 1.44 (m, 2H), # 0.93 (t, 3H, J = 7.5 Hz).  !#+#!13C NMR (125 MHz, CDCl3), # 144.2, 137.0, 129.4, 127.5, 80.4, 74.5, 60.3, 49.8, 47.8, 29.6, 21.4, 20.9, 13.5.  Preparation of N-Ts enamide carbonate IV-13.  To a solution of NaH (38.66 mg, 1.61 mmole, 2.5 equiv, 60% dispersion in oil) and NaHCO3 (676 mg, 8.05 mmole, 20 equiv) in dry DMF (2.8 mL) was added TBAF (4.43 mL of 1M solution in THF, 4.43 mmole, 11.0 equiv) solution.  While bubbling CO2, the aziridinol IV-13a (118 mg, 0.4026 mmole, 1.0 equiv) in DMF (0.9 mL) was added drop wise within 10 min at 0 ¡C. The reaction was warmed to room temperature and stirred for 4 h. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x with portions of ethyl acetate and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product IV-13 in 62% yield.  IV-13: 4-methylene-6-propyl-5-tosyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrol-2-one IV-13a-C2H syn0 ¡C to rt, 4h, 62%NTsOHNTsOOONaH, NaHCO3, TBAF, DMFIV-13!#+&!1H NMR (500 MHz, CDCl3) # 7.6 (d, 2H, J = 8.5 Hz), # 7.2 (d, 2H, J = 8.5 Hz), # 5.6 (s, 1H), # 5.2 (d, 1H, J = 6.5 Hz), # 4.9 (s, 1H), # 4.6 (d, 1H, J = 6.5 Hz), # 4.4 (t, 1H, J = 7.0 Hz), # 2.4 (s, 3H), # 1.6 (m, 2H), # 1.4 (m, 2H), # 0.9 (t, 2H, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3), #152.2, 145.0, 139.7, 134.2, 129.8, 126.9, 104.1, 80.7, 79.6, 75.6, 67.3, 53.4, 35.9, 30.8, 21.5, 18.3, 14.0, 13.6.  HRMS (ESI) (m/z): [M+H]+ calculated for [C16H20NO5S]+: 338.1062; Found [M+H]+: 338.1077. gCOSY spectra is attached at the end of this section. Preparation of compound IV-59.  The aldehyde IV-37c (0.68 g, 1.844 mmole, 1.0 equiv) was dissolved in dry dichloromethane (67 mL) and cooled to -78 ¡C. Ethynyl magnesium bromide (18.5 mL of 0.5 M solution in THF, 9.22 mmole, 5.0 equiv) was added drop wise over 15 min and the reaction was stirred for 3.0 h. After the completion of reaction, it was quenched with saturated NH4Cl. The aqueous phase was extracted with portions of dichloromethane (3 X 70 mL) and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 IV-59-C2H antiIV-59-C2H synMgBr, CH2Cl2-78 ¡C, 3h, 50%IV-37cHNTsONTsOHNTsOHTBSOTBSOTBSO!#+'!hexanes/ethyl acetate) to give the mixture of diastereomers with a ratio of 79:21 in 50% yield.  IV-59-C2H syn: 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-tosylaziridin-2-yl)prop-2-yn-1-ol 1H NMR (500 MHz, CDCl3) # 7.83 (d, 2H, J = 8.5 Hz), # 7.28 (d, 2H, J = 8.0 Hz), # 4.65 (m, 1H), # 3.83 (m, 1H), # 3.73 (m, 1H), # 3.12 (m, 3H), # 2.46 (d, 1H, J = 2 Hz), # 2.40 (s, 3H), # 0.79 (s, 9H), # -0.07 (s, 3H), # -0.06 (s, 3H). 13C NMR (125 MHz, CDCl3), # 144.4, 136.5, 129.5, 127.5, 80.3, 74.6, 61.01, 61.05 50.5, 46.8, 25.7, 21.5, 18.1, -5.5.  HRMS (ESI) (m/z): [M+H]+ calculated for [C19H30NO4SSi]+: 396.1665; Found [M+H]+: 396.1666. Preparation of compound IV-28.  Compound IV-11c (100 mg, 0.374 mmole, 1.0 equiv), DABCO (29.3 mg, 0.261 mmole, 0.7 equiv), and methyl acrylate (161 mg, 1.87 mmole, 5.0 equiv) were stirred at room temperature for two days (addition of few drops of CH2Cl2 to facilitate stirring, had no effects on the result). The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted with ethyl HNTsO, DABCONTsOOOHOMeOIV-11crt, 2 days, 60%IV-28!#+(!acetate (3 X 5mL). The combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give compound IV-28 in 60% yield with >99:1 dr (ratios for all syn vs anti diastereomers were determined by analyzing the integrations of crude NMR).  IV-28: methyl 2-((3-ethyl-2-methyl-1-tosylaziridin-2-yl)(hydroxy)methyl)acrylate Melting point: 96-98 ¡C. 1H NMR (500 MHz, CDCl3) # 7.82 (d, 2H, J = 8.0 Hz), # 7.28 (d, 2H, J = 8.0 Hz), # 6.41 (t, 1H, J = 1 Hz), # 6.20 (d, 1H, J = 1.5 Hz), # 5.00 (s, 1H), # 3.97 (d, 1H, J = 2.5 Hz), # 3.74 (s, 3H), # 3.39 (t, 1H, J = 7 Hz), # 2.40 (s, 3H), # 1.34 (m, 2H), 1.18 (s, 3H), # 0.72 (t, 3H, J = 7 Hz).  13C NMR (125 MHz, CDCl3), # 165.8, 143.9, 138.7, 137.5, 129.4, 127.6, 127.2, 71.3, 59.4, 53.7, 51.8, 21.5, 20.4, 12.2, 11.3.  HRMS (ESI) (m/z): [M+H]+ calculated for [C17H23NO5S]+ 354.1375; Found [M+H]+ 354.1377. gCOSY spectrum is attached at the end of this section. Preparation of compound IV-29.  HNTsO, DABCONTsCNOHCNIV-11crt, 8h, 85%IV-29!#+)!Compound IV-11c (100 mg, 0.374 mmole, 1.0 equiv), DABCO (21 mg, 0.187 mmole, 0.5 equiv), and acrylonitrile (99.3 mg, 1.87 mmole, 5.0 equiv) were stirred at room temperature for 8 h (addition of few drops of CH2Cl2 to facilitate stirring, had no effects on the result). The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted with dichloromethane (3 X 5mL). The combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give compound IV-29 in 85% yield.  IV-29: 2-((3-ethyl-2-methyl-1-tosylaziridin-2-yl)(hydroxy)methyl)acrylonitrile Melting point: 91-92 ¡C. 1H NMR (600 MHz, CDCl3) # 7.80 (d, 2H, J = 8.4 Hz), # 7.30 (d, 2H, J = 8.4 Hz), # 6.34 (dd, 1H, J = 2.4 Hz, J = 0.6 Hz), # 6.1 (dd, 1H, J = 1.2 Hz, J = 2.1), # 4.66 (d, 1H, J = 2.4 Hz), # 4.03 (d, 1H, J = 3.0 Hz), # 3.16 (dd, 1H, J = 4.2 Hz, J = 9.0 Hz), # 2.41 (s, 3H), # 1.62 (m, 1H), # 1.28 (m, 1H), 1.25 (s, 3H), # 0.8 (t, 3H, J = 7.8 Hz). 13C NMR (150 MHz, CDCl3), # 144.3, 136.9, 132.0, 129.5, 127.2, 121.4, 116.8, 72.9, 57.9, 53.4, 21.5, 20.2, 12.0, 11.7.  HRMS (ESI) (m/z): [M+H]+ calculated for [C16H21N2O3S]+ 321.1273; Found [M+H]+ 321.1271.   !#+*!Preparation of compound IV-46.  Compound IV-29 (98.1 mg, 0.3064 mmole, 1.0 equiv), was added to a solution of NaH (6.1 mg, 0.1532 mmole, 0.5 equiv, 60% dispersion in oil) in dry DMF (1.6 mL) at -30 ¡C under completely moisture free conditions. The reaction was stirred for 45 min, while warming up to 0 ¡C. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted with ethyl acetate (3 X 5 mL) and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product IV-46 in 74% yield.  IV-46: 6-ethyl-5-hydroxy-5-methyl-1-tosyl-1,4,5,6-tetrahydropyridine-3-carbonitrile Melting point: 180-181 ¡C. 1H NMR (500 MHz, CDCl3) # 7.68 (d, 2H, J = 8.5 Hz), # 7.41 (s, 1H), # 7.29 (d, 2H, J = 8.5 Hz), # 3.68 (dd, 1H, J = 9.7 Hz, J = 3 Hz), # 2.38 (s, 3H), # 2.22 (dd, 1H, J = 18 Hz, J = 2Hz), # 1.98 (dt, 1H, J = 18 Hz, J = 1.5 Hz), # 1.50 (m, 1H), # 1.24 (s, 3H), # 1.04 (t, 3H, J = 7.5 Hz). IV-29NTsCNOHNTsOHCNNaH (0.5 equiv), Dry DMF, -30 ¡C to 0 ¡C45 min, 74% yield (100% conversion)IV-46!#$+!13C NMR (125 MHz, CDCl3), #144.7, 136.7, 135.4, 129.9, 127.3, 118.9, 87.9, 67.3, 65.3, 34.0, 26.3, 24.3, 21.5, 14.1, 11.1. HRMS (ESI) (m/z): [M+H]+ calculated for [C16H21N2O3S]+ 321.1273; Found [M+H]+ 321.1278.  Preparation of compound IV-60.  Compound IV-29 (98.1 mg, 0.3064 mmole, 1.0 equiv), was added to a solution of NaH (3.6 mg, 0.092 mmole, 0.3 equiv, 60% dispersion in oil) in regular DMF (1.6 mL) at -30 ¡C. The reaction was stirred for 30 min, while warming up to 0 ¡C. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted with portions of dichloromethane (3 X 5 mL). The combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product IV-60 in 30% yield (85% conversion).  IV-60: 6-ethyl-5-hydroxy-5-methyl-1-tosyl-1,2,5,6-tetrahydropyridine-3-carbonitrile 1H NMR (500 MHz, CDCl3) # 7.73 (d, 2H, J = 8.5 Hz), # 7.31 (d, 2H, J = 8.5 Hz), # 6.42 (m, 1H), # 4.21 (dd, 1H, J = 18 Hz, J = 1.5 Hz), # 3.91 (dd, 1H, J = IV-29NTsCNOHNaH (0.3 equiv), regular DMF, -30 ¡C to 0 ¡C 30 min, 30% yield (85% conversion)NTsOHCNIV-60!#$$!4.5 Hz, J = 10.5 Hz), # 3.48 (dd, 1H, J = 18 Hz, J = 2.0 Hz), # 2.58 (s, 1H), # 2.41 (s, 3H), # 1.47 (m, 1H), # 1.26 (s, 3H), # 0.75 (t, 3H, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3), # 146.5, 144.3, 136.3, 130.0, 127.3, 115.8, 111.0, 68.2, 63.1, 40.1, 24.1, 21.5, 20.7, 11.4.  IR (neat, cm-1) 3446, 1643, 1456, 1379, 1333, 1155.  HRMS (ESI) (m/z): [M+H]+ calculated for [C16H21N2O3S]+ 321.1273; Found [M+H]+ 321.1282. Preparation of compound IV-43.  Compound IV-28 (55.7 mg, 0.157 mmole, 1.0 equiv), was added to a solution of NaH (3.1 mg, 0.0785 mmole, 0.5 equiv, 60% dispersion in oil) in dry DMF (0.8 mL) at -30 ¡C. The reaction was stirred for 30 min, while warming up to 0 ¡C. After the completion of reaction by TLC analysis, the reaction was quenched with saturated NH4Cl. Aqueous phase was extracted with ethyl acetate (3 X 5 mL). The combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product IV-43 in 91% yield as a single diastereomer.  NTsCO2MeOHNTsOHCO2MeNaH (0.5 equiv), Dry DMF-30 ¡C to 0 ¡C, 30 min, 91% yieldIV-43IV-28!#$%!IV-43: methyl 6-ethyl-5-hydroxy-5-methyl-1-tosyl-1,2,5,6-tetrahydropyridine-3-carboxylate 1H NMR (500 MHz, CDCl3) # 7.74 (d, 2H, J = 8.0 Hz), # 7.27 (d, 2H, J = 7.5 Hz), # 6.95 (s, 1H), # 4.28 (d, 1H, J = 18 Hz), # 3.93 (dd, 1H, J = 4.5 Hz, J = 10.5), # 3.73 (s, 3H), # 3.53 (dd, 1H, J = 18 Hz), # 2.39 (s, 3H), # 2.33 (s, 1H), # 1.42 (m, 1H), # 1.27 (s, 3H), # 1.10 (m, 1H), # 0.79 (t, 3H, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3), # 165.2, 143.7, 140.8, 137.0, 129.8, 127.7, 127.2, 68.9, 63.4, 52.0, 39.1, 24.1, 21.5, 20.8, 11.5.  HRMS (ESI) (m/z): [M+H]+ calculated for [C17H24NO5S]+ 354.1375; Found [M+H]+ 354.1369. One-pot method for preparation of compound IV-43.  Compound IV-11c (100 mg, 0.374 mmole, 1.0 equiv), DABCO (29.3 mg, 0.261 mmole, 0.7 equiv), and methyl acrylate (161 mg, 1.87 mmole, 5.0 equiv) with few drops of dichloromethane were stirred at room temperature for two days. After two days, the reaction was completed. Solvent was removed completely under reduced pressure. DMF (1.2 mL) and NaH (7.5 mg, 0.187 mmole, 0.5 equiv, 60% dispersion in oil) were added at -30 ¡C. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x IV-11cIV-43HNTsO, DABCOOMeONTsOHCO2Me2) NaH, DMF, -30 ¡C to 0 ¡C    rt, 2 days, 51%1)!#$"!with portions of ethyl acetate and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the product in 51% yield. Characterization data are given in previous part.  Preparation of compound IV-37.  Compound IV-37c (205 mg, 0.555 mmole, 1.0 equiv), DABCO (31.2 mg, 0.277 mmole, 0.5 equiv), and acrylonitrile (269 mg, 2.71 mmole, 5.0 equiv) with few drops of dichloromethane were stirred at room temperature for 1 day. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x with portions of ethyl acetate and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the two diastereomers with a ratio of 60:40 with 20% yield.  IV-37 (major diastereomer): 2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-1-tosylaziridin-2-yl)(hydroxy)methyl)acrylonitrile 1H NMR (500 MHz, CDCl3) # 7.84 (d, 2H, J = 8.5 Hz), # 7.31 (d, 2H, J = 8.0 Hz), # 6.28 (d, 1H, J = 2 Hz), # 6.09 (d, 1H, J = 1.5 Hz), # 4.63 (d, 1H, J = 9.0 Hz), # 3.87 (dd, 1H, J = 11.5 Hz, J = 3.0 Hz), # 3.8 (s, 1H, broad), # 3.56 (dd, HNTsOTBSOTBSONTsCNOHTBSONTsCNOH, DABCOCNrt, 1d, 20%IV-37cIV-37 synIV-37 anti!#$#!1H, J = 6.0 Hz, J = 11.5 Hz), # 3.30 (m, 1H), # 2.85 (dd, 1H, J = 4.5 Hz, J = 9.0 Hz), # 2.42 (s, 3H), # 0.76 (s, 9H), -0.09 (s, 3H), -0.13 (s, 3H). 1H NMR (500 MHz, CDCl3 and D2O), # 7.84 (d, 2H, J = 8.5 Hz), # 7.28 (d, 2H, J = 8.0 Hz), # 6.30 (d, 1H, J = 2 Hz), # 6.10 (d, 1H, J = 1.5 Hz), # 4.63 (d, 1H, J = 9.0 Hz), # 3.87 (dd, 1H, J = 11.5 Hz, J = 3.0 Hz), # 3.58 (dd, 1H, J = 6.0 Hz, J = 11.5 Hz), # 3.31 (m, 1H), # 2.83 (dd, 1H, J = 4.5 Hz, J = 9.0 Hz), # 2.42 (s, 3H), # 0.76 (s, 9H), -0.09 (s, 3H), -0.12 (s, 3H). 13C NMR (125 MHz, CDCl3), # 144.7, 136.3, 131.8, 129.6, 127.5, 121.5, 116.5, 69.6, 61.0, 49.5, 47.7, 25.6, 21.6, 18.1, -5.6, -5.7.  HRMS (ESI) (m/z): [M+H]+ calculated for [C20H31N2O4SSi]+ 423.1774; Found [M+H]+ 423.1779. gCOSY data is attached.  IV-37 (minor diastereomer): 2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-1-tosylaziridin-2-yl)(hydroxy)methyl)acrylonitrile 1H NMR (500 MHz, CDCl3), # 7.84 (d, 2H, J = 8.0 Hz), # 7.31 (d, 2H, J = 8.0 Hz), # 6.05 (s, 1H), # 5.98 (s, 1H), # 4.62 (s, 1H), # 4.13 (m, 1H), # 3.09 (m, 1H), # 3.19 (m, 2H), # 2.43 (s, 3H), # 2.40 (s, 1H, broad), # 0.86 (s, 9H), 0.01 (s, 6H).  13C NMR (125 MHz, CDCl3), # 144.7, 136.3 132.4, 129.7, 127.6, 122.1, 116.5, 68.0, 60.1, 47.1, 46.0, 25.7, 21.6, 18.2, -5.4, -5.4.  IR (neat, cm-1) 3442, 2084, 1646, 1471, 1327, 1253, 1161, 1090.  HRMS (ESI) (m/z): [M+H]+ calculated for [C20H31N2O4SSi]+ 423.1774; Found [M+H]+ 423.1776. gCOSY data is attached. !#$&!Preparation of compound IV-36.  Compound IV-37c (214 mg, 0.581 mmole, 1.0 equiv), DABCO (32.6 mg, 0.290 mmole, 0.5 equiv), and methyl acrylate (250 mg, 2.90 mmole, 5.0 equiv) with few drops of dichloromethane were stirred at room temperature for 2 days. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x with portions of dichloromethane. The combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give IV-36 with >95:5 diastereomeric ratio and 24% yield.  IV-36: methyl 2-((3-(((tert-butyldimethylsilyl)oxy)methyl)-1-tosylaziridin-2-yl)(hydroxy)methyl)acrylate 1H NMR (500 MHz, CDCl3) # 7.83 (d, 2H, J = 8.0 Hz), # 7.29 (d, 2H, J = 8.0 Hz), # 6.31 (s, 1H), # 6.03 (s, 1H), # 4.78 (s, 1H), # 4.55 (s, 1H), # 3.76 (s, 3H), # 3.72 (s, 2H), # 3.29 (m, 1H), # 2.92 (m, 1H), # 2.41 (s, 3H), # 0.81 (s, 9H), # -0.069 (s, 3H), # -0.087 (s, 3H).  13C NMR (125 MHz, CDCl3), # 165.8, 144.3, 138.9, 136.8, 129.5, 127.5, 127.1, 68.5, 61.1, 51.9, 51.1, 48.0, 31.5, 25.7, 21.5, -5.6.  IR (neat, cm-1) 3503, 2953, 2928, 2856, 1722, 1323, 1160, 1090, 838.  HNTsOTBSOTBSONTsCO2MeOHTBSONTsCO2MeOH, DABCOCO2MeIV-37cIV-36 synIV-36 antirt, 2 d, 24%!#$'!HRMS (ESI) (m/z): [M+H]+ calculated for [C21H34NO4SSi]+ 456.1876; Found [M+H]+ 456.1875. Preparation of compound IV-30.  Compound IV-14c (206 mg, 0.653 mmole, 1.0 equiv), DABCO (51.2 mg, 0.457 mmole, 0.7 equiv), and methyl acrylate (281.4 mg, 3.26 mmole, 5.0 equiv) with few drops of dichloromethane were stirred at room temperature for 2 days. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x with portions of dichloromethane and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the desired compound IV-30 syn in 70% yield with 83:16 diastereomeric ratio.  IV-30: methyl 2-(hydroxy(2-methyl-3-phenyl-1-tosylaziridin-2-yl)methyl)acrylate 1H NMR (500 MHz, CDCl3) # 7.87 (d, 2H, J = 8.5 Hz), # 7.30 (d, 2H, J = 8.5 Hz), # 7.16 (m, 3H), # 6.94 (m, 2H), # 6.45 (t, 1H, J =1.5 Hz), # 6.25 (t, 1H, J = 1.5 Hz), # 5.22 (s, 1H), # 4.72 (s, 1H), # 3.84 (s, 3H), # 2.41 (s, 3H), # 0.95 (s, 3H). CO2MePhHNTsO, DABCOPhNTsOOOHIV-14crt, 2 days, 70%IV-30!#$(!13C NMR (125 MHz, CDCl3), # 165.9, 144.2, 138.4, 137.2, 133.1, 129.5, 128.0, 127.9, 127.6, 127.1, 126.7, 71.2, 60.8, 53.2, 51.9, 21.5, 12.1.  HRMS (ESI) (m/z): [M+H]+ calculated for [C21H24NO5S]+ 402.1375; Found [M+H]+ 402.1366. Preparation of compound IV-31.  Compound IV-14c (205 mg, 0.652 mmole, 1.0 equiv), DABCO (51.2 mg, 0.456 mmole, 0.7 equiv), and acrylonitrile (323.6 mg, 3.26 mmole, 5.0 equiv) with few drops of dichloromethane were stirred at room temperature for 20 h. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x with portions of dichloromethane and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the desired compound in 95% yield with >99:1 diastereomeric ratio.  IV-31:  2-(hydroxy(2-methyl-3-phenyl-1-tosylaziridin-2-yl)methyl)acrylonitrile 1H NMR (500 MHz, CDCl3) # 7.90 (d, 2H, J = 8.5 Hz), # 7.36 (d, 2H, J = 8.5 Hz), # 7.22-7.26 (m, 5H), # 6.46 (d, 1H, J = 1.5 Hz), # 6.23 (d, 1H, J = 2.0 Hz), # 4.92 (d, 1H, J = 2.5 Hz), # 4.49 (s, 1H), # 4.20 (d, 1H, J = 3.0 Hz), # 2.47 (s, 3H), # 1.06 (s, 3H). IV-31PhHNTsO, DABCOPhNTsCNOHCNrt, 20h, 95%IV-14c!#$)!13C NMR (125 MHz, CDCl3), # 144.7, 136.8, 132.5, 131.9, 129.7, 128.2, 128.1, 127.2, 127.1, 120.9, 117.3, 72.6, 59.5, 52.3, 21.6, 11.7.  HRMS (ESI) (m/z): [M+H]+ calculated for [C20H21N2O3S]+ 369.1279; Found [M+H]+ 369.1291. Preparation of compound IV-61 and IV-62.  Compound IV-31 (128.7 mg, 0.349 mmole, 1.0 equiv), was added to a solution of NaH (4.2 mg, 0.175 mmole, 0.5 equiv, 60% dispersion in oil) in dry DMF (1.9 mL) at -30 ¡C. The reaction was warmed to 0 ¡C and stirred for 60 min. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted 3x with portions of ethyl acetate and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the compound IV-61 in 61% and IV-62 in 18% yield.  IV-61: 5-hydroxy-5-methyl-6-phenyl-1-tosyl-1,4,5,6-tetrahydropyridine-3-carbonitrile 1H NMR (500 MHz, CDCl3) # 7.82 (d, 2H, J = 2.5 Hz), # 7.38 (d, 2H, J = 8.0 Hz), # 7.16 (m, 1H), # 7.11 (t, 2H, J = 8.0 Hz), # 7.05 (d, 1H, J = 8.5 Hz), # 6.91 (d, 2H, J = 8.0 Hz), # 4.81 (d, 1H, J = 1.5 Hz), # 2.30 (s, 3H), # 2.22-2.28 PhNTsCNOHIV-31NTsPhOHCNNTsPhOHCNNaH, -30 ¡C to 0 ¡C60 min, DMF61% (IV-61), 18% (IV-62)IV-62IV-61!#$*!(dd, 1H, J = 2 Hz, J = 17.5 Hz), # 2.09-2.13 (dd, 1H, J = 2 Hz, J = 17 Hz), # 2.2 (s, 1H), # 1.07 (s, 3H). 13C NMR (125 MHz, CDCl3), # 144.6, 138.5, 137.1, 134.8, 129.5, 128.5, 128.2, 127.1, 126.9, 119.3, 85.0, 67.6, 67.2, 32.5, 26.1, 21.4.  IR (neat, cm-1) 3443, 2210, 1632, 1376, 1168.  HRMS (ESI) (m/z): [M+H]+ calculated for [C20H21N2O3S]+ 369.1273; Found [M+H]+ 369.1271.  IV-62: 5-hydroxy-5-methyl-6-phenyl-1-tosyl-1,2,5,6-tetrahydropyridine-3-carbonitrile 1H NMR (500 MHz, CDCl3) # 7.39 (d, 2H, J = 8.5 Hz), # 7.16-7.24 (m, 4H), # 7.04-7.06 (d, 2H, J = 8.5 Hz), # 6.97 (d, 2H, J = 9.0 Hz), # 6.72 (s, 1H), # 5.08 (s, 1H), # 4.33 (dd, 1H, J = 18 Hz, J = 2 Hz), # 3.5 (dd, 1H, J = 18 Hz, J = 2 Hz), # 2.97 (s, 1H, broad), # 2.30 (s, 3H), # 1.08 (s, 3H).  13C NMR (125 MHz, CDCl3), # 147.2, 144.0, 134.4, 134.0, 129.4, 128.8, 128.6, 128.4, 127.4, 115.8, 111.1, 68.3, 66.1, 41.7, 24.1, 21.4.  HRMS (ESI) (m/z): [M+H]+ calculated for [C20H21N2O3S]+ 369.1273; Found [M+H]+ 369.1288. Preparation of compound IV-44. PhNTsCO2MeOHIV-30NaH, DMF, -30 ¡C to 0 ¡C30 min, 77 %NTsPhOHCO2MeIV-44!#%+!Compound IV-30 (103.7 mg, 0.259 mmole, 1.0 equiv), was added to a solution of NaH (7.2 mg, 0.181 mmole, 0.7 equiv, 60% dispersion in oil) in dry DMF (1.4 mL) at -30 ¡C. The reaction was warmed to 0 ¡C and stirred for 30 min. The reaction was quenched with saturated NH4Cl. The aqueous phase was extracted with ethyl acetate (3 X 5 mL). The combined organics were washed with brine and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (8:2 hexanes/ethyl acetate) to give the compound IV-44 in 77% yield as a single diastereomer.  IV-44: methyl 5-hydroxy-5-methyl-6-phenyl-1-tosyl-1,2,5,6-tetrahydropyridine-3-carboxylate 1H NMR (500 MHz, CDCl3) # 7.4 (d, 2H, J = 8.5 Hz), # 7.1-7.2 (m, 3H), # 7.0 (m, 5H), # 5.0 (s, 1H), # 4.4 (dd, 1H, J = 18 Hz), # 3.8 (s, 3H), # 3.5 (d, 1H, J = 18 Hz), # 2.2 (s, 3H), # 1.0 (s, 1H), # 2.1-2.2 (m, 1H), # 2.2 (s, 1H), # 1.0 (s, 3H).  13C NMR (125 MHz, CDCl3), # 144.6, 138.5, 137.1, 134.8, 129.5, 128.5, 128.2, 127.1, 126.9, 119.3, 85.0, 67.6, 67.2, 32.5, 26.1, 21.4.  HRMS (ESI) (m/z): [M+H]+ calculated for [C21H23NO5S]+ 402.1375; Found [M+H]+ 402.1369.     !#%$!          REFERENCES    !#%%!REFERENCES    $,!-./012!3,2!45!/6,2!789:/;<=>?>@!A6B@1.>C/.4!D0E>F>51;.G!3/59;/6!H@@9;;40@42!I>161:>@/6!-@5>J>5B!/0C!K;1.L4@5.!M1;!NE4;/L495>@!-LL6>@/5>10!"!#$%&'($)&*+,-./011$%&02!!"""2!222!$'#&<$')+,!!%,!O4;6/2!I,P,Q,2!P,R!3>@15;/2!O,!2!7A404;/6!85;/54:>4.!M1;!5E4!8B05E4.>.!1M!D?>01.9:/;.!/0C!34S!-LL;1/@E4.!N1S/;C.!D?>01.9:/;!P>F;/;>4.!"!3*(+-456$0-7-8*+/9-:%)2!!""#,!!",!K4/;.102!=,8,=,2!45!/6,2!7T4@405!-CJ/0@4.!>0!5E4!N15/6!8B05E4.>.!1M!K>L4;>C>04!-U/.9:/;.!"!;<&!-3!-=&>!-?($1!2!!""$2!%$&*<%$*$,!!#,!P442!T,V,2!45!/6,2!7D0E>F>5>10!1M!WXK<A/6!=95/.4!/0C!=B@1F/@54;>/6!A/6/@5/0!I>1.B05E4.>.!FB!KB;;16>C>04!-0/61:94.!1M!A/6/@51M9;/01.4!"!#$%&'($)&*+-:$%%!2!%&&'2!@A2!'(""<'("',!!&,!Q1?L/>02!K,=,2!H,!T,!!2!7D?>01.9:/;.G!K/.52!K;4.405!/0C!O959;4!"!3*(+-456$0-7-8*+/9-:%)2!!""#,!!',!Y/5.102!K,8,2!I,!Z>/0:2!/0C!I,!8@1552!7-!X>/.54;41.464@5>J4!8B05E4.>.!1M!%2#<X>.9F.5>5954C!K>L4;>C>04.G!8@/MM16C.!M1;!X;9:!X>.@1J4;B!"!=&>!-:$%%!2!!"""2!B2!"'(*<"')$,!!(,!-./012!3,2!45!/6,2!789:/;<=>?>@!A6B@1.>C/.4!D0E>F>51;.G!3/59;/6!H@@9;;40@42!I>161:>@/6!-@5>J>5B!/0C!K;1.L4@5.!M1;!NE4;/L495>@!-LL6>@/5>10!"!#$%&'($)&*+,-./011$%&02!!"""2!222!$'#&<$')+,!!),!Y10:2!Q,[,2!45!/6,2!78L4@>M>@>5B2!D0E>F>5>102!/0C!8B05E45>@!W5>6>5B!1M!/!T4@1?F>0/05![9?/0!-6LE/<$2"<O9@1.B6<N;/0.M4;/.4!"!3!-.1!-?($1!-8*C!2!%&&!2!22D2!("%$<("%%,!!*,!I16.2!=,2!T,A,![/U4662!/0C!D,I,!NE1?.402!7$<-U/M/:1?>04G!-![BC;1\BE4\/EBC;1LB;>C/U>04!5E/5!K154056B!D0E>F>5.!V0UB?/5>@!A6B@1.>C4!Q64/J/:4!"!?($1!-;<&!-3!2!%&&'2!@2!*#+<*#(,!!$+,![1;40.54>02!I,-,2!T,O,!]/F>0.^>2!/0C!_,P,!8@E;/??2!7-!34S!Q6/..!1M!Q<39@641.>C4!-0/61:.!<!$<`8a<-;B6<$2#<X>C41\B<$2#<D?>01<X<T>F>516.2!N;/0.>5>10<85/54!-0/61:!D0E>F>51;.!1M!39@641.>C4![BC;16/.4!"!#$%&'($)&*+-:$%%!2!%&&(2!@D2!(%$"<(%$',!!#%"!$$,!P442!T,V,2!45!/6,2!7D0E>F>5>10!1M!WXK<A/6!=95/.4!/0C!=B@1F/@54;>/6!A/6/@5/0!I>1.B05E4.>.!FB!KB;;16>C>04!-0/61:94.!1M!A/6/@51M9;/01.4!"!#$%&'($)&*+-:$%%!2!%&&'2!@A2!'(""<'("',!!$%,!=1;>B/?/2![,2!45!/6,2!7-U/.9:/;<I/.4C!==Kb-X-=!D0E>F>51;.!/.!-05>L.1;>/5>@!-:405.!"!3!-E$)!-?($1!2!!"")2!DF2!$*"+<$*"),!!$",!V0C4;.2!X,!/0C!=,!c6/552!7-.B??45;>@!8B05E4.>.!S>5E!`8a<%<=45E1\B?45EB6LB;;16>C>04!`8=Ka!<!-!K>1044;!-9\>6>/;B!"!80+%($/5/2!%&&*2!$#+"<$#$),!!$#,!d/?/?1512!d,2!45!/6,2!7-!Q10J40>405!8B05E4.>.!1M!V0/05>1?4;>@!K/>;.!1M!%2&<X>.9F.5>5954C!KB;;16>C>04.!1M!Q<%<8B??45;B!"!80+%($/5/2!%&&(2!%*)<"+%,!!$&,!c1E2!c,2!T,3,!I402!/0C!N,!X9;.52!7-!O/@>64!8B05E4.>.!1M!HL5>@/66B!-@5>J4!Q%<8B??45;>@!%2&<X>.9F.5>5954C!KB;;16>C>04.!/0C!H5E4;!2<X>EBC;1\B/?>04.!"!#$%&'($)&*+-:$%%!2!%&&)2!@G2!"(&<"(),!!$',!Q1;4B2!V,Z,2!45!/6,2!7K16BM90@5>10/62!85;9@59;/66B!X4M>04C!Q/5/6B.5.!M1;!5E4!V0/05>1.464@5>J4!-CC>5>10!1M!X>/6^B6U>0@!T4/:405.!51!-6C4EBC4.!"!3!-=&>!-?($1!2!%&&"2!GG2!()#<()',!!$(,!X43>0012!=,K,2!T,D,!K4;04;2!/0C!P,!P>e4S.^>2!7V0/05>1.464@5>J4!T4C9@5>10.!1M!%<-@B6<$2"<X>5E>/04.!W.>0:!5E4!Q1;4B!H\/U/F1;16>C>04!Q/5/6B.5!"!#$%&'($)&*+-:$%%!2!%&&"2!@22!(#$&<(#$),!!$),!Z104.2!N,c,2!45!/6,2!7-0!-.B??45;>@!8B05E4.>.!1M!=c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f94!QE>;/6!8B05E10!"!O/C-.)P2!!"%)2!D2!&#+&<&#&%,!!%&,![/02!=,<d,2!Z,<d,!Z>/2!/0C!Y,!Y/0:2!7T4@405!-CJ/0@4.!>0!H;:/01@/5/6B5>@!-.B??45;>@!8B05E4.>.!1M!K16B.9F.5>5954C!KB;;16>C>04.!"!#$%&'($)&*+-:$%%!2!!"%)2!GG2!()#<(*#,!!%',!d92!Z,2!O,!8E>2!/0C!P,<],!A10:2!7I;g0.54C<-@>C<Q/5/6BU4C!-.B??45;>@!=965>@1?L10405!T4/@5>10.!M1;!5E4!O/@>64!8B05E4.>.!1M![>:E6B!V0/05>140;>@E4C!85;9@59;/66B!X>J4;.4!3>5;1:4019.![454;1@B@64.!"!.CC!-?($1!-O$/!2!!"%%2!DD2!$$&'<$$($,!!%(,!K/0C4B2!A,2!K,!I/04;e442!/0C!8,T,!A/C;42!7Q10.5;9@5>10!1M!V0/05>1L9;4!KB;;16>C>04!T>0:!8B.54?!J>/!-.B??45;>@!h"i%j<QB@61/CC>5>10!1M!-U1?45E>04!d6>C4.!"!?($1!-O$P!2!!""*2!2QH2!##)#<#&$(,!!%),!O46L>02!O,<k,!/0C!Z,!P4F;45102!7T4@405!-CJ/0@4.!>0!5E4!N15/6!8B05E4.>.!1M!K>L4;>C>04!/0C!KB;;16>C>04!3/59;/6!-6^/61>C.!S>5E!T>0:<Q61.>0:!=45/5E4.>.!/.!/!c4B!854L!"!;<&!-3!-=&>!-?($1!2!!""(2!BQQ@2!"'*"<"($%,!!%*,!8@E1?/^4;2!Z,=,2!45!/6,2!7X>/.54;41?4;>@/66B!/0C!V0/05>1?4;>@/66B!K9;4!%2"<X>.9F.5>5954C!KB;;16>C>04.!M;1?!%2"<-U>;>C>0<$<16.!W.>0:!/!896M1\10>9?!d6>C4Gl!-!H04<Q/;F10![1?161:/5>J4!T46/B!T>0:!V\L/0.>10!"!3!-.1!-?($1!-8*C!2!!""'2!2BL2!$**'<%++",!!"+,!8@E1?/^4;2!Z,=,2!45!/6,2!7N45;/.9F.5>5954C!KB;;16>C>04.!J>/!/!N/0C4?!-U/<K/B04b[BC;1/?>0/5>10!T4/@5>10!"!3!-.1!-?($1!-8*C!2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!"#$!Chapter V: Halenium Induced 1,3-Benzoate Transposition Of Tertiary Allylic Amides V-1 Introduction  In Chapter 2, we discussed the intramolecular halocyclization reactions of olefins in full (Scheme V-1-a).1-10 Our group and others have also developed methodologies for the halofunctionalization reactions of alkenes in an intermolecular fashion such as dihalogenation, aminohalogenation, haloesterification, and halohydrin synthesis.5, 11-28 Outcompeting the intramolecular halocyclization reactions to favor intermolecular processes was accomplished through two different approaches (Scheme V-1-b-c). First, if the external nucleophile (NuE) is stronger than the internal nucleophile, or if it is used in excess amount, then the intermolecular attack is favored easily (Scheme V-1-b). Second, we explored the intermolecular halofunctionalization of olefins while the internal nucleophile was protected (Scheme V-1-c). In this approach, the intramolecular halocyclizations cannot occur because the internal nucleophile has been deactivated. As a part of a project aimed at improving the scope and utility of a diastereoselective synthesis of chlorohydrin V-2 from unsaturated tertiary amide V-1, we accidentally formed a side product V-3 in a 1:1 ratio (Scheme V-2). This piqued our interest to develop a new methodology for the synthesis of halohydrin esters directly from olefins in one step in high regio- and diastereoselectivities. !"#%! Halohydrin esters are versatile intermediates in organic synthesis and serve as valuable building blocks in the synthesis of numerous natural and unnatural bioactive compounds29-31 and also lipids.32-36 A common tactic for their synthesis is conversion of 1,2-diols to 1,2-haloesters.37-46 Another family of transformations uses epoxides as starting materials. For example, epoxides can be transformed to halohydrin esters through a two-step procedure in one-pot; 1) ring opening by a halide nucleophile and 2) the subsequent O-acylation of the resulting halohydrin derivatives.47-49  They can also be prepared from direct reaction of an epoxide with an acyl halide with or without a transition metal catalyst&50-55 Ring opening of symmetric cyclic NuXNu!!XIntramolecularCatalystHNuXHIntermolecularCatalyst, NuEHNuHNuEXa)b)c)HHNu!!X-H-HNuHNuEXNuXRIntermolecularCatalyst, NuEHNuRNuEXH-HNuRNuEXScheme V-1 General scheme for halofunctionalization of olefins. !"#'!ethers by organic acid halides could also afford the 1,4- and 1,5-halohydrin esters.56-64!  In general, most of these methods suffer from low diastereoselectivities and mixtures of regioisomers are obtained when using unsymmetrical 1,2-diols, cyclic ethers, or epoxides. They also suffer from limitations such as tedious reaction procedures, polymerization, and pH conditions that degrade other functional groups, low yields and the hygroscopic nature of the catalysts. These requirements restrict them from extensive industrial applications. To overcome these problems, the development of more general and convenient processes using readily accessible and inexpensive substrates is a continuing goal. In this Chapter, we wish to advance a simple and efficient protocol for the preparation of 1,2-halohydrin esters through an electrophile initiated 1,3-benzoate transposition of tertiary allylic amides. In the presence of stoichiometric quantities of electrophiles, the title reaction N!!!!NOHClAcetone: H2O(1:2), 1 d, rt 32% yield65% conv.(50:50) V-2:V-3DCDMHDABCO33!!!!NHOCl3V-2V-3OOV-1OScheme V-2 Accidental formation of halohyrin ester V-3. !"#(!proceeds with exquisite regio- and diastereoselectivity owing to the anchimeric participation of the amide functional group in intercepting the putative intermediates. We also demonstrate that Lewis bases or Bronsted acids are capable of accelerating the reaction. V-2 Optimization of reaction conditions for the synthesis of chloroesters: We chose the conversion of amide V-4 into chloroester V-5 as our initial test reaction (Table V-1). Different chlorenium sources in TFE (trifluoroethanol) were evaluated for this reaction. Among several chlorine sources screened for the test reaction, DCDMH and dichloramineT (TsNCl2) emerged as the best candidates, thus affording the benzoate-transposed products V-5 and V-6 in 95-97% yield in 2 days (Table V-1, entries 7-8). This illustrates that active chlorine sources afford the product in shorter times but the secondary amine undergoes further chlorination under these reaction conditions to afford the side product V-6. To avoid this, we evaluated various quenching conditions to de-chlorinate V-6 to provide the desired chloroester V-5 (Table V-2). We discovered that adding 50% aq HCl to the reaction mixture after completion of the reaction, results in exclusive formation of V-5 with 95% yield (Table V-2, entry 2). All other harsh conditions used such as NaOH, acetic acid, Na2SO3, or TsOH were not successful in achieving high yields for delivering compound V-5. Finally the reaction mixture was stirred !")*!with 50% aq HCl (0.03 M) for 2 h and then it is neutralized with NaOH to pH 7-8 before the extraction.   Next we evaluated the influence of solvent on benzoyl transposition of allylic amide V-4. TFE emerged as the best solvent for delivering V-5 in 95% yield (Table V-3, entry 1). CH2Cl2, toluene and CHCl3:Hexanes (1:1) led to the  Table V-1 Initial chlorine screening for formation of chloroester V-5. Entry Cl+ source Time (d) Conv.[b] (%) Yield[a] (%) Ratios[b] (V-5:V-6) 1 TCCA 2 - messy messy 2 CDSC 2 - messy messy 3 Et4NCl3 2 5 - 100:0 4 Ch.T 7 24 - 100:0 5 PhICl2 2 88 52 32:68 6 NCS 7 100 - 50:50 7 DiChT 2 100 78 15:85 8 DCDMH 2 100 79 9:91 [a] Isolated yield of V-5. [b] Conversion and ratios were measured by 1H NMR analysis. V-4TFE (0.025 M), rtPhNBnOPhPhNHOClPhOPhNBnOClPhOClBnV-5V-6source (1.1 equiv.)Cl!")+!formation of V-5 in moderate yields, 82%, 75%, and 66% yields, respectively (Table V-3, entries 2-4).!Other solvents afforded inferior results and led to low or zero conversion into the desired product (Table V-3, entries 5-8).  !  Table V-2 Screening of various quenching conditions or additives for formation of chloroester V-5. Entry Solvent Quenching solutions or additives Ratios[a] (V-5:V-6) 1 TFE - 9:91 2 TFE HCl (50% aq) 100:0 3 TFE Na2SO3 (10% aq) 55:45 4 TFE:HFIP (5:1) Na2SO3 (10% aq) 72:28 5 DCM Acetic acid (50% aq) 0:100 6 DCM TsOH (1 equiv) 0:100 7 DCM NaOH (50% aq) 48:52 8 DCM HCl (2% aq) 45:55  [a] Conversion and ratios were measured by 1H NMR analysis. V-4solvent (0.025 M), rtPhNBnOPhPhNHOClPhOPhNBnOClPhOClBnV-5V-6DCDMH (1.1 equiv.)!")#! V-3 Effects of catalyst and additive on the rate of the reaction  We found that the choice of DCDMH and TFE at room temperature without any need for catalyst could afford the desired chloroester V-5 in 95% yield after 2 days (Table V-4, entry 1). Addition of DABCO (0.1 equiv) as a catalyst led to the faster reaction times (1 d) and slightly lower yield (Table V-Table V-3 Effect of solvent on formation of chloroester V-5. Entry Solvent Conv.% [a] Yield% 1 TFE 100 95 2 DCM 100 82 3 toluene 100 75 4 CHCl3:Hex (1:1) 100 66 5 Et2O 57 - 6 THF - Messy 7 MeCN - Messy 8 acetone - Messy  [a] Conversion was measured by 1H NMR analysis. Yields were measured by isolation of the product.  V-4solvent (0.025 M), rt, 1-2 dPhNBnOPhPhNHOClPhOBnV-51) DCDMH (1.1 equiv.)2) quenched with HCl!"))!4, entry 2). Interestingly, increasing the DABCO loading to 50 or 100 mol% led to significantly diminished yields (39% and 26%, respectively) but much faster rates (Table V-4, entries 3-4). The commercially available cinchona alkaloid dimer, (DHQD)2PHAL (10 mol%), could afford V-5 in higher yield of 98% and only 6 h (Table V-4, entry 5). However, due to the high cost of this catalyst, we chose entry 1 as the best optimized condition to afford the desired product in high yield and excellent regioselectivity as one single diastereomer.  Table V-4 Effect of catalyst on the rate of formation of chloroester V-5. V-4TFE (0.025 M), catalyst, rtPhNBnOPhPhNHOClPhOBnV-51) DCDMH (1.1 equiv.)2) quenched with HClEntry Catalyst (mol%) Time (h) Yield% 1 - 48 h  95 2 DABCO (10 mol%) 24 h 92 3 DABCO (50 mol%) 5 h 39 4 DABCO (100 mol%) 4 h 26 5 (DHQD)2PHAL (10 mol%) 6 h 98  [a] Yields were measured by isolation of the product.  !")"!As shown in Table V-5, relative rate studies revealed that incorporation of 4 † molecular sieves does not influence the rate of the reaction, however addition of H2O (1.0 equiv) slightly increases the rate (at different time intervals and conversions: (kH2O/k)=1.2).   V-4TFE (0.025 M), additive, rtPhNBnOPhPhNHOClPhOBnV-51) DCDMH (1.1 equiv.)2) quenched with HClTable V-5 Effect of moisture on the rate of formation of chloroester V-5. Entry Additive Time (h) Conv.%[a] 1 - 4.5 h  43 2 4 † ms 4.5 h 43 3 H2O (1 equiv) 4.5 h 50 4 - 8.5 h 56 5 4 † ms 8.5 h 56 6 H2O (1 equiv) 8.5 h 60 7 - 30.5 h 63 8 4 † ms 30.5 h 60 9 H2O (1 equiv) 30.5 h 73 [a] Conversion was measured by 1H NMR analysis. !"),!V-4 Substrate scope for chlorenium induced benzoyl transposition of unsaturated tertiary amides In order to probe the substrate scope for this reaction, a series of aromatic olefins were subjected to the optimized reaction conditions (Scheme V-3). Tertiary alkyl amides gave good yields and exclusive formation of chloro ester V-7 in 84% yield. The optimized condition converted the tertiary aryl amides to compound V-5 in 95% yield. Substitution of the aryl group with p-Scheme V-3 Substrate scope for the formation of chloroester products. then HCl (aq) quench> 99:1 drR1NR2R3OR1NHR2OClOR3DCDMH (1.1 equiv) TFE (0.025 M), rt, 2-4 daysNHOClOOMeV-945% yieldNHOClOV-1071% yieldNHOClOV-784% yieldBrNHOClOV-595% yieldNHOClOV-874% yieldNO2!")$!OMe p-NO2, and p-Br gave 45%, 74%, and 71% of V-9, V-8 and V-10, respectively. V-9 could be formed in higher yields of 65% or 64% upon replacing DCDMH with PhICl2 or NCS, respectively after 5 days. The final structure (and the relative stereochemistry) of the benzoate-transposed chloroester V-10 was confirmed by X-ray crystallography. Next, we evaluated the substrate scope of aliphatic olefins (Table V-6). The benzoyl transposition of aliphatic olefins provided the desired chloroester V-12 and the chlorohydrin V-13 as the side product, in 1:1 ratio in the absence of any catalyst (Table V-6, entry 1). After the chlorenium attack, aliphatic olefinic intermediates lack the stabilized benzylic carbocation, which leads to the formation of both regioisomers. Addition of DABCO, benzoic acid (BA) or (DHQD)2PHAL as catalysts and/or additives did not improve the regioselectivity (Table V-6, entries 2 and 5). After quenching the reaction with 50% aq HCl, we neutralized the solutions with NaOH to various pHs before extraction. We obtained benzoyl-transposed regioisomers as both chlorohydrin V-13 and chloroester V-14 when DABCO was used and the pH was adjusted to 5-6 (Table V-6, entry 3). The structure of the regioisomer V-13 has been confirmed through derivatization studies, 1H NMR, 13C NMR, and 2D-NMR analysis (Scheme V-4 and V-5). Apparent from gHMQC spectrum, the carbinol proton overlaps with the hydrogen atom attached to the carbon bearing the chlorine. The !")%!carbinol was shifted downfield upon acylation, its COSY correlation with aliphatic protons b/bÕ next to nitrogen atoms, confirmed the structure of V-13.  As shown in Scheme V-4 the expanded 2D-HMQC spectrum reveals the chemical shifts of the carbinol proton and the hydrogen atom attached to Entry Additive pH[a] Time  Yield% Ratio[b] (V-12:V-13:V-14) 1 - 8-9 3 d 51% 45:55:0 2 DABCO (0.2 equiv) 8-9 2 d 85% 50:50:0 3 DABCO (0.2 equiv) 5-6 2 d 72% 56:22:22 4 BA (1.0 equiv) 5-6 4 d 84% 53:47:0 5 (DHQD)2PHAL (0.1 equiv) 8-9 6 h 98% 38:62:0 [a] After HCl quenching the reaction mixture was neutralized to the given pHs before the extraction. [b] Ratio of three products were measured by 1H NMR analysis of crude mixture. TFE, rt, additive2) HCl (aq) quenchNBnOPhNHOClPhOBnV-121) DCDMH (1.1 equiv)V-11NBnClOHV-13OPhNHBnClOV-14OPhTable V-6 Benzoyl transposition of aliphatic olefins. !")'!the carbon bearing chlorine are overlapped (protons c and d, 3.8 ppm), since they correlate with two different carbon signals resonating at 65 and 75 ppm.  In order to clarify the regioselectivity of the unknown chlorohydrin, it was converted to the corresponding chlorobenzoate derivative V-15. Protecting the free hydroxyl group as an ester helps to reveal the real identity of the regioisomers (Scheme V-5-a), since the carbinol proton is shifted downfield in 1H NMR spectrum upon acylation. Chemical shift of carbinol proton moved downfield from 3.8 ppm to 5.7 ppm upon derivatization (Scheme V-5-b). Higher temperatures 1H NMR was obtained to remove conformational ambiguities.  Thus, the derivatization study unravels the exact chemical shift of the carbinol proton (5.7 ppm) and hydrogen atom attached to the carbon bearing the chlorine atom (4.2 ppm). Finally, COSY correlation of carbinol proton with neighboring diastereotopic protons b and bÕ next to nitrogen atom (Scheme V-5-c) elucidates the structure of this regioisomer V-13 as shown in Table V-6. !")(! NClOHBzNOHClBzora/a'b/b'cPhPhda/a'b/b'cda, aÕ b b', d, c Scheme V-4 Benzoyl transposition of aliphatic olefins. !""*! Scheme V-5 Derivatization study (a), 1H NMR (b), and 2D-COSY spectra (c).  V-13, rt V-15, rt V-15, 90 ¡C c a, a' d b, bÕ NClOHBzNOHClBzora/a'b/b'cPhPhda/a'b/b'cdEt3N, BzClDMAP, DCM8h, 0 ¡C to rtNClOBzBzNOBzClBzora/a'b/b'cPhPhda/a'b/b'cd30% yieldV-13V-15a b c !""+!In addition to aromatic and aliphatic trans olefins, we investigated the chlorenium induced benzoyl transposition of 1,1-disubstituted olefins and cyclohexene amide derivatives. Generality of this transformation is illustrated with 1,1-disubstituted and cyclic olefins as well (Scheme V-6) giving the expected regioselectivity based on the stability of the carbocation. Compounds V-16 and V-18 were transformed to chlorohydrins V-17 and V-18 under the same optimized conditions providing 97% and 54% yield, respectively. High regio- and diastereoselectivities obtained in these two reactions suggests that the chlorohydrin products were formed upon O/N-trans-acylation of the benzoyl-transposed chloroester intermediates; i.e. after the transposition, the benzoyl protecting group of the ester intermediate will be transferred to the secondary amine. Various reaction conditions were tested to interrupt the O/N-trans-acylation event after the transposition reaction to obtain chloroester compounds. Addition of NaHCO3, Cs2CO3, and benzoic acid additives in various equivalents (ranging from 1-5 equiv), led to similar yields and only isolation of the chlorohydrin V-17. The X-ray crystal structure of V-17 and 2D-NMR analysis of V-19 elucidated the regioselectivity. !""#! V-5 Benzoyl transposition of tertiary amides using different electrophilic sources 1,3-Benzoate transposition of aromatic olefin V-4 was investigated with other electrophilic sources. Phenylselenyl chloride (PhSeCl), phenylselenyl bromide (PhSeBr), or N-(phenylseleno)phthalamide did not form the seleno-induced benzoyl transposed adducts and mostly the starting materials were recovered. Further experiments for activation of these sources with various Lewis base or Bronsted acid additives did not succeed. Other commonly used halenium sources such as IDSI (iodo diethyl sulfonium iodopentachloroantimonate), NIS (N-iodosuccinimide), DAST (diethylaminosulfur trifluoride), SelectFluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-tetrafluoroborate), and XtalFluor (diethylamino-difluorosulfonium tetrafluoroborate) did not form any traces of Scheme V-6 Benzoyl transposition of V-16 and V-18. PhNBnPhOV-16PhNBnPhOOHClrt, 3 d, 97% yieldDCDMH (1.1 equiv), TFE (0.025 M)V-17NBnPhONBnPhOOHClV-18V-19rt, 2 d, 54% yield, >99:1 drDCDMH (1.1 equiv), TFE (0.025 M)!"")!the desired iodo- or fluoro-induced benzoyl transposed products. Surprisingly BDSB (bromodiethylsulfonium bromopentachloroantimonate (V)) did successfully afford the bromo-induced transposed product in great yields, regio- and diastereoselectivity. Scheme V-7 shows the substrate scope for the bromo-induced benzoyl transposition of unsaturated tertiary amides. Bromoesters V-20 to V-25 were formed as one single diastereomer in great yields, under similar optimized reaction conditions used for the formation of chloroesters. There was no need to use HCl for quenching these reactions, since bromination of final secondary amine is not an issue, as the brominated tertiary amides are less stable than their chlorinated counterparts. Substituting the benzoyl group with electron-withdrawing groups leads to lower yields (V-23). We also discovered that along with benzoyl transposition, a bromo-induced acetyl transposition could also occur to provide bromoester V-21 in 65% yield. The use of different bromenium sources such as NBS or DBDMH resulted in formation of products in much lower yields.   Next, we moved our attention toward bromo-induced benzoyl transposition of aliphatic olefins (Scheme V-8). We observed similar regioselectivity problem obtained in formation of chloroesters (Table V-6). Bromoester V-26 and O/N-trans-acylated regioisomer V-27 were formed in 1:4 ratio and an overall 81% yield. !"""!  Scheme V-7 Substrate scope for the formation of bromoester products. 2-4 days, > 99:1 drR1NR2R3OR1NHR2OBrOR3BDSB (1.1 equiv) TFE (0.025 M), rtNHOBrOV-2267% yieldNHOBrOV-2345% yieldNHOBrOV-2087% yieldNO2NHOBrOOMeV-2477% yieldNHOBrOV-2565% yieldNHOBrOMeV-2165% yieldBrCl!"",!V-6 Mechanistic rationale on the formation of benzoyl-transposed haloesters or halohydrins Based on the high diastereo- and regioselectivities observed in the formation of haloesters or halohydrins, we believe in an intramolecular reaction mechanism pathway. The first step is the reaction of electrophilic halenium ions with nucleophilic olefins to form an ill-defined intermediate (the real identity of having a bridged or a carbocationic intermediate is not clear at this point). The ill-defined intermediate bearing a tertiary amide moiety, then proceeds through an intramolecular halocyclization reaction (similar to our previously reported chlorocyclization of secondary amides)65 to afford the putative intermediate V-29 (Scheme V-8). The halocyclization reaction could occur through stepwise or a concerted reaction mechanism. Intermediate V-29, where the N atom is ÔblockedÕ by an alkyl or aryl R2 substituent, gives an iminium ion that could be hydrolyzed to provide intermediate V-30. This intermediate leads to the formation of final products through two different paths. If bond ÒaÓ breaks benzoyl-transposed haloesters is formed. Breaking Scheme V-8 Bromo-induced benzoyl transposition of aliphatic olefin V-11. 3 d, 81% yieldV-26:V-27(20:80)NBnOPhNHOBrPhOBnV-26BDSB (1.1 equiv)TFE (0.025 M), rtV-11NBnBrOHV-27OPh!""$!bond ÒbÓ forms halohydrins containing tertiary amides. Halohydrins could also be formed through O/N-trans-acylation of haloesters. It warrants emphasis that halohydrin products are analogous to those one might obtain from a diastereo- and regioselective intermolecular halohydrin formation of allylic amine derivatives.!However, halohydrins obtained from our methodology could not be the direct outcome of halenium intermediates V-28 through nucleophilic attack by water. This is because only one single diastereomer is Scheme V-9 Mechanistic rational on formation of haloesters and halohydrins. R1NHR2OXOArR1NR2OHXOArFormation of HaloestersFormation of HalohydrinsR1NR2ArOONXR1R2ArR1NR2ArOXXH2OONXR1R2ArOHab"b" breaks"a" breaksO/N transacylationV-28tertiary amidesV-29V-30!""%!obtained in these transformations, and yet intermolecular halohydrin formations results in a mixture of diastereomers or regioisomers.   V-7 Synthesis of unsaturated tertiary amides  As shown in Scheme V-9, different paths were taken for the synthesis of unsaturated tertiary amides  (starting material for benzoyl transposition methodology). Trans olefins could be synthesized through reductive amination followed by acyl protection (Scheme V-9-a). They could be also derived from nitrile reduction, followed by acyl protection and alkylation steps (Scheme V-9-b). 1,1-Disubstituted olefins were obtained from Mitsunobu reaction of allylic alcohols, followed by Gabriel hydrolysis and late stage protection/alkylation of free amine (Scheme V-9-c).  !Scheme V-10 Synthesis of unsaturated amides. R1CNLiAlH4, Et2O-78 ¡C to rtR1NH21. Et3N, DMAP    ArCl, DCM, rt2. NaH, R2-Br    THF, 0 ¡C to rtR1OR2-NH2R1NHR2R1NR2Et3N, DMAP, rtOAr, EtOHArCl, DCMR1OHR1NH21. Et3N, DMAPArCl, DCM, rt1. DIAD, PPh3    Phthalimide    THF, 0 ¡C to rt2. NaH, R2-Br    THF, 0 ¡C to rt2. NH2NH2    MeOH, rtR1NR2ArO NaBH4, 0 ¡C to rta)b)c)!""'!V-8 Future direction  As a future goal, this methodology could be further expanded toward substituted amides (methylene hydrogen next to tertiary amide is replaced by an alkyl or aryl group) as starting materials such as V-32 (Scheme V-10). We have developed a simple two-step procedure for the synthesis of V-32 through a metal-free substitution reaction of allylic alcohols with benzyl amine, followed by benzoyl protection of secondary amine. Chlorenium-induced benzoyl transposition of V-32 provided V-33 in 45% yield as one single isomer. Low yields were due to low stability of the final products during chromatographic purifications. Further efforts are essential toward improving the yield of this reaction by using different purification techniques. The relative stereochemistry of V-33 should be reconfirmed through X-ray crystallography or derivatization studies to a known compound.  This methodology is highly diastereoselective and could potentially be expanded to various substitutions on the methylene carbon. This methodology has great potential for one-pot synthesis of secondary amines with three chiral centers. The final chloroester could be formed as one single enantiomer if non-racemic V-32 is used in this methodology.  !""(! More investigations are needed for generalizing this methodology to other electrophilic sources other than chlorenium and bromenium ions. Enantioselective version of this transformation could be examined using different chiral catalysts. Computational calculations, kinetic studies, and O18 tracing techniques could help elucidate the mechanism of this transformation.      PhNBnOPhPhDCDMH (1.1 equiv)TFE (0.025 M)100% conv, rt 2 days, 45% yieldPhNHBnPhOClPhO DMAP, pyridine 50 ¡C, 24 h92% yieldPhOHPhH2NBn, HFIPPhNHPhBnPhCOCl, DCM17 h, rt, 62% yieldV-31V-32V-33(E)-1,3-diphenylprop-2-en-1-olScheme V-11 Synthesis of substituted amide V-32 and formation of chloroester V-33. !",*!V-9 Conclusion:  In conclusion, we have demonstrated the use of DCDMH or BDSB as chlorenium or bromenium sources in TFE as an effective method to obtain high yields for the formation of vicinal halohydrins or haloesters synthesis from unsaturated tertiary amides. The reaction can be applied to a variety of 1,2-trans, 1,1-disubstituted, or cyclic olefins with excellent diastereoselectivities. When using aromatic olefins, exclusively high regioselectivity was observed. This protocol has great potential towards the synthesis of organic molecules in a more efficient manner. Indeed, this methodology offers numerous advantages including high yields, formation of one single diastereomer, readily accessed starting materials and handling of reagents, and straightforward reaction conditions, while eliminating the need to use any metals or catalysts.  Finally this method could find wide application in the highly diastereo- and regioselective synthesis of haloesters, and halohydrins directly form olefin as the starting point.       !",+!V-10 Experimental All reagents were purchased from commercial sources and were used without purification. THF and Et2O were freshly distilled from Na-benzophenone ketyl whereas CH2Cl2 and PhCH3 were distilled over CaH2. Trifluoroethanol (>99%) and hexafluoroisopropanol (>99.5%) were purchased from Aldrich or Synquest Labs, used without further purification. TLC analyses were performed on silica gel plates (pre-coated on glass; 0.20 mm thickness with fluorescent indicator UV254) and were visualized by UV, I2 complex formation or charring in anisaldehyde, KMNO4 or PMA stains. 1H NMR spectra were measured at a 500 MHz on a Varian VXR-500 or 600 MHz Inova NMR spectrometer. Chemical shifts are reported relative to residual solvent peaks (! 7.24, 2.04, and 1.94 ppm for CDCl3, (CD3)2CO, and CD3CN respectively). 13C NMR spectra were measured were measured on 125 MHz Varian or 150 MHz Inova NMR spectrometer and referenced using deuterated chloroform, unless otherwise mentioned. Chemical shifts are reported relative to residual solvent peaks (! 77.0, 29.8, and 118.3 ppm for CDCl3, (CD3)2CO, CD3CN respectively).Flash silica gel (32-63 mm, Silicycle 60 †) was used for column chromatography. Ratios of products were determined by crude NMR analysis. All known compounds were characterized by 1H and 13C NMR and are in complete agreement with samples reported elsewhere. All new compounds were characterized by 1H, 13C NMR and HRMS.  !",#!V-10A General procedure for synthesis of vic-halohydrin esters  A 10 to 20 mL glass vial equipped with a magnetic stir bar was charged with the substrate (0.14 mmol, 1.0 equiv) and dissolved in CF3CH2OH (5.6 mL, 0.025 M). This was followed by the addition of DCDMH (30.2 mg, 0.15 mmol, 1.1 equiv) or BDSB (83.7 mg, 0.15 mmol, 1.1 equiv) in a single portion at ambient temperature. The vial was capped and the reaction was stirred at ambient temperature for 2-7 days. The reaction was then quenched with 50% aqueous HCl solution (1.0 mL for 0.03 mmol substrate) and stirred for 1-2 h. Then the solution was neutralized with NaOH (15% aqueous solution, to pH around 8) and was extracted with CH2Cl2 (3 x 2 mL).  The combined organics were washed with brine and then dried over anhydrous Na2SO4 and filtered.  Conversions and diastereomeric ratios were determined by 1H NMR analysis of the crude reaction mixture. Pure products and unreacted substrates were subsequently isolated using column chromatography on silica gel as stationary phase (EtOAc-Hexanes gradient) or using HPLC on silica gel as stationary phase (IPA-Hexanes elution).     2-7 days, rtR1NR2R3OR1NHR2OXOR3DCDMH or BDSB, TFE!",)!Analytical data for chlorohydrin and chlorohydrin esters V-5: 3-(benzylamino)-2-chloro-1-phenylpropyl benzoate  1H NMR (500 MHz, CDCl3) ! 8.06 (d, J = 7.5 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.20-7.50 (m, 12H), 6.30 (d, J = 5.5 Hz, 1H), 4.56 (ddd, J = 3.5 Hz, J = 5.5 Hz, J = 7.5 Hz, 1H), 3.85 (d, J = 13.0 Hz, 1H), 3.77 (d, J = 13.0 Hz, 1H), 3.09 (dd, J = 4.5 Hz, J = 13.0 Hz, 1H), 3.02 (dd, J = 8.0 Hz, J = 13.5 Hz, 1H). 13C NMR (125 MHz, CDCl3), ! 165.0, 140.0, 136.6, 133.3, 129.74, 129.71, 128.6, 128.5, 128.4, 128.3, 128.1, 127.4, 127.1, 76.5, 63.4, 53.3, 51.1. HRMS (ESI) Calculated Mass for C23H22NO2Cl: ([M+H]+) = 380.1417, Found ([M+H]+) = 380.1420. V-6: 3-(benzylchloroamino)-2-chloro-1-phenylpropyl benzoate  1H NMR (500 MHz, CDCl3) ! 8.09 (d, J = 7.0 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.29-7.41 (m, 10H), 6.40 (d, J = 4.5 Hz, 1H), 4.86 NHOClONOClOCl!","!(ddd, J = 4.0 Hz, J = 7.0 Hz, J = 7.0 Hz, 1H), 4.16 (d, J = 13.0 Hz, 1H), 4.12 (d, J = 13.0 Hz, 1H), 3.21 (m, 2H). 13C NMR (125 MHz, CDCl3), ! 165.1, 135.8, 135.3, 133.3, 129.8, 129.7, 129.5, 128.6, 128.5, 128.5, 128.3, 128.2, 127.7, 75.5, 68.6, 64.8, 59.9. 2D-HSQCAD spectrum is included.   V-7: 3-(butylamino)-2-chloro-1-phenylpropyl benzoate  1H NMR (500 MHz, CDCl3) ! 8.08 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.0 Hz, 1H), 7.43-7.47 (m, 4H), 7.31-7.37 (m, 3H), 6.26 (d, J = 6.0 Hz, 1H), 4.51 (ddd, J = 4.0 Hz, J = 6.0 Hz, J = 8.5 Hz, 1H), 3.02 (dd, J = 4.0 Hz, J = 13.0 Hz, 1H), 2.93 (dd, J = 9.0 Hz, J = 13.0 Hz, 1H), 2.57 (m, 2H), 1.30-1.46 (m, 4H), 1.46 (br s, 1H), 0.88 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3), ! 165.1, 136.6, 133.3, 129.8, 129.7, 128.6, 128.5, 128.4, 127.3, 63.6, 51.9, 49.1, 32.2, 20.4, 13.9. HRMS (ESI) Calculated Mass for C20H24NO2Cl: ([M+H]+) = 346.1574, Found ([M+H]+) = 346.1581.  NHOClO!",,!V-8-Cl: 3-(benzylchloroamino)-2-chloro-1-phenylpropyl 4-nitrobenzoate  1H NMR (500 MHz, CDCl3) ! 8.30 (d, J = 9.5 Hz, 2H), 8.24 (d, J = 9.0 Hz, 2H), 7.25-7.40 (m, 10H), 6.44 (d, J = 4.0 Hz, 1H), 4.89 (ddd, J = 4.0 Hz, J = 5.5 Hz, J = 7.5 Hz, 1H), 4.16 (d, J = 13.0 Hz, 1H), 4.11 (d, J = 13.0 Hz, 1H), 3.20 (dd, J = 5.5 Hz, J = 13.0 Hz, 1H), 3.14 (dd, J = 8.0 Hz, J = 13.0 Hz, 1H). 13C NMR (125 MHz, CDCl3), ! 163.3, 150.7, 135.6, 135.1, 134.4, 130.9, 129.6, 128.9, 128.6, 128.4, 128.3, 127.8, 123.7, 76.3, 68.7, 64.7, 59.5. V-9: 3-(benzylamino)-2-chloro-1-phenylpropyl 4-methoxybenzoate  1H NMR (500 MHz, CDCl3) ! 8.01 (d, J = 8.5 Hz, 2H), 7.30-7.44 (m, 10H), 6.93 (d, J = 9.0 Hz, 2H), 6.24 (d, J = 6.0 Hz, 1H), 4.59 (ddd, J = 3.5 Hz, J = 5.5 Hz, J = 8.5 Hz, 1H), 3.90 (d, J = 13.0 Hz, 1H), 3.88 (s, 3H), 3.80 (d, J = NHOClOOMeNOClONO2Cl!",$!13.0 Hz, 1H), 3.11 (dd, J = 3.5 Hz, J = 13.0Hz, 1H), 3.01 (d, J = 9.0 Hz, J = 13.0 Hz, 1H). 13C NMR (125 MHz, CDCl3), ! 164.8, 163.7, 136.6, 131.9, 129.0, 128.7, 128.5, 128.4, 128.3, 127.3, 122.0, 113.8, 76.2, 63.0, 55.5, 53.1, 50.8. HRMS (ESI) Calculated Mass for C24H24NO3Cl: ([M+H]+) = 410.1523, Found ([M+H]+) = 410.1527. V-10: 3-(benzylamino)-2-chloro-1-phenylpropyl 4-bromobenzoate  1H NMR (500 MHz, CDCl3) ! 7.88 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.33-7.43 (m, 5H), 7.25-7.28 (m, 5H), 6.26 (d, J = 6.0 Hz, 1H), 4.52 (ddd, J = 3.5 Hz, J = 5.5 Hz, J = 7.5 Hz, 1H), 3.83 (d, J = 13.0 Hz, 1H), 3.75 (d, J = 13.0 Hz, 1H), 3.04 (dd, J = 4.5 Hz, J = 13.0 Hz, 1H), 2.98 (dd, J = 8.0 Hz, J = 13.0 Hz, 1H). 13C NMR (125 MHz, CDCl3), ! 164.4, 139.6, 136.3, 131.9, 131.2, 128.8, 128.6, 128.5, 128.4, 128.1, 127.4, 127.1, 76.8, 63.2, 53.3, 51.1. HRMS (ESI) Calculated Mass for C23H21NO2ClBr: ([M+H]+) = 458.0522, Found ([M+H]+) = 458.0534.  NHOClOBr!",%!V-10-Cl: 3-(benzylchloroamino)-2-chloro-1-phenylpropyl 4-bromobenzoate  1H NMR (500 MHz, CDCl3) ! 7.91 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.29-7.40 (m, 10H), 6.37 (d, J = 4.0 Hz, 1H), 4.84 (ddd, J = 4.5 Hz, J = 7.5 Hz, J = 13.5 Hz, 1H), 4.14 (d, J = 12.5 Hz, 1H), 4.09 (d, J = 12.5 Hz, 1H), 3.16 (dddd, J = 6.0 Hz, J = 13.5 Hz, J = 13.5 Hz, J = 13.5 Hz, 2H). 13C NMR (125 MHz, CDCl3), ! 164.4, 135.8, 134.9, 131.9, 131.3, 129.5, 128.7, 128.6, 128.5, 128.3,128.2, 127.7, 75.7, 68.6, 64.8, 59.7. V-12: 1-(benzylamino)-2-chlorohexan-3-yl benzoate  1H NMR (500 MHz, CDCl3) ! 8.01 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.30-7.20 (m, 5H), 5.38 (ddd, J = 3.5 Hz, J = 5.5 Hz, J = 9.0 Hz, 1H), 4.31 (ddd, J = 3.5 Hz, J = 5.0 Hz, J = 9.0 Hz, 1H), 3.85 (d, J = 13.0 Hz, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.01 (d, J = 4.0 Hz, J = 12.5 Hz, 1H), NHOClONOClOBrCl!",'!2.94 (d, J = 9.0 Hz, J = 12.5 Hz, 1H), 1.85 (m, 1H), 1.70 (br s, 1H), 1.73 (m, 1H), 1.47-1.30 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3), ! 165.9, 139.8, 133.1, 129.9, 129.7, 128.4, 128.1, 127.1, 74.7, 63.3, 53.3, 51.5, 32.7, 18.4, 13.9. HRMS (ESI) Calculated Mass for C20H24NO2Cl: ([M+H]+) = 346.1574, Found ([M+H]+) = 346.1581. V-13: N-benzyl-N-(3-chloro-2-hydroxyhexyl)benzamide   1H NMR (500 MHz, CDCl3) ! 7.47-7.29 (m, 8H), 7.16 (d, J = 7.5 Hz, 2H), 4.8 (br s, 1H), 4.64 (d, J = 16.0 Hz, 1H), 4.59 (d, J = 16.0 Hz, 1H), 3.86-3.81 (m, 3H), 3.65 (d, J = 13.0 Hz, 1H), 1.88 (m, 1H), 1.58 (m, 2H), 1.37 (m, 1H), 0.90 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3), ! 174.9, 136.0, 135.2, 130.2, 128.9, 128.6, 127.9, 127.0, 126.8, 74.8, 64.8, 54.7, 50.5, 35.7, 19.4, 13.5. HRMS (ESI) Calculated Mass for C20H24NO2Cl: ([M+H]+) = 346.1574, Found ([M+H]+) = 346.1584. 2D-gCOSY, HSQCAD, HMBC spectra are included.   NClOHO!",(!V-17: N-benzyl-N-(3-chloro-2-hydroxy-2-phenylpropyl)benzamide  1H NMR (500 MHz, CDCl3) ! 7.56 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.26-7.38 (m, 9H), 6.98 (d, J = 7.5 Hz, 2H), 5.03 (s, 1H), 4.48 (d, J = 16.0 Hz, 1H), 4.41 (d, J = 14.5 Hz, 1H), 3.92 (s, 2H), 3.82 (d, J = 16.5 Hz, 1H), 3.51 (d, J = 14.0 Hz, 1H). 13C NMR (125 MHz, CDCl3), ! 174.9, 141.8, 136.0, 135.4, 129.9, 128.9, 128.6, 128.5, 127.9, 127.8, 126.9, 126.5, 125.7, 77.9, 54.4, 53.1, 52.5. HRMS (ESI) Calculated Mass for C23H22NO2Cl: ([M+H]+) = 380.1417, Found ([M+H]+) = 380.1416.  V-19: N-benzyl-N-((1-chloro-2-hydroxycyclohexyl)methyl)benzamide  1H NMR (500 MHz, CDCl3) ! 7.27-7.45 (m, 8H), 7.09 (d, J = 8.0 Hz, 2H), 5.57 (br s, 1H), 4.76 (d, J = 16.0 Hz, 1H), 4.71 (d, J = 16.0 Hz, 1H), 4.16 (s, 1H), NOOHClNOOHCl!"$*!3.81 (d, J = 14.5 Hz, 1H), 3.48 (d, J = 15.0 Hz, 1H), 2.32 (t, J = 11.5 Hz, 1H), 1.69-1.81 (m, 4H), 1.47-1.56 (m, 3H). 13C NMR (125 MHz, CDCl3), ! 176.1, 136.4, 135.5, 130.0, 128.9, 128.6, 127.8, 126.9, 126.7, 74.8, 63.4, 55.8, 54.8, 31.2, 29.9, 20.7, 20.0. HRMS (ESI) Calculated Mass for C21H24NO2Cl: ([M+H]+) = 358.1574, Found ([M+H]+) = 358.1575. 2D-gCOSY, HSQCAD, and HMBC spectra are included. V-33: 3-(benzylamino)-2-chloro-1,3-diphenylpropyl benzoate  1H NMR (500 MHz, CDCl3) ! 7.97 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.26-7.48 (m, 17H), 6.05 (br s, 1H), 4.82 (br s, 1H), 4.08 (br s, 1H), 3.72 (d, J = 11.5 Hz, 1H), 3.58 (d, J = 13.0 Hz, 1H). 13C NMR (125 MHz, CDCl3), ! 164.7, 136.6, 133.3, 129.7, 128.6, 128.49, 128.47, 128.42, 128.1, 128.0, 127.2, 76.0, 67.1, 62.5, 50.6. HRMS (ESI) Calculated Mass for C29H26NO2Cl: ([M+H]+) = 456.1730, Found ([M+H]+) = 456.1739.    NHOClO!"$+!Analytical data for bromohydrin and bromohydrin esters V-33: 3-(benzylamino)-2-bromo-1-phenylpropyl benzoate  1H NMR (500 MHz, CDCl3) ! 8.06 (d, J = 9.0 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.22-7.48 (m, 12H), 6.35 (d, J = 5.5 Hz, 1H), 4.66 (dd, J = 6.5 Hz, J = 12.5 Hz, 1H), 3.88 (d, J = 13.5 Hz, 1H), 3.79 (d, J = 13.5 Hz, 1H), 3.11 (d, J = 6.0 Hz, 2H). 13C NMR (125 MHz, CDCl3), ! 164.9, 139.2, 136.9, 133.3, 129.8, 129.6, 128.7, 128.5, 128.4, 128.3, 128.2, 127.3, 127.2, 76.6, 56.5, 53.1, 51.1. HRMS (ESI) Calculated Mass for C23H22NO2Br: ([M-H]+) = 422.0756, Found ([M-H]+) = 422.0760. V-21: 3-(benzylamino)-2-bromo-1-phenylpropyl acetate  1H NMR (500 MHz, CDCl3) ! 7.51 (m, 2H), 7.23-7.36 (m, 8H), 6.01 (d, J = 6.0 Hz, 1H), 4.83 (ddd, J = 2.5 Hz, J = 5.0 Hz, J = 9.0 Hz, 1H), 4.29 (d, J = 13.0 Hz, 1H), 4.20 (d, J = 13.0 Hz, 1H), 3.31 (dd, J = 3.0 Hz, J = 13.5 Hz, 1H), 3.13 (dd, J = 10.0 Hz, J = 13.5 Hz, 1H), 2.06 (s, 3H). NHOBrONHOBrOMe!"$#!HRMS (ESI) Calculated Mass for C18H20NO2Br: ([M+H]+) = 362.0756, Found ([M+H]+) = 362.0762. V-22: 3-(benzylamino)-2-bromo-1-phenylpropyl 4-chlorobenzoate  1H NMR (500 MHz, CDCl3) ! 8.10 (d, J = 8.5 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.30-7.50 (m, 7H), 7.06 (d, J = 9.0 Hz, 2H), 6.40 (d, J = 8.5 Hz, 2H), 6.35 (d, J = 5.5 Hz, 1H), 4.60 (ddd, J = 3.5 Hz, J = 5.0 Hz, J = 8.5 Hz, 1H), 3.72 (dd, J = 4.0 Hz, J = 14.5 Hz, 1H), 3.50 (dd, J = 8.5 Hz, J = 14.5 Hz, 1H). 13C NMR (125 MHz, CDCl3), ! 165.0, 136.7, 133.6, 129.8, 129.4, 129.3, 128.9, 128.7, 128.6, 126.8, 114.7, 76.8, 54.9, 46.7. HRMS (ESI) Calculated Mass for C22H19NO2ClBr: ([M+H]+) = 444.0366, Found ([M+H]+) = 444.0370.        NHOBrOCl!"$)!V-24: 3-(benzylamino)-2-bromo-1-phenylpropyl 4-methoxybenzoate  1H NMR (500 MHz, CDCl3) ! 8.01 (d, J = 9.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.20-7.40 (m, 8H), 6.93 (d, J = 8.5 Hz, 2H), 6.31 (d, J = 6.0 Hz, 1H), 4.65 (m, 1H), 3.88 (s, 3H), 3.87 (d, J = 13.0 Hz, 1H), 3.78 (d, J = 13.0 Hz, 1H), 3.11 (m, 2H). 13C NMR (125 MHz, CDCl3), ! 164.7, 163.7, 137.1, 131.9, 128.6, 128.5, 128.4, 128.2, 127.3, 127.2, 121.9, 113.8, 76.3, 56.6, 55.5, 53.0, 51.2. HRMS (ESI) Calculated Mass for C24H24NO3Br: ([M+H]+) = 454.1018, Found ([M+H]+) = 454.1036. V-25: 3-(benzylamino)-2-bromo-1-phenylpropyl 4-bromobenzoate  1H NMR (500 MHz, CDCl3) ! 7.86 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.25-7.40 (m, 10H), 6.29 (d, J = 6.0 Hz, 1H), 4.61 (dd, J = 7.5 Hz, J = NHOBrOOMeNHOBrOBr!"$"!12.0 Hz, 1H), 3.85 (d, J = 12.5 Hz, 1H), 3.75 (d, J = 12.5 Hz, 1H), 3.07 (s, 1H), 3.05 (d, J = 4.0 Hz, 1H). 13C NMR (125 MHz, CDCl3), ! 164.3, 136.6, 131.9, 131.2, 128.8, 128.52, 128.50, 128.48, 128.46, 128.2, 127.3, 57.0, 56.1, 53.0, 51.0. HRMS (ESI) Calculated Mass for C23H21NO2Br2: ([M+H]+) = 502.0017, Found ([M+H]+) = 502.0028. V-26: 1-(benzylamino)-2-bromohexan-3-yl benzoate  1H NMR (500 MHz, CDCl3) ! 8.02 (d, J = 8.0 Hz, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.23-7.36 (m, 7H), 5.39 (ddd, J = 3.5 Hz, J = 5.5 Hz, J = 9.0 Hz, 1H), 4.47 (m, 1H), 3.89 (d, J = 13.0 Hz, 1H), 3.83 (d, J = 13.0 Hz, 1H), 3.07 (m, 2H), 1.89 (m, 1H), 1.75 (m, 1H), 1.20-1.50 (m, 2H), 0.93 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3), ! 165.8, 133.2, 129.8, 129.7, 128.5, 128.4, 128.2, 127.2, 126.7, 74.6, 56.8, 53.0, 51.6, 33.6, 18.5, 13.9. HRMS (ESI) Calculated Mass for C20H24NO2Br: ([M+H]+) = 390.1069, Found ([M+H]+) = 390.1076.   NHOBrO!"$,!V-27: N-benzyl-N-(3-bromo-2-hydroxyhexyl)benzamide 1H NMR (500 MHz, CDCl3) ! 7.27-7.47 (m, 8H), 7.16 (d, J = 7.0 Hz, 2H), 4.80 (br s, 1H), 4.62 (m, 2H), 3.85 (m, 2H), 3.66 (d, J = 13.0 Hz, 1H), 1.88 (m, 1H), 1.60 (m, 2H), 1.37 (m, 1H), 0.90 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3), ! 174.8, 136.0, 135.2, 130.2, 128.9, 128.6, 127.9, 127.0, 126.8, 74.6, 59.8, 54.7, 51.1, 36.2, 20.6, 13.4. HRMS (ESI) Calculated Mass for C20H24NO2Br: ([M+H]+) = 390.1069, Found ([M+H]+) = 390.1076. V-10B1 General procedure for synthesis of starting materials (Path A)  To a solution of alkyl- or aryl-amines (14.4 mmol) in EtOH (45 mL), cinnamaldehyde (2.0 g, 15.1 mmol) was added and the solution was heated to 60 ¡C. After stirring for 2-4 h, NaBH4 (0.56 g, 14.4 mmol) was slowly added at 0 ¡C. After the reaction was complete (monitored by TLC), H2O was added. The organic layer was extracted with ethyl acetate and washed with brine, dried over Na2SO4 and then concentrated. The residue was further purified NBrOHOR1OR2-NH2R1NHR2R1NR2Et3N, DMAPOAr, EtOHArCl, DCM, rt NaBH4, 0 ¡C to rt!"$$!with column chromatography. To the mixture obtained above (3.4 mmol) in CH2Cl2 (19.0 mL) was added Et3N (1.4 mL, 10.2 mmol) at room temperature. DMAP (3.0 mg, 0.017 mmol) and the appropriate acyl chloride (5.1 mmol) were added successively. After the reaction was complete (monitored by TLC), H2O was added. The organic layer was extracted with CH2Cl2 and washed with brine, dried over Na2SO4 and then concentrated. The residue was purified by flash chromatography to afford the unsaturated tertiary amides.  V-1: N-butyl-N-cinnamylbenzamide  1H NMR (500 MHz, CDCl3) ! (50:50 ratio of two conformers at room temperature) 7.20-7.45 (m, 10H), 6.58 (d, J = 15.5 Hz, 0.5H), 6.44 (d, J = 7.0 Hz, 0.5H), 6.30 (m, 0.5H), 6.01 (m, 0.5H), 4.31 (br s, 1H), 4.00 (br s, 1H), 3.55 (br s, 1H), 3.23 (br s, 1H), 1.67-0.67 (m, 7H). 13C NMR (125 MHz, CDCl3), ! 171.7, 136.9, 132.8, 132.4, 129.3, 128.6, 128.5, 128.4, 127.9, 127.7, 126.5, 124.9, 53.4, 51.2, 48.2, 46.6, 48.2, 46.6, 44.7, 30.6, 29.4, 20.3, 19.7, 13.9, 13.6. HRMS (ESI) Calculated Mass for C20H23NO: ([M+H]+) = 294.1858, Found ([M+H]+) = 294.1856. NO!"$%!V-4: N-benzyl-N-cinnamylbenzamide  1H NMR (500 MHz, CDCl3) ! (50:50 ratio of two conformers at room temperature) 7.22-7.52 (m, 15H), 6.44 (m, 1H), 6.32 (br s, 0.5H), 6.07 (br s, 0.5H), 4.85 (br s, 1H), 4.56 (br s, 1H), 4.29 (br s, 1H), 3.96 (br s, 1H). HRMS (ESI) Calculated Mass for C23H21NO: ([M+H]+) = 328.1701, Found ([M+H]+) = 328.1716. V-4: N-benzyl-N-cinnamyl-4-nitrobenzamide  1H NMR (500 MHz, CD3SOCD3, 25 ¡C) ! (64:36 ratio of two conformers at room temperature) 8.30-8.24 (dd, J = 8.5 Hz, J = 8.0 Hz, 3.1 H), 7.79-7.73 (dd, J = 8.5 Hz, J = 8.0 Hz, 3.2 H), 7.4-7.2 (m, 17.6 H), 6.52 (d, J = 16.0 Hz, 0.56 H), 6.41 (d, J = 15.5 Hz, 1H), 6.33 (m, 0.58H), 6.22 (m, 1H), 4.73 (s, 2H), 4.45 (s, 1.1), 4.19 (d, J = 5.5 Hz, 1H), 3.86 (d, J = 5.5 Hz, 2H), 3.35 (s, 1.4H). NONONO2!"$'!1H NMR (500 MHz, CD3SOCD3, 120 ¡C) ! 8.24 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.21-7.41 (m, 10H), 6.44 (d, J = 16.0 Hz, 1H), 6.18 (m, 1H), 4.68 (br s, 2H), 4.08 (br s, 2H). 13C NMR (125 MHz, CD3SOCD3, 120 ¡C), ! 169.9, 148.9, 143.5, 137.8, 137.2, 133.5, 129.2, 129.1, 128.9, 128.6, 128.3, 127.9, 127.1, 125.4, 124.3, 50.5, 49.8. HRMS (ESI) Calculated Mass for C23H20N2O3: ([M+H]+) = 373.1552, Found ([M+H]+) = 373.1554. V-11: (E)-N-benzyl-N-(hex-2-en-1-yl)benzamide  1H NMR (500 MHz, CDCl3) ! 7.10-7.50 (m, 10H), 5.22-5.60 (m, 2H), 4.40-4.80 (m, 2H), 3.65-4.12 (m, 2H), 2.04 (m, 2H), 1.42 (ddddd, J = 7.5 Hz, J = 7.5 Hz, J = 7.5 Hz, J = 7.5 Hz, J = 7.5 Hz, 2H), 0.92 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3), ! 171.2, 134.9, 130.6, 129.5, 128.9, 128.5, 128.6, 128.4, 127.4, 126.7, 126.6, 124.5, 50.0, 46.8, 34.3, 22.3, 13.6.   HRMS (ESI) Calculated Mass for C20H23NO: ([M+H]+) = 294.1858, Found ([M+H]+) = 294.1865.  NO!"$(!V-35: N-benzyl-N-cinnamyl-4-methoxybenzamide  1H NMR (500 MHz, CDCl3) ! (50:50 ratio of two conformers at room temperature) 7.48 (d, J = 8.5 Hz, 2H), 7.40-7.20 (m, 10H), 6.89 (s, 2H), 6.44 (d, J = 16.0 Hz, 1H), 6.29 (s, 0.8H), 6.09 (s, 0.9H), 4.80 (s, 1.3H), 4.60 (s, 1.2H), 4.22 (s, 1.2H), 4.0 (s, 1.4H), 3.82 (s, 3H). 1H NMR (500 MHz, CD3SOCD3, 100 ¡C) ! 7.43 (d, J = 8.0 Hz, 2H), 7.37-7.23 (m, 10H), 6.97 (d, J = 8.5 Hz, 2H), 6.43 (d, J = 16.0 Hz, 1H), 6.20 (ddd, J = 6.5 Hz, J = 6.5 Hz, J = 16.5 Hz, 1H), 4.65 (s, 2H), 4.06 (d, J = 5.5 Hz, 2H), 3.80 (s, 3H). 13C NMR (125 MHz, CD3SOCD3, 100 ¡C), ! 170.3, 159.8, 137.1, 136.0, 131.7, 128.2, 127.9, 127.0, 126.9, 126.5, 125.8, 124.8, 113.4, 54.8, 49.0, 48.5. HRMS (ESI) Calculated Mass for C24H23NO2: ([M+H]+) = 358.1807, Found ([M+H]+) = 358.1810.     NOOMe!"%*!V-36: N-benzyl-4-bromo-N-cinnamylbenzamide  1H NMR (500 MHz, CDCl3) ! 7.55 (m, 2H), 7.15-7.42 (m, 12H), 6.42 (br m, 1H), 5.90-6.35 (m, 1H), 4.82 (m, 1H), 4.53 (m, 1H), 4.26 (m, 1H), 3.93 (m, 1H). 13C NMR (125 MHz, CDCl3), ! 171.1, 133.1, 131.7, 128.7, 128.4, 128.1, 127.6, 126.7, 126.4, 124.0, 123.9, 51.8, 50.2, 47.5, 46.8. HRMS (ESI) Calculated Mass for C23H20NOBr: ([M+H]+) = 406.0807, Found ([M+H]+) = 406.0811. V-37: N-benzyl-N-cinnamylacetamide  1H NMR (500 MHz, CDCl3) ! 7.20-7.41 (m, 10H), 6.43 (t, J = 15.0 Hz, 1H), 6.05-6.20 (m, 1H), 4.66 (s, 1H), 4.55 (s, 1H), 4.16 (d, J = 6.5 Hz, 1H), 3.99 (dd, J = 1.0 Hz, J = 5.5 Hz, 1H), 2.22 (s, 1.5H), 2.18 (s, 1.5H). 1H NMR (500 MHz, CD3SOCD3, 100 ¡C) ! 7.20-7.41 (m, 10H), 6.47 (d, J = 16.0 Hz, 1H), 6.18 (m, 1H), 4.58 (s, 2H), 4.07 (d, J = 6.0 Hz, 2H), 2.12 (s, 3H). NOCH3NOBr!"%+!13C NMR (125 MHz, CDCl3), ! 170.9, 137.5, 136.6, 136.5, 136.1, 133.1, 131.9, 129.0, 128.7, 128.6, 128.56, 128.3, 128.0, 127.7, 127.6, 127.4, 126.4, 126.3, 124.4, 123.8, 50.9, 49.8, 48.1, 47.3, 21.7, 21.6. HRMS (ESI) Calculated Mass for C18H19NO: ([M+H]+) = 266.1545, Found ([M+H]+) = 266.1553. V-38: N-(4-chlorophenyl)-N-cinnamylbenzamide  1H NMR (500 MHz, CDCl3) ! 7.19-7.41 (m, 12H), 6.99 (d, J = 8.5 Hz, 2H), 6.49 (d, J = 15.5 Hz, 1H), 6.37 (ddd, J = 6.5 Hz, J = 6.5 Hz, J = 16.0 Hz, 1H), 4.66 (d, J = 7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3), ! 170.2, 142.1, 136.5, 135.6, 133.6, 132.3, 129.9, 129.3, 128.9, 128.7, 128.5, 128.4, 127.9, 127.8, 126.5, 124.1, 52.8. HRMS (ESI) Calculated Mass for C22H18NOCl: ([M+H]+) = 348.1155, Found ([M+H]+) = 348.1161. V-10B2 General procedure for synthesis of starting materials (Path B)  NOClPhNBnOPhPh DMAP, pyridine 50 ¡C, 24 h92% yieldPhOHPhH2NBn, HFIPPhNHPhBnPhCOCl, DCM17 h, rt, 62% yieldV-31V-32(E)-1,3-diphenylprop-2-en-1-ol!"%#!Onto an open-air tube containing a 1 M solution of the allylic alcohol (500 mg, 2.4 mmol, 1.0 equiv) in HFIP (2.4 mL) was added benzyl amine (0.39 mL, 3.60 mmol, 1.5 equiv). The reaction mixture was then stirred for 24 h at 50 ¡C, After which the volatiles were evaporated, and the crude compounds were purified by flash chromatography to afford V-31 in 92% yield.66 To the V-31 (0.63 g, 2.11 mmol, 1.0 equiv) in CH2Cl2 (22 mL) was added pyridine (0.41 mL, 5.1 mmol, 2.41 equiv) at room temperature. DMAP (30 mg, 0.211 mmol, 0.1 equiv) and benzoyl chloride (0.49 mL, 4.22 mmol, 2.0 equiv) were added successively. After the reaction was complete (monitored by TLC), H2O was added. The organic layer was extracted with CH2Cl2 and washed with brine, dried over Na2SO4 and then concentrated. The residue was purified by flash chromatography to afford the unsaturated tertiary amides V-32 in 62% yield.  V-31: (E)-N-benzyl-1,3-diphenylprop-2-en-1-amine  1H NMR (500 MHz, CDCl3) ! 7.23-7.50 (m, 15H), 6.62 (d, J = 15.5 Hz, 1H), 6.35 (d, J = 7.5 Hz, J = 16.0 Hz, 1H), 4.43 (d, J = 7.5 Hz, 1H), 3.82 (d, J = 14.0 Hz, J = 20.0 Hz, 2H), 1.78 (br s, 1H). NH!"%)!13C NMR (125 MHz, CDCl3), ! 142.9, 140.4, 136.9, 132.6, 130.3, 128.6, 128.5, 128.4, 128.1, 127.4, 127.3,127.2, 126.9, 126.4, 64.6, 51.4. HRMS (ESI) Calculated Mass for C22H21N: ([M+Na]+) = 300.1752, Found ([M+H]+) = 300.1757. V-32: (E)-N-benzyl-N-(1,3-diphenylallyl)benzamide  1H NMR (500 MHz, CDCl3) ! 8.13 (d, J = 8.0 Hz, 0.5H), 7.10-7.60 (m, 19.5H), 6.10-6.60 (br m, 3H), 5.80 (br s, 1H), 5.17 (br s, 1H), 4.34 (br s, 1H). 13C NMR (125 MHz, CDCl3), ! 170.7, 138.8, 136.6, 136.2, 133.5, 130.5,130.1, 129.6, 128.7, 128.5, 128.4, 127.9, 127.5, 127.3, 126.8, 126.5, 64.8, 46.3. HRMS (ESI) Calculated Mass for C29H25NO: ([M+Na]+) = 426.1834, Found ([M+H]+) = 426.1837. V-10B3 General procedure for synthesis of starting materials (Path C)  To a stirred solution of the crude allyl alcohol (100 mg, 0.75 mmol, 1.0 NONOPhOHPhNH21. Et3N, DMAP, rt    PhCOCl, DCM1. DIAD, PPh3    Phthalimide    THF, 0 ¡C to rt2. NaH, BnBr    THF, 0 ¡C to rt2. NH2NH2    MeOH, rt2-phenylprop-2-en-1-olV-162-phenylprop-2-en-1-amine!"%"!equiv) in dry THF (2 mL) was added triphenylphosphine (196 mg, 0.75 mmol, 1.0 equiv) under N2 at ambient temperature. The solution was cooled to 0 ¡C and phthalimide (132 mg, 0.89 mmol, 1.2 equiv) was added. To the reaction mixture was added DIAD (0.18 mL, 0.89 mmol, 1.2 equiv) dropwise over an hour. The reaction mixture was allowed to stir for one hour, slowly warming to ambient temperature. After 2 h, the solvent was evaporated under reduced pressure and the crude was directly used for the next reaction.  To the mixture above (0.75 mmol) in MeOH (5 mL) was added NH2NH2.H2O (1 mL) at room temperature. The reaction was stirred for 12 h (this reaction could be refluxed also in EtOH for 3 h to complete). Water was added, and MeOH was removed under reduced pressure. Concentrated HCl (0.5 mL) was added at 0 ¡C and the solution was stirred for 1 hour. The solids were filtered, and the filtrate was basified by NaOH (1N) to pH=10. The aqueous layer was extracted with EtOAc and the combined organic layers were evaporated under reduced pressure. The crude amine was used for the next step without further purification.  To the mixture obtained above (0.75 mmol, 1.0 equiv) in CH2Cl2 (5 mL) was added Et3N (0.21 mL, 1.5 mmol, 2.0 equiv) at room temperature. DMAP (1 mg, 0.0075 mmol, 0.01 equiv) and benzoyl chloride (158 mg, 1.13 mmol, 1.5 equiv) were added successively. After the reaction was complete (monitored by TLC), H2O was added. The organic layer was extracted with CH2Cl2 and washed with brine, dried over Na2SO4 and concentrated. The !"%,!residue was purified by flash chromatography to afford the unsaturated secondary amide.  The secondary amide from the previous step (0.5 g, 2.11 mmol, 1.0 equiv) was added to a solution of NaH (101 mg, 2.53 mmol, 1.2 equiv) in THF (10 mL) at 0 ¡C. The reaction was warmed to room temperature and then refluxed for 1 h. After this time, benzyl bromide (0.3 mL, 2.53 mmol, 1.2 equiv) was added drop wise and the reaction mixture was heated for additional 4 h. After the reaction was complete (monitored by TLC), H2O was added. The reaction was extracted with EtOAc and washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford the unsaturated tertiary amide V-16 in 93% yield.  V-16: N-benzyl-N-(2-phenylallyl)benzamide  1H NMR (500 MHz, CDCl3) ! 7.10-7.60 (m, 15H), 5.56 (s, 1H), 5.10-5.31 (m, 1H), 4.84 (s, 1H), 4.64 (s, 1H), 4.34 (s, 1H), 4.19 (s, 1H). 13C NMR (125 MHz, CDCl3), ! 172.1, 143.6, 138.7, 137.1, 136.4, 136.2, 129.7, 129.5, 128.7, 128.4, 128.1, 127.5, 127.1, 126.5, 126.1, 115.3, 114.1, 51.8, 51.2, 47.4, 46.5. NO!"%$!HRMS (ESI) Calculated Mass for C23H21NO: ([M+H]+) = 328.1701, Found ([M+H]+) = 328.1706. V-10B4 General procedure for synthesis of starting materials (Path D)  To a solution of LiAlH4 (80 mg, 2.05 mmol, 1.1 equiv) in Et2O (20 mL) was added cyclohexene carbonitrile (200 mg, 1.86 mmol, 1.0 equiv) drop wise at 0 ¡C. The reaction was warmed to room temperature and stirred till completion. The reaction was quenched with H2O and NaOH, producing a white precipitate, which was filtered through celite. The organic solvents were removed under reduced pressure to afford the crude cyclohexene amine in 61% yield. To the mixture obtained above (123 mg, 1.11 mmol, 1.0 equiv) in CH2Cl2 (7.0 mL) was added Et3N (0.31 mL, 2.22 mmol, 2.0 equiv) at room temperature. DMAP (2 mg, 0.011 mmol, 0.01 equiv) and benzoyl chloride (0.20 mL, 1.68 mmol, 1.5 equiv) were added successively. After the reaction was complete (monitored by TLC), H2O was added. The organic layer was extracted with CH2Cl2 and washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford the unsaturated secondary amides in 48% yield.  NOV-18LiAlH4, Et2O-78 ¡C to rt1. Et3N, DMAP    PhCOCl, DCM, rt2. NaH, BnBr    THF, 0 ¡C to rtCNNH2cyclohex-1-ene-1-carbonitrilecyclohex-1-en-1-ylmethanamine!"%%!The secondary amide from previous step (111 mg, 0.51 mmol, 1.0 equiv) was added to a solution of NaH (25 mg, 0.62 mmol, 1.2 equiv) in THF (2 mL) at 0 ¡C. The reaction was warmed to room temperature and then refluxed for 1 h. Benzyl bromide (0.1 mL, 0.62 mmol, 1.2 equiv) was added drop wise and the reaction mixture was heated for an additional 4 h. After the reaction was complete (monitored by TLC), H2O was added. The reaction was extracted with EtOAc and washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford the unsaturated tertiary amide V-18 in 48% yield.  V-18: N-benzyl-N-(cyclohex-1-en-1-ylmethyl)benzamide  1H NMR (500 MHz, CDCl3) ! 7.05-7.49 (m, 10H), 5.51 (m, 1H), 4.71 (s, 1.2H), 4.43 (s, 0.8H), 4.05 (s, 0.8H), 3.67 (s, 1.2H), 2.03 (s, 3H), 1.50-1.75 (m, 5H). 13C NMR (125 MHz, CDCl3), ! 172.2, 137.5, 136.8, 136.5, 132.6, 129.3, 128.5, 128.3, 127.3, 127.2, 126.9, 126.6, 125.2, 124.8, 54.4, 51.1, 49.2, 46.7, 26.3, 26.0, 25.0, 22.5, 22.3, 22.2. HRMS (ESI) Calculated Mass for C21H23NO: ([M+H]+) = 306.1858, Found ([M+H]+) = 306.1868.   NO!"%'!          REFERENCES    !"%(!REFERENCES    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5,HTDC10<B2010=.<B7=4A?=.3]!6!8?b/0=.01!T1N137130!W4=71=2D31!@1;<.3D/C!"!F%3*?$%4*:/5!!""&5!H,5!$%+,H$%+(&!!$#&!@.22.7D5!M&M&!.37!I&P&!U.b.2S.5!>G31H940!8B30<1/D/!4A!mH-<24=41/01=/!`D.!0<1!M1.;0D43!4A!6;D7!-<24=D71/!PD0<!V10=.<B7=4A?=.3!D3!0<1!9=1/13;1!4A!V=D;<24=4b4=.31!"!@A/3$!'#:&&)/!5!!""!5!P'C<5!+((%H!#**+&!!$)&!-421/5!8&_&5!10!.2&5!>WDdRRRe!E.2D71/!./!JAAD;D130!-.0.2B/0/!A4=!0<1!GH6;B2.0DK1!-21.K.F1!4A!V10=.<B7=4A?=.3/]!63!JcN17D0D4?/!J30=B!04!V10=.2D3/!"!F%3*?$%4*:/5!!""&5!H,5!"""%H"",#&!!$"&!@DC1=45!9&5!-&!8.2?LL45!.37!M&!6C4?=4?c5!>M1FD4;430=42217!MD3F!GN13D3F!4A!#H@10<B2010=.<B7=4A?=.3![D0<!6;D7!-<24=D71/!.37!R47D71/!"!F%3*?$%4*:/'J%33!5!#''$5!C=5!+,,)H+,,$&!!$,&!_.F.3.0<.35!6&5!10!.2&5!>6!-.0.2B0D;!6/BCC10=D;!-<24=4;B;2DL.0D43!4A!Y3/.0?=.017!6CD71/!"!./0%1!'#$%&!'2/3!'(4!5!!"##5!=B5!#,()H#,($&!!$$&!V=D2245!9&5!6&!W.1L.5!.37!-&!Z.g1=.5!>:2?4=D3.017!62;4<42/!./!9=4C401=/!A4=!0<1!@10.2H:=11!TD=1;0!8?b/0D0?0D43!M1.;0D43!4A!622B2D;!62;4<42/![D0<!ZD0=4F13.0175!8D2B2.0175!.37!-.=b43!Z?;214N<D21/!"!+!'7*0!'#$%&!5!!"#!5!--5!%)""H%),"&!!!!"#$!Chapter VI: Asymmetric Organocatalytic Chlorocyclization of Phenols VI-1 Introduction  Despite all the progress in asymmetric organocatalytic halofunctionalization reactions1-7 (discussed in Chapter II) numerous shortcomings and limitations are evident in the current state of the art for enantioselective alkene halogenation reactions; these include the lack of generality with regards to diverse nucleophiles and electrophiles as well as paucity of target-driven reaction discovery endeavors. Naturally occurring organohalogen compounds have been recognized as a large class of molecules dispersed through nature. They often contain unique structures or show significant biological activities.8 This provides the necessary enticement to develop a facile and efficient route for construction of complex architectures encountered in bioactive molecules.  In our lab, we aim to develop and incorporate unprecedented alkene halogenation reactions that will aid in the assembly of Ôprivileged motifsÕ in numerous natural products. These studies will enable an expedited and redox-economical synthesis of natural products enabled by the strategic incorporation of alkene halogenation reactions (Chapter II). We can also use our newly developed parameter, the Halenium affinity (HalA) scale, as needed if chemoselectivity issues are suspected in the synthesis of halogenated natural products (Chapter I).9 !"#%! In this chapter significant efforts will be devoted to target-driven reaction discovery, where the strategic incorporation of enantioselective alkene halogenation allows us to devise the shortest routes yet to various chlorinated natural products. We have focused our attentions on developing a new asymmetric organocatalytic chlorocyclization of phenol derivatives. This enables the construction of the chiral chromane core for various natural products. Scheme VI-1 illustrates a few potential targets.10-15 It should be noted that the oxygen of the chromane core originates from a phenol group before it is oxidized to the quinone functionality in some instances such as napyradiomycin A1, azamerone, and cochlioquinone D (Scheme VI-1). The halogen post chloroetherification reaction could be further modified or removed completely in the total synthesis of chartaceone A2, naringenin, rubioncolin B, and cochlioquinone D (Scheme VI-1). Our interest has focused on the napyradiomycin family of molecules. The first member of the chlorinated napyradiomycin family of natural products was isolated in 1986 by Shiomi and coworkers from a soil-derived organism Chainia rubra.16, 17 Since then, dozens of compounds that share common structural features such as stereodefined chlorine atoms and the dihydroquinone motif have been isolated from various terrestrial and marine Streptomyces bacteria by using cultivation and fractionation techniques.18-20 Bioactivity assays have revealed potent anti-microbial activity for many of these compounds against gram-positive bacteria including numerous !"#&!contemporary and clinically relevant Methicillin and Vancomycin resistant strains of bacteria.21 Given the rapid worldwide rise in infections by the latter OOOHHOOMeMeClClMeMeMeNapyradiomycin A1Chartaceone A2OOOHHOOOHAzameroneNNOOOClOHOHClOOOOCH3H3CHOHCH3CH3Hepi-Cochlioquinone DNaringeninOOOHHOOOOOMeO2CHOOHCO2MeHRubioncolin BOHR2!!!!OR2ClR1R1ConditionScheme VI-1 Use of asymmetric chlorocyclization reactions in synthesis natural products.  !"##!bugs, the napyradiomycins have witnessed a renewed interest as possible therapeutics.21 More recent studies have established mitochondrial Complex I and II inhibition as the mode of action for the potent cytotoxic activity ascribed to the napyradiomycins against numerous human cancer cell lines.22 Nonetheless, the molecular basis for the cytotoxicity as well as the biological target for these molecules is as yet unknown. Furthermore, subtle structural variations have pronounced effects on the cytotoxicity and anti-bacterial activity of these compounds.18, 21 The development of these molecules as anti-bacterial or anti-cancer therapeutics will require a detailed SAR study in order to reduce cytotoxicity and enhance bioavailability. Equally important for developing potent analogs, is the understanding of molecular target of the napyradiomycins. Both these endeavors require sufficient quantities of the natural products as well as the unnatural analogs, which are inaccessible at present owing to the lack of efficient synthetic routes for this class of molecules. One racemic and one enantioselective synthesis of napyradiomycin A1 has been achieved.23, 24 Nonetheless, neither route is well suited to tackle the SAR study owing to the lengthy synthetic sequences, the lack of convergence in the synthesis that precludes a straightforward analog library synthesis as well as inefficient means to incorporate the chlorine atoms in an enantioselective fashion. Our proposed synthesis seeks to address many of these issues primarily aided by the incorporation of an unprecedented enantioselective phenol chlorocyclization in the synthesis. !"#'! Dr. Jaganathan has worked on racemic synthesis of napyradiomycin A1. The retrosynthetic pathway involving the protected !-lapachone motif VI-7 (Scheme VI-2) is an ideal precursor for a convergent access to a variety of napyradiomycins. The 5-step, multi-gram scale route to the key phenol chlorocyclization precursor is shown in Scheme VI-2. The non-asymmetric chlorocyclization of VI-4 proceeds cleanly to afford the racemic chlorinated benzo-pyran VI-5 by employing DCDMH in a mixed solvent system comprised of 1:1 C2H4Cl2-(CF3)2CHOH (HFIP). Oxidation of the aryl ring by CAN gave the bromoquinone VI-6, which was then subjected to a regioselective Diels-Alder reaction/aromatization cascade25, 26 to furnish VI-7. The completion of the racemic synthesis is currently under way and will involve the conjugate addition of geranyl stannane followed by the !-chlorination of the ketone and finally a global deprotection.  !"'(! 3.0 equiv CAN3:1 MeCN-H2O0 ¡C, 5 minOOOBrClMeMe68% yield(unoptimized)OMeTBSOOOOCH3CH3ClOMeTBSO1.2. SiO2, EtOAc    30% (unoptimized)MeMeMeSnBu31.1 equiv nBuLi,CuI, LiBrOHOOCH3CH3ClOMeTBSOH3CCH3CH31.  NCS2.  BBr3OMeCHOOMeOMeOHOMeBrMeOOO1.05 equiv1% CuCl2, 1.2 equiv DBU, MeCN, -20 ¡C, 68%OMeOOMeBr1. Lindlar reduction2. Xylene, refluxOMeOHOMeBrMeMe3  steps, 80% yield55%, 2 steps2.0 g scale1.1 equiv DCDMH1:1 HFIP-DCE0¡C, 15 minOMeOOMeBrClMeMe(±)-VI-5100% conv.75% yield20 mol% Et3NPhCH3, 50 ¡CVI-1VI-2VI-3VI-4VI-6VI-7VI-8OOOCH3CH3ClOHHOH3CCH3CH3ClNapyradiomycin A1Scheme VI-2 Toward the racemic synthesis of napyradiomycin A1. !"')!An enantioselective route to the natural product will necessitate an asymmetric chlorocyclization of VI-4 to VI-5. Our experience with other asymmetric chlorocyclization reactions27-30 indicates that the presence of a hydrogen-bonding element in close proximity to the alkene is essential to anchor the substrate within the chiral environment of the Lewis base catalyst. We surmised that the phenol moiety could serve as the hydrogen-bonding motif. Nonetheless, we were cognizant that its distance from the alkene and the lack of any precedence for phenols as compatible nucleophiles in halocyclizations were potential issues. In this chapter we will illustrate the efforts toward the development of new asymmetric chloroetherification of phenol derivatives. VI-2 Optimization of asymmetric organocatalytic chlorocyclization of phenols We began the evaluation of asymmetric variants of the phenol cyclization using the test substrate VI-9. Various chiral organocatalysts were examined for achieving high enantioselectivity in this methodology. The first class of catalysts included chiral phosphoric acids, thioureas, imidazolidinone, and pyrrolidines (Table VI-1). Chiral catalysts VI-11 to VI-17 were evaluated in TFE (trifluoroethanol) with DichT (dichloramineT) as the chlorine source. The product was obtained in 63-89% yield with up to 24% ee.  !"'*! Entry Catalyst Yield[a] (%) ee[b] (%) 1 VI-11 75% 20% 2 VI-12 76% 24% 3 VI-13 71% 0% 4 VI-14 64% -4% 5 VI-15 63% 8% 6 VI-16 89% 0% 7 VI-17 77% 6% [a] Isolated yield of V-10. [b] ee% was measured by chiral HPLC. OHOMePhOPhClMeO1.1 equiv DiChTcatalyst (5 mol%)TFE (0.025M), -30 ¡CVI-9VI-10PhPhOOPOHOt-But-BuOOPOHOt-But-BuVI-11VI-12NHNOMeMeMeHClVI-13NHOOHHOVI-15Me2NONHNHSt-BuNHHOt-BuOt-BuOVI-14BnMeNONHNHSt-BuNHHOt-But-BuVI-16PhPhOOPONHTfVI-17Table VI-1 Catalyst screening (1) for chlorocyclization of VI-9. !"'+! The second family of chiral organocatalysts (VI-18 to VI-23) was tested for chlorocyclization of VI-9 as shown in Table VI-2. VI-22 gave the highest yield (98%) but as a racemate. The highest enantioselectivity after screening of both families of organocatalysts was achieved by using catalyst VI-20 (30% ee). Next, we turned our attention to the family of monomeric and dimeric cinchona alkaloids (Table VI-3).  Monomeric cinchona alkaloids VI-24, VI-25, and VI-26 led to the formation of racemic product. We obtained more promising results with dimeric catalysts. (DHQD)2PHAL catalyst and its derivatives VI-27 and VI-30 gave the product in 69%, 56%, and 62% ee, respectively (Table VI-3, entries 4, 7, 11). This shows the importance of the phthalazine linker and the two nitrogen atoms in this asymmetric transformation, since catalysts (DHQD)2PYR, (DHQ)2AQN, V-31 and V-32 formed product V-10 in good yields but low enantioselectivities (entries 9-10, 14-15). Substitutions on the quinoline group present in catalysts VI-28 and VI-29 reduced the asymmetric induction to 6% and 11% ee (Table VI-3, entries 5-6). Mono- and bis-triflated salts of (DHQD)2PHAL was prepared through reaction of its quinuclidine moiety with triflic acid; these catalysts formed the product in 58% and 20% ee, respectively (entries 12-13). This shows the importance of free quinuclidine part of (DHQD)2PHAL in inducing chirality. After screening of all three classes of chiral organocatalysts (Table VI-1, VI-2, and VI-3), we chose (DHQD)2PHAL as the optimum chiral catalyst for asymmetric chlorocyclization reaction of phenols. !"'"! OHOMePhOPhClMeO1.1 equiv DiChTcatalyst (5 mol%)TFE (0.025M), -30 ¡CVI-9VI-10NHNNNNNHHNTf2VI-18NHNNNNNHHNTf2VI-19HNTf2NNONNNOMeNNOVI-22NNOONRNRR= Ts,  VI-20R= Me, VI-21NNONBrBrNOVI-23Entry Catalyst Yield[a] (%) ee[b] (%) 1 VI-18 89% 8% 2 VI-19 50% 0% 3 VI-20 79% 30% 4 VI-21 72% 0% 5 VI-22 98% 0% 6 VI-23 57% 4% [a] Isolated yield of V-10. [b] ee% was measured by chiral HPLC. Table VI-2 Catalyst screening (2) for chlorocyclization of VI-9. !"'$!  Table VI-3 Catalyst screening (3) for chlorocyclization of VI-9. OHOMePhOPhClMeO1.1 equiv DiChTcatalyst (mol%)TFE (0.025M), -30 ¡CVI-9VI-10NNPhOHBrVI-24NNOHVI-25NNClNNOVI-26NONOHNNHNOi-prNOHHVI-27NNOHNNHNNOHHRRR = Bu, VI-28R = H,   VI-29NMeONOHHNOMeNOHHOOVI-31NMeONOHNNHNOMeNOHHVI-30NMeONOHFFHNOMeNOHHVI-32FFi-prNMeONOHNNHNOMeNOHH(DHQD)2PHAL!"'%!  The absolute stereochemistry of the final product V-10 was determined by single crystal XRD using anomalous dispersion techniques. Next, we investigated various factors to improve the enantioselectivity of this transformation by screening different chlorine sources (Table VI-4). The mild chlorenium source NCS did not yield the product (entry 1). Use of chloramineM (CH3SO2NClNa) as the chlorine source led to a sluggish Entry Catalyst Loading (mol%) Yield[a] (%) ee[b] (%) 1 VI-24 10 49% 0% 2 VI-25 10 57% 0% 3 VI-26 10 46% -4% 4 VI-27 5 70% 56% 5 VI-28 10 53% 6% 6 VI-29 10 45% -11% 7 VI-30 10 98% 62% 8 VI-30 5 71% 52% 9 VI-31 10 88% 10% 10 VI-32 10 97% 18% 11 (DHQD)2PHAL 10 68% 69% 12 (DHQD)2PHAL-(Tf2NH) 5 72% 58% 13 (DHQD)2PHAL-(Tf2NH)2 5 88% 20% 14 (DHQ)2AQN 10 44% -11% 15 (DHQD)2PYR 10 75% 4% 16 (DHQD)2PYR-(Tf2NH) 5 77% 8% [a] Isolated yield of V-10. [b] ee% was measured by chiral HPLC. Table VI-3 (ContÕd) !"'&!reaction (entry 2). DCDPH and TCCA formed chloroether VI-10 in moderate yields with 39% and 44% ee, respectively (entries 3-4). DCDMH successfully delivered V-10 in 82% yield and 64% ee. DiChT afforded the desired product in 68% yield and 69% ee.   DiChT and (DHQD)2PHAL were chosen as the leads to further optimize this reaction. Table VI-5 shows the influence of solvent on the enantioselectivity. Nitropropane and benzene did not yield the chromane VI-10 in any quantity (entries 1-2). Chlorocyclization of V-9 in acetone, OHOMePhOPhClMeO1.1 equiv Cl+ source(DHQD)2PHAL (10 mol%)TFE (0.025M), -30 ¡CVI-9VI-10Entry Catalyst Yield[a] (%) ee[b] (%)   1[c] NCS - - 2 ChloramineM messy - 3 DCDPH 44% 39% 4 TCCA 70% 44% 5 DCDMH 82% 64% 6 DiChT  68% 69% [a] Isolated yield of V-10. [b] ee% was measured by chiral HPLC. [c] Low conversion after 1 day at room temperature. Table VI-4 Screening of various chlorine sources. !"'#!acetonitrile, nitromethane, methyl chloroform and isobutanol solvents led to moderate yields but formed racemic product VI-10 (entries 3-7).        Entry Solvent Temp ¡C Yield[a] (%) ee[b] (%) 1 C3H7NO2 -78 messy - 2 C6H6 rt messy - 3 acetone -30 38% 0% 4 CH3CN -30 45% 0% 5 CH3NO2 -30 44% 0% 6 CH3CCl3 -30 62% 0% 7 iso-BuOH -30 76% 0% 8 n-PrOH -30 76% 28% 9 EtOH -30 61% 40% 10 TFE -30 71% 68% [a] Isolated yield of V-10. [b] ee% was measured by chiral HPLC. Table VI-5 Screening of various solvents. OHOMePhOPhClMeO1.1 equiv DiChT source(DHQD)2PHAL (5 mol%)solvent (0.025M), T ¡CVI-9VI-10!"''!Alcoholic solvents such as propanol, ethanol, and trifluoroethanol afforded VI-10 in moderate enantioinduction, 28%, 40% and 68% ee, respectively (entries 8-10). The solvent screening led to TFE as the best choice for the chlorocyclization of phenol VI-9 in combination with (DHQD)2PHAL (5 mol%) and DCDMH at -30 ¡C.   Next, we investigated the effect of temperature and additives on chlorocyclization of VI-9 (Table VI-6). Temperature significantly affects the enantioinduction; lowering the temperature from 25 ¡C to -30 ¡C led to a 63% increase in ee (entries 1-3). p-Toluenesulfonic acid and triethyl amine additives led to a messy reaction (entries 1-2). Benzoic acid, sodium bicarbonate, cesium carbonate, sodium carbonate, potassium carbonate, and tosylamine additives led to the formation of VI-10 in lower enantioselectivities (44-66% ee, entries 6-12). However, addition of lithium carbonate (0.5 equiv) was effective and VI-10 was formed in 71% yield and 72% ee (entry 13). Increasing lithium carbonate from 1.0 to 5.0 equiv resulted in lower enantioselectivities (entries 14-15). The optimization data shown in this chapter show an inverse relationship between yield and enantioselectivity, conditions that lead to higher yields gave lower selectivities and visa versa.    !$((!  Entry Additive Temp ¡C Yield[a] (%) ee[b] (%) 1 - rt 81% 3% 2 - 0  61% 10% 3 - -30 71% 68% 4 p-TsOH -30 messy - 5 Et3N -30 messy - 6 Benzoic Acid -30 80% 44% 7 NaHCO3 -30 66% 60% 8 Cs2CO3 -30 63% 62% 9 Na2CO3 -30 71% 64% 10 K2CO3 -30 65% 66% 11 p-TsNH2 -30 59% 66%   12[c] p-TsNH2 -30 89% 58% 13 Li2CO3 -30 71% 72%   14[d] Li2CO3 -30 83% 64%   15[e] Li2CO3 -30 97% 62% [a] Isolated yield of V-10. [b] ee% was measured by chiral HPLC. [c] p-TsNH2 (1.0 equiv) was used. [d] Li2CO3 (1.0 equiv) was used. [e] Li2CO3 (5.0 equiv) was used. Table VI-6 Effects of temperature and screening of additives. OHOMePhOPhClMeO1.1 equiv DiChT source(DHQD)2PHAL (5 mol%)TFE (0.025M), T ¡C additive (0.5 equiv)VI-9VI-10!$()! Optimization of various factors such as catalyst, solvent, temperature, and additive led to a moderate selectivity (up to 72% ee). Moderate enantioselectivity is due to the uncatalayzed or background reaction (vida infra). Next, we examined the effect of catalyst loading and concentration on the chlorocyclization of VI-9. Increasing the catalyst loading could increase the rate of the catalyzed reaction and outcompete the background reaction. As shown in Table VI-7 (entries 1-4), 5 mol% catalyst was utilized while the concentration of substrate was varied from 0.05 to 0.00625 M. In this study, the enantioselectivity was slightly lowered (60-68% ee), while yield was increased from 77% to 94%. Lowering the catalyst loading to 2 mol% provided VI-10 in 52% ee (entry 5). Increasing the catalyst loading to 10 and 20 mol% led to 69% and 56% ee, respectively (entries 6-7). Later we increased the loading to 50 mol% and screened it with various concentrations of substrate and catalyst (entries 8-9). This led to a selectivity of up to 70% ee (entry 8). However due to the cost of the chiral catalyst we chose 5 and 10 mol% loadings as the optimum condition in this investigation for further optimization studies.    !$(*! Numerous other attempts including incorporation of dehydrating agents, order and rate of additions were tested, but yet failed to improve enantioselectivity (Table VI-8). Under standard conditions the substrate in TFE (cooled to -30 ¡C) is quickly added to a solution of premixed chiral catalyst and DiChT at -30 ¡C (entry 1). Drop-wise addition of substrate to the reaction mixture resulted in a small drop in selectivity (64% ee, entry 2). Changing the order of addition where DiChT in TFE was added dropwise to a Entry Catalyst loading (mol%) [Sub] M [Cat] M Yield[a] (%) ee[b] (%) 1 5 0.05 0.0025 77% 64% 2 5 0.025 0.00125 71% 68% 3 5 0.0125 0.000625 87% 66% 4 5 0.00625 0.000313 94% 60% 5 2 0.025 0.0005 97% 52% 6 10 0.025 0.0025 68% 69%   7[c] 20 0.025 0.005 30% 56% 8 50 0.0025 0.00125 65% 36% 9 50 0.025 0.0125 80% 70% [a] Isolated yield of V-10. [b] ee% was measured by chiral HPLC. [c] DCDMH was used instead of DiChT. Table VI-7 Effects of concentration and catalyst loading (1). OHOMePhOPhClMeO1.1 equiv DiChT source(DHQD)2PHAL (x mol%)TFE, -30 ¡CVI-9VI-10!$(+!solution of catalyst and substrate in TFE at -30 ¡C gave only 56% ee (entry 3). Use of molecular sieves lowered the selectivity (56% ee, entry 4). Use of higher amounts of DiChT (5.0 equiv) formed VI-10 in only 60% ee (entry 6). The reaction was then tested at -80 ¡C in solid form for 5 days, resulting in only 46% ee (entry 7).   The highest enantioselectivity achieved under various optimization studies was found to be 72% ee (Table VI-6, entry 13). In order to utilize this methodology for the asymmetric synthesis of various natural products, the selectivity needs to be improved further. To better realize the source of moderate enantioselectivity, the rate of the uncatalyzed reaction was compared to the catalyzed process. Figure VI-1 shows the rate of uncatalyzed reaction of VI-9 with 1.1 equivalent DiChT in TFE (0.025 M) at -30 ¡C. The reaction has achieved 60% conversion, suggesting that within the initial 3 min, moderate enantioselectivity is the result of high rate of the background reaction. To reduce the background reaction, lower temperatures were necessary. However, TFE, the optimal solvent freezes below -30 ¡C. As such we screened various co-solvents in combination with TFE to lower the temperature and improve enantioselectivity (Table VI-9).  !$("!   Table VI-8 Effects of concentration and catalyst loading (2). Entry Change in condition Yield[a] (%) ee[b] (%) 1 - 71% 68% 2 dropwise addition of substrate  95% 64% 3 dropwise addition of DiChT 94% 56% 4 M.S. 4† 58% 56% 5 5.0 equiv DiChT 62% 60%   6[c] Solid phase reaction at -80 ¡C 85% 46% [a] Isolated yield of V-10. [b] ee% was measured by chiral HPLC. [c] all reactions were ran for 1 h except entry 6 for 5 days. OHOMePhOPhClMeO1.1 equiv DiChT source(DHQD)2PHAL (5 mol%)TFE (0.025 M), -30 ¡CVI-9VI-10!$($! Table VI-9 shows the results for screening various co-solvents at different temperatures.  Combining HFIP as a co-solvent led to a significant drop in the selectivity from 68% ee (Table VI-8) to 22% ee (Table VI-9, entry 1). TFE and DCM as a 1:1 mixture gave only 30% ee, whereas TFE and EtOH afforded VI-10 in 56% ee (entries 2-3).  OHOMePhOPhClMeO1.1 equiv DiChT sourceTFE (0.025 M), -30 ¡CVI-9VI-100204060801001200246810121416ConditionA-no catConditionB-WO/cat%ConversionTime (min)!!Figure VI-1 Rate of uncatalyzed reaction monitored by GC. !$(%! Entry Solvent Temp ¡C Yield (%) ee (%) 1 TFE:HFIP (1:1) -30 ¡C 97% 22% 2 TFE:DCM (1:1) -30 ¡C 98% 30% 3 TFE:EtOH (1:1) -30 ¡C 99% 56% 4 TFE:MeCl3 (9:1) -40 ¡C 88% 32% 5 TFE:C7H8 (9:1) -50 ¡C 69% 40% 6 TFE:CHCl3 (9:1) -50 ¡C 74% 62% 7 TFE:CH2Cl2 (9:1) -50 ¡C 77% 63% 8 TFE:Et2O (9:1) -50 ¡C 90% 76% 9 TFE:THF (9:1) -50 ¡C 99% 78% 10 TFE:MeCN (9:1) -50 ¡C 95% 86% 11 TFE:MeCN (9:1) -40 ¡C 58% 58% 12 TFE:MeCN (9:1) -60 ¡C 57% 88%   13[a] TFE:MeCN (9:1) -70 ¡C 54% 68% 14 TFE:MeCN (1:1) -50 ¡C 71% 64% 15 TFE:MeCN (1:1) -70 ¡C 54% 72% 16 TFE:MeCN (4:1) -60 ¡C 86% 88%   17[b] TFE:MeCN (4:1) -60 ¡C 80% 90%   18[c] TFE:MeCN (4:1) -60 ¡C 79% 88% 19 TFE:MeCN (4:1) -70 ¡C 27% 68% 20 TFE:MeCN (11:1) -60 ¡C 83% 86%   21[d] TFE:MeCN (20:1) -40 ¡C 72% 80% [a] It freezes after sometimes at -70 ¡C. [b] 10 mol% catalyst loading was used. [c] 0.5 equiv Li2CO3 was used. [d] It freezes below -50 ¡C. OHOMePhOPhClMeO1.1 equiv DiChT source(DHQD)2PHAL (5 mol%)Solvent (0.025 M), T ¡CVI-9VI-10Table VI-9 Screening of various co-solvents and temperatures. !$(&! To lower the temperature below -30 ¡C, TFE and different co-solvents were combined in a 9:1 ratio. Combination of TFE with chlorinated solvents such as MeCCl3, CHCl3, CH2Cl2 or toluene at -40 to -50 ¡C did not enhance the result, providing up to 63% ee (entries 4-7). Surprisingly we saw an enhancement in enantioselectivity when Et2O, THF, or MeCN were used as co-solvents at -50 ¡C to afford the desired products in 76%, 78%, and 86% ee, respectively (entries 8-10). The ratio of TFE and MeCN were changed in parallel with differing temperatures. Finally we achieved the chlorocyclized product VI-10 in 80% yield and 90% ee by using a solvent mixture of TFE:MeCN (4:1) at -60 ¡C with 10 mol% catalyst loading (entry 17).  Kinetic studies by GC analysis revealed that the improvement in enantioselectivity is the result of slower background reaction in TFE:MeCN (9:1) at -50 ¡C (condition B, Figure VI-2) as compared to TFE at -30 ¡C (condition A). With the appropriate choice of co-solvent at temperatures below -30 ¡C, the background reaction is outcompeted, enhancing the selectivity from 68% ee (TFE, -30 ¡C) to 88% ee (TFE:MeCN (4:1), -60 ¡C). Increasing the catalyst loading to 10 mol% improved the selectivity to 90% ee. !$(#!  The correlation of enantioselectivity to the conversion of the reaction was investigated as shown in Figure VI-3. The enantioselectivity of VI-10 was monitored at different conversions. More data points are necessary to 0204060801001200246810121416ConditionA-no catConditionB-WO/catConditionB-W/cat%ConversionTime (min)!ABCTFE, -30 ¡CTFE:MeCN (9:1), -50 ¡CTFE:MeCN (9:1), -50 ¡C (DHQD)2PHAL (5 mol%)OHOMePhOPhClMeO1.1 equiv DiChTSolvent (0.025 M)ConditionVI-9VI-10A C B !!!Figure VI-2 Comparison of rates of reaction under three different conditions A-C. !$('!reconfirm this dependency. However based on the results thus far, the first data point shows 74% ee at 40% conversion. Higher conversion of 55%, 58%, and 60% gave 76%, 84%, and 84% ee, respectively. The desired product was obtained in 86% ee at 100% conversion. Moving to higher conversions, the enantioselectivity of the product produced during the course of the reaction increases; similarly more ChloramineT (side-product) is formed through further consumption of DiChT. A possibility is autoindution or asymmetric amplification, observed at higher conversions, as a result of increasing the amount of product or ChT higher. Interaction of the product or ChT with the catalyst might lead to the formation of a complex capable of higher asymmetric induction. Conversely, interaction of DichT with the catalyst could lead to slight deactivation of the catalyst, resulting in lower enantioselectivity at higher DiChT concentrations. To further confirm these scenarios the enantioselectivities and rate of uncatalyzed reactions should be measured at different conversions with various amount of product, DiChT, or ChT added at the beginning of the reaction.      !$)(! The exact model for the substrate-catalyst interaction and transition state geometry to explain the source of enantioinduction has not been calculated. However, based on the data for catalyst screening (Tables VI-3) we believe that the phthalazine linker plays an important role in 72747678808284868830405060708090100110% ee% ConversionOHOMePhOPhClMeO1.1 equiv DiChT(DHQD)2PHAL (5 mol%)TFE:MeCN (9:1) (0.025 M) -50 ¡CVI-9VI-10Figure VI-3 Dependence of induction of VI-10 on various conversions. !$))!enantioinduction. This reiterates the idea that the nitrogen atoms are necessary. Removal of the quinuclidine nitrogen atoms also results in lower enantioselectivities. We believe that the hydrogen on the phenol group (Ar-OH) is involved in non-covalent interactions such as hydrogen bonding with quinuclidine or phthalazine nitrogen atoms. The importance of hydrogen bonding between the substrate and the catalyst was tested in two experiments. We synthesized protected phenols VI-33 and VI-34 and treated them under the conditions that led to 68% ee of the desired product VI-10 (Scheme VI-3). Acyl-protected phenol VI-33 failed to afford any product and mainly the intermolecular incorporation of TFE into the olefin was obtained without the loss of acetyl group. TMS (trimethyl silyl) protected phenol VI-34 led to the formation of VI-10 in 60% yield and only 32% ee. The latter two simple experiments suggest that interference in hydrogen bonding between the substrate and catalyst leads to significant drop in enantioselectivity. Besides hydrogen bonding, other factors such as "-stacking interactions could also be a source of selectivity.    !$)*!VI-3 General schemes for the synthesis of starting materials  Unsaturated phenol derivatives were synthesized through different paths. Unsubstituted cinnamylphenol and those substituted with electron donating groups were synthesized through a simple ortho alkylation of OHRPhPhClOHRNa, benzene, 80 ¡C, 12hthen KOH, HClR = EDGOHRPhOHRNaH, Et2O0 ¡C to rt, 5 hORNaPhClNa, benzene, 80 ¡C, 12hthen KOH, HClR = EDGScheme VI-4 General scheme for synthesis of 1,2,4-substituted phenols. Scheme VI-3 Chlorocyclization of protected phenols.  R = Ac,      VI-33       MessyR = TMS,   VI-34     60% yield, 32% eeOROMePhDichT(1.1 equiv.)(DHQD)2PHAL (5 mol%)TFE (0.025 M), -30 ¡C, 4h!!!!OPhClMeOVI-10!$)+!phenols in the presence of sodium in benzene at 80 ¡C (Scheme VI-4). This transformation occurs in one-pot directly from phenols and cinnamyl chloride. It can also occur through a two-step sequence via isolation of sodium salt of the phenol derivatives in ether by recrystallization, followed by its reaction with cinnamyl chloride.  For unsymmetrical phenol derivatives or phenols containing electron-withdrawing groups, a more general synthetic plan was designed. This route enables the production of substrates with both electron donating and withdrawing groups with different substitution patterns for both aryl groups (phenolic and cinnamyl aryl) as shown in Scheme VI-5. Grignard addition to benzaldehyde-substituted derivatives yields propargyl alcohols, which upon Mitsunobu reaction provide propargyl ethers in high yields. Reduction of alkyne to alkenes in the presence of poisoned palladium catalyst yields allylic ethers. Final step involves the aromatic Claisen rearrangement of allylic ethers to the desired unsaturated phenols with various substitution patterns (R1 and R2).  A variety of substrates have been synthesized through both routes. The scope of the reaction should be tested using our final optimized condition utilized for phenol VI-9 (Table VI-9, entries 16-17). More mechanistic underpinnings of this transformation should also be investigated in future. This methodology could be applied for total synthesis of a variety of halogenated natural products such as those shown in Scheme VI-1. !$)"! VI-4 Conclusion  In summary, we have developed a highly stereoselective chlorocyclization of unsaturated phenols to yield chiral chromane hetereocycles using DiChT as the chlorine source and commercially available chiral catalyst (DHQD)2PHAL in trifluoroethanol and acetonitrile at low temperatures. This reaction is operationally simple with no need for anhydrous or inert conditions. The development of this methodology could aid in the assembly of Ôprivileged motifsÕ in numerous natural products. DIAD, PPh3, toluene0 ¡C to rt 5% Pd on BaSO4EtOAc, quinolineHOBrMgTHF, 0 ¡C to rttoluene120 ¡CR1R1OHOHR2R1OR2R1OR2R2OHR1Scheme VI-5 General scheme for synthesis of unsaturated phenols. !$)$!VI-5 Experimental NMR spectra were obtained using a 300, 500, or 600 MHz NMR spectrometers (VARIAN INOVA). Chemical shifts are reported in parts per million (ppm) and are referenced using the residual 1H peak from the deuterated solvent. All reagents were purchased from commercial sources and were used without purification. THF and Et2O were freshly distilled from Na-benzophenone ketyl whereas CH2Cl2 and PhCH3 were distilled over CaH2. TLC analyses were performed on silica gel plates (pre-coated on glass; 0.20 mm thickness with fluorescent indicator UV254) and were visualized by UV, I2 complex formation or charring in anisaldehyde, KMNO4 or PMA stains. Flash silica gel (32-63 mm, Silicycle 60 †) was used for column chromatography. Ratios of products were determined by crude NMR analysis. All known compounds were characterized by 1H and 13C NMR and are in complete agreement with samples reported elsewhere. All new compounds were characterized by 1H, and 13C NMR. Enantiomeric excess for all products was judged by HPLC analysis using DAICEL CHIRALCEL¨ OJ-H and OD-H or DAICEL CHIRALPAK¨ IA-H, AS-H, and AD-H columns.     !$)%!VI-5A General procedure for synthesis of chlorocyclized chromane products  A screw-capped vial, equipped with a magnetic stir bar, was charged with the DiChT (11.0 mg, 0.046 mmol, 1.1 equiv) and (DHQD)2PHAL (5-10 mol%) in a proper solvent, TFE or TFE/MeCN (0.9 mL), and cooled to the right temperature of -30 ¡C or -60 ¡C. Substrate (0.042 mmol, 1.0 equiv) in TFE or TFE/MeCN (0.8 mL) was also cooled to the same temperature and was introduced to the reaction mixture in a single portion. The vial was capped and the resulting suspension was stirred at the same temperature till the reaction was completed (monitored by TLC). The reaction was quenched with saturated aqueous Na2SO3 solution and extracted with CH2Cl2. The combined organics were washed with brine and dried over anhydrous Na2SO4 and filtered. Column chromatography (SiO2/EtOAc-Hexanes gradient elution 5-20%) gave the desired product.  Analytical data for synthesis of chromane products V-10: 3-chloro-6-methoxy-2-phenyl-2!3,3!3-chromane  1H NMR (500 MHz, CDCl3) " 7.30-7.42 (m, 5H), 6.85 (d, J = 8.5 Hz, 1H), 6.73 (dd, J = 3.0 Hz, J = 9.0 Hz, 1H), 6.58 (d, J = 3.0 Hz, 1H), 5.00 (d, J = 8.0 Hz, !!!!OClMeO!$)&!1H), 4.40 (ddd, J = 5.0 Hz, J = 8.0 Hz, J = 8.0 Hz, 1H), 3.75 (s, 3H), 3.26 (dd, J = 5.5 Hz, J = 16.5 Hz, 1H), 3.15 (dd, J = 8.0 Hz, J = 16.5 Hz, 1H). 13C NMR (125 MHz, CDCl3), " 154.0, 147.7, 138.4, 128.7, 128.5, 127.0, 119.9, 117.3, 114.2, 113.5, 81.5, 55.9, 55.7, 34.9. HRMS (APCI) Calculated Mass for C16H15O2Cl: ([M-HCl]-) = 238.0994, Found ([M-HCl]-) = 238.0986. Resolution of enantiomers: DAICEL chiralcel¨ AD-H column, 5% IPA-Hexanes, 0.3 mL/min, 254 nm, RT1 = 23.8 min, RT2 = 26.3 min. VI-35: 3-chloro-6-nitro-2-phenyl-2!3,3!3-chromane  1H NMR (500 MHz, CDCl3) " 8.09 (dd, J = 3.0 Hz, J = 9.0 Hz, 1H), 8.01 (d, J = 3.0 Hz, 1H), 7.28-7.42 (m, 5H), 7.04 (d, J = 9.0 Hz, 1H), 5.29 (d, J = 6.5 Hz, 1H), 4.48 (ddd, J = 5.5 Hz, J = 7.0 Hz, J = 0.0 Hz, 1H), 3.27 (dd, J = 5.0 Hz, J = 17.0 Hz, 1H), 3.15 (dd, J = 7.0 Hz, J = 17.0 Hz, 1H). 13C NMR (125 MHz, CDCl3), " 158.7, 137.3, 129.1, 128.9, 126.3, 125.7, 124.5, 119.7, 117.2, 82.1, 54.3, 33.0. HRMS (APCI) Calculated Mass for C15H12NO3Cl: ([M-HCl]-) = 253.0739, Found ([M-HCl]-) = 253.0733. Resolution of enantiomers: DAICEL chiralcel¨ OD-H column, 5% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 = 20.5 min, RT2 = 27.4 min. !!!!OClO2N!$)#!VI-36: 3-chloro-6-methyl-2-phenyl-2!3,3!3-chromane  (Note: the racemic synthesis of VI-36 using 1:1 (DHQD)2PHAL:(DHQ)2PHAL in TFE (0.05 M) and DiChT (1.1 equiv) gave 80:20 dr; the impurity observed in NMR spectra  is due to the minor diastereomer) 1H NMR (500 MHz, CDCl3) " 7.31-7.42 (m, 5H), 6.99 (d, J = 9.0 Hz, 1H), 6.87 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.05 (d, J = 8.0 Hz, 1H), 4.42 (ddd, J = 5.5 Hz, J = 8.5 Hz, J = 8.5 Hz, 1H), 3.25 (dd, J = 5.0 Hz, J = 16.5 Hz, 1H), 3.14 (dd, J = 9.0 Hz, J = 16.5 Hz, 1H), 2.29 (s, 3H).  13C NMR (125 MHz, CDCl3), " 151.5, 138.5, 130.5, 129.5, 128.8, 128.7, 128.5, 126.9, 118.9, 116.3, 81.5, 56.0, 34.5, 20.5. HRMS (APCI) Calculated Mass for C16H15OCl: ([M-HCl]-) = 222.1045, Found ([M-HCl]-) = 222.1035. Resolution of enantiomers: DAICEL chiralcel¨ IA-H column, 5% IPA-Hexanes, 0.5 mL/min, 254 nm, RT1 = 9.7 min, RT2 = 10.2 min. VI-37: 6-bromo-3-chloro-2-phenyl-2!3,3!3-chromane   !!!!OClMe!!!!OClBr!$)'!1H NMR (500 MHz, CDCl3) " 7.31-7.42 (m, 5H), 7.28 (dd, J = 2.5 Hz, J = 8.5 Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 5.10 (d, J = 7.0 Hz, 1H), 4.24 (ddd, J = 5.5 Hz, J = 7.5 Hz, J = 8.5 Hz, 1H), 3.23 (dd, J = 5.5 Hz, J = 16.5 Hz, 1H), 3.11 (dd, J = 7.5 Hz, J = 16.5 Hz, 1H). 13C NMR (125 MHz, CDCl3), " 152.8, 137.9, 131.8, 131.1, 128.8, 128.7, 126.7, 121.3, 118.4, 113.2, 81.5, 55.0, 33.8. HRMS (APCI) Calculated Mass for C15H12OBrCl: ([M-HCl]-) = 285.9993, Found ([M-HCl]-) = 285.9982. Resolution of enantiomers: DAICEL chiralcel¨ IA-H column, 5% IPA-Hexanes, 0.5 mL/min, 254 nm, RT1 = 11.3 min, RT2 = 12.3 min. VI-38: 3-chloro-2-phenyl-6-(trifluoromethyl)-2!3,3!3-chromane   1H NMR (500 MHz, CDCl3) " 7.29-7.42 (m, 7H), 7.01 (d, J = 8.5 Hz, 1H), 5.18 (d, J = 6.5 Hz, 1H), 4.44 (ddd, J = 5.0 Hz, J = 8.0 Hz, J = 8.0 Hz, 1H), 3.26 (dd, J = 5.5 Hz, J = 17.0 Hz, 1H), 3.14 (dd, J = 7.5 Hz, J = 17.0 Hz, 1H). 13C NMR (125 MHz, CDCl3), " 156.1, 137.7, 128.9, 128.7, 126.7 (m), 126.6, 125.5 (m), 123.3 (m), 119.5, 116.9, 81.7, 54.8, 33.5. Resolution of enantiomers: DAICEL chiralcel¨ IA-H column, 5% IPA-Hexanes, 0.5 mL/min, 254 nm, RT1 = 10.3 min, RT2 = 11.3 min. !!!!OClF3C!$*(!VI-39: 3-chloro-6-methoxy-2-(4-methoxyphenyl)-2!3,3!3-chromane   1H NMR (500 MHz, CDCl3) " 7.31 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 1H), 6.72 (dd, J = 3.0 Hz, J = 9.0 Hz, 1H), 6.57 (d, J = 3.0 Hz, 1H), 4.93 (d, J = 8.5 Hz, 1H), 4.36 (ddd, J = 5.0 Hz, J = 8.5 Hz, J = 8.5 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.28 (dd, J = 5.5 Hz, J = 17.0 Hz, 1H), 3.16 (dd, J = 9.0 Hz, J = 17.0 Hz, 1H). 13C NMR (125 MHz, CDCl3), " 159.8, 153.9, 147.8, 130.4, 128.3, 120.1, 117.3, 114.2, 113.9, 113.4, 81.3, 56.1, 55.7, 55.3, 35.3. HRMS (APCI) Calculated Mass for C17H17O3Cl: ([M-HCl]-) = 269.1178, Found ([M-HCl]-) = 269.1168. Resolution of enantiomers: DAICEL chiralcel¨ OJ-H column, 20% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 = 30.0 min, RT2 = 37.0 min. VI-40: 3-chloro-2-(4-methoxyphenyl)-6-nitro-2!3,3!3-chromane   1H NMR (500 MHz, CDCl3) " 8.08 (dd, J = 3.0 Hz, J = 8.5 Hz, 1H), 8.01 (d, J = 3.0 Hz, 1H), 7.24 (t, J = 4.0 Hz, 2H), 7.00 (d, J = 9.0 Hz, 1H), 6.91 (d, J = !!!!OClMeOOMe!!!!OClO2NOMe!$*)!8.5 Hz, 2H), 5.20 (d, J = 7.0 Hz, 1H), 4.43 (ddd, J = 5.0 Hz, J = 8.0 Hz, J = 8.0 Hz, 1H), 3.80 (s, 3H), 3.30 (dd, J = 5.0 Hz, J = 16.5 Hz, 1H), 3.17 (dd, J = 8.0 Hz, J = 16.5 Hz, 1H). 13C NMR (125 MHz, CDCl3), " 160.1, 158.9, 129.2, 127.8, 125.6, 124.4, 119.8, 117.2, 114.2, 81.9, 55.3, 54.4, 33.4. HRMS (APCI) Calculated Mass for C16H14NO4Cl: ([M-HCl]-) = 283.0845, Found ([M-HCl]-) = 283.0838. Resolution of enantiomers: DAICEL chiralcel¨ IA-H column, 5% IPA-Hexanes, 1.0 mL/min, 254 nm, RT1 = 21.7 min, RT2 = 24.7 min. VI-41: 3-chloro-2-phenyl-2!3,3!3-chromane   (Note: the racemic synthesis of VI-41 using 1:1 (DHQD)2PHAL:(DHQ)2PHAL in TFE (0.05 M) and DiChT (1.1 equiv) gave 85:15 dr; the impurity observed in NMR spectra  is due to the minor diastereomer) 1H NMR (500 MHz, CDCl3) " 7.33-7.41 (m, 5H), 7.16 (m, 1H), 7.05 (m, 1H), 6.90-6.94 (m, 2H), 5.05 (d, J = 7.5 Hz, 1H), 4.41 (ddd, J = 5.0 Hz, J = 7.5 Hz, J = 7.5 Hz, 1H), 3.28 (dd, J = 5.5 Hz, J = 16.5 Hz, 1H), 3.17 (dd, J = 9.0 Hz, J = 16.5 Hz, 1H). 13C NMR (125 MHz, CDCl3), " 153.7, 138.3, 129.2, 128.7, 128.6, 128.2, 127.0, 121.2, 119.4, 116.6, 81.6, 55.8, 34.6. !!!!OCl!$**!HRMS (APCI) Calculated Mass for C15H13OCl: ([M-HCl]-) = 208.0888, Found ([M-HCl]-) = 208.0895. Resolution of enantiomers: DAICEL chiralcel¨ IA-H column, 5% IPA-Hexanes, 0.5 mL/min, 254 nm, RT1 = 9.5 min, RT2 = 10.5 min. VI-5B General procedure for synthesis of phenols through path A31   In an oven-dried round-bottom flask, phenol (3.07 mmol, 1.0 equiv) was dissolved in benzene (12 mL). Na (72 mg, 3.07 mmol, 1.0 equiv) was added and the reaction was refluxed at 80 ¡C for 1 h. Cinnamyl chloride (700 mg, 4.60 mmol, 1.5 equiv) was added drop wise and the mixture was refluxed for another 5-12 h. Upon the completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, solvent was removed and ClaisenÕs alkali (8 mL, prepared by dissolving 35.0 g of potassium hydroxide in 25 mL water and methanol up to 100 mL) was added to the residue. The alkaline solution was washed with hexane, acidified with HCl and extracted with dichloromethane. Solvent was removed under reduced pressure, dried over Na2SO4 and purified by gradient column chromatography. Note: this reaction can be carried out in two steps. The sodium salt of phenol derivatives is isolated via treatment with sodium in ether, recrystallized, and then is OHRPhPhClOHRNa, benzene, 80 ¡C, 12hthen KOH, HCl!$*+!converted to final product with cinnamyl chloride in benzene at 80 ¡C similar to the procedure described above. VI-5C General procedure for synthesis of phenols through path B   Under an N2-atmosphere, ethynyl magnesium bromide (45 mL, 0.5 M in THF, 1.2 equiv) was added dropwise to a solution of benzaldehyde derivatives (18.9 mmol, 1.0 equiv) in THF (19 mL) at -78 ¡C. The mixture was stirred slowly warming to room temperature. After 2-4 h, the reaction was complete (monitored by TLC). Next it was quenched with saturated NH4Cl, extracted with dichloromethane, and dried with Na2SO4. Solvent was removed under reduced pressure, and the crude product was purified by column chromatography (5-20% EtOAc-Hex) to afford propynol as a yellow oil. DIAD, PPh3, toluene0 ¡C to rt 5% Pd on BaSO4EtOAc, quinolineHOBrMgTHF, 0 ¡C to rttoluene120 ¡CR1R1OHOHR2R1OR2R1OR2R2OHR1!$*"! To a solution of propynol (3.80 mmol, 1.0 equiv) in toluene (40 mL) was added Ph3P (1.5 g, 5.68 mmol, 1.5 equiv) and phenol derivatives (3.80 mmol, 1.0 equiv). The solution was cooled to 0 ¡C and DIAD (1.2 mL, 5.68 mmol, 1.5 equiv) was added. The solution was warmed to room temperature over 1 h. After the completion of the reaction the mixture was concentrated in reduced pressure to afford the crude product, which was purified using flash chromatography (5% EtOAc-Hex) to yield propargyl ether as a yellow oil.  To a solution of alkyne (0.82 mmol) in EtOH (12 mL) was added LindlarÕs catalyst (40 mg). A H2 balloon was fitted to the flask and the reaction mixture was stirred for 5-30 min until the reaction was completed and the balloon was removed (note: longer times result in the formation of over reduced product). HCl (8 mL, 1M) was added, the mixture was filtered through celite and washed with ether. Solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford allyl ether.  In the last step of the route, the allyl ether (0.45 mmol) was refluxed in toluene (5 mL) at 110 ¡C. After 2 days when the reaction was completed (monitored by TLC), solvent was removed and the crude product was purified by column chromatography to afford the desired unsaturated cinnamyl phenol derivatives in high yields.   !$*$!Analytical data for synthesis of starting materials VI-42: 2-cinnamyl-4-methoxyphenol  1H NMR (500 MHz, CDCl3) " 7.34 (d, J = 7.5 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 6.0 Hz, 1H), 6.75 (s, 1H), 6.68 (dd, J = 3.0 Hz, J = 8.0 Hz, 1H), 6.48 (d, J = 15.5 Hz, 1H), 6.35 (ddd, J = 7.0 Hz, J = 7.0 Hz, J = 16.0 Hz, 1H), 4.65 (s, 1H), 3.75 (s, 3H), 3.52 (d, J = 6.0 Hz, 2H). 13C NMR (125 MHz, CDCl3), " 153.8, 147.9, 137.1, 131.6, 128.5, 127.7, 127.3, 126.9, 126.2, 116.5, 116.0, 112.6, 55.7, 34.3. HRMS (APCI) Calculated Mass for C16H16O2: ([M-H]-) = 239.1072, Found ([M-H]-) = 239.1063. VI-43: 2-cinnamylphenol   1H NMR (500 MHz, CDCl3) " 7.33 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.12-7.21 (m, 3H), 6.89 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.50 (d, J = 15.5 Hz, 1H), 6.39 (ddd, J = 6.0 Hz, J = 6.0 Hz, J = 15.5 Hz, 1H), 4.91 (s, 1H), 3.55 (d, J = 6.0 Hz, 2H). OHOMeOH!$*%!13C NMR (125 MHz, CDCl3), " 153.9, 137.1, 131.5, 130.5, 128.5, 127.9, 127.3, 126.2, 125.7, 121.0, 115.7, 34.1. HRMS (APCI) Calculated Mass for C15H14O: ([M-H]-) = 209.0966, Found ([M-H]-) = 209.0956. VI-44: 4-bromo-2-cinnamylphenol   1H NMR (500 MHz, CDCl3) " 7.20-7.40 (m, 7H), 6.71 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.35 (ddd, J = 7.0 Hz, J = 7.0 Hz, J = 16.0 Hz, 1H), 4.92 (s, 1H), 3.53 (d, J = 6.0 Hz, 2H). 13C NMR (125 MHz, CDCl3), " 153.1, 132.9, 132.1, 130.6, 128.6, 128.5, 127.5, 126.8, 126.2, 126.1, 117.5, 112.9, 33.8. HRMS (APCI) Calculated Mass for C15H13OBr: ([M-H]-) = 287.0072, Found ([M-H]-) = 287.0063. VI-45: 2-cinnamyl-4-nitrophenol   1H NMR (500 MHz, CDCl3) " 8.12 (d, J = 2.5 Hz, 1H), 8.07 (dd, J = 3.0 Hz, J = 9.0 Hz, 1H), 7.36 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 9.0 OHBrOHNO2!$*&!Hz, 1H), 6.89 (d, J = 9.5 Hz, 1H), 6.55 (d, J = 15.5 Hz, 1H), 6.35 (ddd, J = 6.5 Hz, J = 6.5 Hz, J = 16.0 Hz, 1H), 5.89 (s, 1H), 3.62 (d, J = 6.5 Hz, 2H). 13C NMR (125 MHz, CDCl3), " 159.7, 141.6, 136.6, 132.8, 128.6, 127.7, 126.9, 126.4, 126.3, 125.9, 124.3, 115.8, 33.7. HRMS (APCI) Calculated Mass for C15H13O3N: ([M-H]-) = 254.0817, Found ([M-H]-) = 254.0810. VI-46: 4-methoxy-2-(3-methylbut-2-en-1-yl)phenol   1H NMR (500 MHz, CDCl3) " 6.73 (d, J = 9.0 Hz, 1H), 6.69 (d, J = 3.0 Hz, 1H), 6.65 (dd, J = 3.0 Hz, J = 8.5 Hz, 1H), 5.29 (t, J = 7.0 Hz, 1H), 4.86 (s, 1H), 3.74 (s, 3H), 3.31 (d, J = 7.5 Hz, 2H), 1.75 (s, 6H). 13C NMR (125 MHz, CDCl3), " 153.6, 148.1, 134.7, 128.1, 121.6, 116.2, 115.7, 111.9, 55.7, 29.8, 25.7, 17.8. HRMS (APCI) Calculated Mass for C12H16O2: ([M-H]-) = 191.1072, Found ([M-H]-) = 191.1064. VI-47: 2-cinnamyl-4-methylphenol OHMeOMeMeOHMe!$*#!1H NMR (500 MHz, CDCl3) " 7.36 (d, J = 7.5 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 6.96 (s, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.49 (d, J = 16.0 Hz, 1H), 6.36 (ddd, J = 7.0 Hz, J = 7.0 Hz, J = 16.5 Hz, 1H), 4.77 (s, 1H), 3.52 (d, J = 6.0 Hz, 2H), 2.26 (s, 3H). 13C NMR (125 MHz, CDCl3), " 151.7, 137.1, 131.4, 130.9, 130.2, 128.5, 128.2, 128.1, 127.3, 126.2, 125.4, 115.6, 34.1, 20.5. HRMS (APCI) Calculated Mass for C16H15O: ([M-H]-) = 223.1123, Found ([M-H]-) = 223.1113. VI-48: (E)-2-(3-(4-fluorophenyl)allyl)-4-methoxyphenol   1H NMR (500 MHz, CDCl3) " 7.28 (dd, J = 5.5 Hz, J = 9.0 Hz, 2H), 6.96 (t, J = 8.5 Hz, 2H), 6.75 (m, 2H), 6.69 (dd, J = 2.5 Hz, J = 8.5 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 6.26 (ddd, J = 7.0 Hz, J = 7.0 Hz, J = 16.0 Hz, 1H), 4.70 (s, 1H), 3.75 (s, 3H), 3.50 (d, J = 6.5 Hz, 2H). 13C NMR (125 MHz, CDCl3), " 163.0, 161.1, 153.8, 147.8, 133.2 (d), 130.2, 127.6 (d), 127.4 (d), 126.8, 116.4, 116.0, 115.4, 115.3, 112.5, 55.7, 34.1. HRMS (APCI) Calculated Mass for C16H15O2F: ([M-H]-) = 257.0978, Found ([M-H]-) = 257.0967.  OHOMeF!$*'!VI-49: (E)-4-methoxy-2-(3-(4-nitrophenyl)allyl)phenol   1H NMR (500 MHz, CDCl3) " 8.11 (d, J = 9.5 Hz, 2H), 7.42 (d, J = 9.0 Hz, 2H), 6.73 (d, J = 9.0 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 3.0 Hz, J = 8.5 Hz, 1H), 6.57 (ddd, J = 6.5 Hz, J = 6.5 Hz, J = 16.0 Hz, 1H), 6.46 (d, J = 16.0 Hz, 1H), 4.88 (s, 1H), 3.74 (s, 3H), 3.55 (dd, J = 6.5 Hz, J = 1.0 Hz, 2H). 13C NMR (125 MHz, CDCl3), " 153.8, 147.6, 146.5, 143.9, 133.5, 129.1, 126.6, 126.3, 123.9, 116.2, 112.5, 55.7, 34.1. HRMS (APCI) Calculated Mass for C16H15O4N: ([M-H]-) = 284.0923, Found ([M-H]-) = 284.0911. VI-50: 2-cinnamyl-3,5-dimethoxyphenol   1H NMR (500 MHz, CDCl3) " 7.33 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 6.47 (d, J = 15.5 Hz, 1H), 6.33 (ddd, J = 6.0 Hz, J = 6.0 Hz, J = 15.5 Hz, 1H), 6.14 (d, J = 2.5 Hz, 1H), 6.10 (d, J = 2.5 Hz, 1H), 5.04 (s, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.55 (dd, J = 5.5 Hz, J = 1.5 Hz, 2H). 13C NMR (125 MHz, CDCl3), " 159.8, 158.8, 155.7, 137.3, 130.4, 128.4, 128.3, 127.1, 126.2, 106.0, 93.8, 91.6, 55.8, 55.3, 26.2. OHOMeNO2OHMeOOMe!$+(!HRMS (APCI) Calculated Mass for C17H18O3: ([M-H]-) = 269.1178, Found ([M-H]-) = 269.1170. VI-51: (E)-4-methoxy-2-(3-(4-methoxyphenyl)allyl)phenol   1H NMR (500 MHz, CDCl3) " 7.29 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 9.0 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H), 6.70 (dd, J = 3.0 Hz, J = 9.0 Hz, 1H), 6.47 (d, J = 16.0 Hz, 1H), 6.24 (ddd, J = 6.5 Hz, J = 6.5 Hz, J = 15.5 Hz, 1H), 4.64 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.52 (dd, J = 7.0 Hz, J = 1.5 Hz, 1H). 13C NMR (125 MHz, CDCl3), " 159.1, 153.8, 148.0, 131.1, 129.8, 127.4, 126.9, 125.3, 116.5, 115.9, 113.9, 112.6, 55.7, 55.3, 34.5. HRMS (APCI) Calculated Mass for C17H18O3: ([M-H]-) = 269.1178, Found ([M-H]-) = 269.1168. VI-52: 2-cinnamyl-4-(trifluoromethyl)phenol   1H NMR (500 MHz, CDCl3) " 7.45 (s, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.0 Hz, 1H), 6.89 (d, J = 8.0 OHOMeOMeOHCF3!$+)!Hz, 1H), 6.54 (d, J = 15.5 Hz, 1H), 6.38 (ddd, J = 6.5 Hz, J = 6.5 Hz, J = 16.0 Hz, 1H), 5.40 (br s, 1H), 3.61 (d, J = 6.5 Hz, 2H). 13C NMR (125 MHz, CDCl3), " 156.7, 136.7, 132.3, 128.6, 127.6, 127.61, 127.5, 126.7, 126.3, 126.2, 125.2 (q), 115.8, 33.9. HRMS (APCI) Calculated Mass for C16H13OF3: ([M-H]-) = 277.0840, Found ([M-H]-) = 277.0832. VI-5D Procedure for synthesis of protected phenols   To a solution of phenol VI-9 (100 mg, 0.42 mmol, 1.0 equiv) in THF (8 mL) was added NaH (25 mg, 0.63 mmol, 1.5 equiv) at 0 ¡C. After stirring for 10 min, acetyl chloride (30 µL, 0.42 mmol, 1.0 equiv) was added and the reaction was stirred till completion. The solution was neutralized with saturated NH4Cl (aq), extracted with dichloromethane, dried over Na2SO4. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (5-10% EtOAc-Hex) to afford VI-33 in 83% yield.   OHOMePhVI-9OAcOMePhNaH, CH3COClTHF,  12 h, 83%VI-33!$+*!VI-33: 2-cinnamyl-4-methoxyphenyl acetate   1H NMR (500 MHz, CDCl3) 7.32 (d, J = 7.5 Hz, 2H), 7.27 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 6.76 (dd, J = 3.0 Hz, J = 8.5 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 6.23 (ddd, J = 7.0 Hz, J = 7.0 Hz, J = 16.0 Hz, 1H), 3.76 (s, 3H), 3.39 (d, J = 7.0 Hz, 2H), 2.25 (s, 3H). 13C NMR (125 MHz, CDCl3), " 169.9, 157.4, 142.5, 137.2, 132.9, 131.6, 128.5, 127.4, 127.2, 126.1, 123.0, 115.6, 112.3, 55.5, 34.1, 20.9. HRMS (APCI) Calculated Mass for C18H18O3: ([M+H]+) = 283.1334, Found ([M+H]+) = 283.1325.    To a solution of phenol VI-9 (100 mg, 0.42 mmol, 1.0 equiv) in THF (3 mL) was added Et3N (0.1 mL, 0.63 mmol, 1.5 equiv) at room temperature. TMSCl (70 µL, 0.50 mmol, 1.2 equiv) was added and the reaction was stirred OAcOMeOHOMePhVI-9OTMSOMePhEt3N, TMSClTHF,  8 h, 62%VI-34!$++!till completion. The solution was neutralized by water, extracted with dichloromethane, dried over Na2SO4. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (5-10% EtOAc-Hex) to afford VI-34 in 62% yield. VI-34: (2-cinnamyl-4-methoxyphenoxy)trimethylsilane   1H NMR (500 MHz, CDCl3) " 7.34 (d, J = 1.5 Hz, 2H), 7.27 (t, J = 7.5 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 6.74 (t, J = 3.5 Hz, 1H), 6.71 (s, 1H), 6.63 (dd, J = 9.0 Hz, J = 3.0 Hz, 1H), 6.42 (d, J = 15.5 Hz, 1H), 6.30 (ddd, J = 7.0 Hz, J = 7.0 Hz, J = 16.0 Hz, 1H), 3.73 (s, 3H), 3.45 (d, J = 7.0 Hz, 2H), 0.25 (s, 9H). 13C NMR (125 MHz, CDCl3), " 153.9, 147.1, 137.6, 131.7, 130.9, 128.7, 128.4, 126.9, 126.1, 119.3, 115.7, 111.8, 55.6, 33.9, 0.47. VI-5E Procedure for synthesis of catalyst VI-2132    An oven-dried round bottom flask was charged with N-methyl (2R)-pyrrolidine methanol (100 mg, 0.87 mmol, 2.0 equiv), 1,4-dichlorophthalazine NNOONMeNMeNNClClNMeOHKOH, K2CO3toluene, refluxOTMSOMe!$+"!(92 mg, 0.43 mmol, 1.0 equiv), K2CO3 (180 mg, 1.30 mmol, 3.0 equiv), and toluene (10 mL). The flask was charged with nitrogen, equipped with a Dean-Stark condenser. Under nitrogen the reaction mixture was refluxed for 2 h. KOH pellets (73 mg, 1.30 mmol, 3.0 equiv) were added and the mixture was refluxed for additional 2 days. After completion of the reaction (monitored by TLC), the solution was cooled to room temperature, mixed with water, and extracted with EtOAc. The organics were dried over Na2SO4, and removed under reduced pressure. The crude product was purified by column chromatography (gradient 50% EtOAC:Hexanes to 50% DCM:MeOH to MeOH) to provide the pure product in 32% yield. VI-21: 1-(((R)-1-methylpyrrolidin-2-yl)methoxy)-4-(((S)-1-methylpyrrolidin-2-yl)methoxy)phthalazine  1H NMR (500 MHz, CDCl3) " 8.17 (dd, J = 2.5 Hz, J = 5.5 Hz, 2H), 7.93 (dd, J = 3.0 Hz, J = 5.5 Hz, 2H), 4.54 (dddd, J = 4.5 Hz, J = 11.0 Hz, J = 11.0 Hz, J = 11.0 Hz, 4H), 3.13 (ddd, J = 4.5 Hz, J = 4.5 Hz, J = 9.0 Hz, 2H), 2.90 (ddd, J = 7.0 Hz, J = 7.0 Hz, J = 13.0 Hz, 2H), 2.56 (s, 6H), 2.41 (dd, J = 8.5 Hz, J = NNOONMeNMe!$+$!17.5 Hz, 2H), 2.15 (dddd, J = 7.5 Hz, J = 7.5 Hz, J = 7.5 Hz, J = 7.5 Hz, 2H), 1.70-1.95 (m, 6H). 13C NMR (125 MHz, CDCl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`Q.C<a!@:.C5!"!6!'8&!'#$%&!'@(D!0!!"#%0!3CF0!)++$$K)++%*,!!)(,!<CC.A30!R,T,0!5;!.C,0!8<CHOC.;53!SC.=./B/5>!FABE!;L5!D.AH!BF!1AOY;B:.AO.!1L.A;.:5.!<>!V5/765!b?A6>!J@$!RBCOE5A.>5!P/L?_?;BA>!"!6!'G?;!'H.(<!0!!"##0!7+0!*""%K*"$+,!!$+#!)),!<A.O.E.0!T,0!5;!.C,0!8P>BC.;?B/0!W1V!<>>?>;53!@;A6:;6A.C!</.CO>5>0!D?B>O/;L5;?:!V?>:6>>?B/>0!./3!D?BCB7?:.C!<:;?=?;?5>!BF!WY?K1B:LC?Bc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c6?/B/5>0!J.YL;LBLO3ABc6?/B/5>!./3!J.YL;LBLO3ABc6?/B/5!V?E5A>!FABE!96_?.!1BA3?FBC?.!./3!-L5?A!1O;B;Bd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c6?/B/5>!FABE!.!J5Z!T.A?/5!<:;?/BEO:5;5!"!6!'G?;!'H.(<!0!!""(0!FK0!'("K')(,!!*),!Q.>;50!J,T,0!5;!.C,0!8D.:;5A?:?3.C!2?/5;?:>!BF!T.A?/5KV5A?=53!J.YOA.3?BEO:?/>!.7.?/>;!1B/;5EYBA.AO!T5;L?:?CC?/K95>?>;./;!@;.YLOCB:B::6>!.6A56>!"!L?.1*%'M.)/>0!!"##0!,0!%#(K%#',!!**,!4.E.EB;B0!2,0!5;!.C,0!8J.YOA.3?BEO:?/!<)0!</!P/L?_?;BA!BF!T?;B:LB/3A?.C!1BEYC5d5>!P!./3!PP!"!6!'8*;1J1(;!0!!"#!0!F=0!*))K*)",!!$+'!*+,!-.;>6;.0!2,0!5;!.C,0!8-L5!S?A>;!-B;.C!@O/;L5>?>!BF!`efKaKJ.YOA.3?BEO:?/!<)!"!#$%&!'N%;;!0!!""!0!)"K)$,!!*",!@/O35A0!@,<,0!N,K4,!-./70!./3!9,!^6Y;.0!8W/./;?B>5C5:;?=5!-B;.C!@O/;L5>?>!BF!`gaKJ.YOA.3?BEO:?/!<)!=?.!<>OEE5;A?:!1LCBA?/.;?B/!BF!./!P>BC.;53!UC5F?/!"!6!'8&!'#$%&!'@(D!0!!""&0!3C30!$&""K$&"$,!!*$,!D.AH5A0!V,0!5;!.C,0!8<33?;?B/!BF!@?COCBdO3?5/5>!;B!*0%KV?_ABEBK)0"KD5/GBc6?/B/5\!</!<YYAB.:L!;B!Q?7LCO!UdO75/.;53!DABEB/.YL;LBc6?/B/5>!FBA!;L5!@O/;L5>?>!BF!-LO>./B/5!"!I%;.?$%<.(*0!!""$0!=,0!*"")K*""',!!*%,!J.ZA.;0!1,1,0!M,![5Z?>0!./3!1,h,!TBB3O0!8@O/;L5>?>!BF!<E?/BK)0"KD5/GBc6?/B/5>!./3!-L5?A!I>5!?/!V?5C>K<C35A!<YYAB.:L5>!;B!;L5!<E?/B/.YL;LBc6?/B/5!</;?_?B;?:>!"!6!'-./!'#$%&!0!!"##0!7F0!&#&*K&##),!!*&,!^.AG./0!<,0!5;!.C,0!8@BC=5/;KV5Y5/35/;!W/./;?B3?=5A75/:5!?/!;L5!1LCBAB:O:C?G.;?B/!BF!I/>.;6A.;53!1.A_.E.;5>!"!#$%&!'5).!'6!0!!"#$0!3,0!'()$K'(*),!!*#,!h.7./.;L./0!<,0!5;!.C,0!8<!1.;.CO;?:!<>OEE5;A?:!1LCBAB:O:C?G.;?B/!BF!I/>.;6A.;53!<E?35>!"!8*/%9!'#$%&!':*;!'5<!0!!"##0!=B0!*$'+K*$'%,!!*',!h.7./.;L./0!<,0!9,h,!@;.YC5>0!./3!D,!DBAL./0!82?/5;?:!95>BC6;?B/!BF!I/>.;6A.;53!<E?35>!?/!.!1LCBAB:O:C?G.;?B/!95.:;?B/\!1B/:BE?;./;!W/./;?BE5A!V?FF5A5/;?.;?B/!./3!S.:5!@5C5:;?=5!<CH5/5!1LCBA?/.;?B/!_O!.!@?/7C5!1.;.CO>;!"!6!'8&!'#$%&!'@(D!0!!"#$0!3C=0!)"#(%K)"#)+,!!+(,!ML?;5L5.30!V,1,0!5;!.C,0!8</!UA7./B:.;.CO;?:!<>OEE5;A?:!1LCBABC.:;B/?G.;?B/!"!6!'8&!'#$%&!'@(D!0!!"#"0!3C40!+*'#K++((,!!+),!1B/>65CB!h?Ei/5G0!T,0!T,<,!T?A./3.0!./3!9,!-BAEB>0!8P/;A.EBC5:6C.A!Wd:?;53K@;.;5!P/;5A.:;?B/>!?/!RL5/BCj@;OA5/5!D?:ABEBYLBA?:!@O>;5E>\!<!RLB;B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