HIGHLY STEREOSELECTIVE INTERMOLECULAR HALOFUNCTIONALIZATION OF OLEFINS !"#!!Bardia Soltanzadeh A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry -Doctor of Philosophy 2018 ABSTRACT HIGHLY STEREOSELECTIVE INTERMOLECUL AR HALOFUNCTIONALIZATION OF OLEFINS By Bardia Soltanzadeh Since the inception of organic chemistry more than a 200 years ago, halogenation of olefins has been a mainstay reaction. Yet, this venerable reaction had not succumbed to an enantioselective process. Two major issues that have thwarted the development of asymmetric alkene halogenations are the rapid stereochemical degradation of chiral halonium ions by olefin -to-olefin halonium transfer, and by isomeriz ation of halonium ions to the open !-halocarbenium ions. The latter scenario changed in 2010, when our lab, among others, successfully demonstrated stereoselective reactions for the intramolecular halocyclization of alkenes with tethered nucleophiles. Not surprisingly, most early example s reported on the intramolecular capture of halonium ions via tethered nucleophiles; the proximity -driven rate enhancement of the cyclization step pr esumably outcompetes any stereo randomizing event. Enantioselectivities of >95:5 are routinely obtained with a variety of halonium precursors and nucleophiles. In contrast, enantioselective intermolecular halofunctionalizations have been more difficult to achieve due to reduced reaction rates, limited choice of compatible nucleophiles, and lack of regiochemical con trol. This dissertation highlights my efforts towards optimizing a variety of intermolecular halofunctionalization methodologies. First, our results that show excellent control of stereo and enantioselectivity in haloetherification and haloesterification of both activated and non -activated olefins will be discussed. The resulting lessons from the latter were parlayed into developing a highly selective olefin dihalogenation, demonstrating the ability to overcome re giochemical scrambling through catalys t controlled process, as opposed to substrate control selectivity, which limits the chemistry to activated olefins. Most recently, the chemistry has been extended to enantioselective haloamination of olefins, setting the stage for the synthesis of privileged moieties found in natural products, bioactive reagents , and pharmaceuticals. Finally, our prel iminary mechanistic investigations suggest that a concerted mechanistic pathway is resp onsible for product formation. The dependence of the course of the reaction on the nature of the nucleophile leads to a suggested explanation for the observed divergence in product facial selectivity. !iv To my lovely parents !v ACKNOWLEDGMENTS During the course of my graduate studies numerous people were helpi ng me, and without their support, this process would be impossible. My advisor professor Babak Borhan was one of those people that influence m e not only in scientific way but also in personal perspective. His mentorship was led me to grow as a scientist an d thought me how to think and fix scientific problems. I am grateful to my committee members, Prof. William Wulff, Prof. James Jackson and Prof. Daniel Jones for their advice and support. I am thankful to Dr. Richard Staples for X-ray crystallography, Dr. Daniel Holmes for helping me to run kinetic studies by means of NMR instruments. Arvind has been fantastic senior for me; he kindly taught me to be a better chemist. I also want to send my thanks to Dr. Chrysoula Vasileiou for her help and encouragement. I am thankful to those graduate students that collaborate with me on different projects - Daniel, Yi and Aritra. Mostly, I express my gratitude to my parents, brother, sister and Hamideh for their unconditional support and lo ve. Without their encouragement and s upport, this long journey would have been impossible . !!! !!vi TABLE OF CONTENTS !LIST OF TABLES ........................................................................................... xii LIST OF FIGURES ........................................................................................ xiv KEY TO SYMBOLS AND ABBREVIATIONS ................................................. xxi Chapter I: Highly Stereoselective Intermolecular Haloetherification and Haloesterification of All yl Amides ................................................................ 1!I-1 Introduction ................................................................................................. 1!I-1-1 Racemization of chiral halonium ion by olefin to olefin halenium transfer ..................................................................................................... 3!I-1-2 Literature precedence for enantioselective intermolecular halo - functionalization of alkenes ..................................................................... 7!I-2 Results and discussion ............................................................................. 14!I-2-1 Prelim inary results ......................................................................... 14!I-2-1-1 TFE-incorporated products was a hint for development of a methodology for intermolecular halofunctionalization ......................... 14 I-2-1-2 Additive studies to improve enantioselectivity of chlorocyclization of amides lead to the development of intermolecular halofunctionalization ........................................................................... 18!I-2-2 Optimization of reaction variables ................................................. 20!I-2-2-1 Influence of the identity and stoichiometry of the chlorenium 20source on the stereoselectivity of the reaction ................................ 20 I-2-2-2 Influence of reaction solvent on enan tioselectivity of chloro etherified products .............................................................................. 21!I-2-2-3 Effect of substituents on the amide moiety in the chloro etherification reaction selectivity ......................................................... 22 I-2-2-4 Reaction optimization for aliphatic substrates ......................... 24!I-2-3 Substrate scope for the intermolecular c hloroetherification reaction ............................................................................................................... 26 I-2-3-1 Substrate with MeOH as the nucleophile ................................ 26 I-2-3-2 Nucleophile scope for the intermolecular chloroetherification reaction ............................................................................................... 31 I-2-3-3 Substrate scope for asymmetric bromination of allyl amide substrates ........................................................................................... 33 !vii I-2-3-4 Subs trate scope for the intermolecular chloroesterification reaction by employing quasi -enantiomeric catalyst ............................ 34 I-2-4 Product distribution arising due to substrate -control and catalyst -control for the intermolecular chloroetherification reaction. ................ 37!I-2-5 Abs olute stereochemistry of the chloroetherification reactions ..... 41!I-2-5-1 Absolute stereochemistry of the chloroetherification products derived from E- alkene ........................................................................ 41 I-2-5-2 Stereodivergence in the formation of halohydrin and oxazoline products .............................................................................................. 43!I-2-6 Experimen tal section ..................................................................... 45!I-2-6-1 General information ................................................................. 45 I-2-6-2 General procedure for optimization of catalytic asymmetric intermolecular haloetherification/haloesterification of unsaturated amides ............................................................................................................ 46!I-2-6-3 General procedure for substrate scope analysis for cataly tic asymmetric intermolecular haloetherification/haloesterification of unsaturated amides ............................................................................ 47!I-2-6-4 Procedure for gram scale catalytic asymmetric intermolecular haloetherification/haloesterification of unsaturated amides ................ 47 I-2-6-5 Synthesis of unsaturate d amide substrates for chlorofunctionalizatio n ........................................................................ 49!I-2-6-6 General procedure for synthesis of aromatic Z-allyl amides ... 50 I-2-6-7 General procedure synthesis of substrates Z-46e-NO2 Ð Z-46j-NO2 ..................................................................................................... 52 I-2-6-8 Analytical data for products ..................................................... 53 I-2-6-9 Analytical da ta for byproduct ................................................... 78!I-2-6-10 Analytical data for substrates ................................................ 79!I-2-6-11 Analytical data for different products of chloroetherification reaction without catalyst ...................................................................... 88!REFERENCES ...................................................................................... 92 !Chapter II: Highly Regio -and Enantioselective Vicinal Dihalogenation of Allyl Amides ................................................................................................. 99!II-1 Introduction .............................................................................................. 99!II-1-1 Racemization of chiral halonium ion by olefin to olefin halenium transfer ................................................................................................. 100!II-1-2 Literature precedence for enantioselective vicinal dihalogenation of alkenes ................................................................................................ 103!!viii II-2 Results and discussions ........................................................................ 113!II-2-1 Catalyst -controlled regioselectivity in enantioselective haloetherification reaction .................................................................... 113!II-2-2 Extension of haloetherification to the enantioselective dihalogenation of alkenes .................................................................... 116!II-2-3 Dichlorination of allyl amides in acetonitrile ............................... 119 II-2-4 Role of the counteri on of chloride in selectivity of dichlorination reactions .............................................................................................. 120!II-2-5 Substrate scope for asymmetric dichlorination reaction ............. 122 II-2-5-1 Substrate scope for Z -allyl amide in asymmetric dichlorination reaction ............................................................................................. 122 II-2-5-2 Substrate scope for E -allyl amide in asymmetric dichlorination reaction ................................................................................................ 125 II-2-5-3 Substrate scope for dichlorination reaction with quasi -enantiomeric (DHQ) 2PHAL catalyst .................................................. 126!II-2-5-4 Substrate scope for regio - and enantioselective hetero -dihalogenation ................................................................................... 127!II-2-6 Influence of reaction c oncentration on the yield for the dichlorination of unsaturated aromatic and trisubstituted allyl amides ....................... 129!II-2-7 Influence of solvents and equivalents of lithium chloride on the chlorobromination reactions ................................................................. 131!II-2-8 Various halenium and halide sources for the enantioselective dihalogenation of unsaturated amides were used ............................... 132 II-2-9 Product distribution arising due to substrate -control and catalyst -control for the dichlorination reactions ................................................. 133!II-2-10 Control experiments indicating that dichlorination re action occurs on LiCl solid surface ............................................................................ 134!II-2-10-1 Screening selectivity ratio with different concentrations ..... 134 II-2-10-2 Effect of rate of stirring (RPM studies) on the selectivity of dichlorination reactio n ....................................................................... 136!II-2-10-3 Effect of LiCl particle size on p roduct distribution of the dichlorination reaction ....................................................................... 138!II-2-10-4 Effect of 12 -crown -4 ether on product distribution of dichlorination reactions ..................................................................... 140!II-2-11: A new unprecedented transformation for the synthesis of N -haloimides revealed by side product ident ification in hetero -dihalogenation ..................................................................................... 141!II-2-11-1 The importance of N -haloimides ........................................ 142!!ix II-2-11-2 Currently used methods for producing N -haloimides ......... 142!II-2-11-3 Highly regio - and enantioselective vicinal dihalogenation of allyl amides .............................................................................................. 143!II-2-11-4 Identifica tion of a hetero -dihalogenation reactionÕs side product .......................................................................................................... 144!II-2-11-5 Substrate scope for expedient synthesis of N -bromo - and N-iodoimides from the corresponding N -chloroimides .......................... 146 II-2-12 Conclusion ............................................................................. 147 II-2-13 Experimental section ................................................................ 148!II-2-13-1 General i nformation ............................................................ 148!II-2-13-2 General procedure for catalytic asymmetric dichlorination of unsaturated amides .......................................................................... 149!II-2-13-3 Procedure for gram scale scope analysis for catalytic asymmetric dichlorination of unsaturated amides in presence of 1% of chiral catalys t .................................................................................... 150!II-2-13-4 Procedure for gram scale scope analysis for synthesis of N -bromo - and N-iodoimides from t he corresponding N -chloroimides ... 150!II-2-13-5 Analytical data for products ................................................ 151!II-2-13-6 Analytical data for byproduct II -45 ...................................... 170 II-2-13-7 Analytical d ata for products in non -catalyzed reaction (II -48C, II-48D, II-48E) .................................................................................. 171!II-2-13-8 Analytical data for substrate II -55A .................................... 173 REFERENCES ................................................................................. 174 !Chapter III: Highly regio -, diastereo -, and enantioselective chloroamination of alkenes ................................................................................................... 181!III-1 Introduction ........................................................................................... 181!III-1-1 Literature precedence for catalytic vicinal haloamination of alkenes ............................................................................................................. 185!III-1-1-1 Literature precedence for catalytic -racemic vicinal haloamination of alkenes .......................................................................................... 185!III-1-1-2 Literature precedence for catalytic -asymmetric vicinal haloamination of alkenes .................................................................. 190!III-2 Result and discussion ........................................................................... 194!III-2-1 Discovery of chloroacetamide product III -34D as a side product in enantioselective dichlorination reactions ............................................. 194!!x III-2-2 Typical Ritter type mechanism leading to the chloroacetamide product III -34D ..................................................................................... 195!III-2-3 Formation of unknown products as intermediates in chloroamination reaction ...................................................................... 196!III-2-4 Designing control experiments to determine the structure of mixture of products .............................................................................. 199!III-2-5 Modified mechanism for the formation of the chloroacetamide III -34D ...................................................................................................... 200!III-2-6 Catalyst -controlled chloroamination reaction ............................ 201 III-2-7 Two distinct types of choloroaminated products were produced from different chlorenium sources ....................................................... 203!III-2-8 Role of HFIP as an additive in enantioselective chloroamination reactions .............................................................................................. 205!III-2-9 Substrate scope for enantioselective chloroamination reaction by employing DCDMH as the chlorenium source ..................................... 209!III-2-10 Optimization studies for the intermolecular enantioselective chloroamidination of E-allyl amides ..................................................... 210!III-2-11 Substrate scope for enantios elective chloroamination reaction by employing TsNCl 2 as the chlorenium source ....................................... 212 III-2-12 Conclusion ............................................................................... 213!III-2-13 Experimental section ............................................................... 214!III-2-13-1 General procedure for catalytic asymmetric chloroamidation of unsaturated allyl amides ........................................................... "".214 III-2-13-2 Analytical data for chloroamide products .......................... 215!REFERENCES ............................................................................................ 222 !Chapter IV: Mechanistic investigation for the observed switch in olefin chlorenium face selectivity ....................................................................... 206 IV-1 Introduction .......................................................................................... 206 IV-1-1 Switch of chlorenium face selectivity in two products of dich lorination reaction .......................................................................... 206 IV-1-2 Switch of chlorenium face selectivity for two products of the chloroetherification reaction. ................................................................ 209 IV-1-3 Classical perception of electrophilic addition to alkenes vs. Nucleophile Assisted Alkene Activation (NAAA) ................................. 211 IV-1-3-1 18O KIE studies prove the role of the nucleophile in the transition states ................................................................................. 215 !xi IV-1-3-2 NMR resonance displaying the interaction of nucleophiles with the alkenes ........................................................................................ 216 IV-1-4 Kinetic studies ........................................................................... 217 IV-1-5 Kinetic competition studies in HDDA reactions ......................... 219 IV-2 Results and discussions ....................................................................... 225 IV-2-1 Kinetic competition studies for chloroetherification reactions ... 225 IV-2-2 Proposed mechanism for chlorenium face selectivity switch for products IV -18B and IV -18C ................................................................ 228 IV-2-3 Exploring mechanism of formation of the minor di asteomer IV -18BÕ ............................................................................................................. 229 IV-2-4 Experimental section ................................................................. 232 REFERENCES ............................................................................................ 234 !!!! !!!!!!!!!!!!!!!!!!!!!!!!!xii LIST OF TABLES !Table I -1: Additive studies in c hlorocyclization of allyl amides reaction ........ 19 Table I -2: Chlorenium Source Optimization .................................................. 21 Table I -3: Influence of co -solvent additives on the chemo - and stereoselectivity of the reaction ............................................................................................. 22 !Table I -4: Orienting studies for enantioselective intermolecular chloroetherification of E-46b-(Br/OMe/NO 2) .............................................. 24 !Table I -5: Reaction optimization for aliphatic substrates ............................... 26 Table II-1: Catalyst -controlled regioselective chlorobromination of allyl alcohols ................................................................................................................... 109 !Table II -2: catalyst -controlled regioselectivity in chloroetherification reactions of Z-allyl amide II-35 ..................................................................................... 115 !Table II -3: Catalyst -controlled regioselectivity in chlo roetherification reactions of E-allyl amide II-39 ..................................................................................... 116 !Table II -4: Summary of optimization studies for dichlorination .................... 119 Table II -5: Dichlorination of allyl amides in acetonitrile ............................... 120 Table II -6: Role of counter ion of chloride ion in selectivity of dich lorination reaction ..................................................................................................... 122 !Table II -7: Dichlorination of aromatic and trisubstituted allyl amides .......... 130 Table II -8: Optimization of chlorobromination reactions .............................. 131 Table II -9: Regio- and enantioselective dihalogenation .............................. 132 Table II -10: Product distribution in catalyzed and non -catalyzed dichlor ination reaction s ................................................................................................... 133 !xiii !Table II -11: Screening selectivity ratio in different concentrations .............. 136 Table II -12: Effect of rate of stirring (RPM Studies) in selectivity of dichlorination reaction ..................................................................................................... 138 !Table II -13: Effect of L iCl particle size on product distribution of the dichlorination reaction ..................................................................................................... 140 !Table II -14: Effect of 12 -crown -4 ether on product distribution of dichlorination reactions ................................................................................................... 129 !Table III -1: Summary of optimization studies in dichlorination reactions ..... 195 Tabl e III -2: Optimization studies for the intermolecular enantioselective chloroamidination of E-allyl amides .......................................................... 211 !Table IV -1: Competitive H 2-transfer vs. addition product in HDDA reaction ........................................................................................................ 238 Table IV -2: Kinetic competition study employing an internal cloc k reactio n ........................................................................................................ 240 Table IV -3: The ratio of the IV -18B and IV -18C is related to the concentration of MeOH ........................................................................................................ 244 ! !xiv LIST OF FIGURES !Figure I-1: Natural products with stereo defined carbon -halogen bonds ........ 1 Figure I -2: (a) Intr amolecular vs intermolec ular halofunctionalization (b) Racemization of chiral halonium ion ................................................................ 2 !Figure I -3: Partial stereorandomization of bromonium ion by olefin to olefin halenium ion transfer ....................................................................................... 4 !Figure I-4: Rapid equilibrium between cyclic and acyclic bro monium ion ....... 6 Figure I-5: The isotopic perturbation of degenerate equilibrium ..................... 7 Figure I -6: First asymmetric intermolecular bromoesterification catalyzed by chiral Br¿nsted acid ......................................................................................... 8 !Figure I-7: Phosphoric acid catalyst for oxyfluorination of enamide ................ 9 Figure I-8: Asymmetric bromohydroxylation of allyl alcohols by quinine -derived catalysts ......................................................................................................... 10 !Figure I -9: Enantioselective intermolecular bromoesterification of allylic sulfonamides .................................................................................................. 11 !Figure I-10: Potential of chiral sulfonium reagents to effect asymmetric hal onium additions to isolated alkenes .......................................................................... 12 !Figure I-11: (a) Enantioselective bromoesterification of aliphatic alkenes (b) Chiral halohydrin synthesis of aliphatic olefins .............................................. 13 !Figure I -12: An organocatalytic asymmetric chlorolactonization reaction of alkenoic acid .................................................................................................. 15 !Figure I-13: (a) Discovery of an asymmetric intermolecular chloroetherification of allyl amides (b) Using Non -nucleophilic 1 -nitropropane yielded cyclized products exclusively ....................................................................................... 18 !xv Figure I-14: Intermolecular chloroetherification of allyl amides ..................... 20 Figure I-15: Substrate Scope for intermolecular chloroetherification for trans allyl amides substrate ........................................................................................... 28 !Figure I-16: Substrate scope of intermolecular chloroetherification for cis allyl amide substrates ........................................................................................... 30 !Figure I-17: Nucleophile scope for the interm olecular chloroetherification reaction ........... .......................................................................................................... 32 !Figure I-18: Substrate scope for asymmetric bromination of allyl amide substrate ........... .......................................................................................................... 34 !Figure I-19: Substrate scope for the intermolecular chloroesterification reaction by employing quasi -enantiomeric cataly st ..................................................... 36 !Figure I -20: The regioselectivity for different products in enantioselective chloroetherification reaction ........................................................................... 38 !Figure I-21: Products distribution For Z-allyl amides .................................... 39 Figure I-22: Product distribution for E-allyl amide ......................................... 41 Figure I -23: Determination of absolute stereochemistry of Cl -bearing stereocenter ................................................................................................... 43 !Figure I -24: (a) Stereodivergence in the formation of halohydrin and oxazoline products. (b) HPLC trace for halohydrins ...................................................... 45 !Figure I-25: General procedure for synthesis of substrates .......................... 49 Figure I-26: General procedure for synthesis of aromatic Z-allyl amides .... 50 Figure I -27: General procedure for the synthesis of substrates Z-46e-NO2 Ð Z-46j-NO2 .......................................................................................................... 52 !Figure II -1: Alkene dihalogenation reaction proceeding by a two -step mechanism .................................................................................................. 100 !xvi !Figure II -2: (a) Challenges in st ereochemical communication (b) Racemization via olefin -to-olefin halenium transfer ............................................................ 101 !Figure II-3: Mechanistic challenges for asymmetric dihalogenation .......... 103 !Figure II -4: Stoichiometric, enantioselective dichlorination of alkene en route to ( -)-Napyradiomycin ......................................................................................... 104 !Figure II -5: Stoichiometric, enantioselective dichlorination of alkenes by employing chiral sulfonium ion salt .............................................................. 105 !Figure II -6: (a) Asymmetric dichlorination of styryl allyl alcohol (b) Proposed working model .............................................................................................. 106 !Figure II-7: Catalytic enantioselective dibromination of allyl alcohols ......... 107 !Figure II-8: Proposed catalytic cycle ........................................................... 108 !Figure II -9: Catalytic chemo - regio - and enantioselective bromochlorination of allylic alcohols .............................................................................................. 110 !Figure II-10: Enantioselective synthesis of (+) -bromochloromyrcene ......... 111 !Figure II-11: Structure of chlorosulfolipid natural products ......................... 112 !Figure II-12: Example of asymmetric alkene dichlorination ........................ 113 !Figure II -13: catalytic asymmetric intermolecular halohydrin formation, haloetherification and haloeste rification ....................................................... 114 !Figure II -14: Potential to extend asymmetric chloroetherification chemistry to the enantioselective dihalogenation reaction ..................................................... 117 !Figure II-15: Substrate scope for Z-allyl amide in dichlorination reaction ... 124 !Figure II-16: Substrate scope f or Z-allyl amide in dichlorination reaction ... 126 !!xvii Figure II-17: Substrate scope for dichlorination reaction with quasi -enantiomeric (DHQ) 2PHAL catalyst .................................................................................. 127 !Figure II-18: Regio- and enantioselective hetero -dihalogenation ............... 129 !Figure II-19: NMR trace for pro duct distribution in catalyzed and non -catalyzed chlorobromination reaction .......................................................................... 134 !Figure II-20: Currently used methods for producing N -Haloimides ............ 143 !Figure II-21: Highly regio - and enantioselective vicinal dihalogenation of allyl amides144 !Figure II-22: (a) Regioselective chloro -bromination of allyl amides (b) LiBr -mediated transformation of DCDMH to DBDMH ......................................... 145 !Figure II-23: Substrate scope for formation of N -bromo and iodoimide ...... 146 !Figure III-1: Biologically active haloamines ................................................. 181 !Figure III-2: Nucleo phile assisted alkene activation (NAAA) ...................... 182 !Figure III -3: (a) highly enantioselective haloetherification of ally amides (b) highly enantioselective dihalogenation of allyl amides ........................................... 184 !Figure III-4: A general procedure for sulfonamidoglycosylation of gly cal ... 186 !Figure III-5: A general process for the haloamination of olefins .................. 187 !Figure III -6: Employing bromoamination reaction, a route to the synthesis of neuramidase inhibitor .................................................................................. 188 !Figure III -7: Indium (III) -catalyzed aminobromination and aminofluorinati on . """ ........................................................................................................ 189 !Figure III-8: Lewis basic selenium catalyzed chloroamination of olefins ..... 189 !Figure III-9: A method for electrophilic deamination of alkenes .................. 190 !!xviii Figure III-10: Highly enantioselective #-bromination of encarbamates ....... 191 !Figure III-11: Sc(OTf) 3-catalyzed enantios elective halogenation of alkene ........................................................................................................ 193 !Figure III -12: Proposed mechanism for the formation of the chloroacetamide III-34D .... ........................................................................................................ 196 !Figure III -13: (a) Unknown products as an interme diate were formed in chloroamination reaction (b) The NMR spectrums for allyl amide substrate III-34, the mixture of unknown products and final chloroacetamide product III-34D198 !Figure III -14: (a) The counter ion of chlorine source is part of the final product (b) Revealing the structures of the mixture of products .................................... 200 !Figure III -15: The modified proposed mechanism for formation of chloroacetamide III-34D ............................................................................... 201 !Figure III-16: Chloroamination of allyl amide III-34 without (DHQD) 2PHAL ............................................................................................. 202 !Figure III-17: Catalyst controlled chloroamination of unsaturated allyl amides . ........... ........................................................................................................ 203 !Figure III -18: Two different types of chlorenium sources lead to two distinct and precious products ........................................................................................ 205 !Figure III-19: Role of fluorinated compounds in chloroamination reactions 207 !Figure III-20: Enantioselective chloroamidation substrate scope ................ 209 !Figure III-21: Enantioselective chloroimidation substrate scope ................. 213 !Figure IV -1: Switching chlorenium face selectivity for two products of the dichlorination reaction .................................................................................. 227 !Figure IV -2: The trans -aryl -substituted alkenes form two products during enantioselective chloroetherification reaction .............................................. 228 !!xix Figure IV -3: Switching chlorenium face selectivity for the two products of th e chloroetherification reaction ......................................................................... 230 !Figure IV -4: (a) The classica l way for indicating halenium face selectivity (b) various nucleophiles would affect the chlorenium face selectivity ............... 231 !Figure IV -5: (a) Classical perception of the electrophilic addition to alkenes (b) Nucleophile Assisted Alkene Activation (NAAA) ......................................... 232 !Figure IV-6: 18O KIE experimental results for IV-3 and IV-4 ....................... 233 !Figure IV -7: NMR resonance of olefinic C and H displaying the interaction of nucleophiles with the alkenes ...................................................................... 234 !Figure IV -8: The Classical way for kinetic studies (Pseudo first order approx imation) ............................................................................................ 235 !Figure IV-9: The nucleophiles were used as co -solvents in the enantioselective chloroetherification reactions ......................................................................... 236 !Figure IV-10: The hexadehydro -Diels-Alder reaction .................................. 237 !Figure IV -11: The kinetic Formulas and ln -ln plot, which the kinetic o rder was obtained ....................................................................................................... 241 !Figure IV-12: Kinetic competition studies for enantioselective chloroetherifications ..................................................................................... 243 !Figure IV-13: The ln-ln plot from which the kinetic order was obtained ...... 245 !Figure IV-14: Proposed mechanism for chlorenium face selectivity s witch 246 !Figure IV-15: Different Substituents on aryl group of allyl amides effects on diastereoselectivities of products ................................................................. 247 !Figure IV-16: Hammett plot for diastereoselectivities of chloroetherified products . ........... ........................................................................................................ 248 !!xx Figure IV-17: Proposed mechanisem f or the formation of intermolecular and intramoleculr products in enantioselective chloroetherification reactions .... 249 ! !xxi KEY TO SYMBOL S AND ABBREVIATION S † Angstrom [#] Specific rotation ! Chemical shift Ac Acetyl Alk Alkyl Ar Aryl br Broad (spectral peak) Cl2 Chlorine CsCl Cesium chloride d Day DCDMH 1,3-Dichloro -5,5-dimethylhydantoin DCDPH 1,3-Dichloro -5,5-diphenylhydantoin DCM Dichloromethane DHQ Dihydroquinine DHQD Dihydroquinidine (DHQ)2PHAL Dihydroquinine 1,4 -phthalazinediyl diether (DHQD)2PHAL Dihydroquinidine 1,4 -phthalazinediyl diether DIAD Diisopropyl diazadicarboxylate DMAP 4-Dimethylaminopyridine DMSO Dimethylsulfoxide !xxii dr Diastereoselectivity ratio ee Enantioselectivity excess ESI Electrospray ionization Et Ethyl EtOAc Ethyl Acetate (Et) 2O Diethyl ether EtOH Ethanol h Hour Me Methyl MeCN Acetonitrile MHz Megahert z Min Minutes Mol Molar MS Molecular sieves NaOH Sodium hydroxide nBu n-butyl NBS N-bromosuccinimide NCS N-chlorosuccinim ide NMR Nuclear magnetic resonance Ph Phenyl PHAL phthalazine R Substituent !xxiii rr Regioselectivity ratio rt Room temperature Sat Saturated TEA Triethylamine TEAC Tetra ethyl ammonium chloride THF Tetrahydrofuran tBu tert -butyl TFE 2,2,2-trifluoroethanol TLC Thin layer chromatography !!1 Chapter I: Highly Stereosel ective Intermolecular Haloetherification and Haloesterification of Allyl Amides I-1 Introduction !Methodologies for enantioselective alkene halof unctionalization have grown at a fast pace in recent years .1-43 The chiral carbon -halogen bond is a versatile motif in bioactive and natural compounds, and also o f value in the traceless total synthesis of natural products . 44-46 In the last 37 years, various catalytic enantiosel ective alkene functionalization reactions, such as epoxidation ,47 dihydro xylation ,48 aziridination 49 and others were successfully developed, exhibiting high ster eoselec tivity. Encouragingly, during the last seven years tremendous advances have been made in asymmetric halogenation of alkenes. There are OClClBrMeAplysiapyranoid C OHHOOOClClH3CCH3CH3Napyrodiomycin A1 OOBrClLembyne-A C6H13ClClOSO 3ClClClClOSO 3Danicalipin A OOOHHHBrBrBrObtusin OOHOBrAplysistatin Figure I -1: Natural products with stereo defined carbon -halogen bonds Over 4000 natural compounds exhibit carbon -halogen bond !2 two different established methodologies for forming chiral halofunctionalized molecules, intramolecular and intermolecula r halogenation (Figure I-2a). In halocyclization (intramolecular version), after the alkenes are activated with various halogen donors , the tethered nucleophiles capture the putative chiral halonium ions and deliver enantioenr iched -halogenated products . In the l atter case, the nucleophiles are not attached to the alkenes and intermolecularly trap the halonium ions. Although some excellent reports have shown a great deal of progress in the halocyclization area ,5, 10, 13, 50-51 enantioselective intermolecular halogenation Figure I -2: (a) Intramolecular vs intermolecular halofunctionalization (b) Racemization of chiral halonium ion HR1HR2Racemization via olefin-to-olefin halonium transfer HHR2R1aR1HHR2HR1R2H2XXXR1HR2NuR2XNuR1HIntramolecular XXR1HHR2Intermolecular NuR2XNuR1HHXXThe isomerization of the halonium ion to the carbocation bR1HHR2R2XR1HXHX!3 stil l remains challenging due to poor level s of enantioselectivity and limited substrate scope .7 Two of the major issues in the development of intermolecular halofunction alization are the rapid racemization of the chiral halonium ion by olefin-to-olefin transfer ,52-53 and the isomerization of c yclic halonium ions to acyclic !-halocarbenium ions (Figure I-2b).32, 54 These two stereorandomizing events will be discuss ed in the next sections. Not surprisingly, the most early examples were reported on the intermolecular capture of halonium ions with tethered nucleophiles; the proximity rate enhancement of the cyclization step pres umably competes with stereorandomizing (olefin to olefin transfer and isomerization) events. Enan tioselectivities of more than 95:5 er are routinely obtained with a variety of halonium precursors and tethered nucleophiles in halocyclization reactions. I-1-1 Racemization of chiral halonium ion by olefin to olefin halenium transfer !In 2010, P rofess or Denmark and his coworkers cleverly showed that the chiral bromonium ions undergo rapid stereochemical degradation by olefin -to-olefin halenium ion transfer .52 Hexafluoroisopropyl alcohol (HFIP) was selected as a solvent to provide a strong ionizing medium, thus treatment of compound I-1 with sodium acetate as a nucleophile form s product I-2 in high yield. The anti diastereoselectivity of product I-2 is evident for in-situ formation of bromonium ion (Figure I-3). It was shown that acetolysis of chiral compound I-1 with two equivalents n -Bu4NOAc in the presence of one equivalent of trans -4-octene I-3 !4 and HFIP as solvent forms acetate prod uct with 80% enantiospecificity (Figure I-3). Interestingly, increasing the amount of n -Bu4NOAc to 5 equivalents led to enhancement in enantiospecificity to 94% es (Figure I-3). These results are consistent with the proximity rate increase of trapping bromonium ion in the presence of higher equivalents of nucleophiles , which can decrease the ero sion of stereoselect ivity cause d by olefin -to-olefin halonium ion transfer. A similar experiment with ch loronium ion shows racemization would not happen in the case of in situ formation of chloronium ion in the presence of excess amount of alkenes. The acetolysis of compound I-4 in Figure I -3: Partial stereorandomization of bromonium ion by olefin to olefin halenium ion transfer !!5 the presence of n-Bu4NOAc and alkene I-3 produces product I-5 with 100% es (Figure I-3). Based on DenmarkÕ s report, development of enantioselective choloro functionalization of alkenes is feasible . Unfortunately, the isomerization of active chloronium ion to !-chlorocarbenium ion can lead to erosion of stereoselectivity. Studies that have evidence for isomerizat ion will be discussed in the next section. Olah and his c oworker s reported landmark studies for trapping various halonium ions and characterizing them under super acid condition s.55 In one instance, the treatment of 1,2 dibromobutane I-6 or I-7 with antimony -pentafluoride -sulfur dioxide at -78 ¡C forms bridge d 1,2-dimethylethylenebromonium ion (I-8 and I-9 in a ratio of 3:7) . Warming up the reaction in the NMR test tube to -40 ¡C produce s different bromonium ions . It was suggested that the bridge d bromonium ion opens up to produce a carbenium ion, subsequent ly followed by 1,2-hydrogen shift and a 1,2-methy l shift to form compound I-11 (Figure I-4). !6 This transformation suggests that the bridge d halonium ion and the acyclic !-bromenium ion are in rapid equilibrium. Interestingly, the trans and cis 1,2 dimethylethylenebromonium ions (I-8 and I-9) were obtained in 7:3 ratio , resp ectively, regardless of super acid treatment with syn or anti dibromobutane (I-6 or I-7). This latter observation is in line with the expectation that the bromonium ion should exchanges via a rapid equilibrium and isomerizes to !-bromenium ion (Figure I-4). In recent reports, Ohta and coworker s investigated the structure of chloronium and bromonium ion s by isotopic perturbation of equilibrium. 56 The 13C NMR shift was consistent with a rapid equilibrium rather than a singular structure such as cyclic halonium ion (Figure I-5). Figure I -4: Rapid equilibrium between cyclic and acyclic bromonium ion !!!7 Figure I-5: The isotopic perturbation of degenerate equilibrium Despite these mechanistic limits for developing intermolecular halofunctionalization reactions , a number of good reports have shown progress in this area. Intermolecular aminohalogenation, 4, 36-37 haloesterification ,34, 38 halohydrin formation ,39-41 and dihalogenation 42-43 have all b een reported. Nonetheless, alcohols have not been shown to be viable nucleophile s in the reported transformation , despite the improvement seen in halocycloetherification 1-1-2 Literature precedence for enantioselective intermolecular halo - functionalization of alkenes !Tang and coworker s published the first enantioselective bromo est erification of unfunctionalized alkenes with moderate yield and enantiosel ectivity (up to 77% yield and 85:15 er).38 The chiral bi nol backbone based B r¿nsted acid I-18 and n-bromo succinamide I-19 were employed as a chiral catalyst and halonium source, respectively. An ion pair of chiral catalyst and halogen source (NBS) has been suggested to explain the stereoselectivity of this reaction. Although, this chemistry is the first asymmetric intermo lecular bromoesterification, it is limited to cycloalkenes like I-16 as the substrate. Additionally, the reported enantioselectivities in most cases are lower than 75:25 er. H3CH3CCD3CD3XH3CH3CCD3CD3XH3CH3CCD3CD3XI-12-A (X = Cl) I-12-B ( X = Br) I-13-A (X = Cl) I-13-B ( X = Br) I-14-A (X = Cl) I-14-B ( X = Br) !8 Toste and coworker s disclos ed chiral oxyfl uorination of enamides using chiral phosphoric acid I-23 as a chiral catalyst. 39 Selectofl uor I-21 was employed as the fluorine donor, contains sufficient moisture to enable as hydroxyl nucleophile for in situ formation of hemiaminal (Figure I-7). Interestingly, both cis and trans enamide deliver oxy -fluorinated product in syn diastereoselectivity as a primary product with high enantioselectivity. As shown in this report that the yield and stereoselectivity for the syn products are promising, but it suffers in delivering anti oxyfluorinated products in high yield and enantioselectivity. Figure I -6: F irst asymmetric intermolecular bromoesterification catalyzed by chiral Br¿nsted acid !!9 Ma and coworker s reported the catal ytic asymmetric intermolecular bromohydroxylation of 2 -aryl -substi tuted allylic alcohols I-24 with quinine -derived alkaloid I-29 as a chiral catalyst in 2013 (Figure I-7).40 Allylic alcohol I-24 reacts with boro nic acid and forms boronate ester. The amino group of the chiral catal yst form s a complex with boron and increase s the nucleophilicity of the remaining hydroxyl group on the boronate ester. In the mean time , NBS can get activated by the chiral catalyst and deliver the bromonium ion. This tight complexion of a substrate, chiral catalyst, and bromonium donor (Complex I-26) would produce cyclic boronate ester I-27; in the second step treating the crude mixture w ith H 2O2 oxidized I-27 and form ed chiral bromohydrin I-25 with high enantioselectivity (Figure I-8). The substrate scope shows these trans formations Figure I -7: Phosphoric acid catalyst for oxyfluorination of enamide !!10 are successful for 1, 1- disubstituted allylic alkenes. However, t he authors have not reported any other kind of allylic alcohols as substrates in this study. In 2013, TangÕ s lab developed the enantioselective bromo esterification of allylic sulfonamide s in the presence of (DHQD) 2PHAL as the chir al catalyst. 34 Using triflate as the protecting group for amines plays an important role to tune the acidity of nitrogen Ðhydrogen bond , putativ ely forming the tighter hydrogen bond with phthalazine of (DHQD) 2PHAL. On the other hand, employing CSA clearly improve s the enantioselectivity. Based on these results the authors suggest that the nitrogen of the phthalazine ring in the (DHQD) 2PHAL forms a hydrogen b ond with the hydrogen atom of the allylic sulfonamide in the substrate . At the same time, one unit of the quinuclidine in the dimeric chinchona alkoxide cat alyst activates the NBS, thus explaining the high enantioselectivity for this Figure I-8: Asymmetric bromohydroxylation of allyl alcohols by quinine -derived catalysts !!11 transformation (see I-31, Figure I-9). The trans aryl allylic sulfonamides I-29 deliver final products I-30 with moderate to high e nantioselectivity (Figure I-9). Unfortunately , employing cis isomer of the aliphatic allyl sulfonamide results in bromo -esterified products with lo w yield and enantioselectivity. Also, nucleophiles other than benzoic acid were not evaluated in this report. Figure I-9: Enanti oselective intermolecular bromoesterification of allylic sulfonamides Snyder and coworker s employed chiral sulfur -derived halonium reagents to accomplish the enantioselective iodohydroxylation on unfunctionalized alkenes. Treatment of chiral dimethyl thiolane I-32 with iodine monochloride in the presence of antimony pentachloride forms the chiral iodo sulfonium ion I-33 in 76% yield (Figure I-10a).41 Optimization studies showed that treating 1.2 -NMeO RNHTfRNHTfOBz Br(DHQD) 2PHAL (20 mol%) PhCO 2H (1.1 equiv) NBS (1.1 equiv) (+)-CSA (20 mol%), rt, 12 h CHCl3I-3014 examples up to 82% yield and 95:5 erI-29NNOONMeO NHEtNNOOHNTfBrHEtI-31 proposed working model !12 dihydronapht halene I-34 with chiral dimethyl iodo sulfonium ion I-33, and subsequently quench ing the reaction with water forms iodohydrin product I-35 in 67% yield and 81:19 er (Figure I-10b). Developing chiral sulfur -derived halonium reagents as both chiral promoter and halogen donor is fascinating. However, the low enantioselectivity and narrow substrate scope is a shortcoming of this study. Despite this progress, challenges remain . First, alcohols are yet to be demonstrated as viabl e nucleophiles in intermolecular haloetherification despite the success seen in ha lo-cycloetherification reactions . Second, substrates with alkyl substituents on the al kene are known to afford poor to moderate levels of enantioselectivity at best . For example, the best enantioselectivity for aliphatic substrate in vicinal halo esterification was reported by Tang and his coworker s in 60:40 er (Figure I-11a).34 Additionaly , Ma reported the enantioselective halohydrin synthesis with 84:16 er (Figure I-11b).40 Third, s ubstrate scope studies were limited to Ôelectronically biasedÕ alkenes and hence possible regioselectivity issues have remained unaddressed. Finally, none of the catalytic SSISbCl 6ICl, SbCl 5OHII-32I-34MeCN-CH 2Cl2 (1:1) -78 ¡C t0 -20 ¡C I-33 76% yield I-35 67% yield 81:19 erabI-33 1.2 equivFigure I-10: Potential of chiral sulfonium reagents to effect asymmetric halonium additions to isolated alkenes !13 systems were demonstrated to be promiscuous enough to allow for the use of different halenium sources and nucleophiles with the same substrates. We sought to develop an enantioselective intermolecular haloetherification reac tion with the intention of both demonstrating the feasibility of this unpreceden ted transformation and address ing some of the limitations detailed above. The rest of this Chapter will deal with effort s to discover and optimiz the first enantio -, diastereo - and regioselective intermolecular chloroetherification of a variety of alkenes including those with no dominant bias for regioselectivit y (i.e. alkenes with alk yl substituents). Figure I -11: (a) Enantioselective bromoesterification of aliphatic alkenes (b) Chiral halohydrin synthesis of aliphatic olefins !!14 I-2 Results and discussion !I-2-1 Preliminary results !I-2-1-1 TFE -incorporated products was a hint for development of a methodology for intermolecular halofunctionalization !In 2010, our lab disclosed the first enantioselective chlorocyclization of alkenoic acid. Commercial ly available (DHQD) 2PHAL as chiral organocatalyst and DCDPH (5,5 -diphenyl-1,3-dichlorohydantoin) I-42 as chloronium donor were employed in this transformation. DCDPH is not commercially available. Nonetheless, our lab has developed the one -step synthesis of DCDPH from the corresponding commercially available hydantoin. In this chemistry, various lactone molecules were synthesized , with up to 89% yield and 95:5 er (Figure I-12a). 28 Later on, we demonstrated that the same cata lytic system along with DCDMH I-45 with little modification could yield products from the enantioselective chlorocyclization of unsaturated amide I-43 as well. The facile, formation of dihydrooxazoles and dihydrooxazine s can overcome many problems, most notably avoiding usage of the stoichiometric amount of chiral amino alcohols. In this w ork, we had indicated that the non -nucleophilic CF 3CH2OH as the reaction medium was crucial for obtaining high yields and enantioselectivities for intramolecular cyclization of aryl substituted allyl amides. As reported, various dihydrooxazine rings I-44 with different substituents were synthesized , with up to 90% yield and >99:1 er (Figure I-12b).16 !15 In our prior work, we had demonstrated a highly diastereo - and enantioselective chlorocyclization of unsaturated amides to furnish dihydrooxazine and oxazoline heterocycles. 16 The use of CF 3CH2OH as the reaction medium was crucial for obtaining high enantioselectivities. In the attempted chlorocyclization of E-46a-Br under optimized reaction conditions, a-47a-TFE-Br was isolated in 82:18 er and 35% yield (>10:1 dr and >10:1 rr) along with the desired product t-48a-Br (40%, 99.5:0.5 er; see Figure I-13a). The reader is referred to the next paragraph for a detailed explanation of our naming Figure I -12: An organocatalytic asymmetric chlorolactonization r eaction of alkenoic acid !!16 system for the starting materials and products in this chapter . The rate of intramolecular nucleophilic capture of the putative chloriranium ion by the pendant amide nucleophile for this substrate is presumably slow enough to allow for a competing intermolecular nucleophilic capture even by the weakly nucleophilic CF 3CH2OH. In the event, a simple solvent -switch from CF 3CH2OH to n-PrNO 2 as the reaction medium alleviated the problem of chemodivergence, affording exclusively t-48a-Br in good yield and excellent enantioselectivity (77%, >99.5: 0.5 er, Figure I-13b).16 While the enantioselectivity and the yield of a-47a-TFE-Br were not synthetically useful, we were intrigued by the excellent diastereo - and regioselectivity of this by -product arising from the intermolecular nucleophilic capture of a sterically and electronically unbiased chloronium/chlorocarbenium ion interme diate. As such, this result represented a good starting point for developing a practical and general intermolecular chlorofunctionalization reaction of alkenes. We have opted to use a systematic naming system that enables the reader to identify the relevan t components of the starting materials and products easily. Since all starting materials are substituted allyl amides, they are defined as E or Z (where appropriate), followed by a number ( 46a, 46b, ...) that is unique to the substitution on the olefin. T he naming is completed by defining the phenyl substituent of the amide moiety (NO 2, Br, ...), which is always on the para position. The naming of the intermolecular products precedes by ' a' or ' s' ( anti or syn), followed by a number ( 47a, 47b, ... ) that corresponds to the substituent on !17 the parent olefin. The third component (in italics ) is the identity of the nucleophile (OMe , OH, ...), followed by the substituent on the phenyl group of the amide. The 6-member ring intramolecular products are ide ntified as either cis or trans ('c' or 't'), followed by the number that corresponds to the substituent on the parent olefin ( 48a, 48b, ...), and then the identifier of the phenyl substituent for the amide. The 5 -member ring products are named as above, w ith the exception of having 'a' or ' s' (anti or syn) that precedes the numbering ( 49a, 49b, ...). !18 I-2-1-2 Additive studies to improve enantioselectivity of chl orocyclization of amides lead to the develop ment of intermolecular halofunctionalization !In line with the above observation, additive studies were performed on the enantioselective allyl amide chl orocyclization reaction to understand the role of TFE as a crucial sol vent for this transformation. 16 Under optimized conditi ons, employing TFE as sol vent produces cyclic product t-48b-Br in >99:1 er (Table I-1, entry 1). Switching the solvent to acetonitrile erode s the enantioselectivity of the product to 90:10 er (Table I-1, entry 2). Figure I-13: (a) Discovery of an asymmetric intermolecular chloroetherification of allyl amides (b) Using Non -nucleophilic 1 -nitropropane yielded cyclized products exclusively !!!!19 Nonetheless, illuminating results we re obtained when TFE was used as an additive for the reaction. As shown in T able I-1, the enantioselecti vity of the chlorocyclized product t-48b-Br was enhanced drastically by employing 1 or 5 equivalents of TFE as an additive (Table I-1, entry 3, 4). These results intrigue d us to test ethanol as a solvent to see the effect of different alcohols in these reactions. However, employing ethanol as solvent forms the intermolecular chloro etherified product a-47b-OEt -Br in 58%yield and 79:21 er along with cyclized t-48b-Br product (42% yield and 91:9 er, s ee Figure I-14). As such, this result is in line with TFE -incorporated product that was discussed in the section above , and represented a good starting point for developing a practical and general intermolecular chlorofunctionalization reaction of alkenes. !Entry Solvent Additive er%a Yield %b 1 TFE None >99:1 89 2 CH3CN None 90:10 84 3 CH3CN 1 equiv TFE 96:4 87 4 CH3CN 5 equiv TFE 98:2 89 [a] Determined by NMR; [b] Determined by chiral HPLC Table I -1: Additive studies in chlorocyclization of allyl amides reaction !!20 Figure I-14: Intermolecular chloroetherification of ally l amides I-2-2 Optimization of reaction variable s !I-2-2-1 Influence of the identity and stoichiometry of the chlorenium source on the stereoselectivity of the reaction . We cho se the intermolecu lar reaction of E-46b-Br with a chlorenium source and EtOH as the test bed to optimize the process. (DHQD) 2PHAL was employed as the chiral catalyst along with various chloronium sources. !With the exception of N-chlorophthalimide (NCP, entry 3 , Table I-2), all other chlorenium sources gave complete conversion to products. The identity of the chlorenium source does not influence the ratio of 47b:48b in a significant manner (ratio was ~6:4). Using 1.1 equivalent of DCDMH and DCDPH showed similar er (80:20) for product a-47b-OEt -Br ( Table I-2, entries 1 and 2). Increasing the DCDMH loading to 2 equiv improved the enantiomeric ratio (entry 5). Further increase in the DCDMH loading to 5 or 10 equivalents did not lead to any improvement in the enantioselectivity (Table 2, entries 5 and 6) for a-47b-OEt -Br. PhHNArOPhOEt ClHNONOPhCl+(DHQD) 2PHAL (0.1 equiv) DCDMH (1.1 equiv) t-48b-Br42% yield 91:9 erEtOH (0.025 M), -30 ¡C Ar = 4-BrPh E-46b-Bra-47b-OEt -Br58% yield 79:21 erArAr!21 I-2-2-2 Influence of reaction solvent o n enantioselectivity of chloro etherified products !Using ethanol as a solvent gave products a-47b-OEt -Br and t-48b-Br in the ratio of 6:4 and enantiomeric ratio of 81:19 for a-47b-OEt -Br (entry 1 , Table I-3). Adding 10 equivalents of TFE decreased the enantioselectivity (entry 2). A 1:1 MeCN-EtOH cosolvent mixture gave slightly improved enantioselectivity (entry 3). Changing the ratio of MeCN to EtOH to 7:3 produced both products in equimolar amounts, but wi th higher er (entry 4 , Table I-3). Finally, decreasing the Table I -2: Chlorenium source optimization !Entry Source equiv of Cl+ Conv. % Ratio a 47b:48b er (47b)b,c 1 DCDMH 1.1 100 6:4 80:20 2 DCDPH 1.1 100 6:4 80:20 3 NCP 1.1 0 nd 0 4 NCSach 1.1 100 6:4 78:22 5 DCDMH 2 100 6:4 81:19 6 DCDMH 5 100 6:4 78:22 7 DCDMH 10 100 6:4 78:22 [a] Determined by NMR; [ b] Determined by chiral HPLC: [c] for compound a-2b-OEt -Br !!22 temperature to -30 ¡C gave higher enantioselectivity of 84:16 er (entry 5 , Table I-3). I-2-2-3 Effect of substituents on the amide moiety in the chloro etherification reaction selectivity !Other optimization studies were focused on var ying the expandable amide moiety . In this study we used MeOH as nucleophile, and the diastreomeric ratio for acyclic haloetherified product was easily obtained with H-NMR. At ambient temperature both the desired chloroether product a-47b-OMe -Br and the cyclized product t-48b-Br were obs erved (93% combined yield) in a 1.8:1 ratio. In line with our prior studies, the cyclized product t-48b-Br had excellent enantioselectivity (96:4 er), whereas a-47b-OMe -Br exhibited lower Table I-3: Influence of co -solvent additives on the chemo - and stereoselectivity of the reaction !Entry Temp Solvent Ratio of 47b:48b a er (47b) b,c 1 -30 EtOH 6:4 81:19 2 -30 EtOH with 10 equiv TFE 6:4 77:23 3 -30 MeCN:EtOH(1:1) 6:4 81:19 4 rt MeCN:EtOH (7:3) 1:1 82:18 5 -30 MeCN:EtOH (7:3) 1:1 84:16 [a] Determined by NMR; [ b] Determined by chiral HPLC: [c] for compound a-47b-OEt -Br !!!23 67:33 er. Lower temperatures and lower concentration s led to slightl y improved enantioselectivity for a-47b-OMe -Br while not significantly improving the dr or the 47b:48 b ratio (see entries 2 and 3 in Table I-4). Further experimentation revealed that employing MeOH as a co -solvent in MeCN led to a significant improvement in the enantioselectivity of a-47b-OMe -Br (Table I-4, entry 4). Other studies focused on varying the expendable amide moiety. Changing the 4 -bromobenzamide motifs to 4 -methoxybenzamide gave practically ident ical results (entry 5 in Table I-4). Nonetheless, employing the electron deficient 4 -NO2-benzamide gave a significant improvement in the enantioselectivity of a-47b-OMe -NO2 (92:8 er, entry 6, Table I-4). As evident from these preliminary results, although usefu l levels of enantioinduction were seen for the intermolecular chloroetherification of E-46b-NO2, the dr (3.4:1) as well the ratio of 47b:48b (~1:1) were not ideal . !24 I-2-2-4 Reaction optimization for aliphatic substrates Gratifyingly, replacing the Ph substituent on the alkene in substrate E-46b-Br with the aliphatic n-C3H7 group gave exclusively the desired intermolecular product a -47c-OMe -Br with near complete diastereo - and regioselectivity (>99:1 dr and rr, see entry 1 in Table I-5) on employing the best con ditions from the pilot studies. More importantly, a-47c-OMe -Br w as isolated in 92% yield and 81:19 er, Table I -4: Orienting studies for enantioselective intermolecular chloroetherification of E-46b-(Br/OMe/NO 2) !!!Entry Substrate Solvent %Yield a 47b:48bb dr (a-47b:s-47b)b er(47b)g er( 48b)g 1c,e E-46b-Br MeOH 93 1.8:1 6.8:1 67:33 96:4 2d,e E-46b-Br MeOH 94 1.8:1 6.8:1 73:27 98:2 3f E-46b-Br MeOH 76 1.8:1 5.7:1 71:29 98:2 4h,f E-46b-Br MeOH:MeCN 76 1.3:1 5.8:1 85:15 99:1 5h,f E-46b-OMe MeOH:MeCN 86 1.3:1 5.0:1 83:17 97:3 6h,f E-46b-NO2 MeOH:MeCN 85 1.1:1 3.4:1 92:8 96:4 [a] Combined yield of a-47b, s-47b and 48b as determined by NMR analysis with MTBE as added external standard; [b] Determined by NMR; [c] The reaction occurs at room temperature [d] the reaction occurs at -30 ¡C [e] The concentration of reaction was 0.03 M [f] the concentration of reaction was 0.01 M [g] Determined by chiral HPLC; [h] MeOH:MeCN ratio was 3:7. !!25 and the formation of the cyclized product was suppressed to a mere 5%. Under the premise that decreasing the nucleophilicity of the amide might completely suppress the formation of the cyclized product, the 4 -bromoben zamide was substituted with the 4 -NO2-benzamide. Indeed, this change afforded exclusively a-47c-OMe -NO2 (entry 2, Table I-5) in 86% yield, 87:13 er, >20:1 rr, and >99:1 dr. cis -Allylic amides were even better substrates for this chemistry as compared to th e trans -allylic amide counterparts. Substrate Z-46c-NO2 gave the corresponding product s-47c-OMe -NO2 in 87% yield and 99:1 er (entry 3, Table I-5). Reactions that were run at ambient temperatures or with lower catalyst loadings showed no loss in the diastereo - and regioselectivi ty and only a small decrease in the enantioselectivity (97:3 er; see entries 4 and 5 in Table I-5). Nonetheless, the yields were lower (75 Ð79%) owing to the formation of side products arising from the competing addition of MeCN across the alkene. While the lack of a cation -stabilizing group can explain the exquisite diastereoselectivity with aliphatic substrates, the origin of the regioselectivity with such an unbiased system is not easily explained . !26 I-2-3 Substrate scope for the intermolecular ch loroetherification reaction I-2-3-1 Substrate with MeOH as the nucleophile !In an effort to map out the generality of this transformation, a number of trans -disubstituted allyl amides were initially exposed to the optimized reaction conditions. Compounds E-46b-NO2 and E-46d-NO2 (Figure I-15) with aryl substituents on the alkene gave moderate isolated yields (due to competing chlorocyclization) and fair diastereoselectivity for the corresponding products a-47b-OMe -NO2 and a-47d-OMe -NO2 (56% an d 64% yields, respectively; ~3.4 :1 dr, mass balance in both cases was the cyclized product t-48b-NO2 and t-48d-NO2, respectively, Figure I-15). Nonetheless, the chloroether products were Table I -5: Reaction optimization for aliphatic substrates. !Entry a Substrate Temp ¡C Product Yield% b erd 1 E-46c-Br -30 a-47c-OMe -Br 92c 81:19 2 E-46c-NO2 -30 a-47c-OMe -NO2 86 87:13 3 Z-46c-NO2 -30 s-47c-OMe -NO2 87 99.5:0.5 4 Z-46c-NO2 24 s-47c-OMe -NO2 75 97:3 5e Z-46c-NO2 -30 s-47c-OMe -NO2 79 97:3 [a] The rr was >20:1 and dr was >99:1 in all instances; [b] Determined by NMR using MTBE as added external standard; [c] 5% of cyclized product was also seen by NMR; [d] Determined by chiral HPLC. [e] 2 mol% catalyst was used. !!27 formed with good enantioselectivity. Trans -substrates with alkyl substituents on the olefin ( a-47c/47a/47e-OMe -NO2) predictably gave products with exquisite levels of diastereo - and regioselectivity. Additionally, high yield and er was observed for a-47c-OMe -NO2 (R1=n-C3H7). The er dropped significantly on introduction of the bulky cyclohexyl group (see a-47a-OMe -NO2, 75:25 er). The benzyloxy substituted compound gave only moderate yields and rr (62%, 7:1 rr), although the enantioselectivity was good (Figure I-15, see a-47e-OMe -NO2, 89:11 er). !28 Aryl substituted Z-alkenes were exceptional substrates, leading to the intermolecular product exclusively, in good yields (73% to 80% , Figure I-16), excellent regioselectivity (>99:1 rr) and high enantioselectivity ( " 98:2 er, see Figure I-16, s-47b/47f/47g-OMe -NO2). Intriguingly, the diastereoselectivity progressively decreases going from a Ph substituent (3.3:1 dr for s-47b-OMe -NO2) to the anisyl substituent (1:1 dr for s-47g-OMe -NO2, Figure I-16) with the p-Figure I -15: Substrate Scope for intermolecular chloroetherificati on for trans allyl amides substrate !!29 toluyl substituted compound Z-46f-NO2 giving an intermediate 1.3:1 dr. These results likely suggest an increased carbocation character at the benzylic position in the transition state with increasing electron density of the aryl sub stituent. Noteworthy, the minor diastereomer for each reaction still retains high levels of enantioselectivity (see values in parentheses, Figure 16 , for products s-47b/47f/47g-OMe -NO2). Z-alkyl substituted olefins afforded the desired products in near complete regio -, diastereo -, a nd e nantioselectivity (see Figure 16 , products s-47h/47c/47i/47e/47j-OMe -NO2). Trisubstituted alkene 46k-NO2 also gives the desired product in moderate yield and excellent enantioselectivity (59%, 99:1 er). !30 Figure I-16: Substrate scope of intermolecular chloroetherification for cis allyl amide substrates !!31 I-1-3-2 Nucleophile scope for the intermolecular chloroetherification reaction Finally, we sought to explore the scope of this reaction with regards to the nucleophilic and electrophi lic components (see Figure I-17). We were delighted to discover that a variety of alcohols and even carboxylic acids may be employed as viable nucleophiles in this chemistry with little or no modification of the optimized reactio n conditions. Replacing MeOH with other alcohols such as ethanol, allyl alcohol, and propargyl alcohol as the co -solvents cleanly afford s the desired products in >20:1 dr and "98:2 er (see s-47c-OEt -NO2, s-47c-OAllyl -NO2 and s-47c-OPropargyl -NO2 in Figure I-17). These results demonstrate the feasibility of introducing diverse functional handles into the products using this chemistry, in addition to the highly stereoselective C -Cl and C -O bond installations during the course of the reaction. Acetic acid can be employed also as the nucleophilic co -solvent to furnish the corresponding chloroesters with excellent enantioselectivity with Z-, E -, as well as tri -substituted alkene substrates ( " 93:7 er, see s-47c-OAc -NO2, a-47c-OAc -NO2 and 47k-OAc -NO2 in Figure I-17). Employing water as the nucleophile leads directly to the corresponding chlorohydrins in excellent yields and ers (see s-47c-OH-NO2 and s-47h-OH-NO2 in Figure I-17). !32 Figure I -17: Nucleophile scope for the intermolecular chloroetherification reaction a !!33 I-2-3-3 Substrate scope for asymmetric bromination of allyl amide substrates Finally, employing NBS in lieu of DCDMH leads to the corresponding bromoether and bromohydrin products in good yields and ers. The substrate in optimized condition along with NBS forms s-47cÕ-OMe -NO2 in 92% yield and 99:1 er (Figure I-18). Combination of water as n ucleophile and NBS as bromonium source is compatible with this chemistry and form s s-47cÕ-OH-NO2, a-47cÕ-OH-NO2 in 99.5:0.5 er and 85:15 er, respectively. Tri -substituted alkene 46k-NO2 forms corresponding brominated product in 62% yield and 99.5:0.5 er (see 46k-OMe -NO2, Figure I-18, The mass balance for this reaction was cyclized product ). !34 I-2-3-4 Substrate scope for the intermolecular chloro esterification reaction by employing quasi -enantiomeric catalyst The quasi -enantiomeric (DHQ) 2PHAL , was also evaluated with different substrates, yielding enantiomeric products in comparable yields and selectivities (Figure I-19). The exception was the result with the least successful category of substrates ( trans -substituted aryls) whi ch forms ent-a-47b-OMe -NO2 in 75:25 er, Figure I -18: Substrate scope for asymmetric bromination of allyl amide substrates a !!35 and does not mirror the (DHQD) 2PHAL catalyzed reaction well , yielding product with lower than expected enantioselectivity. However, the cis allyl amide substrates ( Z-46f-NO2 and Z-46c-NO2) gave practically identical results favoring the opposite enantiomeric antipode of the products (Figure I-19, ent-s-47f-OMe -NO2 and ent-s-47c-OMe -NO2). Tri substituted alkene 46k-NO2 produced product end exactly mirror ed the result with (DHQD) 2PHAL catalyzed reaction well (Figure I-19). !36 It warrants emphasis that a large excess of the nucleophile (>100 equiv) is currently required to prevent the formation of cyclized products. Our lab is currently in the process of addressing this limitation to enable the use of highly functionalized nucleophiles in this chemistry . Figure I -19: Substrate scope for the intermolecular chloroesterification reaction by employing quasi -enantiomeric catalyst !!37 I-2-4 Product distribution arising due to substrate -control and catalyst -control for the intermolecular chloroetherification reaction. The different ratios observed for the regioselectivity of the chiral chlo roetherified products requi re an attempted rationalization . As shown in Figure I-20, the aryl substituted ally l amide forms a chiral product in 99:1 rr, but switching from aryl substituent to alkyl ally l amide, yields products with lower regioselectivity ratios (Figure I-20). MeOH as the nucleophile can open up the putative chloronium ion from both sites and forms two regioisomers. However, in the case of aryl substituents, one r egioisomer is obtained due to benzylic stabilization of the carbocation. Interestingly unbiased alkene Z-46c-NO2 forms corresponding product with high regioselectivity (24:1 rr, s-47c-OMe -NO2, Figure I-20). The benzyloxy group (OBn) resu lts in a drop in re giosel ectivity (7:1 rr, Figure I-20, s-47e-OMe -NO2,). However, adding one carbon restores the rr and yields product with 23:1 rr (Figure I-20, s-47j-OMe -NO2). These results show that the electron -donating group as a substituent can stabilize the carbocation and forms the product with higher regioselectivity . !38 With these observations, we questioned whether the observed regioselectivity is only as a result of substrate control or the chiral catalyst Figure I -20: The regioselectivity for different products in enantioselective chloroetherification reaction !!39 (DHQD) 2PHAL has some role in determining the r atio of the two regio isomers . Reactions run in the absence of any catalyst gave a mixture of numerous products for the intermolecular chloroetherification reaction of both E- and Z- allyl amides. In contrast, reactions run in the presence of (DHQD) 2PHAL gave predominantly the desired chloroether product. The numerous products seen in the latter reactions were meticulously isolated and characterized. The Z-46c-NO2 gave 3 major products. As seen from the HPLC trace of the crude reaction mixture, along with the desired product s -47c-OMe -NO2, the constitutional Figure I -21: Products distribution For Z-allyl amides !!40 isomer s-50c-OMe -NO2 as well as the cyclized oxazoline product s-49c-NO2 was seen (Figure I-21). Under optimized reaction conditions that employed (DHQD) 2PHAL, the major product was the chloroether s-47c-OMe -NO2. Small amount of the constitutional isomer s-50c-OMe -NO2 was seen; no cyclized products were observed. A similar analysis was also performed with the E-46c-NO2. As seen from the scheme below, the non -catalyzed reaction gave 2 constitutional isomers for both the chloroether product as well as the cyclized produ ct. Although all these compounds were seen in the (DHQD) 2PHAL catalyzed reaction as well, the selectivity for the desired chloroether product was significantly higher (Figure I-22). !!41 Figure I-22: Product distributi on for E-allyl amides !I-2-5 Absolute stereochemistry of the chloroetherification reactions I-2-5-1 Absolute stereochemistry of the chloroetherification products derived from E- alkene !Attention must be drawn to the fact that the Cl bearing stereocenter has the same chirality for products derived from either the cis or trans -alkene substrates. The absolute stereochemistry of s-47h-OH-NO2 and s-47c-OMe -NO2, and the relative stereochemistr y of a-47c-OH-NO2 were established by single crystal X -ray diffraction. Since the absolute stereochemistry of a-47c-OH-NO2 could not be determined from X -ray analysis, we resorted to the chemical trans formations detailed in Figure I-23 for proof of structure. This was verified by C3H7OMe ClHNArOHNArOC3H7NOArClC3H7C3H7ClOMe HNArONOArC3H7Clcatalyst 2.0 equiv DCDMH 7:3 MeCN-MeOH rt+E-46c-NO 2a-47c-OMe -NO 2a-50c-OMe -NO 2t-48c-NO 2a-49c-NO 2a-47c-OMe -NO 2a-47c-OMe -NO 2t-48c-NO 2t-48c-NO 2a-50c-OMe -NO 2a-50c-OMe -NO 2a-49c-NO 2a-49c-NO 2without catalyst with catalyst !42 the TPAP -NMO mediated oxidation of the diastereomeric chlorohydrins s-47c-OH-NO2 and a-47c-OH-NO2, derived from substrates Z-46c-NO2 and E-46c-NO2, respectively (see Figure I-23). Both substrates gave the chloroketone product with the same absolute stereochemistry (verified by both, HPLC and optical rotation). This is only possible if the face selectivity of the chlorenium delivery was the same for these two classes of substrates . !43 I-2-5-2 Stereodivergence in the formation of halohydrin and oxazoline products !The intermolecular chloroetherification reaction of many substrates gave variable amounts of the chlorocyclized products in addition to the desired products. Intriguingly, the Cl -bearing stereocenter of both these products formed Figure I -23: Determination of absolute stereochemistry of Cl -bearing stereocenter !!44 in the same reaction had the opposite stereochemistry based on chemical transformations and corroborating crystallographic evidence detailed below. While the chloroether product had an R-configuration for the Cl -bearing stereocenter, the chlorocyclized product had an S-configurati on. With crystallographic evidence supporting the latter observation, we sought to unequivocally establish this divergence in stereoselectivity by chemical derivatization. An attempted synthesis of halohydrin a-47b-OH-Br from substrate E-46b-Br gave the chlorocyclized product t-3b-Br (36%, 97:3 er) in addition to the desired product a-47b-OH-Br (43%, 82:18 er). The stereochemistry of the Cl bearing stereocenter of t-48b-Br was assigned as S based on our prior studies. The absolute stereochemistry of the Cl -bearing stereocenter in a-47b-OH-Br, on the other hand was inferred to be R (based on the crystal structures of s-47c-OMe -NO2 and s-47h-OH-NO2 and chemical transformations il lustrated in Fi gure I-24a). In order to unequivocally establish this stereodivergence, t-48b-Br was transformed to a-47b-OH-Br by means of a two -step t ransformation shown in Figure I-23a. Optical rotation as well as HPLC co -injection confirmed that it was indeed the enantiomer of a-47b-OH-Br that had resulted fro m this transformation (Figure I-24b). These results lead us to conclude that two distinct mechanisms are in play that leads to e ither the cyclized dihydrooxazine products or the desired intermolecular addition of the nucleophile and halenium ion across the alkene in the same reaction "!!45 Figure I-24: (a) Stereodivergence in the formation of halohydrin and oxazoline products. (b) HPLC trace for halohydrins !I-2-6 Experimental section !I-2-6-1 General information Commercially available reagents were purchased from Sigma -Aldrich or Alfa -Aesar and used as received. CH 2Cl2 and acetonitrile were freshly distilled over CaH 2 prior to use. THF was distilled over sodium -benzophenone ketyl. All other solvents were used as purchased. 1H and 13C NMR were recorded on 500 MHz Varian NMR machines using CDCl 3 or CD 3CN as solvent and were referenced to residual solvent peaks. Flash silica gel (32 -63 mm, Silicycle 60 †) PhOHClHNpBr-PhO10 mol% (DHQD) 2PHAL 2.0 equiv DCDMH (2R,3S)-a-47b-OH-Br43% yield 82:18 erNOpBr-PhPhCl+RSt-48b-Br36% yield 97:3 erMeCN:H 2O (9:1) -10 ¡C PhHNOr-PhB pRS1) 1.5N aq. HCl reflux, 22 h PhOHClHNpBr-PhO(2S,3R)-a-47b-OH-BrRS2) 4-Br-BzCl Et3N, cat. DMAP E-46b-BrBoth intra and intermolecular processes proceed with anti addition, albeit with opposite face selectivity of the olefin. PhOHClHNpBr-PhORS(2R,3S)-a-47b-OH-BrPhOHClHNpBr-PhO(2s,3R)-a-47b-OH-BrRSab!46 was used for column chromatography. Enantiomeric excess for all products was determined by HPLC analysis using DAICEL CHIRALCEL ¨ OJ-H and OD -H or CHIRALPAK ¨ IA and AD -H columns. Optical rotations of all products were measured in chlo roform. I-2-6-2 General procedure for optimization of catalytic asymmetric intermolecular haloetherification/haloesterification of unsaturated amides The substrate (0.04 mmol, 1.0 equiv) was suspended in acetonitrile (MeCN, 2.8 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 (3 mg, 10 mol%) and 1.2 mL of methanol or acetic acid was then introduced. After stirring for 2 min DCDMH (15 .8 mg, 0.08 mmol, 2.0 equiv) or NBS ( 14.3 mg, 2.0 equiv) was added. The stirring was continued at -30 ¡C till the reaction was complete (TLC). The reaction was quenched by the addition of saturated aq. Na2SO3 (1 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous laye r was extracted with DCM (3 ! 3 mL). The combined organics were dried over anhydrous Na 2SO4, concentrated and dissolved in 1 mL of CDCl3. An equivalent amount (0.04 mmol) of MTBE was added and the solution was analyzed by NMR to obtain the NMR yield of the desired product. This solution was then concentrated in the presence of small quantity of silica gel. Column chromatography (SiO 2/EtOAc Ð Hexanes gradient elution) gave the desired product. !47 Following modifications were used for halohydrin synthesis: MeCN :H2O ratio was 9:1; Reaction temperature: -10 ¡C. I-2-6-3 General procedure for substrate scope analysis for catalytic asymmetric intermolecular haloetherification/haloesterification of unsaturated amides The substrate (0.1 mmol, 1.0 equiv) was suspended in acetonitrile (MeCN, 7.0 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 (7.8 mg, 10 m ol%) and 3.0 mL of methanol or acetic acid was then introduced After stirring f or 2 min DCDMH (39.4 mg, 0.2 mmol, 2.0 equiv) or NBS (35.6 mg, 2.0 equiv) was added. The stirring was continued at -30 ¡C till the reaction was complete (TLC). The reaction was quenched by the addition of saturated aq. Na 2SO3 (4 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 ! 3 mL). The combined organics were dried over anhyd. Na 2SO4 and concentrated in the presence of small quantity of silica gel. Column chromatography (SiO 2/EtOAc Ð Hexanes gra dient elution) gave the desired product. Following modifications were used for halohydrin synthesis: MeCN:H 2O ratio was 9:1; Reaction temperature: -10 ¡C. I-2-6-4 Procedure for gram scale catalytic asymmetric intermolecular haloetherification/haloesterification of unsaturated amides Z-1c-NO2 (1.0 g, 4.0 mmol, 1.0 equiv) was suspended in acetonitrile (MeCN, 14.0 mL) in a screw -capped vial equipped with a stir bar. The resulting !48 suspension was cooled to -30 ¡ C in an immersion cooler. (DHQD) 2PHAL (311.6 mg, 10 mol%), 7.0 mL of methanol was then introduced. After stirring for 2 min DCDMH (1500 mg, 8.0 mmol, 2.0 equiv) was added. The stirring was continued at -30 ¡C till the reaction was complete (TLC). The reaction was quenched by the addition of saturated aq. Na 2SO3 (20 mL) and diluted with DCM (15 mL). The organics were separated and the aqueous layer was extracted with DCM (3 ! 15 mL). The combined organics were dried over anhyd. Na 2SO4 and concentrated in the presence of sili ca gel. Column chromatography (SiO 2/EtOAc Ð Hexanes gradient elution) gave the desired product. Following modifications were used for gram scale synthesis of halohydrin s-2c-OH-NO2: MeCN:H 2O ratio was 9:1 (20 mL); catalyst loading: 2 mol% (DHQD) 2PHAL, Reaction temperature: -10 ¡C. Allyl alcohols I-52 was synthesized from the corresponding aldehydes or ketone by a Horner -Wadsworth -Emmons (HWE) olefination reaction follow by DIBAL reduction of resulting ester. 16 !!!!49 I-2-6-5 Synthesis of unsaturated amide substrates for chlorofunctionalization 57-58 !Figure I-25: General procedure for synthesis of substrates !Allyl alcohols I-52 (1.0 equiv), phthalimide (1.1 equiv) and PPh 3 (1.1 equiv) was added to the reaction vessel and dissolved in THF (5 mL/mmol). The flask was immersed in an ice bath and DIAD (1.1 equiv) was added drop wise. After TLC analysis revealed the complete consumption of starting material ( "30 min), 3 equivalents of hydrazine hydrate was added to the reaction vessel and the resulting suspension was stirred overnight at room temprature. The reaction was diluted with water, concentrated HCl (3 mL) was added, and the resulting suspension was stirred for further 30 min at ambient temperature. The precipitated solids were filtered and the filter cake was washed with 10% aq. HCl (2 ! 2 mL). The combined filtrates were washed with ether (3 ! 5 mL) and the aqueous phase was concentrated under reduced pressure giving the amine salts I-53, which were used in the next reaction without any purification. A solution of crude ammonium chloride salt I-53 from the previous step (1 equiv), triethyl amine (5 equiv) and catalytic amount of DMAP in THF (20 mL) were cooled in an ice bath. To this suspension was added p-nitro benzoyl chloride (1.5 equiv). After the addition was completed, the reaction was warmed R1OHR1NH3Cl1) 1.1 equiv phthalimide 1.1 equiv DIAD 1.1 equiv PPh 32) NH 2-NH 2.H2O rt,4 h 3) HCl 10% 1.4 equiv 4-NO 2-C6H4-C(O)Cl 5.0 equiv NEt 3, cat. DMAP R1NHOO2NTHF rt I-52 I-53 E-(46a,46b,46c,46d,46e)-NO 2Z-(4 6c,46h,46i)-NO 246K-NO 2R2R2R2!50 to room temperature. After 3 h, the reaction was quenched with methanol (1.0 mL) and then diluted with an equal amount of water, concentrated under reduced pressure, and extracted with DCM (3 ! 25 mL). The combined organic layer was washed with brine (1 ! 20 mL), dried over anhyd. Na 2SO4 and concentrated under reduced pressure in the presence of silica gel. Column chromatography (EtOAC -Hexanes gradient elution) gave the desired products ( E-(46a,46b,46c,46d,46e)-NO2, Z-(46c,46h,46i)-NO2, 46k-NO2). I-2-6-6 General procedure for synthesis of aromatic Z-allyl amides !Figure I-26: General procedure for synthesis of aromatic Z-allyl amides Iodo benzene I-54 (1.0 equiv) and propargyl alcohol was dissolved in triethylamine (10 mL/mmol) at room temperature after which CuI (0.2 equiv) and Pd(PPh 3)Cl 2 (5 mol%) were added to reaction vessel. After TLC analysis revealed consumption of starting material, the reaction was diluted with water, concentrated under reduced pressure, and extracted with DCM (3 ! 25 mL). The Z-(46b,46f,46g) -NO 2IOHCuI (0.2 equiv) Pd(PPH 3)2Cl2 (5 mol%) NEt 3RRROHI-54 R = H, Me, OCH 3OHH2, Pd/BaSO 4QuinolineMeOH RNHRef 16ONO2+I-55 I-56 I-57 !51 combined organic layer was washed with brine (1 ! 20 mL), dried over anhyd. Na2SO4 and concentrated under reduced pressure in the presence of silica gel. Column chromatography (20% EtOAC -Hexanes gradient elution) gave the desired products I-56. (70 -85 % yield for different substrates) 3-Phenylprop -2-yn-1-ol I-56 (1.0 equiv), palladium on barium sulfate (10 wt%) and quinoline were dissolved in methanol (10 mL/mmol). The reaction vessel was purged with hydrogen gas and then stirred under balloon pressure of H 2. When GC analysis revealed complete consumption of starting material, the catal yst was filtered and the filtrate was concentrated. Column chromatography (EtOAC -Hexanes gradient elution) gave the desired products ( I-57). Allyl amides Z-(46b,46f,46 g)-NO2 were synthesized as reported previously. 16 !52 I-2-6-7 General procedure synthesis of substrates Z-46e-NO2 Ð Z-46j-NO2 !Figure I-27: General procedure for the s ynthesis of substrates Z-46e-NO2 Ð Z-46j-NO2 Alkyne I-58 (1.0 equiv) was dissolved in THF in a flamed dried round bottom flask. n-BuLi (1.1 equiv) was added to cooled solution at -78 ¡C. The reaction was then warmed to 0 ¡C. After 30 min paraformaldehyde (1.2 equiv) was added in a single port ion at -78 ¡C and the reaction was warmed to room temperature. After 2 h, the reaction was quenched with sat. aq. NH 4Cl solution (15.0 mL). The mixture was diluted with water and concentrated under reduced pressure and then extracted with DCM (3 ! 10 mL). The combined organic layer was washed with brine (1 ! 10 mL), dried over anhyd. Na 2SO4, and concentrated under reduced pressure in the presence of silica gel. Column chromatography (EtOAC -Hexanes gradient elution) gave the desired products I-59. The Z allylic alcohol I-60 was synthesized from alkynol I-59 by a Lindlar reduction that was reported in page 49. OPG OPG OHn-BuLi (1.1 equiv) -78 ¡C to 0 ¡C nnPG = Bn, TBDPS n = 1, 2 then, (CH 2O)n (1.2 equiv) -78 ¡C to rt H2, Pd/BaSO 4QuinolineMeOH PGO OHnRef 16PGO NHnONO2Z-46e-NO 2, Z-46j-NO 2I-58 I-59 I-60 !53 Allyl amides Z-46e-NO2, Z-46j-NO2 were synthesized as reported previously .16 I-2-6-8 Analytical data for products a-47b-OMe -NO2: N-((2R,3S)-2-chloro -3-methoxy -3-phenylpropyl) -4-nitrobenzamide Rf : 0.20 ( 30%EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.88 (d, J = 9.0 Hz, 2H), 7.40-7.33 (m, 5H), 6.82 (br s, 1H), 4.45 (d, J = 4.5 Hz, 1H), 4.25 -4.22 (m, 1H), 4.11-4.06 (m, 1H), 3.66 -3.61 (m, 1H), 3.34 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.26, 149.64, 139.66, 136.87, 137.22, 128.76, 128.12, 127.18, 123.87, 86.33, 62.60, 57.98, 42.54 HRMS analysis (ESI): Calculated for [M+H] +: C 17H18ClN2O4: 349.0955; Found: 349.0950 Resolution of enantiomers: DAICEL Chiralcel ¨ Oj-H column, 20% IPA -Hexanes, 1.0 mL/min, 265 nm, RT1 (minor) = 27.0 min, RT2 (major) = 30.1 min [#]D20 = +46.7 (c 0.5, CHCl 3, er = 92:8) a-47d-OMe -NO2: N-((2R,3S)-2-chloro -3-(4-fluorophenyl) -3-methoxypropyl) -4-nitrobenzamide HNONO2OMe Cl!54 Rf : 0.19 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H), 7.33-7.30 (m, 2H), 7.09 -7.06 (m, 2H), 6.77 (br s, 1H), 4.38 (d, J = 4.5 Hz, 1H) 4.19-4.18 (m, 1H), 4.13 -4.09 (m, 1H), 3.65 -3.63 (m, 1H), 3.31 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.32, 149.65, 139.81, 133.74, 129.08 (d, JCF = 30 Hz) 128.12, 123.91, 115.81, 115.63, 85.55, 62.79, 57.79, 42.77 HRMS analysis (ESI): Calculat ed for [M+H] +: C 17H17ClFN2O4: 367.0861; Found: 367.0844 Resolution of enantiomers: CHIRALCEL OJ -H 12% IPA -Hexane, 0.7 ml/min, RT1 (minor) = 64.6, RT2 (major) = 69.6; [ #] D 20 = -5.0 (c 0.1, CHCl 3, er = 89:11) a-47c-OMe -NO2: N-((2R,3S)-2-chloro -3-methoxyhexyl) -4-nitrobenzamide Rf : 0.38 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 2H), 7.24 (br s, 1H), 4.16 -4.10 (m, 2H), 3.60 -3.56 (m, 1H), 3.49 -3.47 (m, 4H), 1.68 -1.62 (m, 2H), 1.54-1.35 (m, 2H), 0.95 (m, 3H) HNONO2OMe ClFHNONO2ClOMe !55 13C NMR (125 MHz, CDCl 3) # 165.40, 149.70, 139.86, 128.14, 123.90, 83,90, 61.78, 59.37, 42.92, 33.69, 18.46, 14.09 HRMS analysis (ESI): Calculated for [M -H]$: C 14H18ClN2O4: 313.0955; Found: 313.0953 Resolution of enantiome rs: DAICEL Chiralcel ¨ AD-H column, 7% IPA -Hexanes, 0.5 mL/min, 254 nm, RT1 (major) = 32.6 min, RT2 (major) = 34.7 min. [#]D20 = -30 (c 0.25, CHCl 3, er = 87:13) a-47a-OMe -NO2: N-((2R,3S)-2-chloro -3-cyclohexyl -3-methoxypropyl) -4-nitrobenzamide Rf : 0.36 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 7.00 (br s, 1H), 4.33 -4.30 (m, 1H), 4.15 -4.10 (m, 1H), 3.63 -3.58 (m, 4H), 3.22 -3.20 (dd, J =7.0, 4.0 Hz 1H), 1.94 -1.91(m, 1H), 1.77 -1.74 (m, 2H), 1.68-1.63 (m, 2H), 1.27 -1.05 (m, 6H) 13C NMR (125 MHz, CDCl 3) # 165.40, 149.69, 139.91, 128.12, 123.88, 89.50, 62.64, 60.87, 42.71, 41.32, 29.67, 28.70, 26.20, 25.99, 25.86 HRMS analysis (ESI): Calculated for [M -H]$: C 17H22ClN2O4: 353.1268; Found: 353.1261 HNONO2ClOMe !56 Resolution of enantiomers: DAICEL Chiralcel ¨ OJ-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 11.8 min, RT2 (minor) = 16.1 min. [#]D20 = -4.0 (c 0.6, CHCl 3, er = 75:25) a-47e-OMe -NO2: N-((2R,3S)-4-(benzyloxy) -2-chloro -3-methoxybutyl) -4-nitrobenzamide Rf: 0.16 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.25 (d, J = 9.0 Hz, 2H), 7.85 (d, J = 9.0 Hz, 2H), 7.35-7.29, (m, 5H), 6.87 (br s, 1H), 4.56 (d, J = 1 Hz, 2H), 4.36 -4.33 (m, 1H), 3.99-3.95 (m, 1H), 3.83 -3.79 (m, 1H), 3.75 -3.72 (dd, J=10.0, 5.0 Hz, 1H), 3.69 -3.66 (dd, J=10.0 , 5.0 Hz, 1H), 3.49 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.24, 149.60, 139.78, 137.45, 128.55, 128.11, 128.02, 127.83, 123.83, 82.33, 73.76, 68.17, 59.11, 59.08, 24.90 HRMS analysis (ESI): Calculated for [M -H]$: C19H20ClN2O5: 391.1061; Found: 391.1057 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 20% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 11.0 min, RT2 (minor) = 11.8 min. [#]D20 = +5.2 (c 0.5, CHCl 3, er = 88:12) HNONO2bs-02-80 ClOMe BnO !57 s-47b-OMe -NO2: N-((2R,3R)-2-chloro -3-methoxy -3-phenylpropyl) -4-nitrobenzamide Rf : 0.22 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.27 (d, J = 9.0 Hz, 2H), 7.86 (d, J = 9.0 Hz, 2H), 7.41-7.24 (m, 5H), 6.57 (br s, 1H), 4.41 (d, J = 4.5 Hz, 1H), 4.29 -4.28 (m, 1H), 4.00-3.95 (m, 1H), 3.56 -3.52 (m, 2H), 3.27(s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.32, 149.75, 139.66, 136.83, 123.84, 128.68, 128.13, 127.49, 123.87, 85.03, 63.63, 57.44, 43.80 HRMS analysis (ESI): Calculated for [M+H] +: C 17H18ClN2O4: 349.0955; Found: 349.0955 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 22.8 min, RT2 (minor) = 29.9 min. [#]D20 = -8.0 (c 0.1, CHCl 3, er = 99.5:0.5) a-47f-OMe -NO2: N-((2R,3R)-2-chloro -3-methoxy -3-(p-tolyl)propyl) -4-nitrobenzamide Rf : 0.27 (30% EtOAc in hexanes, UV) HNONO2OMe ClHNONO2OMe ClMe!58 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 9.0 Hz, 2H), 7.22-7.18 (m, 4H), 6.86 (br s, 1H), 4.24 (d, J = 5.5 Hz, 1H), 4.23 -4.20 (m, 1H), 4.10-4.05 (m, 1H), 3.65 -3.60 (m, 1H), 3.33 (s, 3H), 2.34 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.27, 149.67, 139.64, 138.74, 133.73, 129.41, 128.13, 127.38, 123.86, 84.94, 63.72, 57.29, 43.75, 21.21 HRMS analysis (ESI): Calculated for [M -H]$: C 18H18ClN2O4: 361.0955; Found: 361.0955 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 265 nm, RT1 (major) = 13.6 min, RT2 (minor) = 16.6 min. [#]D20 = +14.9 (c 0.7, CHCl 3, er = 97:3) s-47f-OMe -NO2: N-((2R,3R)-2-chloro -3-methoxy -3-(p-tolyl)propyl) -4-nitrobenzamide Rf : 0.27 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl3) # 8.29 (d, J = 9.0 Hz, 2H), 7.85 (d, J = 9.0 Hz, 2H), 7.22-7.10 (m, 4H), 6.55 (br s, 1H), 4.39 (d, J = 5.0 Hz, 1H), 4.38 -4.24 (m, 1H), 3.95-3.94 (m, 1H), 3.55 -3.50 (m, 1H), 3.30 (s, 3H), 2.35 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.22, 149.63, 139.91, 138.63, 134.15, 129.46, 128.12, 127.10, 123.85, 86.22, 62.65, 57.86, 42.56, 21.19 HNONO2OMe ClMe!59 HRMS analysis (ESI): Calculated for [M -H]$: C 18H18ClN2O4: 361.0955; Found: 361.0955 Resolution of enantiomers: DAICEL Chiralcel ¨ OD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 17.8 min, RT2 (minor) = 25.0 min. [#]D20 = -7.1 (c 0.6, CHCl 3, er = 99:1) 47g-OMe -NO2: N-2-chloro -3-methoxy -3-(4-methoxyphenyl)propyl) -4-nitrobenzamide (note: the relative stereochemistry of the two diastereomeric products below was not identified.) Rf : 0.16 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.28 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 8 Hz, 2H), 6.92 (d, J = 8 Hz, 2H), 6.57 (br s, 1H), 4.37 (d, J = 5.5 Hz, 1H), 4.27 -4.23 (m, 1H), 3.96 -3.92 (m, 1H), 3.80 (s, 3H), 3.53 -3.48 (m, 1H), 3.29 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.24, 159.87, 149.64, 139.89, 129.09, 128.44, 128.13, 123.87, 114.10, 85.91, 62.79, 57.70, 55.28, 42.67 HRMS analysis (ESI): Calculated fo r [M -H]$: C 18H18ClN2O5 377.0904; Found: 377.0899 Resolution of enantiomers: DAICEL Chiralcel ¨ OD-H column, 2% IPA -Hexanes, 01.0 mL/min, 254 nm, RT1 (minor) = 21.6 min, RT2 (major) = 25.7 min. HNONO2OMe ClMeO !60 [#]D20 = +17 (c 0.25, CHCl 3, er = 99:1) epi-47g-OMe -NO2:, N-((2R,3R)-2-chloro -3-methoxy -3-(4-methoxyphenyl)propyl) -4-nitrobenzamide Rf : 0.16 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.90 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.85 (br s, 1H), 4.39 (d, J = 6.0 Hz, 1H) 4.22 -4.18 (m, 1H), 4.11 -4.06 (m, 1H), 3.80 (s, 3H), 3.65 -3.60 (m, 1H), 3.31 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.27, 159.97, 149.68, 139.63, 128.69, 128.12, 123.86, 114.08, 84.66, 63.83, 57.18, 55.27, 43.71 HRMS analysis (ESI): Calculated for [M -H]$: C 18H18ClN2O5 377.0904; Found: 377.0901 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 20% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 11.9 min, RT2 (minor) = 13.8 min. [#]D20 = -13.0 (c 0.25, CHCl3, er = 92:8) s-47h-OMe -NO2: N-((2R,3R)-2-chloro -3-methoxypentyl) -4-nitrobenzamide HNONO2OMe ClMeO !61 Rf : 0.20 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.30 (d, J = 9.0 Hz, 2H), 7.94 (d, J = 9.0 Hz, 2H), 6.83 (br s, 1H), 4.28 -4.25 (m, 1H), 4.14 -4.09 (m, 1H), 3.60 -3.51 (m, 1H), 3.46 (s, 3H), 3.61 -3.34 (m, 1H), 1.75 -1.69 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.49, 149.69, 139.69, 128.16, 123.90, 84.10, 60.96, 58.21, 43.92, 22.90, 9.92 HRMS analysis (ESI): Calculated for [M+H] +: C 13H16ClN2O4 299.0799; Found: 299.0796 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 7% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 22.2 min, RT2 (major) = 24.7 min. [#]D20 = +30.0 (c 0.39, CHCl 3, er = 98:2) s-47c-OMe -NO2: N-((2R,3R)-2-chloro -3-methoxyhexyl) -4-nitrobenzamide Rf : 0.25 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 2H), 6.79 (br s, 1H), 4.25 -4.23 (m, 1H), 4.13 -4.08 (m, 1H), 3.61 -3.55 (m, 1H), 3.45 -3.41(m, 4H), 1.68 -1.62 (m, 2H), 1.54 -1.35 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H) HNONO2bs-02-80 ClOMe HNONO2ClOMe !62 13C NMR (125 MHz, CDCl 3) # 165.44, 149.74, 139.73, 128.14, 123.90, 82,70, 61.04, 58.27, 43.78, 32.08, 18.90, 14.04 HRMS analysis (ESI): Calculated for [M+H] +: C 14H20ClN2O4: 315.1112; Found: 315.1116 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 12.1 min, RT2 (minor) = 14.0 min. [#]D20 = +19.0 (c 0.1, CHCl 3, er = 99.5:0.5) Absolute stereochemistry was determined by single crystal X -ray diffraction (XRD). Crystals for XRD were obtained by crystallization from CH 2Cl2 layered with hexanes in a silicone -coated vial. ent-s-47c-OMe -NO2: N-((2S,3S)-2-chloro -3-methoxyhexyl) -4-nitrobenzamide Rf : 0.25 (30% EtOAc in hexanes, UV) 64% yield with (DHQ) 2PHAl 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 2H), 6.79 (br s, 1H), 4.25 -4.23 (m, 1H), 4.13 -4.08 (m, 1H), 3.61 -3.55 (m, 1H), 3.45 -3.41(m, 4H), 1.68 -1.62 (m, 2H), 1.54 -1.35 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H) HNONO2ClOMe !63 13C NMR (125 MHz, CDCl 3) # 165.44, 149.74, 139.73, 128.14, 123.90, 82,70, 61.04, 58.27, 43.78, 32.08, 18.90, 14.04 HRMS analysis (ESI): Calculated for [M+H] +: C 14H20ClN2O4: 315.1112; Found: 315.1116 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 11.4 min, RT2 (major) = 14.4 min. [#]D20 = -19.8 (c = 0.5, CHCl 3, er = 95.0:5.0) s-47i-OMe -NO2: N-((2R,3R)-2-chloro -3-methoxynonyl) -4-nitrobenzamide Rf : 0.30 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.33 (d, J = 9.0 Hz, 2H), 7.97 (d, J = 9.0 Hz, 2H), 6.85 (br s, 1H), 4.30 -4.27 (m, 1H), 4.16 -4.15 (m, 1H), 3.64 -3.58 (m, 1H), 3.45 (s, 3H), 3.44 -3.41 (m, 1H), 1.72 -1.68 (m, 2H), 1.39 -1.25 (m, 8H), 0.90 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.46, 149.70, 139.70, 128.15, 123.91, 82.90, 61.09, 58.25, 43.82, 31.68, 29.92, 29.25, 25,57, 22.55, 14.06 HRMS analysis (ESI): Calculated for [M -H]$: C 16H22ClN2O4: 341.1268; Found: 341.1272 HNONO2ClOMe !64 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 10.5 min, RT2 (minor) = 12.7 min. [#]D20 = +16.5 (c 0.6, CHCl 3, er = 95:5) s-47e-OMe -NO2: N-((2R,3R)-4-(benzyloxy) -2-chloro -3-methoxybutyl) -4-nitrobenzamide Rf : 0.23 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.25 (d, J = 9.0 Hz, 2H), 7.85 (d, J = 9.0 Hz, 2H), 7.34-7.32 (m, 5H), 6.79 (br s, 1H), 4.55 (s, 2H), 4.38 -4.35 (m, 1H), 4.17 -4.03 (m, 1H), 3.80 -3.77 (dd, J = 9.5, 4.5 Hz, 1H), 3.78 -3.67 (m, 3H), 3 .48 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.40, 149.60, 139.76, 137.46, 128.53, 128.01, 127.82, 123.83, 81.28, 73.82, 68.40, 59.72, 58.85, 43.76 HRMS analysis (ESI): Calculated for [M -H]$: C 19H20ClN2O5: 391.1061; Found: 391.1060 Resolution of enantiomers: D AICEL Chiralcel ¨ IA column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 24.6 min, RT2 (major) = 26.8 min. [#]D20 = +4.1 (c 0.45, CHCl 3, er = 99:1) HNONO2bs-02-80 ClOMe BnO !65 s-47j-OMe -NO2: N-((2R,3R)-5-((tert -butyldiphenylsilyl)oxy) -2-chloro -3-methoxypentyl) -4-nitrobenzamide Rf : 0.38 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.28 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 7.65-7.63 (m, 5H), 7.41 -7.37 (m, 5H), 6.77 (br s, 1H), 4.27 (m, 1H) 4.10 -4.07 (m, 1H), 3.81 -3.76 (m, 3H), 3.61 -3.58 (m, 1H), 3.42 (s, 3H), 1.99-1.94 (m, 1H), 1.81 -1.78 (m, 1H), 1.25 -1.21 (m,2H), 1.04 (s, 9H) 13C NMR (125 MHz, CDCl 3) # 165.37, 149.73, 139.76, 135.54, 133.49, 133.44, 129.77, 128.13, 127.74, 123.90, 79.76, 61.18, 59.98, 58.42, 43.73, 32.90, 26.86, 19.18 HRMS analysis (ESI): Cal culated for [M+H] +: C 29H36ClN2O5Si: 555.2082; Found: 555.2089 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 3% IPA -Hexanes, 0.7 mL/min, 254 nm, RT1 (minor) = 34.3 min, RT2 (major) = 37.0 min. [#]D20 = +17.0 (c 0.1, CHCl 3, er = 99.5:0.5) 47k-OMe -NO2: (R)-N-(2-chloro -3-methoxy -3-methylbutyl) -4-nitrobenzamide HNONO2ClOMe TBDPSO HNOMeNO2OMe ClMe!66 Rf : 0.20 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 2H), 6.93(br s, 1H), 4.23 -4.19 (m, 1H) 4.07 -4.054 (m, 1H), 3.25 -3.48 (m, 1H), 3.56-3.52 (m, 1H), 3.30 (s, 3H), 1.35 (s, 3H), 1.32 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.32, 149.68, 139.89, 128.10, 123.86, 77.38, 66.77, 49.95, 42.89, 22.97, 21.09 HRMS analysis (ESI): Calculated for [M+H] +: C 13H18ClN2O4: 301.0955; Found: 301.0959 Resolution of enantiomers: DAICEL Chiralcel ¨ OJ-H column, 5% IPA -Hexanes, 0.7 mL/min, 254 nm, RT1 (minor) = 28.3 min, RT2 (major) = 31.0 min. [#]D20 = +14.0 (c 0.1, CHCl 3, er = 99.5:0.5) s-47c-OEt -NO2: N-((2R,3R)-2-chloro -3-ethoxyhexyl)-4-nitrobenzamide Rf : 0.25 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 6.92 (br s, 1H), 4.25 -4.24 (m, 1H), 4.12 -4.07 (m, 1H), 3.64 -3.57 (m, 3H), 3.55 -3.52 (m, 1H), 1.72 -1.66 (m, 1H), 1.61 -1.55 (m, 1H), 1.55 -1.43 (m, 1H), 1.43 -1.35 (m, 1H), 1.20 (t, J = 6.5 Hz 3H), 0.95 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.35, 149.68, 139.75, 128.15, 123.90, 81.33, 66.15, 60.75, 43.70, 32.30, 19.03, 15.61, 14.05 OEt ClHNONO2!67 HRMS analysis (ESI): Calculated for [M -H]$: C 15H22ClN2O4: 329.1268; Found: 329.1273 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 5% IPA -Hexanes, 1. 0 mL/min, 254 nm, RT1 (major) = 20.3 min, RT2 (minor) = 22.0 min. [#]D20 = +21.3 (c 0.7, CHCl 3, er = 99.5:0.5) s-47c-OAllyl -NO2: N-((2R,3R)-3-(allyloxy) -2-chlorohexyl) -4-nitrobenzamide Rf : 0.40 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.28 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 6.87 (br s, 1H), 5.94 -5.87 (m, 1H), 5.30 (dd, J = 15.0, 1.5 Hz, 1H), 5.21 (dd , J = 15.0, 1.5 Hz, 1H), 4.26 -4.23 (m, 1H), 4.12 -4.06 (m, 3H), 3.64 -3.59 (m, 2H), 1.72 -1.70 (m, 1H), 1.64 -1.57 (m, 1H), 1.54 -1.37 (m, 2H), 0.93 (t, J = 9 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.36, 149.69, 139.65, 134.22, 128.20, 123.86, 118.10, 80.57, 71.44, 60.62, 43.70, 32.20, 18.97, 14.04 HRMS analysis (ESI): Calculated for [M -H]$: C 16H20ClN2O4: 339.1112; Found: 339.1107 Resol ution of enantiomers: DAICEL Chiralcel ¨ IA column, 7% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 16.9 min, RT2 (major) = 17.8 min. OClHNONO2!68 [#]D20 = +13.7 (c 0.5, CHCl 3, er = 99.5:0.5) s-47c-OPropargyl -NO2: N-((2R,3R)-2-chloro -3-(prop -2-yn-1-yloxy)hexyl) -4-nitrobenzamide Rf : 0.40 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.28 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 6.87 (br s, 1H), 4.36 -4.33 (dd, J = 16.5, 2.5 Hz, 1H), 4.32 -4.29 (m,1H), 4.25 -4.21 (dd, J = 16.5, 2.5 Hz, 1H), 4.10 -4.05 (m, 1H), 3.83 -3.80 (m, 1H), 3.69 -3.64 (m, 1H), 1.72 -1.70 (m, 1H), 1.64 -1.57 (m, 1H), 1.54 -1.37 (m, 2H), 0.96 (t, J = 9 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.49, 149.72 , 139.70, 128.21, 123.88, 79.61, 79.02, 75.15, 60.60, 56.67, 43.70, 31.90, 18.72, 14.05 HRMS analysis (ESI): Calculated for [M -H]$: C 16H18ClN2O4: 337.0955; Found: 337.0951 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 10% IPA -Hexanes, 1.0 mL/min, 265 nm, RT1 (minor) = 18.8 min, RT2 (major) = 20.3 min. [#]D20 = +14.0 (c 0.1, CHCl 3, er = 98:2) s-47c-OAc -NO2: (2R, 3R)-2-chloro -1-(4-nitrobenzamido)hexan -3-yl acetate OClHNONO2!69 Rf : 0.30 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.30 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.5 Hz, 2H), 7.10 (br s, 1H), 5.17 -5.14 (m, 1H), 4.16 -4.13 (m, 1H), 4.00 -3.95 (m, 1H), 3.36 -3.24 (m, 1H), 2.17 (s, 3H), 1.84 -1.81 (m, 1H), 1.63 -1.61 (m, 1H), 1.35 -1.31 (m, 2H), 0.91 (t, J = 7.5, 3H) 13C NMR (125 MHz, CDCl 3) # 172.10, 165.13, 149.83, 139.21, 128.20, 123.92, 72.11, 60.32, 42.70, 33.68, 20.92, 18.65, 13.64 HRMS analysis (ESI): Calculated for [M+H] +: C 15H20ClN2O5: 343.1061; Found: 343.1062 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 7% IPA -Hexanes, 01.0 mL/min, 254 nm, RT1 (major) = 17.6 min, RT2 (minor) = 18.9 min. [#]D20 = -8.0 (c 0.1, CHCl 3, er = 98:2) s-47c-OH-NO2: N-((2R,3R)-2-chloro -3-hydroxyhexyl) -4-nitrobenzamide Rf : 0.12 (30% EtOAc in hexanes, UV) OClHNONO2OOHClHNONO2!70 1H NMR (500 MHz, CD 3CN) # 8.28 (d, J = 9.0 Hz, 2H), 7.98 (d, J = 8.5 Hz, 2H), 6.93 (br s, 1H), 4.14 -4.11 (dt, J = 7.0, 2.0 Hz, 2H), 3.90 -3.84 (m, 1H), 3.79 -3.76 (m, 1H), 3.60 -3.55 (m,1H) 3.41 (d, J = 6.5 Hz, 1H), 1.60 -1.56 (m, 1H), 1.53 -1.42 (m, 2H), 1.36 -1.31 (m, 1H), 0.91 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 166.39, 150.08, 140.11, 128.83, 124.02, 70.37, 65.07, 43.79, 36.47, 19.04, 13.61 HRMS analysis (ESI): Calculated for [M -H]$: C 13H16ClN2O4: 299.0799; Found: 299.0796 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 15% IPA -Hexanes, 1.0 mL/min, 265 nm, RT1 (major) = 12.3 min, RT2 (minor) = 13.8 min. [#]D20 = +14.6 (c 0.9, CHCl 3, er = 99:1) a-47c-OAc -NO2: (2R,3S)-2-chloro -1-(4-nitrobenzamido)hexan -3-yl acetate Rf : 0.28 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.30 (d, J = 9.0 Hz, 2H), 7.94 (d, J = 9.0 Hz, 2H), 6.65 (br s, 1H), 5.13 (m, 1H), 4.19 (m, 2H), 3.49 (m, 1H), 2.19 (s, 3H), 1.79 -1.70 (m, 2H), 1.42 -1-33 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 170.81, 165.26, 149.7 3, 139.60, 128.20, 123.93, 73.53, 61.47, 42.00, 33.34, 20.95, 18.34, 13.77 OClHNONO2O!71 HRMS analysis (ESI): Calculated for [M -H]$: C 15H18ClN2O5: 341.0904; Found: 341.0903 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 12.95 min, RT2 (minor) = 13.9 min. [#]D20 = +14.0 (c 0.15, CHCl 3, er = 93:7) s-47h-OH-NO2: N-((2R,3R)-2-chloro -3-hydroxypentyl) -4-nitrobenzamide Rf : 0.20 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CD 3CN) # 8.29 (d, J = 9.0 Hz, 2H), 7.99 (d, J = 9.0 Hz, 2H), 7.60 (br s, 1H), 4.17 -4.14 (dt, J = 6.5, 1.5 Hz, 1H), 3.90 -3.85 (m, 1H), 3.70 -3.65 (m, 1H), 3.61 -3.55 (m, 1H), 3.42 (d, J = 6.5 Hz, 1H), 1.66 -1.54 (m, 2H), 0.93 (t, J = 8.0 Hz, 3H) 13C NMR (125 MHz, CD 3CN) # 166.38, 1 50.10, 140.12, 128.84, 124.03, 72.10, 64.63, 43.77, 27.37, 9.87 HRMS analysis (ESI): Calculated for [M -H]$: C 12H14ClN2O4: 285.0642; Found: 285.0645 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 1 3.7 min, RT2 (major) = 15.2 min. [#]D20 = +6.0 (c 0.45, CHCl 3, er = 99:1) OHClHNONO2!72 Absolute stereochemistry was determined by single crystal X -ray diffraction (XRD). Crystals for XRD were obtained by crystallization from CH 2Cl2 layered with hexanes in a silicone -coated vial. 47k-OAc -NO2: ((R)-3-chloro -2-methyl -4-(4-nitrobenzamido)butan -2-yl acetate Rf : 0.20 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.30 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 6.54 (br s, 1H), 4.60 -4.58 (dd, J =10.0, 2.5 Hz, 1H) 4.31 -4.26 (m, 1H), 3.39 -3.33 (m, 1H), 2.03 (s, 3H), 1.62 (s, 3H),1.60 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 170.04, 165.45, 149.80, 139.57, 128.19, 123.93, 82.13, 66.63, 42.44, 23.62, 22.78, 22.17 HRMS analysis (ESI): Calculated for [M+H] +: C 14H17ClN2O5: 329.0904; Found: 304.0906 MeOClHNONO2MeOMe!73 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 22.1 min, RT2 (minor) = 24.4 min. [#]D20 = +39.2 (c 0.7, CHCl3, er = 98:2) s-47cÕ-OMe -NO2: N-((2R,3R)-2-bromo -3-methoxyhexyl) -4-nitrobenzamide Rf : 0.20 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.30 (d, J = 9.0 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 6.84 (br s, 1H), 4.38 -4.35 (m, 1H), 4.19 -4.12 (m, 1H), 3.73 -3.68 (m, 1H), 3.39 -3.36 (m, 1H), 1.79 -1.73 (m, 2H), 1.45 -1.39 (m, 2H), 0.98 (t, J = 8.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.33, 149.70, 139.70, 128.14, 123.92, 82.75, 58.12, 54.75, 44.23, 32.99,18.90,14.02 HRMS analysis (ESI): Calculated for [M+H] +: C 14H29BrN2O4: 359.0606; Found: 359.0604 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 11.9 min, RT2 (minor) = 12.6 min. [#]D20 = +24.4 (c 0.9, CHCl 3, er = 99:1) OMe BrHNONO2!74 Absolute stereochemistry was determined by single crystal X -ray diffraction (XRD). Crystals for XRD were obtained by crystallization from CH 2Cl2 layered with hexanes in a silicone -coated vial. s-47cÕ-OH-NO2: N-((2R,3R)-2-bromo -3-hydroxyhexyl) -4-nitrobenzamide Rf : 0.15 (30% EtOAc in hexanes, UV) 62 % yield 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.94 (d, J = 9.0 Hz, 2H), 6.89 (br s, 1H), 4.30 -4.27 (m, 1H), 4.22 -4.16 (m, 1H), 3.75 -3.70 (m, 1H), 3.65 -3.62 (m, 4H), 2.17 (d, J = 8 Hz), 1.70 -1.63 (m, 1H), 1.58 -1.35 (m, 3H), 0.95 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.82, 149.78, 139.39, 128.21, 123.94, 71.79, 60.17, 45.04, 38.31, 18.73, 13.88 HRMS analysis (ESI): Calculated for [M+H] +: C 13H18BrN2O4: 345.0450; Found: 345.0434 Resolution of enantiomers: DAICEL Chiralcel ¨ Ia column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 22.9 min, RT2 (minor) = 24.7 min. HNONO2BrOH!75 [#]D20 = +11.6 (c = 0.5, CHCl 3, er = 99.5:0.5) a-47cÕ-OH-NO2: N-((2R,3S)-2-bromo -3-hydroxyhexyl) -4-nitrobenzamide Rf : 0.20 (30% EtOAc in hexanes, UV) 51% yield 1H NMR (500 MHz, CDCl 3) # 8.32 (d, J = 9.0 Hz, 2H), 7.97 (d, J = 9.0 Hz, 2H), 6.89 (br s, 1H), 4.39 -4.32 (ddd, J = 15.5, 7.5, 4.0 Hz, 1H), 4.14 (d, J = 4.0 Hz 1H), 407 -4.04 (m, 1H), 3.73 -3.68 (ddd, J = 15.0, 5.5, 3.5 Hz, 1H), 3.66 -3.63 (m, 1H), 1.82 -1.77 (m, 1H), 1.61 -1.49 (m, 2H), 1.41 -1.35 (m, 1H), 0.93 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 166.88, 149.94, 138.89, 128.34, 124.01, 72.00, 58.49, 42.87, 35.90, 18.94, 13.94 HRMS analysis (ESI): Calculated for [M+H] +: C 13H18BrN2O4: 345.0450; Found: 345.0439 Resolution of enantiomers: DAICEL Chiralcel ¨ OD-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 24.5 min, RT2 (major) = 29.7 min . [#]D20 = -15.6 (c = 0.6, CHCl 3, er = 85.0:15.0) 47kÕ-OMe -NO2: (S)-N-(2-bromo -3-methoxy -3-methylbutyl) -4-nitrobenzamide HNONO2BrOH!76 Rf : 0.25 (30% EtOAc in hexanes, UV) 62% yield 1H NMR (500 MHz, CDCl 3) # 8.33 (d, J = 9.0 Hz, 2H), 7.97 (d, J = 9.0 Hz, 2H), 6.99 (br s, 1H), 4.31 -4.23 (m, 2H), 3.65 -3.60 (m, 1H), 3.33 (s, 3H), 1.42 (d, J = 8.5 Hz, 6H) 13C NMR (125 MHz, CDCl 3) # 165.22, 149.66, 139.86, 128.12, 123.91, 77.06, 61.19, 50.05, 43.45, 23.41,22.42 HRMS analysis (ESI): Calculated for [M+H] +: C 13H18ClN2O4: 345.0450; Found: 345.0441 Resolution of enantiomers: DAICEL Chiralcel ¨ OJ-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 28.8 min, RT2 (major) = 33.9 min. [#]D20 = +23.8 (c = 0.7, CHCl 3, er = 99.5:0.5) ent-47kÕ-OMe -NO2: (S)-N-(2-bromo -3-methoxy -3-methylbutyl) -4-nitrobenzamide Rf : 0.25 (30% EtOAc in hexanes, UV) 59% yield with (DHQ) 2PHAll 1H NMR (500 MHz, CDCl 3) # 8.33 (d, J = 9.0 Hz, 2H), 7.97 (d, J = 9.0 Hz, 2H), 6.99 (br s, 1H), 4.31 -4.23 (m, 2H), 3.65 -3.60 (m, 1H), 3.33 (s, 3H), 1.42 (d, J = 8.5 Hz, 6H) HNOMeNO2OMe BrMeHNOMeNO2OMe BrMe!77 13C NMR (125 MHz, CDCl 3) # 165.22, 149.66, 139.86, 128.12, 123.91, 77.06, 61.19, 50.05, 43.45, 23.41,22.42 HRMS analysis (ESI): Calculated for [M+H] +: C 13H18ClN2O4: 345.0450; Found: 345.0439 Resolution of enantiomers: DAICEL Chiralcel ¨ OJ-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 27.8 min, RT2 (minor) = 32.4 min. [#]D20 = -33.8 (c = 1.0, CHCl 3, er = 99.5:0.5) !78 I-2-6-9 Analytical data for byproduct 47c-NHAc -NO2: N-(3-acetamido -2-chlorohexyl) -4-nitrobenzamide Note: Relative and absolute stereochemistry was not established. Rf : 0.10 (20% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.30 (d, J = 9.0 Hz, 2H), 8.25 (br s, 1H), 8.07 (d, J = 9.0 Hz, 2H), 5.58 (d, J = 9.5 Hz, 1H), 4.34 -4.26 (m, 2H), 4.13 -4.09 (m, 1H), 2.93 -2.87 (m, 1H), 2.85 (s, 3H), 1.67 -1.53 (m, 2H), 1.37 -1.32 (m, 2H), 0.88 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 172.09, 164.7 6, 149.71, 139.19, 128.35, 123.85, 61.12, 49.31, 42.35, 34.75, 23.29, 19.24, 13.65 HRMS analysis (ESI): Calculated for [M+H] +: C 15H21ClN3O4: 342.1221; Found: 342.1229 MeHNClHNOOMeNO2!79 I-2-6-10 Analytical data for substrates E-1b-NO2: N-cinnamyl -4-nitrobenzamide Rf : 0.31 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.28 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.34-7.25 (m, 5H), 7.23(d, J =16.0 Hz, 1H), 6.62 (br s, 1H), 6.59 -6.23 (m, 1H), 4.25 (t, J = 6.5 Hz, 2H) 13C NMR (125 MHz, CDCl 3) # 165.25, 149 .57, 139.90, 136.11, 133.26, 128.65, 128.14, 128.02, 126.39, 124.42, 123.83, 42.44 HRMS analysis (ESI): Calculated for [M+H] +: C 16H15N2O3: 283.1083; Found: 283.1085 E-1d-NO2: (E)-N-(3-(4-fluorophenyl)allyl) -4-nitrobenzamide Rf : 0.30 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.32 (d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.5 Hz, 2H), 7.34-7.31 (m, 2H), 7.01 -6.97 (m, 1H), 7.58 (d, J =15.5 Hz, 1H), 6.28 (br s, 1H), 6.21-6.15 (m, 1H), 4.25 (t, J = 6.0 Hz, 2H) HNONO2HNONO2F!80 13C NMR (125 MHz, CD Cl3) # 165.23, 149.69, 139.91, 132.18, 128.14, 128.02 (d, JCF = 30 Hz) , 124.26 (d, JCF = 7.5 Hz) 123.89, 115.70, 115.53, 42.39 HRMS analysis (ESI): Calculated for [M+H] +: C 16H14FN2O3: 301.0988; Found: 301.0991 E-1c-NO2: (E)-N-(hex -2-en-1-yl)-4-nitrobenzamide Rf : 0.30 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.27 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 6.14 (br s, 1H), 5.72 -5.68 (m, 1H) 5.55 -5.51 (m, 1H), 4.02 (t, J = 6.0 Hz, 2H), 2.03-1.995 (m, 2H), 1.41 -1.37 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.09, 149.58, 140.21, 134.96, 128.08, 124.90, 123.81, 42.35, 34.30, 22.19, 13.65 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17N2O3: 249.1239; Fo und: 249.1243 E-1a-NO2: (E)-N-(3-cyclohexylallyl) -4-nitrobenzamide HNONO2!81 Rf : 0.44 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.27 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 6.12 (br s, 1H), 5.67 -5.50 (m, 1H), 5.48 -5.44 (m, 1H), 4.02 (t, J = 6.0 Hz, 2H), 1.94 (m, 1H), 1.71 -1.54 (m, 5H), 1.28 -1.041 (m, 5H) 13C NMR (125 MHz, CDCl 3) # 165.07, 140.86, 140.22, 128.09, 123.80, 122.26, 116.59, 42.47, 40.36, 32.71, 26.06, 25.93 HRMS analysis (ESI): Calculated for [M+H] +: C 16H21N2O3: 289.1552; Found: 289.1541 E-1e-NO2: (E)-N-(4-(benzyloxy)but -2-en-1-yl)-4-nitrobenzamide Rf : 0.20 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.26 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.32-7.26 (m, 4H), 6.27 (br s, 1H), 5.83 (m, 2H), 4.51 (s, 2H), 4.10-4.01(m, 4H) 13C NMR (125 MHz, CDCl 3) # 165.18, 149.62, 139.91, 137.96, 129.87, 128.42, 128.11, 127.99, 127.76, 127.75, 123.82, 72.66, 69.91, 41.67 HRMS analysis (ESI): Calculated for [M+H] +: C18H19N2O4: 327.1345; Found: 327.1336 HNONO2HNONO2BnO !82 Z-1c-NO2: (Z)-N-(hex -2-en-1-yl)-4-nitrobenzamide Rf : 0.33 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.25 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 6.17 (br s, 1H), 5.63 -5.60 (m, 1H), 5.51 -5.46 (m, 1H), 4.01 (t, J = 6.0 Hz, 2H), 2.12-2.077 (m, 2H), 1.42 -1.39 (m, 2H), 0.90 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 158.14, 142.24, 133.03, 127.60, 120.97, 117.17, 116.67, 30.34, 22.31, 15.46, 6.57 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17N2O3: 249.1239; Foun d: 249.1244 Z-1h-NO2: (Z)-4-nitro -N-(pent -2-en-1-yl)benzamide Rf : 0.35 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.28 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 6.08 (br s, 1H), 5.66 -5.62 (m, 1H), 5.47 -5.43 (m, 1H), 4.12 (t, 6.0 Hz, 2H), 2.17 -2-19 (m, 2H), 1.02 (t, J = 8.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.27, 149.50, 140.10, 136.47, 128.09, 123.79, 123.49, 37.35, 20.76, 14.13 NHONO2NHONO2!83 HRMS analysis (ESI ): Calculated for [M+H] +: C 12H25N2O3: 235.1083; Found: 235.1079 Z-1i-NO2: (Z)-4-nitro -N-(non -2-en-1-yl)benzamide Rf : 0.27 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.27 (d, J = 9.0 Hz, 2H), 7,92 (d, J = 9.0 Hz, 2H), 6.08 (br s, 1H), 5.65 -6.61 (m, 1H), 5.50 -5.47 (m, 1H), 4.11 (t, J =5.5 Hz, 2H), 2.14 (dd, J = 14.0, 7.0 Hz, 2H), 3.46 -3.43 (m, 1H), 1.72 -1.68 (m, 2H), 1.39 -1.25 (m, 8H,) 0.90 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.25, 149.54, 140.11, 135.13, 128.07, 123.99, 123.88, 73.45, 31.67, 29.41, 28.92, 27.46, 22.60, 14.07 HRMS analysis (ESI): Calculated for [M+H] +: C 16H23N2O3: 291.1709; Found: 291.1708 1k-NO2: N-(3-methylbut -2-en-1-yl)-4-nitrobenzamide Rf : 0.30 (30% EtOAc in hexanes, UV) NHONO2HNONO2MeMe!84 1H NMR (500 MHz, CDCl 3) # 8.26 (d, J = 7.5 Hz, 2H), 7.91 (d, J = 7.5 Hz, 2H), 6.08 (br s, 1H), 5.28 (t, J = 5.5 Hz, 1H), 4.03 (t, J = 5.5 Hz, 2H), 1.74 (s, 3H), 1.71 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.95, 149.53, 140.24, 137.71, 128.73, 123.33, 119.29, 38.38, 25.67, 17.96 HRMS analysis (ESI): Calculated for [M+H] +: C 12H15ClN2O3: 235.1083; Found: 235.1085 Z-1b-NO2: (Z)-4-nitro -N-(3-phenylallyl)benzamide Rf : 0.31 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.25 (d, J = 9.0 Hz, 2H), 7.86 (d, J = 9.0 Hz, 2H), 7.37-7.26 (m, 5H), 6.41 (d, J = 11.5 Hz, 1H), 6.22 (br s, 1H), 5.78 -5.73 (m, 1H) 4.39-4.36 (m, 2H) 13C NMR (125 MHz, CDCl 3) # 165.25, 149.62, 139.94, 136.09, 123.62, 128.71, 128.47, 128.08, 127.55, 126.85, 123.81, 38.60 HRMS analysis (ESI): Calculated for [M+H] +: C 16H15N2O3: 283.1083; Found: 283.1091 NHONO2!85 Z-1f-NO2: (Z)-4-nitro -N-(3-(p-tolyl)allyl)benzamide Rf : 0.32 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.26 (d, J = 9 Hz, 2H), 7.87 (d, J = 9 Hz, 2H), 7.17 -7.13 (m, 4H), 6.64 (d, J = 12.0 Hz, 1H), 6.17 (br s, 1H), 5.73 -5.68 (m, 1H) 4.39 -4.36 (m, 1H), 2.34 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.29, 149.47, 139.89, 137.39, 133.13, 132.31, 129.10, 128.62, 128.09, 126.12, 123.17, 38.66, 21.15 HRMS analysis (ESI): Calculated for [M+H] +: C 117H17N2O3: 297.1239; Found: 297.1234 Z-1g-NO2: (Z)-N-(3-(4-methoxyphenyl)allyl) -4-nitrobenzamide Rf : 0.25 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.27 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.61 (d, J = 11.5 Hz), 6.17 (br s, 1H), 5.68 -5.63 (m, 1H), 4.39 -4.36 (m, 2H), 3.80 (s, 3H) 13C NMR (125 MHz, CDCl 3) # 165.29, 158.96, 149.54, 139.94, 132.08, 130.04, 128.59, 128.13, 125.10, 123.80, 113.85, 55.28, 38.68 NHONO2NHONO2MeO !86 HRMS analysis (ESI): Calculated for [M -H]$: C 17H15N2O4: 311.1032; Found: 311.1027 Z-1e-NO2: (Z)-N-(4-(benzyloxy)but -2-en-1-yl)-4-nitrobenzamide Rf : 0.27 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.15 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.33-7.28 (m, 5H), 6.47 (br s, 1H), 5.92 -5-80 (m, 2H), 4.53 (s, 2H), 4.17 (d, J = 16.0 Hz, 2H), 4.11 (t, 2H) 13C NMR (125 MHz, CDCl 3) # 164.96, 149.43, 139.82, 137.63, 130.36, 129.22, 128.60, 128.06, 128.04, 128.00, 123.71, 73.00, 65.85, 37.22 HRMS analysis (ESI): Calculated for [M+H] +: C 18H19N2O4: 327.1345; Found: 327.1350 Z-1j-NO2: (Z)-N-(5-((tert -butyldiphenylsilyl)oxy)pent -2-en-1-yl)-4-nitrobenzamide Rf : 0.35 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) # 8.18 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.66-7.63 (m, 5H), 7.37 -7.24 (m, 5H), 6.02 (br s, 1H), 5.70 -5.67 (m, 1H) 5.62-NHONO2BnO NHONO2TBDPSO !87 5.60 (m, 1H) 4.06 (t, J = 6.5 Hz, 2H), 3.74 (t, J =6.5 Hz, 2H), 2.40 (dt, J = 6.5 Hz, 2H), 1.03 (s, 9H) 13C NMR (125 MHz, CDCl 3) # 165.22, 149.47, 140.02, 135.53, 135.48, 133.75, 131.24, 129.72, 128.02, 127.70, 126.16, 123.80, 123.72, 63.21, 37.41, 30.85, 26.87, 26.77, 19.28 HRMS analysis (ESI): Calculated for [M+H] +: C 28H33N2O4Si: 489.2210; Found: 489.2214 ! !88 I-2-6-11 Analytical dat a for different products of chloroetherification reaction without catalyst !s-5c-OMe -NO2: 3-chloro -2-methoxyhexyl) -4-nitrobenzamide 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 2H), 6.52 (br s, 1H), 4.05 -4.02 (m, 1H), 3.92 -3.86 (m, 1H), 3.63 -3.54 (m, 2H), 3.51 (s, 3H), 1.87 -1.72 (m, 2H), 1.66 -1.59 (m, 1H), 1.47 -1.38 (m, 1H), 0.95 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.49, 149.73, 139.79, 128.11, 123.92, 81,53, 62.18, 59.22, 40.56, 35.49, 19.93, 13.4 s-4c-NO2: 1-chlorobutyl -2-(4-nitrophenyl) -4,5-dihydrooxazole 1H NMR (500 MHz, CDCl 3) # 8.27 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 8.5 Hz, 2H), 4.93-4.89 (m, 1H), 4.22 (dd, J = 15.0, 10.0 Hz, 1H), 4.17 (dd, J = 15.0, 10.0 Hz, 1H), 3.99 -3.97 (m, 1H), 1.85 -1.71 (m, 2H), 1.69 -1.63 (m, 1H), 1.51 -1.45 (m, 1H), 0.97 (t, J =7.5 Hz, 3H) ClOMe HNONO2NONO2Cl!89 13C NMR (125 MHz, CDCl 3) # 162.22, 149.57, 132.98, 129.27, 123,59, 81.69, 62.92, 57.85, 35.51, 19.66, 13.45 HRMS analysis (ESI): Calc ulated for [M+H] +: C 13H16N2O3Cl: 283.0849; Found: 283.0861 Relative stereochemistry was determined by single crystal X -ray diffraction (XRD). Crystals for XRD were obtained by crystallization from CH 2Cl2 layered with hexanes in a silicone -coated vial. a-5c-OMe -NO2: 3-chloro -2-methoxyhexyl) -4-nitrobenzamide 1H NMR (500 MHz, CDCl 3) # 8.29 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 2H), 6.55 (br s, 1H), 4.11 -4.07 (m, 1H), 3.99 -3.95 (m, 1H), 3.56 -3.51 (m, 1H), 3.50 -3.47 (m, 4H), 1.84 -1.79 (m, 1H), 1.69 -1.63 (m, 1H), 1.48 -1.41 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 165.46, 149.63, 139.86, 128.12, 123.89, 81.70, 61.21, 57.93, 39.79, 36.26, 19.96, 13.53 ClOMe HNONO2!90 a-4c-NO2: chlorobutyl -2-(4-nitrophenyl) -4,5-dihydrooxazole 1H NMR (500 MHz, CDCl 3) # 8.26 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.5 Hz, 2H), 4.82-4.77 (m, 1H), 4.21 (dd, J = 16.0, 10.0 Hz, 1H), 4.09 -4.03 (m, 2H), 1.85 -1.83 (m, 1H), 1.69 -1.66 (m, 2H), 1.47 -1.43 (m, 1H), 0.98 (t, J =7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 161.86, 149.54, 133.11, 129.19, 123.59, 82.03, 63.02, 57.96, 35.85, 19.28, 13.49 t-3c-NO2: 5-chloro -2- (4-nitrophenyl) -6-propyl -5,6-dihydro -4H-1,3-oxazine 1H NMR (500 MHz, CDCl 3) # 8.21 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 8.5 Hz, 2H), 4.26 (dt, J = 8.5, 3.0 Hz, 1H), 3.02 -3.94 (m, 2H), 3.70 (dd, J = 16.5, 7.0 Hz, 1H), 1.99-194 (m, 1H), 1.71 -1.64 (m, 2H), 1.55 -1.51 (m, 1H), 1.03 (t, J =7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) # 153.32, 149.22, 138.64, 128.19, 123.30, 78.85, 52.44, 50.48, 34.48, 18.02, 13.84 HRMS analysis (ESI): Calculated for [M+H] +: C 13H16N2O3Cl: 283.0849; Found: 283.0863 NONO2ClNOClNO2!91 Relative stereochemistry was determined by single crystal X -ray diffraction (XRD). 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T., Catalytic Aminohalogenation of Alkenes and Alkynes. ACS Catal. 2013, 3 (6), 1076 -1091. 51. Hennecke, U., A new approach towards the asy mmetric fluorination of alkenes using anionic phase -transfer catalysts. Angew. Chem. Int. Ed. Engl. 2012, 51 (19), 4532 -4534. 52. Denmark, S. E.; Burk, M. T.; Hoover, A. J., On the Absolute Configurational Stability of Bromonium and Chloronium Ions. J. Am. Chem. Soc. 2010, 132 (4), 1232 -1233. 53. Neverov, A. A.; Brown, R. S., Br+ and I+ Transfer from the Halonium Ions of Adamantylideneadamantane to Acceptor Olefins. Halocyclization of 1, %-Alkenols and Alkenoic Acids Proceeds via Reversibly Formed Intermedia tes. J. Org. Chem. 1996, 61 (3), 962 -968. 54. Olah, G. A.; Bollinger, J. M., Stable carbonium ions. 33. Primary alkoxycarbonium ions. J. Am. Chem. Soc. 1967, 89 (12), 2993 -6. 55. Olah, G. A.; Westerman, P. W.; Melby, E. G.; Mo, Y. K., Onium ions. X. Struct ural study of acyclic and cyclic halonium ions by carbon -13 nuclear !98 magnetic resonance spectroscopy. Question of intra - and intermolecular equilibration of halonium ions with haloalkylcarbenium ions. J. Am. Chem. Soc. 1974, 96 (11), 3565 -3573. 56. Ohta, B. K.; Hough, R. E.; Schubert, J. W., Evidence for beta -chlorocarbenium and beta -bromocarbenium ions. Org. Lett. 2007, 9 (12), 2317 -20. 57. Lei, A.; Wu, S.; He, M.; Zhang, X., Highly Enantioselective Asymmetric Hydrogenation of &-Phthalimide Ketone: ' An Effi cient Entry to Enantiomerically Pure Amino Alcohols. J. Am. Chem. Soc. 2004, 126 (6), 1626 -1627. 58. Panzik, H. L.; Mulvaney, J. E., Polyampholyte synthesis by cyclopolymerization. J. Polym. Sci., Part A: Polym. Chem. 1972, 10 (12), 3469 -3487. !99 Chapter II: Highly Regio -and Enantioselective Vicinal Dihalogenation of Allyl Amides II-1 Introduction ! Halogenated natural products represent a class of structurally diverse molecules with some estimates suggesting that greater than 4000 molecules belong to this ever -growing class of natural products. 1-4 They are challenging synthetic targets, at least in part, due to the paucity of methods available to install C-halogen bonds in an enantioselective fashion. The devel opment of enantioselective vicinal dihalogenation of easily accessed alkenes represents a straightforward means of accessing these motifs and avoids circuitous functional group transformations to convert chiral alcohols or epoxides to alkyl halides. With the advent of numerous methodologies for asymmetric halofunctionalization of alkenes in recent years, 5-43 the challenging asymmetric vicinal dihalogenation reaction of alkenes has come into focus. Most of the well -established asymmetric halofunctionalizations reported till date, have achieved enantio selective C -X (X = Cl, Be, I or F) bond formation along with a concomitant formation of a C -O, C -N or even a C -C bond formation depending on the nucleophile employed in intercepting the putative intermediate. In contrast, halide nucleophiles that could lead to dihalogenated products have not been employed with the same levels of success. !100 II-1-1 Racemization of chiral halonium ion by olefin to olefin halenium transfer ! Olefin dihalogenation proceeds in two steps: first the halonium ion is formed f ollowed by subsequent nucleophilic attack to the putative halonium ion, the absolute configuration of the dihalide products is decided during the first step (formation of halonium ion intermediate). For producing chiral halonium ion, the halenium ion trans fers to alkenes from the halogenating agent should be irreversible, and the halonium ion should be stable prior to nucleophilic trapping (Figure II-1). !!A simple difficulty in formation of enantioselective halonium ion is the distance between olefin and chiral catalyst that is covalently or through hydrogen binding associated with the halogen donor. This range arises because the alkene should approach the !* orbita l of the Cat *-X bond. The anticipated coordination geometry for this approach is 180¡. This stereoelectronic approach leads to a Figure II-1: Alkene dihalogenation reaction proceeding by a two -step mechanism !!101 significant distance between the chiral catalyst and the alkene, thus induction of enantioselectivity from the catalyst to alke nes for the formation of chiral halonium ion is difficult (Figure II-2a). Generally, electrophilic species such as osmium tetraoxide that can approach to alkenes with !* orbitals enable more diverse geometries. 15 Therefore, the enantiomeric induction and communication between the catalyst and alkenes is simpler than the first case (Figure II-2a). As we mentioned in Section I-1-2, even if chiral halonium ions can be formed with high enantioselec tivity, these chiral intermediates (especially bromonium ions) are most likely undergo through rapid stereochemical degradation by olefin -to-olefin halonium tion ransfer (Figure II-2b). 44 !!If the chiral halonium ion is formed and the nucleophilic attack event is kinetically more competitive than olefin -to-olefin racemization, still dihalogenation Figure II-2: (a) Challenges in stereochemical communication (b) Racemization via olefin -to-olefin halenium transfer !!102 transformation represents a unique challenge in that a poor regiosele ctivity in the halide opening of the putative chiral halonium ion intermediate can erode the enantioselectivity of the transformation; the two Ôconstitutional isomersÕ resulting from the regioselectivity of the transformation are in fact the two enantiomer s of the product (see Figure II-3). Hence, in addition to exquisite face selectivity in alkene halogenation, excellent control of regioselectivity is also imperative (Figure II-3). It is perhaps not surprising that many of the substrates that have succumbe d to highly enantioselective dihalogenations are electronically biased Ð employing styryl systems leads to an inherent bias for the halide opening at the benzylic position. 15, 45 The development of a catalyst-controlled regioselectivity as opposed to a substrate controlled process holds promise in significantly improving the scope of the transformation and thereby offers an efficient means to synthesizing natural products. !!Figure II-3: Mechanistic challenges for asymmetric dihalogenation !!103 II-1-2 Literature precedence for enantioselective vicinal dihalogenation of alkenes ! A few landmark achievements in dihalogenation chemistry merit mention. SnyderÕs group has reported an enantioselective total synthesis of ( -)-Napyradiomycin II-4 that featured an asymmetric dichlorination of an advanced precursor using chlorine gas and an exce ss of a chiral 1,1 !-biphenanthryl II-3 promoter. 46 Employing four equivalents of chiral dialkoxyboran es forms a chiral 2:1 complex with alkene II-1, subsequent treatment with Cl 2 gas resulted in dichloride product II-2 in 93.5:6.5 er. In the proposed working model, it was suggested that the chiral boran e would co ordinate to carbonyl groups of the precursor and shield one enantioface of the alkene. !104 !!The same group has also reported the asymmetric dichlorination of unfunctionalized olefins with a chiral sulfide compound as a stoichiometric chiral reagent. 46 However, employing the chiral sulfonium salt II-6 in the presence of dihydron aphthalene II-5 in CH 2Cl2 delivers dichlorinated product II-7 in 57% yield but the enantioselectivity is only 57:43 er (Figure II -5). Figure II -4: Stoichiometric, enantioselective dichlorination of alkene en route to ( -)-Napyradiomycin !!105 !! The Nicolaou group reported the first practical, catalytic asymmetric dichlorination of allyl alcohols using the (DHQ) 2PHAL/ArICl 2 (II-10) reagent system. 45 The trans cinnamyl alcohols II-8 produce the dichlorinated product II-9 in moderate to good yield (Figure II -6a). However , cis cinnamyl alcohol s and aliphatic substituted allyl alcoho ls are generally less selective and form the final product with low enantioselectivity. In the stereoinduction model, the author suggests that the quinuclidine nitrogen of the chiral catalyst activates the iodine (III) of the dichlorinating agent II-10. Notably, the potential hydrogen bonding between the hydroxyl group of the substrate and the nitrogen atom of the phthalazine ring of (DHQ) 2PHAL would bring the ally l alcohols in the chiral catalyst Õs binding pocket and produce vicinal dichlorinated products in high enantioselectivities (Figure II -6b). Figure II -5!"" Stoichiometric, enantioselective dichlorination of alkenes by employing chiral sulfonium ion salt !!106 Burns and coworkers demonstrated that cinnamyl alcohols II-11 in the presence of 20 mol% of a chiral dio l (TADDOL) II-13 and dibromomalonate II-14 (as the bromo nium source), and a bromotitanium triisopropoxide (as a bromide source) would deliver dibrominated products II-12 up to 72% yield and 92:8 er.47 Slightly higher enantioselectivities (5 to 10% ee) can b e obtained when one equivalent of TADDOL II-13 was used (Figure II -7). Figure II -6: (a) Asymmetric dichlorination of styryl allyl alcohol (b) Proposed working model !!107 The catalytic cycle for this transformation showed that the ligand exchange on titanium might form the co ordinatively saturated complex II-15, that contain s the substrate, bromide ion, diethyl dibromomalonate II-14 and chiral diol II-13. The species in this complex are arranged in a manner to allow for both intramolecular bromonium delivery and intramolecular bromide capture. Ch arge separation in complex II-16 may increase the nucleophilicity of the bromide, which then can add to bromoniu m ion through transition state II-17 (Figure II-8). Ligand exchange at Ti with i-PrOH is reversible and releases the dibrominated product. In this mechanistic scenario, the authors claimed the bromonium ion formation is reversible, and the bromide delivery is the enantiodetermining step. If that is true, this scenario may manifest itself through dynamic kinetic resolution. However, the authors did mention that the enantiodetermining irreversible Figure II -7: Catalytic enantioselective dibromination of allyl alcohols !!108 bromonium ion formation, or even concerted dibromination step, could not be ruled out with the results in hand. In a further development, the highly regio - and enantioselective vicinal asymmetric chlorobromination of aliphatic allyl alcohols using N -bromosuccinimide/ClTi(O i-Pr)3 reagent system was also reported by the same group. 48 Using 50 mol% of the chiral diol II-13, the chlorobrominated p roducts were produced with 1:2 site selectivity. Interestingly , Schiff base as the chiral catalyst II-18 form s the chlorobrominated product II-20 exclusively (>20:1, see Figure II -8: Proposed catalytic cycle !!109 Table II -1, entry 2 ). Bas ed on these results, II-18 can overturn the intrinsic (substrate control) site selectivity of the chloride io n addition to bromonium ion intermediate. The substrate scope for this regioselective chlorobr omination indicates that using (10 Ð30 mol%) tridentate S chiff base II-18 as catalyst in the p resence of chlorotitanium triis opropoxide forms intermediate II-23. Subsequently , formation of the bromonium ion and nucleophili c attack with chloride would form the chlorobrominatad product II-24 in 89% yield, 96:4 er and >20:1 rr (Figure II -9). Table II -1: Catalyst -controlled regioselective chlorobromination of allyl alcohols !!entry Conditions 20:21 ee% (20), ee% (21) 1 50 mol% II-13, CH2Cl2, rt 1:2 6:8 2 10 mol% II-18, hexane, -20 ¡C >20:1 94,nd !110 For the a pplication of this new method, B urns and coworkers employ ed this enantioselective chlorobromination for the gram -scale total synth esis of (+) -bromochloromyrcene II-28 (Figure II-10).49 It was the first time the asymmetric dihalogenation reaction was used in a total synthesis, and the catalyst -controlled regio site selectivity in the halogenation step is impressive. Figure II -9: Catalytic chemo - regio - and enantioselective bromochlorination of allylic alcohols !!111 After this development in enantioselective dihalogenation reactions, Burns and coworker reported prelim inary results for the catalytic and enantioselective dichlorination of allylic alcohol s that have aliphatic substituents. 50 The formation of vicinal dichlorinated product s is a powerful means of entry to chlorosulfolipids natural products synthesis . In this area dichlorinat ed aliphatic ally l alcohol is known as an essential motif for the synthesis of deschloromytilipin A II-29, mytilip in A II-30, danicalipin A II-31 and malhamensilipin A II-32 (Figure II-11). Due to lack the of enantioselective dichlorination methodology , these natural products are either synthesized in a racemic fashion 51 or in the case of danicalipin A , the kinetic re solution of epoxide opening was use d as a precursor for the formation of chiral vicinal dichloride products. 52 NBS (1.05 equiv) ClTi(O i-Pr)3 (1.1 equiv) II-18 (10-30 mol%) Hexane, -20 ¡C OHClOHBrDMP NaHCO3ClOBrClBrPh3PCH2II-26 82% yield, 84% eeII-28 (+)-bromochloromyrcene II-25 II-27 Figure II-10: Enantioselective synthesis of (+) -bromochloromyrcene !112 In the developed enantioselective dichlorination of aliphatic allyl alcohols, the tert-butyl hypochlorite ( t-BUOCl) was used as the Cl + source. 50 However, the chiral catalyst and halide sources were the sam e as in other reports. As s hown in Figure II -12, allyl alcohol II-33 produces the corresponding dichlorinated product II-34 in 95:5 er by employing 30 mol% Schiff base II-18. In this transformation, t-BuOCl and ClTi(O i-Pr)3 were used as chloronium and chloride sources, respectively. Figure II -11: Structure of chlorosulfolipid natural products !!113 Notably, these results indicate the first regio -enantioselective dihalogenation of unbiased (non -aryl -substituted) alkenes, but s till, two shortcomings are apparant with these methodologies; 1: the enantioselectivities for dichlorination of the aliphatic alcohol s are moderate (around 81% ee); 2: the hydroxy l group was used as the chiral catalyst -directing group. Thus , this transformation could only be use d for the alkenes that are tethered to the hydroxyl group. With these shortcomings in mind , I sought to develop highly a regio -, diastereo - and enantioselective dihalogenation methodologies for alkenes. II-2 Results an d discussions II-2-1 Catalyst -controlled regioselectivity in enantioselective haloetherification reaction ! As discussed in Chapter I, our group has recently reported a highly enantioselective intermolecular haloetherif ication and haloesterificati on reaction of unsaturated amides (Figure II -13).29 One of the key feature s of the transformation was the excellent catalyst -controlled regioselectivity that renders a wide variety of alkyl -substituted alkenes as compatible substrates for the chemistry . Figure II -12: Example of asymmetric alkene dichlorination PhOHt-BuOCl (1.05 equiv) ClTi(O i-Pr)3 (1.1 equiv) II-18 (30 mol%) Hexane, -20 ¡C PhOHClClII-33 II-34 61% yield, 95:5 er !114 To figure out if the enantioselective chloroetherification methodology can extend to catalytic enantioselective dihalogenation reactions, we designed the control experiment to indicate whether the cataly st dictates the regioselectivity for the haloetherification reactions . The chloroetherification reaction of Z-allyl amide II-35 was conducted in optimized condition s without (DHQD) 2PHAL as the chiral catalyst. In line with desired product II-36, the regioi somer product II-37 and cyclized product II-38 were formed in the ratio of 57:16:27, respectively (Table II-2, entry 1). However employing (DHQD) 2PHAL produce d chloroetherified pro duct II-36 with high selectivity ( Table II-2, entry 2). Figure II -13: Catalytic asymmetric intermolecular halohydrin formation, haloetherification and haloesterification R2NuCl/Br R1HNOArR1HNArOR210 mol% (DHQD) 2PHAL 2.0 equiv DCDMH or NBS Nucleophile:MeCN (3:7), 0.01 M, -30 oC H2O:MeCN (1:9), -10 oCAr = 4-NO 2-PhR1, R2 = H, Ar, Alk >25 examples up to > 99.5:0.5 dr, er, rrNucleophile: R-OH, R-CO 2H or H 2O!115 Notably, the same control experiment was conducted with E-allyl amide II-39 and in this case a mixture of regioisomers ( II-40, II-41) and cyclic products ( II-42, II-43) were formed in the ratio of 43:15:26:16 , respectively (Table II-3, entry 1). Interestingly, when the chira l catalyst is employed, the desired chloroetherified product II-40 forms in high selectivity (87%, Table II-3, entry 2). Noteworthy is the fact that the chiral catalyst is responsible not o nly for the high enantioselectivities but also for the exquisite regioselectivity for the reactions employing aliphatic substrates (for example, noncatalyzed reactions gave rr values of ~4:1 for substrate II-35 and 3:2 for substrate II-39). These results h int at extensive pre -organization of the substr ateÐnucleophile Ðcatalyst complex in Table II -2: Catalyst -controlled regioselectivity in chloroetherification reactions of Z -allyl amide II-35 "HNArOC3H7OMe ClHNArOcatalyst 2.0 equiv DCDMH MeOH:MeCN (3:7) 0.01 M, rt, 3 h NOArC3H7Cl+C3H7ClOMe HNArOC3H7II-35 II-36 II-37 II-38 Entry Catalyst II-36:II-37:II-38a rr (II-36:II-37) a 1 None 57:16:27 4:1 2 10% (DHQD) 2PHAL 96:4:0 24:1 aRegioselectivity and ratio of uncyclized to cyclized products were determined by HPLC !!116 addition to the halogen source catalyst H -bonded complex that we have previously established. II-2-2 Extension of haloetherification to the enantioselective dihalogenation of alkenes ! Based on these results, w e reali zed the potential to extend the asymmetric chloroetherification chemistry to the enantioselective dihalogenation of alkenes by discovering an appropriate halide salt to intercept the same halonium putative intermediate (Figure II -14). Table II -3!"Catalyst -controlled regioselectivity in chloroetherification reactions of E-allyl amide II-39 ""Entry Catalyst II-40:II-41:II-42:II -43a rr (II-40:II-41) a 1 None 43:15:26:16 3:2 2 10% (DHQD) 2PHAL 87:4:7:2 10:1 aRegioselectivity and ratio of uncyclized to cyclized products were determined by HPLC !117 Our studies commenced with identifying conditions that could transform II -35 to II -44. Pilot studies indicated that the best enantioselecti vities were seen when MeCN or CF 3CH2OH (TFE) was used as the solvent. It should be noted that competing intermolecular processes such as interception of the intermediate by the solvent leads to side products II -45 (from TFE incorporation) or II -47 (the Ritter product when CH 3CN is employed). Also, the intramolecular halocyclization path yields the oxazoline II -46 as a side product. Our initial screening of reaction conditions had to not only deliver the desired dihalogenated products in acceptable yields an d enantioselectivity, but also avoid the production of side products II -45-II-47 (see Table II -4). Numerous chloride sources were evaluated for this test reaction in the presence of 2.0 equivalents of DCDMH, 10 mol% of (DHQD) 2PHAL and acetonitril e (ACN) as a solvent. Initially, soluble quaternary ammonium chloride salts were evaluated. Disappointingly, a mixture of products with a marginal preference for the desired product II -44 as a racemate were produced (II -44:II-46 HNArOR1NuCl/Br HNArO10 mol% (DHQD) 2PHAL Cl or Br Nucleophile: R-OH, R-CO 2H or H 2OR2R1R2>25 examples up to >99% dr, rr, eeR1,R2 = Ar, Alk, H (DHQD) 2PHAL Cl or Br Nucleophile: XXCl/Br HNArOR1R2?Figure II-14: Pote ntial to extend asymmetric chloroetherification chemistry to the enantioselective dihalogenation reaction !118 =55:45, 50:50 er, Table II-4, entry 1). Use of NaCl predominantly produces the Ritter product II -47 (Table II-4, entry 2). Encouragingly, LiCl fared much better despite its sparing solubility in organic solvents. Reactions run at ambient temperature with 15 equivalents of LiCl gave significant amounts of the chlorocyclized by -product II -46 (II -44:II-46 = 79:21, Table II-4, entry 3). Lowering the temperature to -30 ¡C gave the dichlorinated product exclusively (II -44:II-46 = 95:5 and 92:8 er, entry 4); although encouraging, this result gave significantly lower enantioselectivity for other substrates (see Table II-5, in Section II -2-5). Further experimentation revealed that employing trifluoroethanol (CF 3CH2OH, TFE) as the reaction s olvent gave reproducibly exquisite enantioselectivity for the desired product, albeit at the expense of the product yield (ca. 40%) due to the formation of II -45 (Table II-4, entry 5). Formation of by -product II -45 could be greatly mitigated by simply incr easing the stoichiometry of LiCl from 15 to 100 equiv (>20:1 II -44:II-45, Table II-4, entry 7). These results were particularly surprising given the low solubility of LiCl in TFE (ca. 20 mg/mL). !119 II-2-3 Dichlorination of allyl amides in acetonitrile Using acetonitrile as the solvent for dichlorination of II-54A produced the corresponding product II-54B in moderate yield and ster eoselectivity (entry 1, Table II -5). Under the same conditions II-39B was formed in high yield and diastereoselectivity (99:1 dr) albeit in low enantioselectivity (61.5:38.5 er, entry 2, "!!!!!!"!!!!!!Entry Solvent Conc Temp (¡C) XCl XCl (equiv) 44:45:46:47a 1 MeCN 0.02 23 TEAC 15 55:0:45:0 2 MeCN 0.02 23 NaCl 15 0:0:13:87 3 MeCN 0.02 23 LiCl 15 79:0:21:0 4 MeCN 0.02 -30 LiCl 15 95:0:5:0 5 TFE 0.02 -30 LiCl 15 45:56:0:0 6 TFE 0.02 -30 LiCl 50 86:14:0:0 7 TFE 0.02 -30 LiCl 100 95:5:0:0 9 TFE 0.40 -30 LiCl 100 95:5:0:0 aDetermined by NMR ; TFE = 2,2,2 -trifluoroethanol; TEAC = Tetraethylammonium chloride !C3H7ClClHNArOHNArOC3H7OTFEClHNArOII-44 II-45 II-35 Ar = 4-NO 2PhC3H7(DHQD) 2PHAL 10 mol% DCDMH (2.0 equiv) XCl, Temp Solvent (0.02 M) NOArC3H7ClII-46 C3H7NHClHNArOII-47 OTable II-4: Summary of optimization studies for dichlorination !120 Table II -5). However, performing the dichlorination reaction in trifluroethanol (TFE) gave a significant improvement in stereoselectivity of II-54B and II-39B (>99:1 er and 93:7 er, respectiv ely, see Figure II -15 and II -16 in Section II-2-5-1 and II-2-5-2). II-2-4 Role of the counterion of chloride in selectivity of dichlorination reactions ! Intrigued by the effect of solid LiCl, we investigated the role of the counterion un der the optimized conditions with various chloride salts that have a wide range of solubilities in TFE. The fully soluble tetraethylammonium chloride (TEAC) produced a mixture of products with a marginal preference for the desired product II -44 in high ena ntioselectivity (93:7 er, Table II-6, entry 2). Treating compound II -35 with sparingly soluble NaCl in TFE (0.03 M solubility) returned predominantly the TFE incorporated product II -45 (Table II-6, entry 3). !Entry R1 R2 Prod %Yield a/dr erb 1 H Ph II-54B 59/>6.3:1 91:9 2 C3H7 H II-39B 89/>99:1 61.5:38.5 aCombined yield, Determined by NMR; bDetermined by chiral HPLC !Table II-5: Dichlorination of allyl amides in acetonitrile !!121 These results are in complete contrast with LiCl (entry 1), which delivers the desired product in high chemo - and enantioselectivity. CsCl, exhibiting similar solubility as LiCl in TFE (0.53 M for CsCl vs. 0.40 M for LiCl) also fails to delive r the product in high selectivity, yielding a nearly 1:1 ratio of II -44:II-45. From these results, it is evident that while solubility of the chloride source might be an important factor that dictates product distribution, the counterion is equally importa nt. Additionally, the presence of undissolved LiCl is also essential for good selectivity. Finally, we ruled out the possibility that in-situ generated Cl 2 gas might be the active chlorenium and chloride source; in this instance very low selectivity was ob served for the desired product (Table II-6, entry 5). Numerous control experiments suggest that these reactions likely occur at the solid -liquid interface. These experiments are discussed later in the chapter. !122 II-2-5 Substrate scope for asymmetric dichlorination reaction !II-2-5-1 Substrate scope for Z -allyl amide in asymmetric dichlorination reaction ! Mapping the generality of the dichlorination reaction, numerous cis -substituted allyl amides were examined under the optimized conditions (0.02 M substrate concentration in TFE, 100 equivalents LiCl and 2.0 equivalents of Entry XCl Solubility (mol/lit) XCl (equiv) 44:45:46:47a eeb(5) 1 LiCl 0.40 100 95:5:0:0 92:8 2 TEAC Fully soluble 100 66:34:0:0 93:7 3 NaCl 0.03 100 0:89:11:0 nd 4 CsCl 0.54 100 55:44:3:0 95:5 5c Cl2 (gas) nd Gas 16:43:41:0 50:5 0 aDetermined by NMR; bDetermined by chiral HPLC; cCl2 gas was generated in situ and bubbled into the reaction; TFE = 2,2,2 -trifluoroethanol; TEAC = Tetraethylammonium chloride Table II -6: Role of chloride counter ion in selectivity of the dichlorination reaction C3H7ClClHNArOHNArOC3H7OTFEClHNArOII-44 II-45 II-35 Ar = 4-NO 2PhC3H7(DHQD) 2PHAL 10 mol% DCDMH (2.0 equiv) XCl, Temp Solvent (0.02 M) NOArC3H7ClII-46 C3H7NHClHNArOII-47 O!123 DCDMH at -30 oC). Dichlorination of Z-aliphatic amides exhibit high diastereoselectivity (Figure II-15, see II -44 and II -48B to II -52B, >99:1 dr). The identity of the benza mide motif had little influence on the enantioselectivity of this reaction; products II -44 and II -48B were both formed in 99.5:0.5 er (Figure II-15, entries 1 and 2). The other Z-alkyl substituted olefins afforded dichlorinated products in complete diaster eo- and enantioselectivity (see II -49B, II -50B). The benzyloxysubstituted alkene II -51A gave lower enantioselectivity (88.5:11.5 er). Aryl -substituted Z-olefins gave corresponding products in high enantioselectivity and regioselectivity (>97:3 er and >99:1 rr, Figure II-15, see II -53B-II-55B). The diastereoselectivities and yields for these entries are varied (1.7:1 to >20:1 dr and 35% to 88% yield); as expected reduced diastereoselectivity was seen with increasing benzylic cation stabilization. The poor yi eld for substrate II -53A is attributed to the formation of cyclized and TFE incorporated products, while the moderate yield for compound II -54B is due to the formation of TFE incorporated product. Nonetheless, the trifluoromethyl substituted olefin II -55A afforded the dichlorinated product with exquisite yield and stereoselectivity (88% yield, >99:1 dr, 99.5:0.5 er, Figure II-15, entry 9). !124 Figure II-15: Substrate scope for Z-allyl amides in dichlorination reaction a,b !!125 II-2-5-2 Substrate scope for E-allyl amide in asymmetric dichlorination reaction ! Trans aliphatic substituted olefins showed high level of diastereoselectivity (>99:1 dr, see II -39B, II -56B and II -57B). Changing the 4 -bromobenzamide motif to the 4 -nitrobenzamide gave identical results (~91:9 er, ~80 % yield, see II -39B, II-56B). The benzyloxy protected substrate II -57A formed dichlorinated product in 85% yield and 89:11 er (Figure II-16, II -57B). Compound II -58A, with aryl substituent on the alkene gave moderate yield (due to competing production of cyclized and TFE -incorporated products) and moderate enantioselectivity for product II -58B (63% yield, 90:10 er, Figure II-16). Trisubstituted alkene II -59A was also compatible with this chemistry and returned the desired product in 73% yield and 92:8 er. It warrants emphasis that for trisubstituted and aryl -substituted olefins, a higher substrate concentration (0.20 M) is requi red for mitigating the formation of TFE incorporated by -product (see Section II -2-6 for concentration studies). !126 II-2-5-3 Substrate scope for dichlorination reaction with quasi-enantiomeric (DHQ) 2PHAL catalyst ! The quasi -enantiomeric catalyst, (DHQ) 2PHAL, transformed two substrates (II -35, II -39A) to the corresponding enantiomeric products in comparable yield and selectivity (Figure II -17, ent-II-44 and ent-II-39B). This Figure II-16: Substrate scope for Z-allyl amides in dichlorination reaction a, b !127 quasi -enantiomeric catalyst forms the mirror image products with similar yields and enantioselectivities when (DHQD) 2PHAL was used (see Figure II -15 and II -16). II-2-5-4 Substrate scope for regio - and enantioselective hetero -dihalogenation ! Gratifyingly, this chemistry also delivers vicinal dibrominated and chloro -brominated products with high stereoselectivity. Treating II -35 in TFE (0.2 M) with 100 equivalents LiCl as the chloride source and 2.0 equivalents of NBS as the aIsolated yield on a 0.1 mmol scale; bEnantioselectivity determined by chiral HPLC R2HNArOClHNArOClII-35 , II-39A R = H, Ar, Alk Ar = 4-NO 2Ph, C3H7ClClHNArOent-II-44 , ent-II-39B ent-II-44 94% yield 99:1 dr98:2 er10 mol% (DHQ) 2PHAL DCDMH (2.0 equiv) LiCl (100 equiv) TFE 0.02 M, -30 ¼C C3H7ClClHNArOent-II-39B 80% yield 99:1 dr96:4 erR2R1R1Figure II-17: Substrate scope for dichlorination reaction with quasi -enantiomeric (DHQ) 2PHAL catalyst a, b !128 bromenium source gave II -35C in 97% yield and 99.5:0.5 er (Figure II-18, entry 1). Using LiBr in conjunction with NBS gave the dibrominated product II -35CÕ in 90% yield and 84:16 er (Figure II-18, entry 2). Z-aromatic olefin II -55A returned chlorobrominated product II -55C in 96% yield with high stereoselectivity (99.5:0.5 er and >99:1 dr, see II -55C, Figure II-18). The chlorobromination of E-amides II -39 and II -58A formed desired products II -39C and II -58C in high diastereoselectivity and good enantioselectivity. The yield for aromatic substrate II-58A suffers due to the formation of the cyclized product (58%, see II -58C, Figure II-18). Ther e are solvent and equilibrium optimization studies for hetero -dihalogenation that will be discussed in Section II -2-7. !129 Figure II-18: Regio- and enantioselective hetero -dihalogenationa, b II-2-6 Influence of reaction concentration on the yield for the dic hlorination of unsaturated aromatic and trisubstituted allyl amides ! The d ichlorination of aromatic allyl amides ( II-54A, II-58A) in optimized concentration (0.02 M) produced the mixture of dichlorinated product and chloroetherification side product in moderate yield and high diastereoselectivity (entries 1 and 2, Table II -7). aIsolated yield on a 0.1 mmol scale; bEnantioselectivity determined by chiral HPLC XHNArOBrR2R1R1HNArOII-35 , II-55A, II-39, II-58A R1, R2 = H, Ar, Alk Ar = 4-NO 2PhR210 mol% (DHQD) 2PHAL NBS (2.0 equiv) LiCl or LiBr (100 equiv) TFE 0.02 M, -30 ¼C C3H7HNArOBrC3H7HNArOClBrII-35C Õ90% yield >99:1 dr84:16 erII-55C 96% yield >99:1 dr 99.5:0.5 erII-35C 97% yield >99:1 dr 99.5:0.5 erBrp-F3C-Ph ClBrHNArOC3H7HNArOClBrII-39C 85% yield >99:1 dr 92:8 erPhHNArOClBrII-58C 58% yield >99:1 dr 89:11 erII-35C II-35C Õ, II-55C, II-39C, II-58C !130 Table II -7: Dichlorination of aromatic and trisubstituted allyl amides "Entry R1 R2 Conc Prod %Yield a/drb B:D 1 H Ph 0.02 II-54B 55c/10:1 4.2:1 2 Ph H 0.02 II-58B 40c/32:1 2.8:1 3 Me Me 0.02 II-59B 44c/na 1:1.8 4 H Ph 0.2 II-54B 62c/15.6:1 15.6:1 5 Ph H 0.2 II-58B 63c/53:1 5.3:1 6 Me Me 0.2 II-59B 73c/na 4.4:1 aYield determined by NMR; bDiastereo selectivity determined by chiral HPLC; cRest of mass balance is TFE incorporated product The trisubstituted olefin II-59A formed the desired product II-59B in 44% yield (see entry 3, Table II-7). The mass balance for these reactions was TFE -incorporated side product II-(54, 58, 59) D. In an attempt to increase the yield and chemoselectivity for these substrates II-(54, 58, 59) A, the reaction was performed at a higher concentration (0.2 M). The higher concentration resulted in higher yields and diastereoselectivities of the desired pro ducts (see entries 4, 5 and 6, Table II-7). 10 mol% (DHQD) 2PHAL 2.0 equiv DCDMH 100 equiv LiCl, TFE M, -30 oCII (54, 58, 59) A Ar = 4-NO 2PhII (54, 58, 59) B II (54, 58, 59) D R1HNR2R2ClClR1HNOOArR2OCH2CF3ClR1HNOArAr!131 II-2-7 Influence of solvents and equivalents of lithium chloride on the chlorobromination reactions Table II -8: Optimization of chlorobromination reactions "Entry Solvent Temp equiv of LiCl C:Ea er (II-35 C)b 1 ACN rt 30 1.0:1.0 76:24 2 ACN -30 100 4.5:1.0 76:24 3 ACN -30 300 4.9:1.0 76:24 4 TFE -30 100 >99:1 98:2 aThe ratio of products , Determined by NMR; bDetermined by chiral HPLC Treating allyl amide II-35 in ACN (0.2 M) with 30 equivalents of LiCl as the chloride source and 2 equivalents of NBS as the bromenium source gave a mixture of products II-35C:II-35E in ratio of 1:1 with 76:24 er for the desired product II-35C (entry 1, Table II -8). Using higher equivalents of LiCl slightly increased the chemoselectivity in favor of dihalogenated product II-35C (entries 2 and 3, Table II -8). Interestingly, performing the chlorobromination reaction in TFE as solvent forms product II-35C with exquisi te chemoselectivity and enantioselectivity (98:2 er, entry 4, Table II -8). C3H7ClBrHNArO(DHQD) 2PHAL (0.10 equiv) NBS (2.0 equiv) LiCl, Temp solvent (0.2 M) NOArC3H7BrHNArOII-35 Ar = 4-NO 2PhC3H7II-35 C II-35 E !132 II-2-8 Various hale nium and halide sources for the enantioselective dihalogenation of unsaturated amides were used !!Table II-9: Regio- and enantioselective dihalogenation !Entry X-source X+ source X1 X2 Prod %Conv %Yield a erb 1 LiCl NBS Cl Br 35C 100 97 98:2 2 LiBr NBS Br Br 35CÕ 100 90 84:16 3 LiBr DCDMH Br Br 35CÕ 100 96 77:23 4 LiF DCDMH F Cl 45 100 nd nd 5 LiI NIS I I - 0 nd nd 6 LiI DCDMH I Cl - 0 nd nd aYield determined by NMR; bEnantioselectivity determined by chiral HPLC !! Treating II-35 (0.2 M ) in TFE with 100 equivalents of LiCl as the chloride source and 2.0 equivalents of NBS as the bromonium source produced II-35C in 97% yield and 98:2 er. With this result in hand we attempted to form the other regioisomer by changing the X - and X + source. U LiBr and NBS formed the dibrominated product II-35CÕ in 90% yield and 84:16 er (Table II -9, entry 2). Surprisingly, employing LiBr and DCDMH led to the dibrominated product II-35CÕ instead of the ch lorobrominated product (Table II -9, entry 3). This observation suggests that in the presence of LiBr, DCDMH is converted to DBDMH, or otherwise generates a bromonium. This has led us to devise a simple proc edure for the synthesis of a variety of bromenium sources from their corresponding II-35 Ar = 4-NO 2PhII-35C II-35C ÕC3H7X1X2HNArOHNArO(DHQD) 2PHAL (0.10 equiv) X source (2.0 equiv) X source (100 equiv) , TFE 0.4 M, -30 oCC3H7C3H7OTFEClHNArOII-45 !133 chlorenium containing parents. These results will discuss in Section II -2-11. Employing LiF as a fluoride source failed to yield chlorofluorinated product and instead return ed the TFE incorporated product II-45 in high yield (Table II -9, entry 4). Lithium iodide does not lead to any product and starting material was recovered (Table II -9, entries 4 and 5). II-2-9 Product distribution arising due to substrate -control and catal yst-control for the dichlorination reactions Table II -10: Product distribution in catalyzed and non -catalyzed dichlorination reactions !Entry Catalyst Ratio (C:D:E )a Regioselectivity a er (II-48C)b 1 None 52:24:24 2:1 50:50 2 (DHQD) 2PHAL 90:5:5 18:1 94:6 aThe ratio of products and regioselectivities, Determined by NMR.; b Enantioselectivity determined by chiral HPLC The dihalogenation reaction without any catalysts gave 3 major products. As shown in the NMR trace (Figure II -19) for the crude reaction, along with the desired product II-48C, the regioisomer II-48D and the cyclized product II-48E LiCl, (100 equiv) TFE 0.02 M, rt cat 2.0 equiv NBS NOBrC3H7BrC3H7ClBrHNArOHNArOII-48 Ar = 4-BrPh C3H7II-48C C3H7BrClHNArOII-48D II-48E !134 were also formed in a ratio of 52:24:24 (Table II -10, entry 1). On the other hand, employing (DHQD) 2PHAL as the chiral catalyst at ambient temperature gave the desired product in significantly higher selectivity with 9 4:6 enantioselectivity (Table II -10, entry 2). These results demonstrate that the chiral catalyst is not only responsible for high enantioselectivity but also for the ex quisite regioselectivity seen for reactions employing aliphatic substrates. "II-2-10 Control experiments indicating that dichlorination reaction occurs on LiCl solid surface II-2-10-1 Screening selectivity ratio with different concentrations ! The fact that these reactions required up to 100 equiv of LiCl for optimal resul ts was counterintuitive given the sparing solubility of LiCl in organic solvents. Additionally, a significant amount of the added LiCl remained undissolved during the reaction and could be recovered at the end. In order to determine whether ##$%&' ""#$%!&'()'* +,(-. !##$%&( "##$%&) ""#$%/0$!&'()'* +,(-. !Figure II -19: NMR trace for product distribution in catalyzed and non -catalyzed chlorobromination reaction !135 suspended LiCl plays a role in this reaction and if indeed the reaction is occurring on a solid -liquid interface, two sets of control experiments were executed. In the first set of experiments, a saturated solution of LiCl in TFE (0.47 M concentration) was prepared and e mployed in dichlorination reactions with different substrate concentrations (Table II-11, entries 1 -4). Two key observations were made. First, all reactions gave similar product ratios regardless of the substrate concentration or the substrate:LiCl ratio ( 5.8-6.6:1 ratio of II -44:II-45). Second, the ratio of II -44:II-45 was significantly worse than that observed under optimized reaction conditions that employed a large excess of LiCl (>20:1 II -44:II-45); i.e. reactions run in the presence of suspended/undis solved LiCl were significantly more selective (Table II-10, entry 5). !136 Table II-11: Screening selectivity ratio in different concentrations Entry TFE (mL) Conc. ( 35) Conc. (LiCl) LiClb (equiv) 44:45a 1 0.5 0.20 0.47 (soluble) 2 5.8:1 2 0.5 0.08 0.47 (soluble) 5 6.6:1 3 2 0.02 0.47 (soluble) 20 6.4:1 4 7 0.006 0.47 (soluble) 67 6.2:1 5 2 0.02 2.0 (insoluble) 100 >20:1 aRatio determined by NMR; b0.47 M solution of LiCl in TFE was prepared by saturating TFE with LiCl, filtering the undissolved LiCl and determining the molarity of the dissolved salt from the difference in mass of recovered LiCl. II-2-10-2 Effect of rate of stirring (RPM s tudies) on the selectivity of dichlorination reaction A second set of control experiments was performed to probe mixing and mass -transfer effects. The stirring speed was altered, first in the soluble regime (15 equiv of LiCl, 0.3 M in LiCl) and then in the insoluble regime. The stirring speed had a remarkable effect on product distribution. In the absence of any stirring (0 rpm) significant amount of by -product II -45 was formed (II -44:II-45= 1:1, Table II-12, entry 1). At 100 and 300 rpm, this ratio improve d to 3.5:1 (entries 2 and 3, Table II-12). In the insoluble regime (100 equiv of LiCl, 0.02 M substrate concentration, entries 4 Ð 7, Table II-12) this effect was even more pronounced. C3H7ClClHNArOHNArOC3H7OTFEClHNArOII-44 II-45 C3H7(DHQD) 2PHAL 10 mol% DCDMH (2.0 equiv) LiCl, 23 ¼CTFE (0.02 M) II-35 Ar = 4-NO 2Ph!137 At 0 rpm, the ratio of II -44:II-45 was 1.5:1. Increasing the rate of st irring to 300 rpm gave the desired product almost exclusively (95% yield, II -44:II-45 = >20:1, Table II-12, entry 5). With a further increase in substrate concentration to 0.20 M, the effects of mass transfer became less pronounced (II -44:II-45 = >20:1 at 0 rpm as well as at 300 rpm, see entries 6 and II-7 in Table II-12). The combination of results from Tables II-6, II-11 and II-12 highlighting the requirement for a Li cation, and also the dependence on the heterogeneous nature of the reaction, strongly su ggests that success in greatly limiting the TFE incorporated side produ ct II -45 is due to the reaction preceding at the liquid -solid interface. !138 Table II -12: Effect of rate of stirring (RPM studies) in selectivity of the dichlorination reaction entry Conc RPM equiv (LiCl) Yield 44:45a,b 1 0.02 0 15 95 1.0:1.0 2 0.02 100 15 88 3.5:1.0 3 0.02 300 15 90 3.5:1.0 4 0.02 0 100 90 1.5:1.0 5 0.02 300 100 95 >20:1 6 0.20 0 100 82 >20:1 7 0.20 300 100 87 >20:1 aRatio determined by NMR; b1% to 3% of cyclized product was seen by NMR. II-2-10-3 Effect of LiCl particle size on product distribution of the dichlorination reaction The suggested role of so lid LiCl on the reaction would presume that particle size should have an influence on the reaction outcome. To pro be the role of insoluble LiCl on the olefin dichlorination reaction, different particle sizes of lithium chloride were produced by sequential sieving through different mesh screens. This was accomplished by taking the salt parti cles that passed from a higher mesh size screen (for example 850 mm) and were trapped onto a smaller mesh size screen (such as 300 mm). In the latter example, the particle sizes are C3H7ClClHNArOHNArOC3H7OTFEClHNArOII-44 II-45 C3H7(DHQD) 2PHAL 10 mol% DCDMH (2.0 equiv) LiCl, 23 ¼CTFEII-35 Ar = 4-NO 2Ph!139 between 850 mm to 300 mm. The mesh ranges in Table II -13 refer to sequen tial sieving with two different mesh screens as described above. The reactions were ran with 50 equivalents of LiCl in each case, since with larger excess the II-58B:II-58D ratio would have been less pronounced (at 100 equivalents the majority of the prod uct is the desired II-58B). As anticipated for a reaction that is dependent on reaction at the solid interface, LiCl particle size makes a difference in the ratio of products. Entry 1, with the largest particle sizes yields the worst ratio of II-58B:II-58D (62:38). As the particle sizes become progressively smaller, the ratio favors the desired II-58B product, which is presumably aided by the reaction taking place at the solid interface. We would anticipate that the reaction to yield II-58D (incorporation of the solvent) is independent of the solid and occurs in the soluble phase. These results corr oborate the RPM studies (Table II -12), which also highlights that the dichlorination reaction is aided by the presence of the solid LiCl, suggestive of the fact that the reaction could occur on solid -liquid interface 1!!!!!!!140 Table II-13: Effect of LiCl particle size on product distribution of the dichlorination reaction "Entry a LiCl particle size ( " m) b Ratio (B:D)c 1 850-300 62:38 2 300-150 66:34 3 150-53 66:34 4 53-45 74:26 aFor all reactions, 50% of the product was the intramolecularly cyclized compound; bLiCl was ground to powder and was sieved to obtain different particle sizes.; cDetermined by NMR II-2-10-4 Effect of 12 -crown-4 ether on product distribution of dichlorination reactions 12-Crown -4 ether is a specific scavenger for lithium cation, yielding a more soluble chloride in the reaction mixture. In the presence of 15 equivalents of LiCl at ambient temperature the desired product II-44 was formed predominantly ( II-44:II -45 = 77:23, Table II -14, entry 1). Adding 12 -crown -4 ether formed II-44 with diminished selectivity; in presence of 3 equivalents of 12 -crown -4 ether the ratio of II-44:II -45 decreased to 68:32 (Table II -14, entry 2). Employing 20 equivalents of crown ether in presence of 50 equivalants of LiCl gave a mixture of products in worse selectivity (61:39 II-44:II -45, Table II -14, entry 6). These results are in line with other control experiments (RPM studies, LiCl particle size) demonstrate that ArHNOPhClClArHNOPhClOCH2CF3ArHNOPh10 mol% (DHQD) 2PHAL 2.0 equiv DCDMH 50 equiv LiCl TFE 0.04 M, rt II-58A Ar = 4-NO 2PhII-58B II-58D !141 insoluble LiCl plays an important role for obtaining high selectivity for dichlorination reactions. Table II -14: Effect of 12 -crown -4 ether on product distribution of dichlorination reactions !Entry Equiv of LiCl Equiv of Crown ether Ratio (44:45)a 1 15 0 77:23 2 15 1 72:28 3 15 3 68:32 4 50 0 89:11 5 50 5 86:14 6 50 20 61:39 aDetermined by NMR II-2-11: A new unprecedented transformation for the synthesis of N -haloimides revealed by side product identification in hetero -dihalogenation ! During exploring substrate scope for hetero -dihalogenation reaction interesting observations leads us to Expedient access to N -bromo - and N -iodoimides from the corresponding N -chloroimides. II-2-11-1 The importance of N -haloimides !C3H7ClClHNArOHNArOC3H7OTFEClHNArOII-44 II-45 C3H7II-35 Ar = 4-NO 2PhLiCl, 12-crown-4 TFE 0.02 M, rt 10 mol% (DHQD) 2PHAL 2.0 equiv DCDMH !142 N-haloimides are among the most widely employed electrophilic halogenating reagents in both academia and industry. These reagents serve as stable and easily handled sources of halogen atoms and often obviate the need to use more corrosive reagents such as molecular chlorine, bromine or iodine. Among this diverse family of reagents, N -bromo and N -iodo imides are particularly useful owing to the higher reactivity of the resulting bromide or iodide products. The typical example, 1,3 -dibromo -5,5-dimethyl-hydantoin (DBDMH), has been employed in radi cal bromination reactions ,53 electrophilic aromatic bromination, 47, 54 oxidation of thiol to disulfides 55 and most recently in enantioselective bromofu nctionalization of alkenes .56 Moreover, DBDMH is used as an active antimicrobial agent; AviBrom ¨ and BoviBrom ¨ are two processing aids tha t are used for disinfection of beef. Is also more prefered over the corresponding chlorinated counterparts as adisinfectant and bactericide for water sources and food industries because its efficien cy is less sensitive to pH . II-2-11-2 Currently used methods for producing N -haloimides ! Two prominent methods are currently used for the synthesis of N -haloimides Ð 1) Treating the parent imide with molecular bromine or iodine in the presence of a strong base such as sodium hydroxide. Although st raightforward, this process is often limited to production facilities that are capable of producing Br2 or I 2 due to the high cost and hazards associated with the transportation and storage of the highly corrosive reagents .57 2) In situ generation of Br 2 or I 2 using readily available bromide or iodide salts by treating with a strong oxidant. While !143 this process avoids handling molecular Br 2 or I 2, the hazardous nature of the oxidants (such as H 2SO4, H 2O2, persulfate salts, Oxone, etc) often preclude the use o f such processes on scale (Figure II -20). 58 Figure II-20: Currently used methods for producing N -haloimides In this Section , we propose an alternative and cost -effective means of generating the N -haloimides in situ by reacting readily available and stable N -Chloroimides with inorganic bromide or iodide salts (LiBr, LiI). This process of in -situ transformation of N -chloroimide s to the corresponding N -bromo or N -iodo imides is unprecedented. Also, all the reagents are easily handled and shelf -stable. II-2-11-3 Highly regio- and enantioselective vicinal dihalogenation of allyl amides As mentioned earlier in this Chapt er, we reported the enantioselective vicinal dihalogenation of allyl amides in the presence of (DHQD)2PHAL as a chiral organocatalyst. An electrophilic halenium (X +) donor along with lithium halide (X -) is needed for completion of this transformation. The employing of large excess (100 equivalents) of lithium halide is essential to obtain high selectivity and yield, it was indicated that reaction occurs on solid surface of Lithium halide. This methodology is compatible with E and Z alkenes with both NHNaOH, I2 or Br2NBr/ IOOOOOr NaOH, halide salt, oxidant !144 aryl an d aliphatic substituents. Various examples of dihalogenated and heterodihalogenated products was evaluated with up to 97% yield and >99.5:0.5 er (Figure II -21). Figure II -21: Highly regio - and enantioselective vicinal dihalogenation of allyl amides II-2-11-4 Identification of a hetero -dihalogenation reactionÕs side product In addition to vicinal dichlorination and dibromination, we were also able to demonstrate heterodihalogenation i.e. bromo -chlorination of the allyl amide. Specifical ly, when II-35 was treated with LiCl as the nucleophilic chloride source and DBDMH as the source of electrophilic bromine, chloro - brominated product II-35C was formed in 97% yield. In an effort to reverse the regiochemistry, we switch ed the halide source to LiBr and the electrophilic halogen donor to DCDMH for accessing bromo -chlorinated product II-35D (regioisomer of II-35C). The reaction did not proceed as planned; instead the dibrominated product II-35CÕ was isolated in 96% yield (Figure II -22a). We su rmised that DCDMH must have reacted with LiBr to afford DBDMH in -situ. We were able to confirm this via NMR. When DCDMH was treated with a slight excess of LiBr in CD 3CN, a rapid and quantitative formation of DBDMH was seen based on 13C NMR. It occurred R1HNArOCl/Br HNArOR1Cl/BrR1, R2 = H, Ar, Alk Ar = 4-NO 2PhR2R2up to 97% yield, 99.5:9.5 19 examples 10 mol% (DHQD) 2PHAL DCDMH or NBS (2.0 equiv) LiCl or LiBr (100 equiv) TFE 0.02 M, -30 ¼C !145 to us that this might represent a general route to access a variety of N -bromoimides from the corresponding N -chloroimides. !!II-2-11-5 Substrate scope for expedient synthesis of N -bromo- and N-iodoimides from the corresponding N -chloroimides Four of the most commonly employed N -bromoimides were accessed from the corresponding N -chloroimides i n high yields. As shown in Figure II -23, DBDMH was isolated in quantitative yield by addition of LiBr to suspended Figure II -22: (a) Regioselective chloro -bromination of allyl amides (b) LiBr -mediated transformation of DCDMH to DBDMH n-C3H7HNArOII-35 Ar = 4-NO 2Ph(DHQD) 2PHAL (0.1 equiv) NBS (2.0 equiv) LiCl(100.0 equiv) , rt TFE (0.2 M) C3H7ClBrHNOArII-35C 97% yield C3H7BrClHNO(DHQD) 2PHAL (0.1 equiv) DCDMH (2.0 equiv) LiBr (100.0 equiv) , rt TFE (0.2 M) Arn-C3H7HNArOII-35 Ar = 4-NO 2PhII-35D Regioisomer of II-35C C3H7BrBrHNOArII-35CÕ 96 % yield Not Observed NNOClClNNOOBrBr2 LiBr 2 LiClOII-60 DCDMH II-60A DBDMH CD3CNab!146 DCDMH in Acetonitrile. The reaction was complete in 1 hour at ambient temperature. Isolation of the product involved a routine aqueous work -up/extraction protocol fol lowed by recrystal lization from EtOAc -Hexanes. This methodology was general. Various N -bromoimides were synthesized by employing LiBr in >90% yield (see products II-60A-II-63A, Figure II -23). !Figure II-23: Substrate scope for formation of N -bromo and N-iodoimidea, b We then turned our attention to potentially accessing N -iodoimides using an analogous approach. With well -documented stability issues , an expedient access to N -iodoimides from the corresponding shelf -stable N -chloroimides would represent an attractive alternative to freshly recrystallizing these reagents NClNNOOBrBrLiBr or LiI (2.2 or 1.1 equiv) ACN (0.5 M) rt, 1 hr NNOOIIII-60B c: 82% yield II-60A c: 100% yield NBr/ INOOBrNOOIII-61A d: 95% yield II-61B d: 92% yield OOOONOOBrII-62A d: 95% yield NOOIII-62B d: 90% yield II-60 - II-62 II-60(A, B) - II-62(A, B) aIsolated yield. bThe reactions were conducted on 10 mmol scales c2.2 equivalents of LiBr or LiI were used. d1.1 equivalents of LiBr or LiI were used !147 prior to use. To our delight, employing LiI in lieu of LiBr affords the N -Iodoimides in high yields ( II-60B-II-62B, Figure II -23). The only by -product formed in this process is LiCl. This is of particular relevance to the synthesis of N -iodoimides Ð all commercial processes to N -iodoimides produce stoichiometric quantities of inorganic iodide waste (I 2/NaOH system). Most water treatment facilities have strict specifications for iodide conten t owing to the numerous adverse effects of inorganic iodides on aquatic and terrestrial organisms. The process is rapid and quantitative in most cases that have been examined thus far. II-2-12 Conclusion !In conclusion, we report an experimentally expedie nt dihalogenation reaction that is catalyzed with (DHQD) 2PHAL, yielding products in high yield and enantioselectivity. Exquisite catalyst controlled regioselectivity has allowed for a broad substrate scope that includes alkyl and aryl substituted allyl amides. The stereochemistry of the double bond is of little conseq uence, as good results are obtained with both E and Z olefins. Of particular interest is the role of LiCl, the chloride source for the reaction. Our exhaustive screening demonstrated TFE as the optimal choice for solvent, although its incorporation as the nucleophile in the reaction was initially a problem. Use of excess LiCl drastically reduces the TFE incorporated side product. Our preliminary investigations strongly suggest not only a role for the solid salt in solution, but also for the presence of Li s alt in particular, for the success of this transformation. Mechanistic investigations are !148 underway to further elaborate the nature of interactions, presumably at the solid/liquid interface, that lead to the observed effects. We report the unprecedented and expedient transformation for generating the N -bromo and N -iodoimides by reacting readily available and stable N -chloroimides with inorganic bromide or iodide salts (LiBr, LiI). All reagents are easily handled, readily available and shelf stable. The trans formation is rapid, hi gh-yield and operationally straightforward. II-2-13 Experimental section II-2-13-1 General information Commercially available reagents were purchased from Sigma -Aldrich or Alfa -Aesar and used as received. CH 2Cl2 and aceton itrile were freshly distilled over CaH 2 prior to use. THF was distilled over sodium -benzophenone ketyl. All other solvents were used as purchased. LiCl and LiBr were purchased from Sigma -Aldrich; the particle size of LiCl and LiBr were <850 mm. 1H and 13C NMR were recorded on 500 MHz Varian NMR machines using CDCl 3 as solvent and were referenced to residual solvent peaks. Flash silica gel (32 -63 mm, Silicycle 60 †) was used for column chromatography. The sieves for obtaining different mesh size of LiCl w ere purchased from H&C sieving systems. Enantiomeric excess for all products was determined by HPLC analysis using DAICEL CHIRALCEL ¨ OJ-H and OD -H or CHIRALPAK ¨ IA and AD -H columns. Optical rotations of all products were measured in chloroform. Allyl amide s II-35, II -39, II -!149 (48 to 59)A (except II-55A) were synthesized as reported previously. 29 Analytical data for byproducts II-46 and II-47 were also reported in the same reference. II-2-13-2 General procedure for catalytic asymmetric dichlorination of unsaturated amides The substrate (0.1 mmol, 1.0 equiv) and LiCl (420 mg, 10 mmol, 100 equiv, reagent grade, <850 mm particle size) were suspended in trifluoroethanol (TFE, 5.0 mL) in a screw -capped 20 mL vial equipped with a micro stir bar (7 # 2 mm). The resulting suspensi on was cooled to -30 ¡C in an immersion cooler. (DHQD) 2PHAL (7.8 mg, 10 mol%) was then introduced. After stirring for 2 min DCDMH (39.5 mg, 0.2 mmol, 2.0 equiv) was added. The stirring at 300 RPM (as indicated by the stirrer) was continued at -30 ¡C till t he reaction was complete (TLC). The reaction was quenched by the addition of saturated aq. Na 2SO3 (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 ! 4 mL). The combined organics were dried over anhydrous Na 2SO4 and concentrated in the presence of small quantity of silica gel. Column chromatography (SiO 2/EtOAc Ð Hexanes gradient elution) gave the desired product. II-2-13-3 Procedure for gram scale scope analysis for catalytic asymmetric dichlorination of unsaturated amides in presence of 1% of chiral catalyst II-35 (1.0 g, 4.0 mmol, 1.0 equiv) and LiCl (17 g, 100 equiv) were suspended in trifluoroethanol (TFE, 20.0 mL) in a round -bottom flask equipped with a stir bar. The resulting susp ension was cooled to -30 ¡C in an immersion !150 cooler. (DHQD) 2PHAL (32.0 mg, 1.0 mol%) was then introduced. After stirring for 2 min DCDMH (1500 mg, 8.0 mmol, 2.0 equiv) was added. The stirring in >300 RPM was continued at -30 ¡C till the reaction was complete (TLC). The reaction was quenched by the addition of saturated aq. Na 2SO3 (20 mL) and diluted with DCM (15 mL). The organics were separated and the aqueous layer was extracted with DCM (3 ! 15 mL). The combined organics were dried over anhyd. Na2SO4 and concentrated in the presence of silica gel. Column chromatography (SiO 2/EtOAc Ð Hexanes gradient elution) gave the desired product in 91% yield and 98:2 enantioselectivity. II-2-13-4 Procedure for gram scale scope analysis for synthesis of N -bromo- and N-iodoimides from the corresponding N -chloroimides. The substrate II-35 (5 mmol, 1.0 gr) was suspended in acetonitrile (ACN, 10 ml). LiBr (2.2 equiv, 0.95 gr) was then introduced. After stirring for 1 hour, the reaction was quenched by the addition of water (10 mL) and diluted with EtOAC (10 mL). The mixture was extracted with EtOAC (3 ! 5 mL), and organic layer concentrated to half of the volume. Following by addition of 5 ml water and extraction with EtOAC (1 ! 5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to the third quarter of the volume. At last, 10 ml of hexane was added to crude and cooled down in fridge to obtain crystalline product 6 in 100% yield. This methodology is general and the same procedure were used for producing various N -Bromo and Iodoimide !151 II-2-13-5 Analytical data for products !II-44: N-((2S,3S)-2,3-dichlorohexyl) -4-nitrobenzamide Rf : 0.60 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.30 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 6.52 (br s, 1H), 4.41 -4.38 (ddd, J = 9.5, 4.5, 2.5 Hz, 1H), 4.18 -4.15 (ddd, J = 9.0, 4.5, 2.0 Hz, 1H), 4.13 -4.07 (ddd, J = 14.0, 7.5, 4.5 Hz, 1H), 3.66 -3.61 (ddd, J = 13.5, 8.5, 5.0 Hz, 1H), 1.93 -1.80 (m, 2H), 1.62 -1.54 (m, 1H), 1.46 -1.38 (m, 1H), 0.96 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.77, 149.81, 139.27, 128.22, 123.96, 63.49, 62.76, 44.92, 37.45, 19.67, 13.40 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17Cl2N2O3: 319.0616; Found: 319.0609 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 8.3 min, RT2 (minor) = 10.8 min. ["]D20 = +47.1 (c 0.65, CHCl 3, er = >99:1) Absolute stereochemistry was determined by single crystal X -ray diffraction (XRD). Crystals for XRD were obtained by crystallization from CH 2Cl2 layered with hexanes in a silicone -coated vial. HNONO2ClCl!152 ent-II-44: N-((2R,3R)-2,3-dichlorohexyl) -4-nitrobenzamide Rf : 0.60 (30% EtOAc in hexanes, UV) 94% yield with (DHQ) 2PHAL 1H NMR (500 MHz, CDCl 3) $ 8.30 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 6.52 (br s, 1H), 4.41 -4.38 (ddd, J = 9.5, 4.5, 2.5 Hz, 1H), 4.18 -4.15 (ddd, J = 9.0, 4.5, 2.0 Hz, 1H), 4.13 -4.07 (ddd, J = 14.0, 7.5, 4.5 Hz, 1H), 3.66 -3.61 (ddd, J = 13.5, 8.5, 5.0 Hz, 1H), 3.66 -3.61(m, 1H), 1.93 -1.80 (m, 2H), 1.62 -1.54 (m, 1H), 1.46-1.38 (m, 1H), 0.96 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.77, 149.81, 139.27, 128.22, 123.96, 63.49, 62.76, 44.92, 37.45, 19.67, 13.40 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17Cl2N2O3: 319.0616; Found: 319.0607 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 8.6 min, RT2 (major) = 11.0 min. ["]D20 = -45.3 (c 1.0, CHCl 3, er = 98:2) HNONO2ClCl!153 II-48B: 4-bromo -N-((2S,3S)-2,3-dichlorohexyl)benzamide Rf : 0.60 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 9.0 Hz, 2H), 6.48 (br s, 1H), 4.40 -4.37 (ddd, J = 9.0, 4.5, 2.5 Hz, 1H), 4.17 -4.14 (ddd, J = 9.0, 4.5, 2.5 Hz, 1H), 4.14 -4.03 (ddd, J = 14.0, 7.0, 4.5 Hz, 1H), 3.64 -3.59 (ddd, J = 14.0, 8.5, 5 Hz, 1H), 1.93 -1.79 (m, 2H), 1.61 -1.53 (m, 1H), 1.45 -1.38 (m, 1H), 0.94 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 166.82, 132.56, 131.96, 128.57, 126.68, 63.62, 62.82, 44.82, 37.55, 19.66, 13.40 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17Cl2NOBr: 351.9871; Found: 351.9865 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 6.7 min, RT2 (minor) = 10.4 min . ["]D20 = +40.5 (c 0.8, CHCl 3, er = >99:1) II-49B: N-((2S,3S)-2,3-dichloropentyl) -4-nitrobenzamide HNOBrClClHNONO2ClCl!154 Rf : 0.50 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.30 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 6.61 (br s, 1H), 4.43 -4.40 (ddd, J = 8.5, 4.0, 2.5 Hz, 1H), 4.12 -4.05 (m, 2H), 3.67 -3.62 (ddd, J = 14.0, 9.5, 5.5 Hz, 1H), 1.96 -1.90 (m, 2H), 1.06 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.77, 149.82, 139.27, 128.23, 123.97, 64.77, 63.17, 44.95, 28.94, 11.21 HRMS analysis (ESI): Calculated for [M+H] +: C 12H15Cl2N2O3: 305.0460; Found: 305.0450 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 9.9 min, RT2 (minor) = 11.3 min. ["]D20 = +36.6 (c 0.6, CHCl 3, er = >99:1) II-50B: N-((2S,3S)-2,3-dichlorononyl) -4-nitrobenzamide Rf : 0.60 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.30 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 6.63 (br s, 1H), 4.41 -4.38 (ddd, J = 9.0, 4.0, 2.0 Hz, 1H), 4.16 -4.07 (m, 2H), 3.66 -3.61 (ddd, J = 14.0, 9.0, 5.5 Hz, 1H), 1.90 -1.85 (m, 2H), 1.57 -1.50 (m, 1H), 1.40 -1.18 (m, 7H), 0.88 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.77, 149.81, 139.28, 128.22, 123.95, 63.46, 63.10, 44.93, 35.52, 31.52, 28.59, 26.37, 22.50, 14.01 HNONO2ClCl!155 HRMS analysis (ESI): Calculated for [M+H] +: C 16H23Cl2N2O3 361.1086; Found: 361.1077 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 6.6 min, RT2 (minor) = 8.0 min. ["]D20 = +27.4 (c 0.7, CHCl 3, er = >99:1) II-51B: N-((2S,3S)-4-(benzyloxy) -2,3-dichlorobutyl) -4-nitrobenzamide Rf : 0.50 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.28 (d, J = 9.0 Hz, 2H), 7.90 (d, J = 9.0 Hz, 2H), 7.36-7.29 (m, 5H), 6.65 (br s, 1H), 4.67 -4.63 (ddd, J = 8.0, 5.0, 2.0 Hz, 1H), 4.57 (s, 2H), 4.29 (dt, J = 7.0, 2.5 Hz 1H), 4.07 -4.02 (ddd, J = 14.0, 7.5, 5.0 Hz, 1H), 3.78 (d, J = 6.5 Hz, 2H), 3.76 -3.70 (ddd, J = 14.0, 8.5, 5.0 Hz, 1H) 13C NMR (125 MHz, CDCl 3) $ 165.60, 149.75, 139.33, 137.13, 128.58, 128.21, 128.13, 127.87, 123.91, 73.77, 70.61, 60.12, 59.61, 44.46 HRMS analysis (ESI): Calculated for [M+H] +: C 18H19Cl2N2O4: 397.0722; Found: 397.0717 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 14.7 min, RT2 (minor) = 17.4 min. ["]D20 = +27.1 (c 0.55, CHCl 3, er = 89:11) HNONO2ClClBnO !156 II-52B: N-((2S,3S)-5-((tert -butyldiphenylsilyl)oxy) -2,3-dichloropentyl) -4-nitrobenzamide Rf : 0.60 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.29 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 2H), 7.64-7.60 (m, 4H), 7.42 -7.34 (m, 6H), 6.57 (br s, 1H), 4.60 (ddd, J = 9.0, 3.5, 2.5 Hz, 1H), 4.48 -4.45 (ddd, J = 8.5, 5.0, 2.5 Hz, 1H), 4.09 -4.04 (ddd, J = 14.5, 7.5, 5.5 Hz, 1H), 3.88 -3.83 (m, 1H), 3.79 -3.71 (m, 2H), 2.15 -2.09 (m, 1H), 2.06 -1.99 (m, 1H), 0.98 (s, 9H) 13C NMR (125 MHz, CDCl 3) $ 165.67, 149.80, 139.27, 135 .50, 135.46, 133.21,133.14, 129.81, 129.80, 128.20, 127.77, 127.75, 123.95, 63.38, 59.81, 59.49, 44.73, 38.29, 26.79, 19.17 HRMS analysis (ESI): Calculated for [M+H] +: C28H33Cl2N2O4Si: 559.1605; Found: 559.1609 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 7% IPA -Hexanes, 0.8 mL/min, 254 nm, RT1 (minor) = 12.5 min, RT2 (major) = 13.3 min. ["]D20 = +21.8 (c 0.45, CHCl 3, er = >99:1) Syn-II-53B: N-((2S,3S)-2,3-dichloro -3-(p-tolyl)propyl) -4-nitrobenzamide HNONO2ClClTBDPSO !157 Rf : 0.60 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.28 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 6.50 (br s, 1H), 5.13 (d, J = 5.5 Hz, 1H), 4.56 -4.53 (m, 1H), 4.10 -4.05 (ddd, J = 14.5, 7.5, 4.0 Hz, 1H), 3.50 -3.44 (ddd, J = 13. 5, 9.0, 5.0 Hz, 1H), 2.34 (s, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.49, 149.80, 139.30, 139.25, 133.79, 129.42, 128.17, 127.67, 123.92, 65.11, 64.35, 44.30, 21.18 HRMS analysis (ESI): Calculated for [M+H] +: C 17H17Cl2N2O3: 367.0614; Found: 367.0616 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 13.4 min, RT2 (minor) = 20.4 min. ["]D20 = -19.4 (c 0.4, CHCl 3, er = 97:3) Anti -II-53B: N-((2S,3R)-2,3-dichloro -3-(p-tolyl)propyl) -4-nitrobenzamide Rf : 0.60 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.30 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 6.50 (br s, 1H), 4.99 (d, J = 8.0 HNONO2ClClHNONO2ClCl!158 Hz, 1H), 4.58 -4.54 (m, 1H), 4.49 -4.44 (ddd, J = 14.0, 6.5 , 3.5 Hz, 1H), 3.67 -3.62 (ddd, J = 13.5, 8.0, 5.0 Hz, 1H), 2.34 (s, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.42, 149.80, 139.39, 139.27, 134.56, 129.50, 128.21, 127.62, 123.92, 64.08, 63.55, 43.90, 21.21 HRMS analysis (ESI): Calculated for [M+H] +: C 17H17Cl2N2O3: 367.0614; Found: 367.0619 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 14.9 min, RT2 (major) = 18.2 min. ["]D20 = +4.0 (c 0.3, CHCl 3, er = 91:9) II-54B: N-((2S,3S)-2,3-dichloro -3-phenylpropyl) -4-nitrobenzamide Rf : 0.50 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.29 (d, J = 9.0 Hz, 2H), 7.88 (d, J = 9.0 Hz, 2H), 7.47-7.35 (m, 5H), 6.50 (br s, 1H), 5.18 (d, J = 5.0 Hz, 1H), 4.59 -4.55 (m, 1H), 4.14-4.01 (ddd, J = 14.0, 7.5, 4.0 Hz, 1H), 3.52 -3.46 (ddd, J = 14.0, 8.5, 4.5 Hz, 1H) 13C NMR (125 MHz, CDCl 3) $ 165.53, 149.81, 139.21, 136.71, 129.23, 128.71, 128.17, 127.80, 123.94, 64.97, 64.25, 44.38 HRMS analysis (ESI): Calculated for [M+H] +: C 16H15Cl2N2O3: 3 53.0460; Found: 353.0452 HNONO2ClCl!159 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 13.5 min, RT2 (minor) = 27.6 min. ["]D20 = -11.3 (c 0.6, CHCl 3, er = >99:1) II-55B: N-((2S,3S)-2,3-dichloro -3-(4-(trifluoromethyl)phenyl)propyl) -4- nitrobenzamide Rf : 0.43 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.30 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H), 7.66 (d, J = 9 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 6.59 (br s, 1H), 5.27 (d, J = 4.5 Hz, 1H) 4.60 -4.56 (m, 1H), 4.19 -4.14 (ddd, J = 14.5, 7.0, 4.0 Hz, 1H), 3.55 -3.50 (ddd, J = 14.5, 8.5, 4.0 Hz, 1H) 13C NMR (125 MHz, CDCl 3) $ 165.75, 149.87, 140.55, 139.02, 131.38 (q, JCF = 32.2 Hz), 128.35, 128.20, 127.2 (q, JCF = 271.6 Hz), 125.63 (q, JCF = 2.8 Hz), 123.99, 64.30, 63.03, 44.62 HRMS analysis (ESI): Calculated for [M+H] +: C 17H14Cl2N2O3F3: 421.0322; Found: 421.0334 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 10.5 min, RT2 (minor) = 19.1 min. ["]D20 = -5.2 (c 1.0, CHCl 3, er = >99:1) HNONO2ClClF3C!160 II-39B: N-((2S,3R)-2,3-dichlorohexyl) -4-nitrobenzamide Rf : 0.56 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.31 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 6.55 (br s, 1H), 4.40 -4.35 (ddd, J = 14.0, 7.0, 3.0 Hz, 1H), 4.28 -4.24 (ddd, J = 10.0, 6.5, 3.0 Hz, 1H), 4.09 -4.05 (ddd, J = 10.0, 6.5, 3.5 Hz, 1H), 3.59 -3.54 (ddd, J = 14.0, 8.5, 5.0 Hz, 1H), 2.04 -1.97 (m, 1H), 1 .85-1.80 (m, 1H), 1.68 -1.61 (m, 1H), 1.49 -1.44 (m, 1H), 0.97 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.54, 149.79, 139.43, 128.21, 123.96, 64.00, 63.59, 43.66, 37.21, 19.30, 13.41 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17Cl2N2O3: 319.0616 ; Found: 316.0610 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 13.0 min, RT2 (minor) = 14.5 min. ["]D20 = +16.6 (c 0.5, CHCl 3, er = 92:7) ent-II-39B: N-((2R,3S)-2,3-dichlorohexyl) -4-nitrobenzamide Rf : 0.56 (30% EtOAc in hexanes, UV) 80% yield with (DHQ) 2PHAL HNONO2ClClHNONO2ClCl!161 1H NMR (500 MHz, CDCl 3) $ 8.31 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 6.55 (br s, 1H), 4.40 -4.35 (ddd, J = 14.0, 7.0, 3.0 Hz, 1H), 4.28 -4.24 (ddd, J = 10.0, 6.5, 3.0 Hz, 1H), 4.09 -4.05 (ddd, J = 10.0, 6.5, 3.5 Hz, 1H), 3.59 -3.54 (ddd, J = 14.0, 8.5, 5.0 Hz, 1H), 2.04 -1.97 (m, 1H), 1.85 -1.80 (m, 1H), 1.68 -1.61 (m, 1H), 1.49 -1.44 (m, 1H), 0.97 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.54, 149.79, 139.43, 128.21, 123.96, 64.00, 63.59, 43.66, 37.21, 19.30, 13.41 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17Cl2N2O3: 319.0616; Found: 319.0611 Resolution of enantiomers: DAICEL Chiralcel ¨ OD-H column, 5 % IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 13.0 min, RT2 (major) = 14.5 min. ["]D20 = -15.2 (c 1.0, CHCl 3, er = 96:4) II-56B: 4-bromo -N-((2S,3R)-2,3-dichlorohexyl)benzamide Rf : 0.54 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 7.65 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 9.0 Hz, 2H), 6.45 (br s, 1H), 4.36 -4.31 (ddd, J = 14.0, 7.0, 3.0 Hz, 1H), 4.26 -4.23 (m, 1H), 4.10-4.04 (ddd, J = 10.0, 6.5, 3.5 Hz, 1H), 3.54 -3.38 (ddd, J = 13.5, 8.0, 4.0 Hz, HNOBrClCl!162 1H), 2.00 -1.95 (m, 1H), 1.88 -1.80 (m, 1H), 1.68 -1.59 (m, 1H), 1.51 -1.42 (m, 1H), 0.95 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 166.58, 132.73, 131.95, 128.53, 126.60, 64.31, 63.70, 43.47, 37.18, 19.35, 13.42 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17Cl2NOBr: 351.9871; Found: 351.9863 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 8.4 min, RT2 (minor) = 9.5 min. ["]D20 = +12.4 (c 0.9, CHCl 3, er = 92:8) II-57B: N-((2S,3R)-4-(benzyloxy) -2,3-dichlorobutyl) -4-nitrobenzamide Rf : 0.50 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.26 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.5 Hz, 2H), 7.37-734, 5H), 6.63 (br s, 1H), 4.63 -4.56 (dd, J = 22.5, 12.0 Hz, 2H), 4.54 -4.50 (ddd, J = 10.5, 6.5, 4.5 Hz, 1H), 4.25 -4.17 (m, 2H), 3.88 (d, J = 5 Hz, 2H), 3.78 -3.73 (ddd, J = 14.0, 8.0, 5.5 Hz, 1H) 13C NMR (125 MHz, CDCl 3) $ 165.38, 149.71, 139.41, 137.13 128.60, 128.18, 128.13, 127.85, 123.88, 73.78, 70.75, 61.05, 60.37, 43.53 HNOONO2ClCl!163 HRMS analysis (ESI): Calculated for [M+H] +: C 18H19Cl2N2O4: 397.072 2; Found: 397.0725 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 16.1 min, RT2 (major) = 17.6 min. ["]D20 = +5.1 (c 0.3, CHCl 3, er = 89:11) II-58B: N-((2S,3R)-2,3-dichloro -3-phenylpropyl) -4-nitrobenzamide Rf : 0.44 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.29 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.43-7.35 (m, 5H), 6.56 (br s, 1H), 5.02 (d, J = 8 Hz, 1H), 4.59 -4.55 (dt, J = 11, 3.5 Hz, 1H), 4.49 -4.44 (ddd, J = 14.5, 7.0, 3.5 Hz, 1H), 3.67 -3.62 (ddd, J = 13.5, 8.5, 5.0 Hz, 1H) 13C NMR (125 MHz, CDCl 3) $ 165.47, 149.77, 139.36, 137.47, 129.22, 128.79, 128.21, 127.75, 123.91, 63.98, 63.55, 43.89 HRMS analysis (ESI): Calculated for [M+H] +: C 16H15Cl2N2O3: 353.0460; Found: 353.0462 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 20% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 10.5 min, RT2 (major) = 11.6 min. ["]D20 = +5.6 (c 1.0, CHCl 3, er = 90:10) HNONO2ClCl!164 II-59B: (S)-N-(2,3 -dichloro -3-methylbutyl) -4-nitrobenzamide Rf : 0.50 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.30 (d, J = 9.0 Hz, 2H), 7.95 (d, J = 9.0 Hz, 2H), 6.63 (br s, 1H), 4.58 -4.53 (ddd, J = 10.5, 7.5, 3.0 Hz, 1H), 4.24 (dd, J = 9.5, 3.0 Hz, 1H), 3.47-3.41 (ddd, J = 14.5, 10.0, 4.5 Hz, 1H), 1.78 (s, 3H), 1.70 (s, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.57, 149.78, 139.51, 128.22, 123.97, 69.68, 69.44, 43.36, 31.29, 28.47 HRMS analysis (ESI): Calculated for [M+H] +: C 12H15N2O3Cl2: 305.0460; Found: 305.0446 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 2% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 113.4 min, RT2 (minor) = 130.4 min. ["]D20 = +42.4 (c 0.8, CHCl 3, er = 92:8) HNOMeNO2ClClMe!165 II-35C: N-((2S,3S)-2-bromo -3-chlorohexyl) -4-nitrobenzamide Rf : 0.52 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.31 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 6.62 (br s, 1H), 4.52 -4.50 (ddd, J = 9.0, 4.0, 2.0 Hz, 1H), 4.17 -4.12 (ddd, J = 15.0, 7.5, 4.5 Hz, 1H), 4.08 -4.05 (m, 1H), 3.75 -3.70 (ddd, J = 14.0, 9.0, 5.0 Hz, 1H), 1.93 -1.84 (m, 2H), 1.62 -1.54 (m, 1H), 1.46 -1.38 (m, 1H), 0.96 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.68, 149.82, 139.29, 128.23, 123.99, 62.70, 57.52, 45.25, 38.51, 19.67, 13.40 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17ClNO3Br: 363.0111; Found: 363.0107 Resolution of enantiomers: DAICEL Chiralcel ¨ OD-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 4.7 min, RT2 (major) = 14.7 min. ["]D20 = +54.3 (c 0.5, CHCl 3, er = >99:1) Absolute stereochemistry was determined by single crystal X -ray diffraction (XRD). Crystals for XRD were obtained by crystallization from CH 2Cl2 layered with hexanes in a silicone -coated vial. HNONO2BrCl!166 II-35C': N-((2S,3S)-2,3-dibromohexyl) -4-nitrobenzamide Rf : 0.60 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.31 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 6.61 (br s, 1H), 4.50 -4.47 (ddd, J = 9.0, 4.0, 2.5 Hz, 1H), 4.23 -4.15 (m, 2H), 3.75 -3.69 (ddd, J = 14. 5, 9.0, 5.5 Hz, 1H), 1.99 -1.93 (m, 2H), 1.62 -1.56 (m, 1H), 1.45 -1.40 (m, 1H), 0.96 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.64, 149.82, 139.27, 128.23, 123.98, 57.50, 56.06, 45.94, 38.68, 20.75, 13.26 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17N2O3Br2: 406.9606; Found: 406.9603 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 14.7 min, RT2 (minor) = 17.9 min. ["]D20 = +32.7 (c 0.4, CHCl 3, er = 83.0:17.0) HNONO2BrBr!167 II-55C: N-((2S,3S)-2-bromo -3-chloro -3-(4-(trifluoromethyl)phenyl)propyl) -4-nitrobenzamide Rf : 0.60 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.29 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 9 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 6.63 (br s, 1H), 5.29 (d, J = 4.0 Hz, 1H) 4.69 -4.65 (m, 1H), 4.25 -4.20 (ddd, J = 14.5, 7.0, 4.0 Hz, 1H), 3.65 -3.59 (ddd, J = 14.5, 9.0, 5.0 Hz, 1H), 13C NMR (125 MHz, CDCl 3) $ 165.68, 149.85, 140.77, 139.04, 131.57 (q, JCF = 32.1 Hz), 128.2 9, 128.19, 126.77 (q, JCF = 271.8 Hz), 125.57 (q, JCF = 3.7 Hz), 123.99, 63.03, 57.82, 44.98 HRMS analysis (ESI): Calculated for [M+H] +: C 17H14ClBrN 2O3: 468.9827; Found: 468.9828 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 11.5 min, RT2 (minor) = 21.7 min. ["]D20 = +2.5 (c 1.0, CHCl 3, er = >99:1) II-39C: N-((2S,3R)-2-bromo -3-chlorohexyl) -4-nitrobenzamide HNONO2ClBrF3CHNONO2BrCl!168 Rf : 0.50 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.30 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 6.62 (br s, 1H), 4.41 -4.35 (m, 2H), 4.15 -4.11 (ddd, J = 10.0, 7.0, 3.5 Hz, 1H), 3.69-3.63 (ddd, J = 15.0, 10.0, 5.5 Hz, 1H), 2.08 -2.02 (m, 1H), 1.91 -1.83 (m, 1H), 1.68-1.60 (m, 1H), 1.52 -1.44 (m, 1H), 0.967 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.46, 149.77, 139.44, 128.22, 123.95, 63.76, 57.32, 44.11, 38.22, 19.32, 13.38 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17ClN2O3Br: 363.0111; Found: 363.0103 Resolution of enantiomers: DAICEL Chiralcel ¨ IA column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 13.7 min, RT2 (minor) = 15.0 min. ["]D20 = +6.6 (c 1.0, CHCl 3, er = 92:8) II-58C: N-((2S,3R)-2-bromo -3-chloro -3-phenylpropyl) -4-nitrobenzamide Rf : 0.50 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.30 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.42-7.35 (m, 5H), 6.57 (br s, 1H), 5.08 (d, J = 9.5 Hz, 1H), 4.68 -4.64 (dt, J = 12.0, 3.5 Hz, 1H), 4.56 -4.51 (ddd, J = 14, 6.5, 3.0 Hz, 1H), 3.81 -3.75 (ddd, J = 14.0, 8.0, 5.5 Hz, 1H), HNONO2ClBr!169 13C NMR (125 MHz, CDCl 3) $ 165.35, 149.80, 139.39, 138.30, 129.24, 128.81, 128.23, 127.61, 123.95, 63.62, 56.95, 44.35 HRMS analysis (ESI): Calculated for [M+H] +: C 16H15ClBrN 2O3: 369.9955; Found: 369.9939 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 20% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 11.4 min, RT2 (major) = 12.5 min. ["]D20 = +26.3 (c 0.7, CHCl 3, er = 89:11) !170 II-2-13-6 Analytical data for byproduct II -45 !II-45: N-(2-chloro -3-(2,2,2 -trifluoroethoxy)hexyl) -4-nitrobenzamide Rf : 0.60 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.30 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 6.68 (br s, 1H), 4.28 -4.25 (m, 1H), 4.15 -4.10 (ddd, J = 14.5, 7.0, 4.5 Hz, 1H), 3.99-3.91 (m, 2H), 3.73 -3.70 (dt, J = 10.5, 3.5 Hz, 1H), 3.59 -3.54 (ddd, J = 13.5, 9.0, 5.0 Hz, 1H), 1.78 -1.73 (m, 1H), 1.67 -1.60 (m, 1H), 1.45 -1.35 (m, 2H), 0.96 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 165.63, 149.76, 139.46, 128.16, 127.03 (q, JCF = 277.8 Hz), 123.93, 82.57, 67.33 (q, JCF = 34.1 Hz), 60.76, 43.44, 32.18, 18.53, 13.96 HRMS analysis (ESI): Calculated for [M+H] +: C 15H19ClN2O4F3: 383.0985; Found: 383.0970 HNONO2ClOCH2CF3!171 II-2-13-7 Analytical data for products in non -catalyzed reaction (II -48C, II-48D, II-48E) !II-48C: 4-bromo -N-((2S,3S)-2-bromo -3-chlorohexyl)benzamide Rf : 0.54 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 7.64 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 6.60 (br s, 1H), 4.51 -4.48 (ddd, J = 8.5, 5.0, 2.5 Hz, 1H), 4.09 -4.03 (m, 2H), 3.73 -3.67 (ddd, J = 14, 9.0, 5.0 Hz, 1H), 1.92 -1.78 (m, 2H), 1.59 -1.52 (m, 1H), 1.44 -1.37 (m, 1H), 0.94 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 166.77, 132.56, 131.94, 128.58, 126.66, 62.74, 57.71, 45.15, 38.61, 19.65, 13.39 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17ClBr 2NO: 395.9365; Found: 395.9374 Resolution of enantiomers: DAICEL Chiralcel ¨ AD-H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 10.2 min, RT2 (minor) = 20.8 min. ["]D20 = +40.1 (c 1.0, CHCl 3, er = 94:6) II-48D: 4-bromo -N-((2S,3S)-3-bromo -2-chlorohexyl)benzamide ClBrHNOBrHNOBrClBr!172 Rf : 0.54 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 7.64 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 6.49 (br s, 1H), 4.32 -4.29 (ddd, J = 9.0, 4.0, 2.5 Hz, 1H), 4.27 -4.24 (ddd, J = 9.0, 4.5, 2.0 Hz, 1H), 4.08 -4.03 (ddd, J = 14.0, 7.0, 4.5 Hz, 1H), 3.65 -3.59 (ddd, J = 14.5, 9.0, 5,0 Hz, 1H), 1.98 -1.87 (m, 2H), 1.62 -1.56 (m, 1H), 1.45 -1.38 (m, 1H), 0.95 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl3) $ 165.80, 132.54, 131.97, 128.57, 126.70, 63.57, 59.32, 45.80, 38.08, 20.72, 13.30 HRMS analysis (ESI): Calculated for [M+H] +: C 13H17ClBr 2NO: 395.9365; Found: 395.9373 II-48E: (S)-5-((S)-1-bromobutyl) -2-(4-bromophenyl) -4,5-dihydrooxazole Rf : 0.30 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 7.80 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 4.86-4.82 (m, 1H), 4.16 -4.11 (dd, J = 15.0, 10.0 Hz, 1H), 4.09 -4.05 (dt, J = 10.0, 3.5 Hz, 1H), 3.98 -3.94 (dd, J = 15.0, 7.0 Hz, 1H), 1.89 -1.82 (m, 1H), 1.80 -1.74 (m, 1H), 1.70 -1.63 (m, 1H), 1.50 -1.42 (m, 1H), 0.95 (t, J = 7.0 Hz, 3H) 13C NMR (125 MHz, CDCl 3) $ 163.04, 131.67, 129.72, 126.27, 126.18, 81.21, 58.30, 56.36, 35.42, 20.78, 13.36 NOBrC3H7Br!173 HRMS analysis (ESI): Calculated for [M+H] +: C 13H16Br2NO: 359.9599; Found: 359.9610 II-2-13-8 Analytical data for substrate II -55A !II-55A: (Z)-4-nitro -N-(3-(4-(trifluoromethyl)phenyl)allyl)benzamide Rf : 0.39 (30% EtOAc in hexanes, UV) 1H NMR (500 MHz, CDCl 3) $ 8.20 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 7.5 Hz, 2H), 7.34 (d, J = 7.5 Hz, 2H), 6.67 (br s, 1H), 6.63 (d, J = 12.0 Hz, 1H), 5.86 -5.81 (m, 1H), 4.32 (t, J = 6.0 Hz, 2H) 13C NMR (125 MHz, CDCl 3) $ 165.42, 149.51, 139.68, 139.57, 139.55, 130.84, 129.72 (q, JCF = 32.2 Hz), 1 29.24, 128.89, 128.10, 127.19 (q, JCF = 270.3 Hz), 125.35 (q, JCF = 3.8 Hz), 38.51 HRMS analysis (ESI): Calculated for [M+H] +: C 17H14N2O3F3: 351.0957; Found: 351.095 NHONO2F3C!174 REFERENCES !175 REFERENCES 1. 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D., A synthesis of the chlorosulfolipid mytilipin A via a longest linear sequence of seven steps. Angew. Chem. Int. Ed. Engl. 2013, 52 (38), 10052 -5. 53. Shibatomi, K.; Zhang, Y.; Yamamoto, H., Lewis acid catalyzed benzylic bromin ation. Chem. Asian J. 2008, 3 (8-9), 1581 -4. 54. Ivanov, A.; Ejaz, S. A.; Shah, S. J.; Ehlers, P.; Villinger, A.; Frank, E.; Schneider, G.; Wolfling, J.; Rahman, Q.; Iqbal, J.; Langer, P., Synthesis, functionalization and biological activity of arylated de rivatives of (+) -estrone. Bioorganic & medicinal chemistry 2017, 25 (3), 949 -962. !180 55. Khazaei, A.; Zolfigol, M. A.; Rostami, A., 1,3 -Dibromo -5,5-Dimethylhydantoin DBDMH as an Efficient and Selective Agent for the Oxidation of Thiols to Disulfides in Soluti on or under Solvent -Free Conditions. Synthesis 2004, 2004 (18). 56. Tan, C. K.; Yeung, Y. -Y., Recent advances in stereoselective bromofunctionalization of alkenes using N -bromoamide reagents. Chem. Commun. 2013, 49 (73), 7985 -7996. 57. Markish, I.; Arrad, O., New Aspects on the Preparation of 1,3 -Dibromo -5,5-dimethylhydantoin. Industrial & Engineering Chemistry Research 1995, 34 (6), 2125 -2127. 58. de Almeida, L. S.; Esteves, P. M.; de Mattos, M. C. S., Tribromoisocyanuric Acid: A New Reagent for Regioselec tive Cobromination of Alkenes. Synlett 2006, 2006 (10), 1515 -1518. !!181 Chapter III: Highly regio -, diastereo -, and enantioselective chloroamination of alkenes III-1 Introduction ! Molecules that contain amines and halogens in their structure are found in different natural products and bioactive compounds (Figure III -1).1-4 Additionally, haloamine compounds are versatile motifs in organic synthesis , where the halogens can serve as a leaving group to yield aziridines or can be utilized in cross -coupling reactions. 5-6 Figure III-1: Biologically active haloamines OHONHClOMe virantmycin antiviral antibiotic FH2NCO2HGABA-AT inactivator NClClHOOChloambucil chemotherapy NNONNNNH2NHOH2NNH2ClpalauÕamine cytoxic and immunosuppressive !182 One of the common methods for synthesizing haloamines is activating the carbon -carbon double bond with various halogen donors as electroph iles and subsequently nucleophilic attack of the putative halonium ion with different amine sources. Recently our lab suggested that the well -known two -step mechanism in halofunctionalization (1 -formation of halonium, 2 - nucleophilic attack to halonium ion intermediate) is not the predominant mec hanism in many halofunctionalization reactions. Base d on kinetic isotopic effect ( KIE ), NMR and kinetic studies our lab proposed a nucleophile dependent path where the nucleophile pre -polarizes the alkene , leading t o a more nucleophilic olefin that can compete effectively with the halenium source for the halogenation. In this manner, the halofunctiona lization occurs via a concerted transition state (Figure III-2).7 Figure III-2: Nucleophile assisted alkene activation (NAAA) For developing new methodology in haloamination reaction, employing amine sources a s the nucleophile in the halofuncti onalization react ion is challenging. The basic nature of amines leads to higher halonium affinity. This is apparent if one consults the reported Hal A values for amines. 8 Therefore for developing the YAH!!YXBAYH!!YXABAXYYABAHAYHYPre-polarization of olefinConcerted TS Path C !183 methodologies for haloamination reaction, choosing nucleophilic amine sources with lower halonium affinity is essential. We have recently begun to explore the intermolecular halofuctionalization of alk enes. 9-10 This possesses additional challenges in comparison to the intramolecular halofunctionalization reactions. Intramolecular reactions always have the nucleophile in close p roximity as it is tethered, allowing for a quick capture of the halonium intermediate or a !-halocarbenium ion. A long -lived cation might erode enantios electivity and diaster eoselectivity. 11 Also, intramolecular reactions (cyclization) often rely on ri ng closure kinetics and molecular geometry leading to the major regioi somer. 12 On the other hand, approaching externally, the intermolecular nu cleophile must be able to differentiate between the two possible positions it can attack. Finally, in some cases, the external nucleophile must outcompete the tethered nucleophile for a reaction at the same location. The first intermolecular catalytic asymmetric reaction we developed was a haloether ification reaction. This was d one via optimizing conditions such as solvent and concentration to outcompete the cyclization reaction and simultaneously afford high enantioselectivity and yield for the intermolecular reaction. We were able to obtain enanti omeric excesses as high as 99% for this methodology (see Chapter I and Figure III -3a).9 We then extended this methodolog y to dihalogenation reactions, such as dichlorination and chlorobromination. This provided the products with high enantioselectivity and yield (see Chapter II and Figure III -3b).10 !184 Figure III -3: (a) Highly enantioselective haloetherification of allyl amides (b) Highly enantioselective dihalogenation of allyl amides Utilizing our experiences for developing catalytic asymmetric intermolecular haloetherification and dihalogenation reactions of alkenes, w e sought to develop a highly enantio -, diastereo - and reg ioselective haloamination . Our goal was for this methodology to work well for a variety of alkenes, including those with no bias for regioselectivity (alkenes with only alkyl substit uents), where other methods have failed . R2NuCl/Br R1HNOArR1HNArOR210 mol% (DHQD) 2PHAL 2.0 equiv DCDMH or NBS Nucleophile:MeCN (3:7), 0.01 M, -30 oC H2O:MeCN (1:9), -10 oCAr = 4-NO 2-PhR1, R2 = H, Ar, Alk >25 examples up to > 99.5:0.5 dr, er, rrNucleophile: R-OH, R-CO 2H or H 2OR2HNArOCl/Br HNArOR2Cl/Br R1, R2 = H, Ar, Alk Ar = 4-NO 2PhR1R1up to 97% yield, 99.5:9.5 er19 examples 10 mol% (DHQD) 2PHAL DCDMH or NBS (2.0 equiv) LiCl or LiBr (100 equiv) TFE 0.02 M, -30 ¼C ab!185 III-1-1 Literature precedence for catalytic vicinal haloamination of alkenes !III-1-1-1 Literature precedence for catalytic -racemic vicinal haloamination of alkenes !A halogen vicinal to an amine has been a useful intermediate in the synthesis of aminated oligosaccharides. D anishefsky and co -workers reported sulfonamidoglycosylation of glycals, a route to oligosaccharide s with 2 -aminohexose subunits in 1990. 5 In this report, benzenesulfonamide was employed as an amine nucleophilic sour ce, and IDCP III-2 was used as iodonium agent to yield haloaminated product III-3 in 78% yield and >99% diastereos electivity. Treating haloamine III-3 with base produced aziridine III-4. This aziridine ring was then opened via a nucleophilic attack o f sugar to form oligosaccharide III-5 in 52% yield after two steps (Figure III -4). ! !186 Figure III-4: A general procedure for sulfonamidoglycosylation of glycals !!!!!!!!!!!!!!!!!!!!!!!!!OBnO BnO OBn H2NSO 2PhI(sym-collidine) 2ClO4 (III-2 )CH2Cl2, MS 4† ONSO2PhOAc AcOAcOOHNSO2PhAcOAcOAcOIIII-3 78% yield LTMP, AgOTf THF, -78 ¡C to 0 ¡C ONHAc OAc AcOAcOOOAcOAcOIII-5 52% yield after 2 steps HOSugar III-1 III-4 NI2III-2 I(sym-collidine) 2ClO4 (IDCP) ClO4!187 A general process for haloamination of alkenes was developed by E. J. Corey and coworkers in 2006. 13 In th is procedure, a Lewis acid catalyzed haloamination of alkenes was reported where N-bromoacetamide serve d as halogen donor, 40 mol% SnCl 4 was employed as a Lewis acid catalyst and acetonitrile with a trace amount of water was used as solvent and nucleophile. Substrate scope shows different cyclic alkenes III-6 were transferred to haloaminated products III-7 with up to 90% yield (Figure III -5a). The formation of bromonium ion III-9 followed by nucleophilic attack by aceton itrile generated nitrilium ion III-10. The reaction of nitrilium ion with water followed by tautomerization forms final bromoaminated product III-12 (Figure III-5b). Figure III-5: A general process for the haloamination of olefins CH3CONHBr (1.2 equiv) SnCl 4 (40 mol%) H2O (1.2 equiv), CH 3CN0 C,nnNHAc BrBrNCCH3BrCH3CNNCBrOHCH3BrNHCOCH3H2OIII-6 III-7 11 examples, up to 90% yield III-8 III-9 III-10 III-11 III-12 ab!188 The same group used the abov e haloamination methodology for the concise synthesis of anti -influenza neuramidase inhibitor (Tamiflu ¨) III-15 (Figure III-6). 6 A mechanistically similar Indium (III) -catalyzed aminobromination and aminofluorination of styrenes were reported by Yadav and coworke rs in 2009. 14 The NBS and selectfluor were employed as halogen donor to yield aminobrominated product III-17A in 87% yield and aminofluorinated product III-17B in 90% yield (Figure III -7). BocHN OOEt 5 mol % SnBr 4NBA, MeCN -40 ¡C, 4 h III-14 75% yield BocHN OOEt NHAc BrH3NOOEt AcHN OH2PO4III-13 III-15 Neuramidase inhibitor (Tamiflu ¨)Figure III -6: Employing bromoamination reaction, a route for the synthesis of neuramidase inhibitor !189 Figure III-7: Indium (III) -catalyzed aminobromination and aminofluorination Yeung and coworkers disclosed a racemic chloroamination of olefins in 2013.15 For facile and efficient chloroamination of alkenes, Lewis basic diphenyl selenide (20 mol%) along with N -chlorosuccinamide (NCS) as chloronium source and ace tonitrile as nitrogen source were used, res pectively. In these conditions, chloroaminated products III-19 were formed in up to 89% yield (Figure III -8). Figure III-8: Lewis basic selenium catalyzed chloroamination of olefins Procopiou and his coworkers developed a racemic Ritter -type reaction for electrophilic diaminati on of alkenes. 16 It was report ed as an one pot reaction involving the addition of N-chlorosacc harin III-21 to the alkene solution in acetonitrile at -42 ¡C to yield chloroimid e III-23, followed by addition of potassium InBr 3 or InF 3 (10 mol%) NBS or selectfluor CH3CN, rt, 15 min NHCOCH3XX = Br III-17A 87% yield X = F III-17B 90% yield III-16 NNClF2BF 4Selectfluor R1R2R3NCS (2 equiv), Ph 2Se (20 mol%) H2O, MeCN, rt R1R2R3AcHN ClIII-18 III-19 8 examples up to 89% yield !190 ethoxide in EtOH to hydrolyze the saccharin ring. Warming the reaction mixture to room temp erature yielded imidazoline III-24 in up to 47% yield (Figure III -9). Figure III-9: A method for electrophilic diamination of alkenes III-1-1-2 Literature precedence for catalytic -asymmetric vicinal haloamination of alkenes In 2012 Masson and co -workers disclosed the bromoamidation of enecarb amates with high enantioselectivity. "# They employed a chiral phosphoric acid to catalyze the reactio n using NBS as the source of bromonium as well as a source of nucleophilic nitrogen. This transformation proceeds under mild condition s (room temperature) and only 1 mol% of chiral catalys t is needed to produce various "-brominated encarbamates in up to 99% yield and 98% ee (Figure III -10a). The proposed transition state III-27 suggest that the chiral R1R2R3III-20 CH3CN, III-21 -42 ¡C R1R2R3NClO2SNOR1NClO2SNOH3CR3R2KOEt, EtOH -42 ¡C to rt R1R2R3NNO2SCO2EtIII-22 III-23 III-24 O2SNOClIII-21 N-chlorosaccharin 14 examples up to 47% yield !191 catalyst act s as a bifun ctional entity that activates both NBS and the encarbamate via hydrogen bo nding (Figure III -10b). Figure III-10: Highly enantioselecti ve "-bromination of encarbamates Feng and coworkers reported their first haloamination using a scandium (III) triflate catalyst with a chiral N,N -dioxane ligand III-29 along with NBS as the halonium source and sulfonamide a s a nitrogen nucleophile to form bromoaminmated products III-31 in exquisite yields and enantioselectivities. 18 They sa w similar results when using NIS as the source of halonium to construct the "-iodo amine products III-32.19 With a slight modification, FengÕs system was able to succeed in the chloroamination. 20 The authors changed the halonium CbzHN RNBS 1 equiv, (R) -TRIP (1 mol%) toluene, RT CbzHN RBrNOOIII-26 16 examples up to 98% yield up to 99:1 erIII-25 R = Alkyl 2 equivOOPOOHHNR2CO2R1ONBrOiPriPriPriPriPriPrabIII-27 !192 source from a succ inimide to the more active N,N -dichloro -4-methylbenzene -sulfonamide and changed the R group of the chiral ligand to the sterically hindered adamantyl group III-30. In this case, the reaction was able to proceed with higher yields and similar enantio - and diastereoselectivity to form a chlorinated product (Figure III -11a). A diverse range of aryl and aryl -substituted chalcone s III-28 were examined in these studi es. These reactions are believed to proceed through a chiral halonium ion. The scandium as Lewis acid coordinates to the carbonyl of the enone and the oxygen of the sulfonyl group. These coordinations place the counter ion of the dihalo -sulfonamide close to the chiral halonium ion (Figure III -11b). !193 Figure III-11: Sc(OTf) 3-catalyzed enantioselective halogenation of alkenes Alt hough enantioselective haloamination and haloamidation reactions have seen success, there are still many limitations . Each method described above can either tolerate alkyl substitution or aryl substitution, never both. Asymmetric chlor oamination has only seen success when the scandium catalyst is used ; no organocatalytic methods have been reported. The substrate scope was limi ted to only the chalcone and ",!-unsaturated keto -ester moieties . III-33 X = Cl up to 99% yield up to >99:1 erR2R1OConditionsLigand - Sc(OTf) 3 (0.050-0.5 mol%) DCMR2R1OXNHTs III-31 X = Br up to 99% yield up to >99:1 erIII-28 R1,R2 = Ar NHONNOHNOORRIII-29 R = PhCH 2CH2III-30 R = 1-Adamantyl X = Br NBS (1.2 equiv.), TsNH 2 (1.1 equiv.), 0 ¡C, Ligand = III-29 X = I NIS (1.2 equiv.), TsNH 2 (1.1 equiv.), rt, dark, Ligand = III-29 X = Cl TsNCl 2 (0.6 equiv.), TsNH 2 (0.6 equiv.), 35 ¡C, Ligand = III-30 III-32 X = I up to 99% yield up to 99:1 erConditions: RArOClScOSONHTsba!194 III-2 Result and discussion !During my graduate studies, I learned that being detail oriented is essential to be successful. Separation and ch aracterization of side products, even if they are 10% of mass balance , can lead us to new methodologies. S ome of these side p roducts can be substantial, valuable and worth attempting to optimize the reaction to get them exclusively. III-2-1 Discovery of chloroacetamide product III -34D as a side product in enantioselectiv e dichlorination reactions !During dichlorination reactions optimization studies to produce dichlorinated product III-34A, competing intermolecular processes such as interception of the intermediate by the solvent leads to side products III-34B (from TFE incorporation) or III-34D (the Ritter product when CH 3CN is employed). 10 Also, the intramolecula r halocyclization path yields the oxazoline III-34C as a side p roduct. As listed in Table III -1, numerous chloride sources in different solvents were evaluated for developing an enantioselective dichlorin ation reaction. It was revealed that employing 100 equivalents of LiCl in TFE (CF 3CH2OH) in the presence of (DHQD) 2PHAL as a chiral catalyst leads to the desired dichlorinated product III-34A in high se lectivity and enantio excess (Table III -1, entry 7). Employing 15 equivalents of NaCl in acetonitrile did not provide any desired dichlorinated product. However, chloroacetamide (Ritter type reaction) product III-34D was formed in good selectivity (Table III -1, entry 2) . We have taken advantage of this previously unintended result for the development of !195 the first organo -catalytic enantioselective chloro amidation. This is also the first example of an asymmetric Ritter type reaction. Table III -1: Summary of optimization studies in dichlorination reactions Entry Solvent Temp (¡C) XCl XCl (equiv) A:B:C:Da 1 MeCN 23 TEAC 15 55:0:45:0 2 MeCN 23 NaCl 15 0:0:13:87 3 MeCN 23 LiCl 15 79:0:21:0 4 MeCN -30 LiCl 15 95:0:5:0 5 TFE -30 LiCl 15 45:56:0:0 6 TFE -30 LiCl 50 86:14:0:0 7 TFE -30 LiCl 100 95:5:0:0 aDetermined by NMR; TFE = 2,2,2 -trifluoroethanol; TEAC = Tetraethylammonium chloride III-2-2 Typical Ritter type mechanism leading to the chloroacetamide product III -34D ! The mechanism for the formation of chloroacetamide III-34D is shown in Figure III -12. Same as the typical Ritter type reaction, after the chloronium ion intermediate formation , acetonitrile attacks the putative interm ediate and forms C3H7ClClHNArOHNArOC3H7OTFEClHNArOIII-34A III-34 Ar = 4-NO 2PhC3H7(DHQD) 2PHAL 10 mol% DCDMH (2.0 equiv) XCl, Temp MeCN or TFE (0.02 M) NOArC3H7ClC3H7NHClHNArOOIII-34B III-34C III-34D !196 the nitrilium ion III-36. The trace amoun t of water in acetonitrile react s with III-36 and yields intermediate III-37. S ubsequently, tautomerization of III-37 yields the final chloroacetamide product III-34D (Figure III-12). 13 Figure III -12: Proposed mechanism for the formation of the chloroacetamide III-34D III-2-3 Formation of unknown products as intermediates in chloroamination reaction ! For optimizing the reaction to obtain the chloroacetamide product III-34D exclusively, the ally l amide III-34 was treated with two equivalents of DCDMH in acetonitrile along with 10 mol% (DHQD) 2PHAL as a chi ral catalyst. Surprisingly, mixtures of unknown products were formed (Figure III -13). Attempting to separate the mixture of products and characterize them was unsuccessful due to HNCH3ArOClHNOArNClHNOArNH3COH3CHIII-34 Ar = 4-NO 2-PhClHNOHNCH3OArTautomerization HOHHNH3CArOH3CNNClRRH3CH3CH3CIII-34D III-35 III-36 III-37 !197 their instability on silica gel. Interestingly, addition of the silica gel to the crude mixture resulted in the conversion of the mixtures of intermediates were transferred to the final chloroacetamiden product III-34D as a single diastereomer in 67% yield and 95:5 er (Figure III -13a). ) The NMR spectrums for allyl amide substrate III-34, the mixture of unknown products and fin al chloroacetamide product III-34D were shown in Figure III -13b. !198 Figure III -13: (a) Unknown products as an intermediate were formed in chloroamination reaction (b) The NMR spectra for allyl amide substrate III-34, the mixture of unknown products and final chloroacetamide product III-34D HNC3H710 mol% (DHQD) 2PHAL 2.0 equiv DCDMH ACN 0.02 M, rt OArIII-34 Ar = 4-NO 2-PhMixtures of products C3H7ClHNOHNOArIII-34D 67% yield 99:1 dr, 95:5 erSiO 2ab HNC3H7OArIII-34 Mixtures of products C3H7ClHNOHNOArIII-34D !199 III-2-4 Designing control experiments to determine the structure of mixture of products ! Due to the instability of unknown p roducts on silica gel, we design ed control experiments to reveal their structure. Under the same condition s, employing TsNCl 2 (N,N -dichloro -p-toluenesulfonamide) instead of DCDMH yielded single chloroimide product III-34E in 78% yield and 95:5 er (Figure III -14a). This chloroamidine produc t III-34E was stable to purification on silica gel. This result indicates that the counter ion of the chlorine source must be part of the final chlorinated product III-34E. Therefore, in the case of employing DCDMH, we assu me the mixture of products is the result of the attack of the two nucleophilic nitrogens atoms in the DCDMH structure. However, the chloroimide product III-34E is stable on silica gel, but the combination of products III-38 in case of using DCDMH is not stable and hydrolyze in the presence of silica gel to form chloroacetamide III-34D in 67% yield and 95:5 enantioselectivity (Figure III -14b) !200 Figure III -14: (a) The counter ion of chlorine source is part of the final product (b) Revealing the structures of the mixture of products III-2-5 Modified mechanism for the formation of the chloroacetamide III -34D ! The updated mechanism for the formation of chloroacetamide was proposed based on the latter results (Figure II I-15). In this modified mechanism, the counter ion of the chloronium ion participates in the nucleophilic attack to HNC3H7Cl10 mol% (DHQD) 2PHAL 2.0 equiv TsNCl 2ACN 0.02 M, -30 oCHNOOArNNHTs ArIII-34 Ar = 4-NO 2-PhNClClSOOC3H7TsNCl 2III-34E 78% yield 99:1 dr, 95:5 erC3H7ClHNONNNHOOArHNC3H710 mol% (DHQD) 2PHAL 2.0 equiv DCDMH ACN 0.02 M, rt OArIII-34 Ar = 4-NO 2-PhC3H7ClHNONArNNHOONNOOClClC3H7ClHNOHNOArIII-34D 67% yield 99:1 dr, 95:5 erIII-38 abDCDMH Silica gel !201 yield chloroamidine III-40. Subsequently, hydrolysis of the chloroamidine III-40 forms chloroacetamide III-34D. Figure III -15: The modified proposed mechanism for formation of chloroacetamide III-34D! III-2-6 Catalyst -controlled chloroamination reaction ! For measuring the background for chloroamid ation reaction, the allyl amide III-34 was treated with DCDMH in acetonit rile at ambient tempe rature. Surprisingly, a reaction with out (DHQD) 2PHAL for ms the final chloroacetamide III-34D along with the cyclized product III-34C in the ratio of 1.0:1.7 (Figure III -16). As mentioned above, in the presence of (DHQD) 2PHAL , the two dimethyl hydantoins incorporated imide products III-38 are formed , which upon addition of silica gel hydrolyze to yield final the chloroacetamide product III-34D (Figure III-NR1R2HNCH3ArOClHNOArNClHNOArNH3CNH3CR2III-34 Ar = 4-NO 2-PhClHNOHNCH3OArHydrolyze HNH3CArOH3CNNClR2R1H3CH3CH3CIII-34D III-35 III-40 R1III-39 !202 14b). Interestingly , without (DHQD) 2PHAL , the final product was formed w ithout employing silica gel for hydrolysis . These observations could suggests that , (DHQD) 2PHAL holds DCDMH in the chiral pocket , thus making the counter ion of DCDMH relatively close to the nitrilium ion intermediate , which the traps it to form imide produ cts (see Figure III -15, III-39). However, without the chiral catalyst, the trace amount of water in acetonitrile is responsible for the nucleophilic attack of the nitrilium ion to yield the intermediate product III-37 (see Figure III -12), followed by tautomerization to deliver the chloroacetamide product. Figure III-16: Chloroamination of allyl amide III-34 without (DHQD) 2PHAL Our lab has previously showen the coordination of N,N-dichloro hydantoin III-41 with (DHQD) 2PHAL via NMR studies .21 The two -gem hydrogen atoms in N,N-dichlorohydantoin resonate as a singlet at 4.35 ppm in CDCl 3. However, adding one equivalent of (DHQD) 2PHAL along with two equivalents of benzoic acid into the NMR tube, leads to the formation of an AB quartet at 4.40 ppm (Figure III -17). We had previously suggested that two scenarios depicted in Figure III -17 as a result of the NMR observations. Both senarios would explain the splitting pattern of the hydrogens atoms of dichlorohydantoin in the presence of (DHQD) 2PHAL. The structural suggestion agrees observations above, ACN 0.02 M, rt 1.0:1.7DCDMH (2 equiv) Without (DHQD) 2PHAL HNC3H7OArIII-34 Ar = 4-NO 2-PhC3H7ClHNOHNOArNOArC3H7ClIII-34D III-34C !203 highlighting the role of chiral catalyst (DHQD) 2PHAL in the enantioselective chloroamination reac tions, yielding the intermediate III-38 suggested in Figure III -14B. Figure III-17: Catalyst controlled chloroamination of unsaturated allyl amides III-2-7 Two distinct types of choloroaminated products were produced from different chlorenium sources ! In our system, two different types of chlorenium sources lead to two distinct and precious products. When DCDMH is employed, the Ritter product can undergo f acile hydrolysis with silica gel, yielding th e amide product III-34D NNOOHHClCl4.35 ppm, s (DHQD) 2PHAL (1 equiv) PhCO 2H (2 equiv) CDCl3, -40 ¡C (500 MHz NMR) NEtRHHNNOOHBHAClCl4.30 ppm, AB quartet ( JAB =16.5 Hz) NEtRHClNNOOHBHAClorNONONNNONO(DHQD) 2PHAL III-41 !204 (Figure III -18a). W hen d ichloramine -T (TsNCl 2) is employed, we have observed that the Ritter product is more stable and does not hydrolyze as easily , leaving the sulfonamide intact (see III-34E, Figure III-18b). These two products have significant synthetic appli cations and both have the potential to undergo hydrolysis to t he chiral 1,3 diamine. The "-chloro amide product has been shown to undergo an aziridina tion reaction when treated with cesium carbonate (Figure III-18a).22 As menti oned before, the unmodified "-haloamide itself can be observed in molecules of biological importance. The chloroamidine product III-34E can be cyclized using sodium carbonate in 40 ¡C to form 2-imidazoline product in 72% yield ( III-43). This chiral imidazoline product could be of interest in medicinal chemis try and can be hydrolyzed to the chiral 1,2,3 triamine product III-44 (Figure III -18b). !205 Figure III -18: Two different types of chlorenium sources lead to two distinct products III-2-8 Role of HFIP as an additive in enantioselective chloroamination reactions ! Under optimized reaction condition s, either two equivalents of HFIP (hexafluoroisopropanol) as an additive were used in CH 3CN or a mixture of 1. 10 mol% (DHQD) 2PHAL 2.0 equiv DCDMH ACN 0.02 M, -30 oCHFIP 2 equiv2. 10.0 equiv SiO 2HNC3H7OArIII-34 Ar = 4-NO 2-PhC3H7ClHNOHNOArIII-34D 81% yield 99:1 dr, >99:1 erC3H7AcNHNOArCs2CO3 (2 equiv) ACN 0.04 M, 40 oCHNC3H7Cl10 mol% (DHQD) 2PHAL 2.0 equiv TsNCl 2HNOOArNNHTs NNTsHNOArArC3H7III-34E 78% yield 99:1 dr, 96:4 erC3H7III-43 72% yield ACN:TFE (8:2) 0.02, -30 oCC3H7NH2NH2NH2HClCs2CO3 (2 equiv) ACN 0.04 M, 40 oCIII-34 Ar = 4-NO 2-PhIII-42 III-44 ab!206 CH3CN:TFE (8:2) was employe d for the enantioselective chloroamination reactions (Figure III-18a, III-18b). We observed that using fluorinated solvents as additive or co -solvent affected the rate of the reaction. The relatively low pka of the fluorinated solvent s presumably protonate s the quinuclidine nitrogen atoms, therefore enabling the catalyst to hydrogen bond with DCDMH (see Figure III -17).21 This coordination can bring the counter ion of the chlorenium source closer to the nitrilium ion intermediate and accelerate the chloroamination reaction. The relative rates with or without HFIP for enantioselective chloroacetamidation of III-34 were show n in Figure III -19. !207 Figure III-19: Role of fluorinated additives in chloroamination reactions III-2-9 Substrate scope for enantioselective chloroamination reaction by employing DCDMH as the chlorenium source ! In an effort to map out the gener ality of the chloroamination reaction in the presence of DCDMH as the chlorenium source, a number of cis -disubstituted allyl amides were initially exposed to the optimized conditions. Compound III-34 forms the corresponding product III-34D in 89% yield with an exquisite level of stereoselectivity (>99:1 er, >99:1 dr). Switching the substituent on the benzamide 1. 10 mol% (DHQD) 2PHAL 2.0 equiv DCDMH ACN 0.02 M, -30 oCHFIP 2 equiv2. 10.0 equiv SiO 2HNC3H7OArIII-34 Ar = 4-NO 2-PhC3H7ClHNOHNOArIII-34D 81% yield 99:1 dr, >99:1 er!"#!"$!"%!"&!"'!!"'#!"!"(!!"'!!!"'(!!"#!!!"#(!!")!!!" Substre Decay Time (sec) None2 equiv HFIP Data were obtained by NMR at ambient temprature NEtRHHNNOOHBHAClClF3CCF3OHHFIPpKa of HFIP = 9.3 pKa of protonated quinuclidine = 11.0 !208 motif to 4 -bromobenzamide gave similar results (see III-45D). The other Z-alkyl substituted olefins ( III-46, III-47) afforded the chl oroacetamide products in high yield and stereoselectivity (see Figure III -20, III-46D and III-47D). Aryl substituted Z-alkene s are also compatible with this chemistry and yield final product III-48D in 82% yield and >99:1 er. The diastereoselectivity for p roduct III-48D is poor (4.7:1.0 dr), which is presumably due to the carbocation character at the benzylic position. Varying the expandable amide moiety for E-alkyl substituted olefins affected the yield and enantioselectivity. The substrate with 4-nitrobenzamide gave slightly higher yield and enantioselectivity compared to the substrate that has 4 -brom obenzamide moiety (see III-49D and III-50D). The aryl substituted E-allyl amide III-51 gave moderate yield (due to competing chlorocyclization) and fair diastereoselectivity (1.5:1 dr). Nonetheless, the chloroacetamide product III-51D was formed in high enantioselectivity (see Figure III -20, III-51D). Benzonitrile can also be employed as nucleophile to furnish the corresponding product with excellent enantioselectivity (see III-52D) !!209 Figure III-20: Enantioselective chloroamidation substrate scope OArHNR1R2CH3CN (0.05 M), -30 ¡C DCDMH (2 equiv.) HFIP (2 equiv.) 2. SiO 2(10 equiv.) HNOArIII-45D Ar = 4-Br-Ph 83% yield 98:2 erIII-50D Ar = 4-Br-Ph 66% yield 96:4 erNHC3H7ClOHNOArNHC2H5ClOIII-46D Ar = 4-NO 2-Ph84% yield 99:1 erHNOArNHC3H7ClOHNOArIII-47D Ar = 4-NO 2-Ph86% yield >99:1 erNHClOHNOArIII-34D Ar = 4-NO 2-Ph89% yield >99:1 erNHC3H7ClOIII-49D Ar = 4-NO 2-Ph75% yield 98:2 erHNOArNHC3H7ClOHNOArIII-51D Ar = 4-NO 2-Ph58% yield 96:4 er1.5:1 drNHPhClOHNOArIII-34F Ar = 4-NO 2-Ph56% yield 99:1 erNHC3H7ClOPhTBDPSO III-34 , III-45 to III-51 R1, R2 = H, Ar, Alk R2HNOHNArR1OIII-34 (D,F), III-45D to III-51D HNOArIII-48D Ar = 4-NO 2-Ph82% yield >99:1 er4.7:1 drNHPhClO!210 III-2-10 Optimization studies for the intermolecular enantioselective chloroamidination of E-allyl amides We choose the E-aliphatic substituted ally l amide III-49 to optimize the enantioselective chloroamidination reactions. 10 mol% (DHQD) 2PHAL was employed as the chiral catalyst along with two equivalents of TsNCl 2 as the chlore nium and nitrogen source. At ambient temperature in acetonitrile, the desired chlorofunctionalized III-49E along with cyclized ( III-49G and III-49C) products were observed in the ratio of 47:35:18, respectively (Table III-2, entry 1). The intermolecular product shows 88:12 er, whereas the cyclized products III-49E and III-49G exhibit lower enantioselectivity (88:12 er for III-49D and 50:50 er for III-49C, Table III -2, entry 1). Lo wer temperature ( -30 ¡C) led to slightly improved selectivity toward desired intermolecular product III-49E (Table III-2, entry 2 ). Decreasing the amount of TsNCl 2 (1.1 equiv) shows significantly higher selectivity for the formation of desired acyclic product III-49C (Table III-2, entry 3). Employing different additives such as 1.1 equivalents of TsNH 2, five equivalents Li 2CO3 and 5 A¡ molecular sieves would not in crease the selectivity of the chloroamidination reaction (Table III-2, entries 4 to 6 ). The reaction that was run with 20 mol% (DHQD) 2PHAL in -30 ¡ C shows slightly higher selectivity compared to using 10 mol% chiral catalyst (Table III-2, entries 7 and 8 ). IN an attempt to reduce the formation of cyclized products ( III-49G and III-49C), t he reactions were conducted in -45 ¡C and -50 ¡C. L ower temperature s led to the formation of the desired chloroamidinated product III-49E exclusively with 96:4 er (Table III-2, entries 9 and 10 ) !211 Entry Temp Mol% cat Additive Equiv of TsNCl 2 E:G:Ca er (E)b er (G)b 1e rt 10 None 2 47:35:18 88:12 78:22 2 -30 10 None 2 70:25:5 95.5:4.5 82:18 3 rt 10 None 1.1 63:28:9 89:11 78:22 4f rt 10 TsNH2 1.1 47:34:19 nd nd 5g rt 10 Li2CO3 1.1 59:30:11 89:11 78:22 6 rt 10 5 A ¡ MS 1.1 58:29:13 89:11 78:22 7 -30 10 None 1.1 78:17:5 95.5:4.5 nd 8 -30 20 None 1.1 81:15:5 nd nd 9c -45 10 None 1.1 90:9:1 96:4 nd 10d -55 10 None 1.1 95:4:1 96:4 nd aDetermined by NMR; bEnantioselectivity determined by chiral HPLC; c Mixture of ACN:TFE (9:1) was used ; dMixture of ACN:TFE (8:2) was used ; eThe enantioselectivity for compound III-49C was 50:50 er ; f1.1 equiv of TsNH2 was used; g5 equiv of Li 2CO3 was used !HNC3H7ClX mol% (DHQD) 2PHAL X equiv TsNCl 2ACN 0.04 M, Temp HNArOOArNC3H7NOArC3H7ClNOArC3H7ClNHTs III-49 Ar = 4-NO 2-PhIII-49E III-49C III-49G Table III -2: Optimization studies for the intermolecular enantioselective chloroamidination of E-allyl amides !212 III-2-11 Substrate scope for enantioselective chloroamination reaction by employing TsNCl2 as the chlorenium so urce ! We sought to explore the scope of this tr ansformation under optimized conditions (1.1 equiv of TsNCl 2, 10 mol% (DHQD) 2PHAL and the mixture of CH3CN:TFE (8:2) as solvent at -50 ¡C). As mentioned before, products of this reaction are stable on silica ge l. Chiral chloroamidine products were formed in high yield and stereoselectivities. Z-alkyl -substituted alkenes afforded the desired products in near complete regio -, diastereo -, and enantioselectivity (Figure III-21, see III-34E, III-46E and III-47E). Benzyloxy substituted olefin gave the isolated product in slightly lower yield and enantioselectivity (78% yield and 95:5 er) as compare d to other Z-alkyl substituted allyl amides (see III-52E). The cis substrate with aryl substituent III-48 produced chloro imide product in 78% yield and 96:4 er. The only trans substrate (III-49) that was evaluated so far in this chemistry produced the product in 82% yield, >99:1 dr and 96:4 er (Figure III-21, III-49E). !213 Figure III-21: Enantioselective chloroimidation substrate scope III-2-12 Conclusion !We report the first enantioselective Ritter type reaction. This chemistry is compatible with aryl and aliphatic substituted alkenes. Interestingly, exquisite regioselectivity was observed even with employing aliphatic substituted (unbiased) a lkenes. Both E- and Z -olefins under optimized conditions deliver chloroamide products with high yield and enantioselevtivities. In this system, two III-49E 82% yield 99:1 dr, 96:4 erIII-48E 78% yield 99:1 dr, 96:4 erIII-52E 78% yield 99:1 dr, 95:5 erC3H7ClHNOArNNHTs ClHNOArNNHTs BnO PhClHNOArNNHTs III-46E 83% yield 99:1 dr, >99:1 erIII-47E 80% yield 99:1 dr, >99:1 erC3H7ClHNOArNNHTs III-34E 85% yield 99:1 dr, >99:1 erClHNOArNNHTs TBDPSO C2H5ClHNOArNNHTs HNR2OArR1III-34 , III-(46 to 49). III-52 Ar = 4-NO 2-PhR1, R2 = H, Ar, Alk ACN:TFE (8:2) 0.04 M, -50 oC10 mol% (DHQD) 2PHAL 1.1.0 equiv TsNCl 2R2ClHNONNHTs ArR1III-34E , III-(46E to 49E), III-52E !214 different types of chlorenium sources lead to two distinct and precious products (chloroacetamide and chloro amidines). Expanding the substrate scope for this transformation is underway. The optimized condition for chloroamidination (1.1 equiv of TsNCl 2, 10 mol% (DHQD) 2PHAL and the mixture of CH 3CN:TFE (8:2) as solvent at -50 ¡C) might be improved by employing less amount of TsNCl 2 (0.6 equivalents). Exploring substrate scope of chloroamidination reaction in the presence of two equivalents of HFIP as an additive in CH 3CN instead of using the mixture of CH 3CN:TFE (8:2) is necessary (see Figure III -21). Kinetic st udies are underway to elaborate on the employing HFIP as an additive and figure out the kinetic order of reactants in enantioselective Ritter type reactions. III-2-13 Experimental section III-2-13-1 General procedure for catalytic asymmetric chloroamidatio n of unsaturated allyl amides The substrate s (0.1 mmol, 1.0 equiv) and (DHQD) 2PHAL (7.8 mg, 0.01 mmol, 10 mol%) were suspended in a cetonitrile (2.0 mL) in a 4 mL vial capped with a septum and equipped with a micro stir bar (7 ! 2 mm). Hexafluoroisopropanol (21.4 µl, 0.2 mm ol, 2.0 equiv) was introduced, and t he resulting suspension was cooled to -30 ¡C in an immersion cooler. After stirring for 2 min DCDMH (39.5 mg, 0.2 mmol, 2.0 equiv) was added. The stirring was continued at -30 ¡C until the reaction was c omplete (TLC). The reaction was quenched by the addition of saturated aq. Na 2SO3 (3 mL), concentrated, and diluted with DCM (3 mL). The organics were separated and the aqueous layer !215 was extracted with DCM (3 ! 4 mL). The combined organics were dried over anhydrous Na 2SO4 and concentrated in a 20 ml vial. The r eact ion was then suspended with 2 mL of DCM and SiO 2 (60.4 mg, 1 mmol, 10.0 equiv) was introduced and allowed to stir for 12 h . SiO 2 was th en filtered via a cotton stuffed column. The c olumn was rinsed with EtOAc (5 mL). The filtrate was then concentrated in the presence of a small quantity of silica gel. Column chromatography (SiO 2/EtOAc Ð Hexanes gradient elution) gave the desired product. III-2-13-2 Analytical data for chloroamide products !III-34D N-((2S,3S)-3-acetamido -2-chlorohexyl) -4-nitrobenzamide 1H NMR (500 MHz, Chloroform -d) # 8.29 (d, J = 9.0 Hz, 3H, 2CH, 1NH), 8.08 (d, J = 9.0 Hz, 2H), 5.71 (d, J = 9.3 Hz, 1H, NH), 4.35 Ð 4.23 (m, 2H), 4.12 (ddd, J = 11.0, 5.2, 1.7 Hz, 1H), 2.93 (ddd, J = 13.7, 11.0, 4.4 Hz, 1H), 2.15 (s, 3H), 1.70 -1.60 (m, 1H), 1.59 -1.49 (m, 1H), 1.41 -1.32 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, Chloroform -d) # 172.2, 164.8, 149.7, 139.2, 128.4, 123.8, 61.2, 49.3, 42.6, 34.7, 23.3, 19.3, 13.7. Resolution of enantiomers: DAICEL Chiralcel AD -H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 8.8 min, RT2 (major) = 14.3 min HNONO2NHC3H7ClO!216 III-45D N-((2S,3S)-3-acetamido -2-chlorohexyl) -4-bromobenzamide 1H NMR (500 MHz, Chloroform -d) # 8.07 (dd, J = 8.6, 4.4 Hz, 1H, NH), 7.78 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 5.75 (d, J = 9.3 Hz, 1H, N H), 4.33 -4.24 (m, 2H), 4.12 (ddd, J = 10.9, 5.2, 1.7 Hz, 1H), 2.90 (ddd, J = 13.5, 10.9, 4.4 Hz, 1H), 2.14 (s, 3H), 1.60 -1.68 (m, 1H), 1.50 -1.58 (m 1H), 1.3 (h, J = 7.4 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl 3) # 171.90, 165.96, 132.49, 131.84, 128.75, 126.45, 61.45, 49.22, 42.46, 34.77, 23.26, 19.24, 13.66. Resolution of enantiomers: DAICEL Chiralcel AD -H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 5.8 min, RT2 (minor) = 7.1 min III-46D N-((2S,3S)-3-acetamido -2-chloropentyl) -4-nitrobenzamide HNOBrNHC3H7ClO!217 1H NMR (500 MHz, CDCl 3) # 8.32 (d, J = 8.8 Hz, 1H, NH), 8.29 (d, J = 5.4 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 5.59 (d, J = 9.3 Hz, 1H, NH), 4.35 ( ddd, J = 13.7, 8.8, 5.1 Hz, 1H), 4.25 -4.08 (m, 2H), 2.94 (ddd, J = 13.7, 10.9, 4. 3 Hz, 1H), 2.17 (s, 2H), 1.77 -1.63 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3) # 172.24, 164.74, 149.70, 139.17, 128.37, 123.82, 60.80, 51.25, 42.53, 25.88, 23.26, 10.61. Resolution of enantiomers: DAICEL Chiralcel AD -H column, 15% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 7.7 min, RT2 (minor) = 8.8 min III-47D N-((2S,3S)-3-acetamido -5-((tert -butyldiphenylsilyl)oxy) -2-chloropentyl) -4-nitrobenzamide 1H N MR (500 MHz, CDCl 3) # 8.48 (dd, J = 8.7, 4.2 Hz, 1H, NH), 8.26 (d, J = 9.0 Hz, 2H), 8.10 (d, J = 9.0 Hz, 2H), 7.58 (ddd, J = 9.6, 8.0, 1.4 Hz, 4H), 7.46 -7.39 (m, 2H), 7.39 -7.32 (m, 4H), 5.56 (d, J = 9.3 Hz, 1H, NH), 4.77 (q, J = 7.4 Hz, 1H), 4.41 (ddd, J = 13.8, 8.9, 5.1 Hz, 1H), 4.17 (ddd, J = 11.2, 5.1, 1.6 Hz, 1H), 3.74 -HNONO2NHC2H5ClOHNONO2NHClOTBDPSO !218 3.61 (m, 2H), 2.93 (ddd, J = 13.7, 11.2, 4.3 Hz, 1H), 2. 11 (s, 3H), 1.89 -1.82 (m, 2H), 0.89 (s, 9H). 13C N MR (125 MHz, CDCl 3) # 172.1, 164.7, 149.6, 139.1, 135.5, 135.4, 133.0, 133.0, 1 29.8, 129.8, 128.4, 127.8, 127.8, 123.8, 61.5, 59.5, 46.4, 42.4, 35.6, 26.7, 23.3, 19.0. Resolution of enantiomers: DAICEL Chiralcel OD -H column, 7% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 22.9 min, RT2 (major) = 26.2 min III-48D N-((2S,3S)-3-aceta mido-2-chloro -3-phenylpropyl) -4-nitrobenzamide 1H NMR (500 MHz, CDCl 3) # 8.32 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.63 (dd, J = 8.7, 3.3 Hz, 1H, NH), 7.44 -7.35 (m, 5H), 6.05 (d, J = 8.5 Hz, 1H, NH), 5.23 (t, J = 8.8 Hz, 1H), 4.52 -4.38 (m, 2H), 3.37 (dt, J = 14.4, 4.4 Hz, 1H), 2.08 (s, 3H). 13C NMR (125 MHz, CDCl 3) # 170.7, 165.5, 149.7, 139.5, 137.6, 129.2, 128.8, 128.4, 127.5, 123.8, 62.1, 56.3, 42.5, 23.4. Resolution of enantiomers: DAICEL Chiralcel OD -H column, 20% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 12.8 min, RT2 (minor) = 17.8 min III-49D N-((2S,3R)-3-acetamido -2-chlorohexyl) -4-nitrobenzamide HNONO2NHPhClO!219 1H NMR (500 MHz, Chloroform -d) # 8.31 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H, NH), 5.49 (d, J = 9.0 Hz, 1H, NH), 4.38 (ddd, J = 14.5, 8.8, 3.8 Hz, 1 H), 4.20 -4.06 (m, 1H), 3.99 -3.90 (m, 1H), 3.37 (ddd, J = 14.6, 4.8, 3. 7 Hz, 1H), 2.09 (s, 3H), 2.01 -1.92 (m, 1 H), 1.51 Ð 1.41 (m, 2H), 1.38 -1.28 (m, 1H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl 3) # 171.30, 165.41, 149.6, 139.65, 128.35, 123.83, 63.14, 51.75, 42.50, 33.22, 23.35, 19.01, 13.72. Resolution of enantiomers: DAICEL Chiralcel AD -H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 10.2 min, RT2 (m inor) = 11.4 min III-50D N-((2S,3R)-3-acetamido -2-chlorohexyl) -4-bromobenzamide HNONO2NHC3H7ClOHNOBrNHC3H7ClO!220 1H NMR (500 MHz, CDCl 3) " 7.73 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.23 (s, 1H, NH), 5.63 (d, J = 9.0 Hz, 1H, NH), 4.27 (ddd, J = 14.5, 8.3, 4.0 Hz, 1H), 4.14 (ddd, J = 9.9, 7.2, 2.8 Hz, 1H), 4.00 (ddd, J = 7.5, 5.7, 4.0 Hz, 1H), 3.37 (ddd, J = 14.5, 5.7, 4.0 Hz, 1H), 2.06 (s, 3H), 1.84 -1.94 (m, 1 H), 1.52 -1.39 (m, 2H), 1.39 -1.28 (m, 1H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) " 171.0, 166.7, 132.8, 131.8, 128.8, 126.4, 63.7, 51.6, 42.7, 32.8, 23.3, 19.0, 13.8. Resolution of enantiomers: DAICEL Chiralcel AD -H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 8.4 min, RT2 (minor) = 10.9 min III-51D N-((2S,3R)-3-acetamido -2-chloro -3-phenylpropyl) -4-nitrobenzamide 1H NMR (500 MHz, CDCl 3) # 8.32 (d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.8 Hz, 3H, NH), 7.41 -7.29 (m, 5H), 6.26 (d, J = 9.7 Hz, 1H, NH), 5.62 (dd, J = 9.7, 1.8 Hz, 1H), 4.55 (ddd, J = 10.5, 5.4, 1.8 Hz, 1 H), 4.39 (ddd, J = 13.8, 8.3, 5.4 Hz, 1H), 3.12 (ddd, J = 13.8, 10.5, 4.7 Hz, 1H), 2.24 (s, 3H). 13C NMR (125 MHz, CDCl 3) # 171.7, 164.9, 149.8, 139.0, 137.0, 128.8, 128.4, 128.3, 126.6, 123.9, 61.1, 52.2, 43.0, 23.4. HNONO2NHPhClO!221 Resolution of enantiomers: DAICEL Chir alcel OJ -H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (major) = 17.0 min, RT2 (minor) = 23.1 min III-34F N-((2S,3S)-3-benzamido -2-chlorohexyl) -4-nitrobenzamide 1H NMR (500 MHz, Chloroform -d) # 8.40 (dd, J = 8.6, 4.4 Hz, 1H NH), 8.33 (d, J = 8.8 Hz, 2H), 8.15 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 6.9 Hz, 2H), 7.62 Ð 7.57 (m, 1H), 7.51 (t, J = 7.6 Hz, 2H), 6.24 (d, J = 9.4 Hz, 1H, NH), 4.53 (tdd, J = 9.1, 5.3, 1.6 Hz, 1H), 4.35 (ddd, J = 13.8, 8.7, 5.2 Hz, 1H), 4.24 (ddd, J = 10.9, 5.2, 1.7 Hz, 1H), 3.00 (ddd, J = 13.7, 10.9, 4.4 Hz, 1H), 1.86 -1.76 (m, 1H), 1.73 -1.63 (m, 1H), 1. 48-1.39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, Chloroform -d) # 169.30, 164.84, 149.73, 139.22, 133.21, 132.46, 128.96, 128.42, 127.03, 123.88, 61.49, 49.63, 42.68, 34.94, 19.37, 13.71. Resolution of enantiomers: DAICEL Chiralcel OD -H column, 10% IPA -Hexanes, 1.0 mL/min, 254 nm, RT1 (minor) = 8.8 min, RT2 (major) = 14.3 min !!!!!HNONO2NHC3H7ClOPh!222 !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!REFERENCES !223 REFERENCES 1. Gribble, G. W., Naturally occurring organohalogen compounds --a comprehensive survey. Fortschr. Chem. Org. Naturst. 1996, 68, 1-423. 2. Nakagawa, A.; Iwai, Y.; Hashimoto, H.; Miyazaki, N.; Oiwa, R.; Takahashi, Y.; Hirano, A.; Shibukawa , N.; Kojima, Y.; Omura, S., Virantmycin, a new antiviral antibiotic produced by a strain of Streptomyces. J. Antibiot. 1981, 34 (11), 1408 -15. 3. Qiu, J.; Silverman, R. B., A new class of conformationally rigid analogues of 4 -amino-5-halopentanoic acids, potent inactivators of gamma -aminobutyric acid aminotransferase. J Med Chem 2000, 43 (4), 706 -20. 4. Chemler, S. R.; Bovino, M. T., Catalytic Aminohalogenation of Alkenes and Alkynes. ACS Catal. 2013, 3 (6), 1076 -1091. 5. Griffith, D. A.; Danishefsky, S. 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J.; Borhan, B., Highly Stereoselective Intermolecular Haloetherification and Haloesterification of Allyl Amides. Angew Chem Int Ed Engl 2015, 54 (33), 9517 -22. 10. Soltanzadeh, B.; Jaganathan, A.; Yi, Y.; Yi, H.; Staples, R. J.; Borhan, B., Highly Regio - and Enantioselective Vicinal Dihalogenation of Allyl Amides. Journal of the American Chemical Society 2017, 139 (6), 2132 -2135. !224 11. Denmark, S. E.; Burk, M. T.; Hoover, A. J., On the Absolute Configurational Stability of Bromonium and Chloronium Ions. Journal of the American Chemical Society 2010, 132 (4), 1232 -1233. 12. Jaganathan, A.; Garzan, A.; Whitehead , D. C.; Staples, R. J.; Borhan, B., A catalytic asymmetric chlorocyclization of unsaturated amides. Angew Chem Int Ed Engl 2011, 50 (11), 2593 -6. 13. Yeung, Y. Y.; Gao, X.; Corey, E. J., A general process for the haloamidation of olefins. Scope and mecha nism. J Am Chem Soc 2006, 128 (30), 9644 -5. 14. Yadav, J. S.; Reddy, B. V. S.; Chary, D. N.; Chandrakanth, D., InX3 -catalyzed haloamidation of vinyl arenes: a facile synthesis of alpha -bromo - and alpha-fluoroamides. Tetrahedron Letters 2009, 50 (10), 1136 -1138. 15. Tay, D. W.; Tsoi, I. T.; Er, J. C.; Leung, G. Y.; Yeung, Y. Y., Lewis basic selenium catalyzed chloroamidation of olefins using nitriles as the nucleophiles. Org Lett 2013, 15 (6), 1310 -3. 16. Booker -Milburn, K. I.; Guly, D. J.; Cox , B.; Procopiou, P. A., Ritter -type reactions of N -chlorosaccharin: a method for the electrophilic diamination of alkenes. Org Lett 2003, 5 (18), 3313 -5. 17. Alix, A.; Lalli, C.; Retailleau, P.; Masson, G., Highly enantioselective electrophilic alpha -brom ination of enecarbamates: chiral phosphoric acid and calcium phosphate salt catalysts. J Am Chem Soc 2012, 134 (25), 10389 -92. 18. Cai, Y. F.; Liu, X. H.; Hui, Y. H.; Jiang, J.; Wang, W. T.; Chen, W. L.; Lin, L. L.; Feng, X. M., Catalytic Asymmetric Bromo amination of Chalcones: Highly Efficient Synthesis of Chiral alpha -Bromo -beta-Amino Ketone Derivatives. Angewandte Chemie -International Edition 2010, 49 (35), 6160 -6164. 19. Cai, Y. F.; Liu, X. H.; Li, J.; Chen, W. L.; Wang, W. T.; Lin, L. L.; Feng, X. M., Asymmetric Iodoamination of Chalcones and 4 -Aryl -4-oxobutenoates Catalyzed by a Complex Based on Scandium(III) and a N,N ' -Dioxide Ligand. Chemistry -a European Journal 2011, 17 (52), 14916 -14921. 20. Cai, Y. F.; Liu, X. H.; Jiang, J.; Chen, W. L.; Lin, L. L.; Feng, X. M., Catalytic Asymmetric Chloroamination Reaction of alpha,beta -Unsaturated gamma-Keto Esters and Chalcones. Journal of the American Chemical Society 2011, 133 (15), 5636 -5639. !225 21. Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B., An Organocatalytic Asymmetric Chlorolactonization. Journal of the American Chemical Society 2010, 132 (10), 3298 -3300. 22. Trost, B. M.; Saget, T.; Hung, C. J., Efficient Access to Chiral Trisubstituted Aziridines via Catalytic Enantioselective Aza -Darzen s Reactions. Angew Chem Int Ed Engl 2017, 56 (9), 2440 -2444. !226 Chapter IV: Mechanistic investigation for the observed switch in olefin chlorenium face selectivity IV-1 Introduction IV-1-1 Switch of chlorenium face selectivity in two products of dichlorination reaction In our prior work, we had demonstrated optimized condition s (0.02 M substrate concentration in TFE, 100 equivalents LiCl and 2 .0 equivalents of DCDMH at -30 ¡ C) for the enantioselect ive dihalogenation reactions of alkenes (Figure IV-1a). The fact that these reactions required up to 100 equivalents of LiCl for optimal results was surprising. Based on different control experiments, it was indicated that the reaction is occurring on a so lid-liquid interface (see Chapter II). On the other hand, treating allyl amide IV-1 with 15 equivalents of LiCl in the presence of 10 mol% (DHQD) 2PHAL and two equivalents of DCDMH at room temperature produce s a mixture of products. In line with the desired dichlorinated product IV-1A, the TFE -incorporated product IV-1B was formed in 45% yield and 92:8 enantioselectivity (Figure IV -1b). The crystal structure for the dichlorinated product IV-1A enabled us to assign the absolute stereo chemistry for the two new ly formed chiral centers. Unfortunately, different attempt s to get single crystal structure for the TFE incorporated product IV-1B were not successful. However, varying the expandable amide moiety from 4 -nitrobenz amide to 4 -bromobenzamide led to get a crys tal structure for the TFE-incorporated product IV-1B. Examination of the latter results leads to an interesting yet puzzling observation . The chloroetherified side -product IV-1B for !227 the dichlorination reactions is formed with a switch in olefin face select ivity d uring the addition of the chlore nium, with overall excellent enantioselectivity (Figure IV-1b). To the best of our knowledg e, this is the first time that two products are produced in high ee under same reaction conditions (same chiral catalyst, sol vent, etc.) , but with different chlor enium face selectivity. Figure IV -1: Switch of chlorenium face selectivity for two products of the dichlorination reaction. R1HNArOCl/Br HNArOR1Cl/BrR1, R2 = H, Ar, Alk Ar = 4-NO 2PhR2R2up to 97% yield, 99.5:9.5 er19 examples 10 mol% (DHQD) 2PHAL DCDMH or NBS (2.0 equiv) LiCl or LiBr (100 equiv) TFE 0.02 M, -30 ¼C (DHQD) 2PHAL (0.1 equiv) DCDMH (2.0 equiv) LiCl (15 quiv), rt CF3CH2OH (0.02 M) HNArOIV-1 C3H7C3H7ClClHNArOIV-1A 37% yield 97:3 erSSC3H7OCH2CF3ClHNArOIV-1B 45% yield 92:8 erRRC3H7ClClHNONO2SSC3H7OCH2CF3ClHNOBrRRab!228 IV-1-2 Switch of chlorenium face selectivity for two products of the chloroetherification reaction. Based on the results above , we were interested in determining if the switch in chlorenium face selectivity can also occur in the enantioselective haloetherification of alkenes .1 When trans -aryl -substi tuted alkenes such as compound IV-2 were subjected to the optimized condition s for the enantioselective h aloetherification reactions two products were produced, t he desired chloroetherified product IV-2B (43% yield and 82:18 er) along with the chlorocyclized product IV-2C (36% yield and 97:3 er, see Figure IV -2). Notably, aliphatic substituted alkenes under the same optimized condition s yielded the desired intermolecular products exclusively in high yield and stereoselectivity . We sought to understand whether the chlor enium face selectivity would switch in these two products (inter - and intramolecular chlorofunctionalized products) , similar to the dich lorination case . We were able to a get crystal structure for cyclized product IV-2C.2 However, several attempts to obtain a single crystal for the intermolecular product IV-2B failed. In order to unequivocally assign the stereo centers of chloroetherified product IV-2B, compound IV-2C was transformed to IV-2B in two step s as shown in Figure IV -3. Figure IV -2: The trans -aryl -substituted alkenes form two products during the enantioselective chloroetherification reaction !PhHNArOPhOHClHNArO10 mol% (DHQD) 2PHAL 2.0 equiv DCDMH IV-2B 43% yield 82:18 erNOArPhCl+RSIV-2C 36% yield 97:3 erMeCN: H2O (9:1) -10 ¡C IV-2 Ar = 4-Br-Ph !229 Treating the chlorocyclized product with 1.5 N HCl at reflux followed by protection of the amine with 4 -bromobenzoylc hloride produces halohydrin ent-IV-2B. Optical rotation, a s well as HPLC co -injection, confirmed that i t was indeed the enantiomer of IV-2B that had resulted from this transformation (Figure IV-3). These results lead us to conclude that the chlorenium face selectivity switches while the two products are formed du ring the enantioselective chlorofunctionalization reactions (both the enantioselective dichlorination and haloetherification reactions) . !230 Figure IV -3!"Switch of chlorenium face selectivity for the two products of the chloroetherification reaction. IV-1-3 Classical perception of electrophilic addition to alkenes vs. Nucleophile Assisted Alkene Activation (NAAA) In a classical way, the chiral catalyst dictates the face selectivity of the alkene (re face or si face) in the formation of halonium ion intermedi ates.3-4 If the chiral cat alyst selects one face of the alkene to form the intermediate ion IV-2Õ, the nature of nucleophile s does not effect the halenium face selectivity (Figure IV -4). PhHNArOPhOHClHNArO10 mol% (DHQD) 2PHAL 2.0 equiv DCDMH IV-2B 43% yield 82:18 erNOArPhCl+RSIV-2C 36% yield 97:3 erMeCN: H2O (9:1) -10 ¡C IV-2 Ar = 4-Br-Ph 1) 1.5N aq. HCl reflux, 22 h PhOHClHNArOent-IV-2B RS2) 4-Br-BzCl Et3N, cat. DMAP NOArPhClRSIV-2C PhOHClHNArORSPhOHClHNArOent-IV-2B RSIV-2B !231 However, our results show various nucleophiles can affect the chlorine face selecti vity. As dep icted in Figure IV -4b, with H2O as the nucleophile the chlorenium face selectivity for the halohydrin product IV-2B has an R configuration. On the other hand, when 4 -bromobenzamide acts as the nucleophile, the chlorine face se lectivity for cyclized product IV-2C result in an S configuration (Figure IV -4b). Figure IV -4: (a) The classical way for indicating halenium face selectivity (b) various nucleophiles dictates face selectivity Mechanistic investigations to understand the latter results are underway. Nonetheless, this observation leads credence to our earlier finding on the RHR2R1H1PhHHClHPhH2ClClAr = 4-Ph-Br IV-2Õ ClNHOArR1 = Ph R2 = CH 2NH(CO)Ar NHOAr+PhHNArOH2OPhOHClHNArOSRClRNOArPhClSRPhHNArOPhOHClHNArO10 mol% (DHQD) 2PHAL 2.0 equiv DCDMH IV-2B 43% yield 82:18 erNOArPhCl+RSIV-2C 36% yield 97:3 erMeCN: H2O (9:1) -10 ¡C IV-2 Ar = 4-Br-Ph RSent-IV-2Õ Ar = 4-Ph-Br IV-2Õ IV-2B ent- IV-2C ab!232 halocyclization reaction that showed in lieu of a stepwise activation of alkenes (electrophilic attack on the alkene) and subsequent nucleophilic bond formation, the reac tion actually proceeds via a concerted mechanism. Our proposed Nucleophile Assisted Alkene Activation (NAAA) pathway suggests that the proximity of the nucleophile to the olefin leads to the activation of the olefin (pre -polarization) for capturi ng of the electrophile from its source. Based on the latter supposition, the nucleophile should be part of the rate -determining step and thus can affect the halogen face selectivity (Figure IV -5a, b). 5 Figure IV -5: (a) Classical perception of the electrophilic addition to alkenes (b) Nucleophile Assisted Alkene Activation (NAAA) YAHABXYYHABXAYHAABXPath A Path B -AH-AHABXABX= F, Cl, Br, I YAH!!YXBAYH!!YXABAXYYABAHAYHYPre-polarization of olefinConcerted TS Path C ba!233 IV-1-3-1 18O KIE studies prove the role of the nucleophile in the transition states Different experiments such as transition state calculation, kinetic isotopic effects (KIE ) and NMR studies have provided support for the NAAA pathway. The summary of two of the experiments performed by Dr. Kumar Ashtekar would be helpful for readers. 5 The 18O KIE experiment for the racemic chlorolactonization reaction would directly probe the role of nucleophile in the NAAA pathway. The 1:1 mixture of IV-3-16O and IV-3-18O were treated with 0.1 equivalents of DCDMH in CHC l3 at room temperature to form the mixture of 16O and 18O chlorocyclized products (IV-3C and IV-3C*). The ratio of these products shows a significant 18O KIE ( K16O/K18O = 1.026). In contrast, the reaction of 4 -methoxy substituted aryl IV-4 as control experiment shows almost unity value 18O KIE ( K16O/K18O = 1.009). These results indicate that the nucleophile should be part of the rate -determining step. Figure IV -6: 18O KIE experimental results for IV-3 and IV-4 PhXHXXXPhClDCDMH (0.1 equiv) CHCl3 (0.05 M) rt, 1 h IV-3C , X = 16OIV-3C* , X = 18OK16O/K18O = 1.026 IV-3 , X = 16OIV-3* , X = 18OArXHXXXArClDCDMH (0.1 equiv) CHCl3 (0.05 M) rt, 1 h IV-4 , X = 16OIV-4C* , X = 18OK16O/K18O = 1.009 Ar = OMe-Ph IV-4 , X = 16OIV-4* , X = 18O!234 IV-1-3-2 NMR resonance displaying the interaction of nucleophiles with the alkenes The NMR studies demonstrate the pre -polarization and activation of alkenes by the tethered nucleophile. The free acid displays proton resonance for olefinic hydrogen s at 6.50 for H a and 5.62 for H b, while 13C resonance appears at 130.4 and 129.8 ppm, respectively. Changing the tethered nucleophile to carboxylate (more nucleophilic than carboxylic acid) lead s to shielding of H a and C-Ha, where as the more proximal H b and C -Hb deshielded relative to the acid. The above NMR studies indicate that the interaction between the nucleophile and the alkene (pre -polarization) would be an important feature for electrophilic addition reactions such as halofunctionalization. Figure IV -7: NMR resonance of olefinic C and H displaying the interaction of nucleophiles with the alkenes ! 13C-Ha(PPM)130.4! 13C-Hb(PPM)129.8127.8133.7PhHaHb!Nuc!Increased electron density leads to shielding of Ha and C-H a!235 IV-1-4 Kinetic studies In order to demonstrate that the enantioselective chlorofunctionalization follows the NAAA pathway, illustrating that nucleophile in these reactions is part of the transition state and exhibits first order kinetic is essential. In the classical kinetic studies, pseudo first order app roximation s are used to figure out kinetic orders of each reactant in reaction. In this a pproximation excess amount of the reactant ([ B]) as compare d to other reactant is used, thus during the reaction the concentration of compound B does not change. By th is approximati on, the rate of reaction is related to the concentration of one component. In this case, plotting rate vs. concentration of A would reveal the order for compound A (Figure IV-8). 6 Figure IV -8: The classical method for kinetic studies (pseudo first order approximation) We have demonstrated the use of various nucleophiles for the enantioselective intermolecular chloroetherification. 1 In all cases, the nucleophiles were employed as a co -solvent to out -compete the cyclization reaction and simultaneously furnish the intermolecu lar products in high yield and selectivity (Figure IV -9). Thus, applying the pseudo first order kin etic approximation to reveal the kinetic order of the nucleophile in the A + BCr = k [A]n[B]nIf [ B]>>[A]r = k! [A]nk! = k [B]nn = Order of reactant in reaction r = Rate of reaction k = Rate constant !236 enantioselective intermolecula r chloroetherification would not be applicable due to the large excess of nucleophile under the optimized conditions. Extensive literature research was performed in an attempt to find a solution for the above problem and determine the kinetic order of nucleophiles in this type of reactions . Figure IV -9: Nucleophiles were used as co -solvents in the enantioselective chloroetherification reactions IV-1-5 Kinetic competition studies in HDDA reactions Hoye and coworkers recently dev eloped a mild and facile path for the synthesis of benzynes as ver satile and reactive interm ediates. 7 These a rynes can be trapped by different nucleophiles. The in situ formation of benzyne from triyne IV-5 at 26 ¡ C followed by intermolecular trapping of the benzyne intermediate IV-6 produces the complex molecule IV-7 in 93% yield (Figure IV -10). These one-pot reactions, known as the hexadehydro -Diels-Alder (HDDA) reactions (Figure IV -10), can produce a plethora of interesting products. !R2NuCl/BrR1HNOArR1HNArOR210 mol% (DHQD) 2PHAL 2.0 equiv DCDMH or NBS Nucleophile :MeCN (3:7), 0.01 M, -30 oC H2O:MeCN (1:9), -10 oCAr = 4-NO 2-PhR1, R2 = H, Ar, Alk >25 examples up to > 99.5:0.5 dr, er, rrNucleophile: R-OH, R-CO 2H or H 2O!237 Figure IV-10: The hexadehydro -Diels-Alder reaction In the course of employing different nucleophiles that would trap the HDDA-derived benzyne IV-10, an interesting observation was made. The HDDA -reaction of triyne IV-8 in neat cyclohexanol IV-9 produced predominant ly the addition products IV-11 in 80% yield (Table IV-1, entry 1). 8 However, a small amount of reduced benzyne product IV-12 was observed ( IV-11: IV-12 = 12:1, entry 1). Surprisingly, treating triyne IV-9 with 1.6 equivalents of cyclohexanol at 85 ¡C reversed the selectivity of products. ( IV-11: IV-12 = 1:17, entry 2). The reduced benzyne product IV-12 was formed in 60% yield under these condition s (Table IV-1, entry 2). OTMS OTMS OSiMe 2tBuCDCl326 ¡C46 hOSiMe 2tBuOTMS OtBuMe 2SiIV-5 IV-6 IV-7 93% yield !238 Table IV -1: Competitive H 2-transf er vs. addition product in HDDA reaction !!!Entry [IV-9] equiv IV-9 11:12 Yield 1 9.5 M (neat) 1000 12:1 80%, IV-11 2 0.013 M (in CDCl 3) 1.6 1:17 60%, IV-12 ! Based on the above results, these two reactions have different kinetic profiles relative to cyclohexanol. The authors investigated the kinetic order of the trapping reagent (such as cyclohexanol) for the addition product IV-11 and the reduced b enzyne products IV-12. However, a pplying pseudo first o rder approximation to examine the kinetic order of the alcohol (trapping age nt) is not possible since an excess amount of cyclohexanol (1000 equivalents) for the formatio n of alcohol addition products IV-11 is used (see Table IV-1, entry 1). OTMS n-PrOH85 ¡COn-PrTMS !!On-PrTMS OHOn-PrTMS HHOIV-8 IV-9 IV10 IV-11 IV-12 IV-13 !239 Hoye and coworkers cleverly design ed the protocol to probe the kinetic order for the benzyne trapping process. 8-9 They designed triyne IV-14 that contains a competing intramolec ular trap serve as an internal clock. By performing the reaction in var ious concentration of the trapping ag ent and determining the ratio of products arising from the intramolecular product IV-15 vs. the product derived from the engagement of trapping agent (bimolecular capture of benzyne such as IV-16a/b, IV-17), the kinetic order of the trapping agent can be calculated. The triyne IV-14 and i-PrOH (70 molar equiv) were dissolved in varying amount of CDCl 3 to produce series of solutions with different initial concentration of tri yne. E ach solution was heated to 68 ¡C and after 18 h the reactions were quenched and concentrated. Various ratio of intermolecular -Diels-Alder product IV-15 and intermolecular products that arise from i-PrOH engagement ( IV-16a/b, IV-17) were observed as a function of the conce ntration of the isopropanol . Notably, the addition products IV-16a/b were formed in the same ratio (10:1) regardless of the isopropanol concentration. !240 Table IV -2: Kinetic competition study employing an internal clock reaction !![i-PrOH] (Bulk) [i-PrOH] (Monomer) 16a/15 17/15 1.31 0.83 1.2 0.46 0.66 0.49 0.37 0.26 0.44 0.35 0.19 0.17 0.33 0.28 0.13 0.12 ! The ratio for the rate expression for the formation of IV-16a and IV-15 is shown in eq (1), and it can be rewritten as eq (2). Since i-PrOH is in excess , its concentrati on approximately remains unchanged during the reaction. Equation (2) can be shown as eq (3), which can also be express ed as eq (4) by mathematic al manipulations (Figure IV -11). Plotting ln([ 16a]/[15]) vs. ln[ i-PrOH ]mono determines the order of isopropanol for the alcohol addition pathway. The same protocol can be used to determine the kinetic order of i-PrOH relative to reduced product IV-17. The plot shows that the kinetic order of isopropanol for the alcohol addit ion pathway is two. However, for the redox reaction pathway, the kinetic order of i -PrOH is one (Figure IV-11).8 NRTsNRTsNRTsBnXYNRTsBnHHi-PrOH CDCl368 ¡C18 hIV-14 IV-15 X YIV-16a i-PrO H IV-16b H i-PrOIV-17 [i-PrOH] bulk/[IV-14 ]o = 70 !241 Figure I V-11: The kinetic Formulas and ln -ln plot, which the kinetic order was obtained !!!!"#!!!!"!!!!!!!!"!!!!"#$% !!!!"!!!!!"!!!"!!!!!!!!!! !!"#!!!"!!!!!!!!!"!!!!"#$% !!!!"!!!!!"!!!"!!!!!!!! !!"#!!!"!!!!!!!!!!"#$% !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! !"!!"#!!!"!!!!!"!"#$% !!"!!!!!!!!!!!!!!!!! Notably, alcohols aggregate in solutions, the entropy and enthalpy energies for different alcohols were determined experimentally and by calculation. The enthalpy and entropy energy associated with dimerization of isopropanol in CCl 4 has been calculated to be -5.7 kcal/mol and -19.5 kcal/mol, respectively. 10 The free energy was calculated for a parti cular temperature by applying to the formula !G = !H - T !S. Subsequently, the equilibrium con stant (Keq) for isopropanol dime rization at 68 ¡C was obtained by employing the following formula ( !G = -RTlnKeq). ln 16a/15 or 17/15!242 IV-2 Results and discussions !IV-2-1 Kinetic competition studies for chloroetherification reactions ! The E-aryl -substituted all yl amide IV-18 in the presence of 10 mol% (DHQD)2PHAL and 100 equivalents of MeOH as a nucleophile in acetonitrile at ambient temperature forms the mixture of products ( IV-18B, IV-18BÕ and IV-18C). Clearly, methanol is engaged in the formation of two diastereomers of the intermolecular chloroetherified products. However, in the chlorocyclized product IV-18C, the tethered amide acts as an intramolecular nucleophil e. The chlorocyclized product IV-18C could be used as an internal clock for the kineti c competition studies similar to what Hoye and coworkers report. 8 Applying kinetic competition form ulas as shown in Figure IV -12 yield the kinetic order of the nucleophile (methanol) for the formation of intermolecular products IV-18B, IV-18BÕ (Figure IV -12). !243 Figure IV -12: Kinetic competition studies for enantioselective chloroetherifications !"!!"#!!!"#!!!!!"!"#$ !!"!!!! !"!!"#!!!!"#!!!!!"!"#$ !!"!!!! The E-allyl amide IV-18 in the presence of 10 mol% (DHQD) 2PHAL and 100 (molar equiv alent) of methanol was dissolved in different amount s of acetonitrile. Adding two equivalents of DCDMH to these series of the soluti on at room temperature forms different ratio s of intermolecular products (IV-18B, IV-18BÕ) and cyclized products IV-18C, as a function of the concentration of methanol (Table IV -3). Conducting the chl orofunctionalization reaction in 1.26 molar methanol gave intermolecu lar chloroetherified products (m ajor diastereomer IV-18B and minor diastereomer IV-18BÕ) and chlorocyclized product IV-18C in the ratio of 26.0: 21.8: 52.3, respect ively (Table IV-3, entry 1). Applying higher concentration of methanol produce d desired chloroetherified diastereomer IV-18B with higher selectivity (see entries 1 to 4). Surprisingly, t he HNArOOMe ClHNArONOArClIV-18 Ar=p-NO 2-Ph+10 mol% (DHQD)2PHAL 2.0 equiv DCDMH 100 equiv MeOH ACN, rt IV-18B Major diastereomer IV-18C RSSROMe ClHNArORRIV-18BÕ Minor diastereomer !244 amount of minor intermolec ular diastereomer did not depend on the concentration of methanol (see entries 1 to 4, the amount of compound IV-18BÕ is constant). Table IV -3: The ratio of the IV-18B and IV-18C is related to the concentration of MeOH Entry Conc MeOH (M) 18B: 18BÕ: 18C a 1 1.26 26.0: 21.8: 52.3 2 1.85 29.7: 22.2: 48.3 3 3.45 34.3: 21.6: 44.1 4 6.06 38.7: 20.6: 40.7 aDetermined by NMR Plotting ln( 18B/18C) vs. ln [MeOH ]mono suggests that the process leading to the major intermolecular diastereomer IV-18B is first orde r for methanol. Interestingly, p lotting ln(18BÕ/18C) vs. ln[MeOH] mono indicates that the kinetic order for formation of minor diastereomer IV-18BÕ is zero for methanol (Figure IV -13). These results lead us to conclude that two distinct mechanisms are in play , HNArOOMe ClHNArONOArClIV-18 Ar=p-NO 2-Ph+10 mol% (DHQD) 2PHAL 2.0 equiv DCDMH 100 equiv MeOH ACN, rt IV-18B Major diastereomer IV-18C RSSROMe ClHNArORRIV-18BÕ Minor diastereomer !245 leading to either the desired interm olecular products IV-18B or the minor intermolecular addition IV-18BÕ. !"!!"#!!!"#!!!!!"!"#$ !!"!!!! !"!!"#!!!!"#!!!!!"!"#$ !!"!!!! IV-2-2 Proposed mechanism for chlorenium face selectivity switch for products IV -18B and IV-18C The NAAA pathway suggests, the nucleophile activates alk enes by pre -polarization, and should be part of the transition state. The fact that the kinetic order for the forma tion of intermolec ular product IV-18B is one with regards to methanol lead us to suggest the NAAA pathway is a factor in chlor enium face selectivity switch in the enantioselective chloroetherification reactions. The tethered benzamide nucleophile activates (pre -polarization ) the alkene from the re face. However, the MeOH as an intermolecular nucleophile activates from the other face of the alkene ( si face). The transition state indicates concerted activation and addition of the electrophilic halogen to alkenes. Our prelimina ry ln (18B/18C) or ln (18BÕ/18C) Figure IV -13: The ln -ln plot from which the kinetic order was obtained !246 mechanistic studies lead us to propose the concerted transition states depicted in Figure IV -14 to explain the divergent chlor enium face selectivity observed in the products of the chloroetherifcation reactions. It merit mentions, m echanistic investigat ions are under way to elaborate on the nature of interaction for different nucleophiles with the chiral catalyst and alkenes to show how the characteristic of the nucleophile can change the face selectivity and enantioselectivity of the products. IV-2-3 Exploring mechanism of formation of the minor diasteomer IV -18BÕ ! As described above, t he kinetic order of methanol for the formation of the minor di astereomer is zero. Therefore, t he NAAA pathway cannot explain the mechanism for the formation of IV-18BÕ. The combined observation s described above for the enantioselective intermolecular chloroetherification report leads us to propose a carbocationic mechanism. As dep icted in Figure IV -16, varying substituents on the aryl group of Z -aryl -substitu ted allyl amides resulted in a Ar1OMeClHNAr2ONOAr2Ar1Cl!!Ar1HHNHOAr2AClBAAr2HHMeOHHNAr2OAClBH3 A!!Ar1HNAr2OAr1 = p-Me-Ph Ar2 = p-NO 2-PhRSSRAABAClNNOOClCl=!!Ar1HHNHOAr2Ar2HHMeOHHNAr2OBH3 !!AABAClABAClIV-18B Major diastereomer IV-18C Figure IV -14: Pr oposed mechanism for switch in chlorenium face selectivity !247 significant effect on the diastereoselectivity of the chloroetherified products. Electron donating substituent s such as methoxy g ave the correspo nding products IV-19B with 1:1 dr (Figure IV -15). However, reducing the electron donation cause formation of chloroe therified products with higher diastereoselectivity (see products IV-19B to IV-22B). Employment of trifluorome thyl group as substituent gave chloroetherified product IV-22B with >20:1 dr. Figure IV -15: Different substituents on aryl group of allyl amides effects diastereoselectivities of products R2OMe ClR1HNOArR1HNArOR210 mol% (DHQD) 2PHAL DCDMH (2 equiv) MeOH :MeCN (3:7), -30 oC, 0.01 MAr = 4-NO 2-PhR1, R2 = H, Ar, Alk >25 examples up to > 99.5:0.5 dr, er, rrArHNOOMe ClIV-21B 82% yield 3.3:1 dr, 99:1 rr >99% ee( 80% ee)ArHNOOMe ClIV-22B 87% yield >20:1 dr, 99:1 rr >99% eeF3CArHNOOMe ClIV-19B 80% yield 1:1 dr, 99:1 rr >99% ee (84% ee)MeO ArHNOOMe ClIV-20B 87% yield 1.3:1 dr, 99:1 rr >96% ee( 94% ee)!248 Hammett analysis of the later data by plotting log( B/BÕ) vs. " (Hammet t value for different substituents), indicate s carbocation formation during the chloroethrification reactions (Figure IV -16). Figure IV-16: Hammett plot for diastereoselectivities of chloroetherified products !!!! HNArOOMe ClHNArOIV-(19-22)Ar=p-NO 2-PhR = H, Me, OMe, CF 310 mol% (DHQD) 2PHAL 2.0 equiv DCDMH IV-(19B-22B)ROMe ClHNArORIV-(19BÕ-22BÕ)RMeOH :MeCN (3:7), -30 oC, 0.01 MR Ratio (B:BÕ) " OMe 1:1 -0.27 CH3 1.3:1 -0.14 H 3.3:1 0 CF3 >20 :1 0.53 -1.4-1.2-1-0.8-0.6-0.4-0.200.2-0.4-0.200.20.40.6Hammett Ploty = -0.44545 - 1.6467x R2= 0.99138 log (3/2)6log (B/BÕ) !249 The mechanism for the formation of two chloroetherified diastereomers and chlorocyclized pro ducts is summarized in Figure IV -17. The NAAA pathway suitably explains the chlor enium face selectivity switch for the major interm olecular product IV-18B and the cyclized product IV-18c. Nonetheless, t he zero kinetic order of the nucleophile for the f ormation of the minor diastereomer IV-18BÕ and the Hammett analysis lead us to prop ose carbocation production for the formation the l atter product. Figure IV -17: Proposed mechanism for the formation of intermolecular and intramolecular products in enantioselective chloroetherification reactions Ar1OMeClHNAr2ONOAr2Ar1Cl!!Ar1HHNHOAr2AClBAAr2HHMeOHHNAr2OAClBH3 A!!RSSRAABAClNNOOClCl=!!Ar1HHNHOAr2Ar2HHMeOHHNAr2OBH3 !!AABAClABAClIV-18B Major diastereomer IV-18C Ar1HNAr2OIV-18 Ar1 = p-Me-Ph Ar2 = p-NO 2-PhAr2HHHNAr2OAClBH3 A!Ar1OMeClHNAr2ORRMeOHIV-18BÕ Minor diastereomer Pre-polarization of olefinPre-polarization of olefinConcerted TS Concerted TS !250 IV-2-4 Experimental section !The E-allyl amide IV-18 (0.04 mmol, 11.8 mg) in the presence of 10 mol% (DHQD) 2PHAL (0.004 mmol, 3.1 mg) and methanol (4 mmol, 160 µl) were dissolved in different amount s of acetonitrile (0.5 mL, 1 mL , 2 mL, 3 mL ) in a screw -capped vial equipped with a stir bar . After stirring for 2 min DCDMH (15.8 mg, 0.08 mmol, 2.0 equiv) was added to these series of solution at room temperature. 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