CATALYTIC ASYMMETRIC DESYMMETRISATION AN D KINETI C RESOLUTION OF UNSATURATED AMI DES VIA HALOFUNCTION ALIZATION By Yi Yi A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry Ð Doctor of Philosophy 2018 ABSTRACT CATALYTIC ASYMMETRIC DESYMMETRISATION AN D KINETIC RESOLUTION OF UNSATURATED AMINDES VIA HALOFUNCTIONALIZ ATION By Yi Yi My doctorate research work with professor Borhan is mainly focused on developing new asymmetric halofunctionalization reactions. Chapter 1 describes the catalytic asymmetric desymmetrisation of diene s via chlorocyclization. Chapter 2 describes the kinetic resolution of propargyl amides via chlorocyclization. Both desymmetrisation and kinet ic resolution using cinchona alkaloid (DHQD) 2PHAL as catalyst afford good diastereoselectivity and enantioselectivity. Chapter 3 discloses efforts to develop asymmetric ipso -halocyclization via dearomatization of phenol derivatives. Chapter 4 describes a n ovel and practical method to access N,O -acetals using commercial ly available XtalFluor -E¨ as catalyst. iii I dedicate this to my mother and father, family and friends for their endless support. iv ACKNOWLEDGMENTS Firstly I would like to express my sincere gratitude to my a dvisor Prof. Borhan for the continuous support of my Ph.D study and research, for his patience, motivation, and immense knowledge in these years. He has always been my role model in science who inspire me to be dedicated to chemistry, and to stay curio us. Secondly I would like to thank all my committee members: Prof. William Wulff, Prof. Ned Jackson and Prof. Mitch Smith. They provided me a lot of guidance about scientific research. I would also like to give regards to other faculty and staff, specifically Dr Daniel Holmes for his help for NMR analysis and Dr Richard Staples for his help for X -ray crystallography. Besides, for those who helped me during my research, specifically Dr Arvind Jaganathan, Dr Kumar Ashtekar, Hadi Gholami, Xiaopeng Yin and my undergraduate Mengke Fan I would like to offer my sincere thanks. Last but not the least, I would like to thank my parents and family who always support me with extensive love and understanding. v TABLE OF CONTENTS LIST OF TABLES .......................................................................................................... viii LIST OF FIGURES .......................................................................................................... x LIST OF SCHEMES ....................................................................................................... xi KEY TO ABBREVIATIONS ........................................................................................... xv CHAPTE R ONE Catalytic Enantioselective Desymmetrisation of Dienes via Chlorocyclization ............................................................................................................ 1 1.1 Introduction ......................................................................................................... 1 1.2 Results and discussion ..................................................................................... 15 1.2.1 Preliminary results ......................................................................................... 15 1.2.2 Solvents study ............................................................................................... 17 1.2.3 Chlorine source study ................................................................................... 20 1.2.4 Additive study ................................................................................................ 21 1.2.5 Screen of other conditions ............................................................................. 22 1.2.6 Summary of optimal condition ...................................................................... 23 1.3 Substrate scope ................................................................................................ 24 1.3.1 Initial application of optimal condition ............................................................ 24 1.3.2 Substrate scope ............................................................................................. 25 1.4 Derivatization of oxazi ne products .................................................................... 32 1.5 Substrate synthesis .......................................................................................... 36 1.6 Summary .......................................................................................................... 40 1.7 Experimental section ........................................................................................ 40 1.7.1 General information ....................................................................................... 40 1.7.2 General procedure for synthesis of substrates .............................................. 41 1.7.3 Analytical data for dienones ........................................................................... 44 1.7.4 Analytical data for substrates ......................................................................... 50 1.7.5 General procedure for desymmetrisation ...................................................... 63 1.7.6 Analytical data for desymmetrisation products .............................................. 64 1.7.7 Derivatization of oxazine product ................................................................... 78 1.8 X -ray crystal structure data ............................................................................... 82 1.8.1 X -ray crystal structure for I-77 ....................................................................... 82 1.8.2 X -ray crystal structure for I-118 ..................................................................... 86 1.8.3 X -ray crystal structure for I-119 ..................................................................... 91 REFERE NCES ....................................................................................................... 95 CHAPT ER TWO Kinetic Resolution of Propargyl Amides in a Chlorocyclization Reaction ...................................................................................................................... 100 2.1 Introduction ..................................................................................................... 100 vi 2.2 Results and discussion .................................................................................. 112 2.2.1 Evaluate the efficiency of kinetic resolution ................................................. 112 2.2.2 Screening of halogen sources ..................................................................... 113 2.2.3 Screen ing of solvents .................................................................................. 114 2.2.4 Catalyst study .............................................................................................. 116 2.2.5 Temperature study ...................................................................................... 117 2.2.6 Variations from standard conditions ............................................................ 119 2.2.7 Substrates scope with TFE as solvent ......................................................... 120 2.2.8 Substrate scope wi th HFIP as solvent ......................................................... 122 2.2.9 Substrate scope with TFE -DCM as solvent at low temperature ................... 123 2.2.10 Large scale reaction .................................................................................. 124 2.3 Kinetic resolution of racemic amides by dehalogenation ................................ 125 2.4 Summary ........................................................................................................ 129 2.5 Acknowledgement .......................................................................................... 130 2.6 Experimental section ..................................................................................... 130 2.6.1 General information ................................................................................. 130 2.6.2 General procedure for screening and optimization of kinetic resolution ... 131 2.6.3 Analytical data for cyclized products ........................................................ 131 2.6.4 General procedure for synthesis of substrates ......................................... 145 2.6.5 Analytical data for kinetic resolution substrates and intermediates ......... 147 2.7 1H NMR study ................................................................................................. 164 2.8 X -ray crystallography structure data .............................................................. 165 2.8.1 X-ray crystal structure data of II-55 .......................................................... 165 2.8.2 X-ray crystal structure data of II-79 .......................................................... 170 REFERENCES ..................................................................................................... 175 CHAPT ER THREE Intramolecular ipso -Halocyclization to Construct a Chiral Spiro -Center ............................................................................................................... 178 3.1 Introduction ..................................................................................................... 178 3.2 Results and discussion ................................................................................... 190 3.2 .1 Screen the halogen source with N-(4-methoxyphenyl) -4-methyl -N-(3-phenylprop -2-yn-1-yl)benzenesulfonamide .............................................. 190 3.2 .2 Asymmetric ipso -halocyclization of N -(4-methoxy -2-methylphenyl) -4-methyl -N-(3-phenylprop -2-yn-1-yl)benzenesulfonamide .......................... 191 3.2.3 Asymmetric ipso -halocyclization with 2 -bromo - 4-methoxy - 1-((3-phenylprop -2-yn-1-yl) oxy) benzene ........................................................ 193 3.2.4 Use of Br ¯nsted acid ( R)-VANOL dihydrogenphosphate as catalyst ....... 195 3.2.5 Asymmetric ipso -halocyclization with N-(4-methoxy -2-methylphenyl) -3-phenyl -N-tosylpropiolamide ..................................................................... 197 3.2.6 Asymmetric ipso -halocyclization with N-(2-hydroxyphenyl) -N-methyl -3-phenylpropiolamide ................................................................................. 201 3.3 Summary and fu ture work .............................................................................. 206 3.4 Experimental section ..................................................................................... 208 3.4 .1 General information ................................................................................. 208 3.4.2 Synthesis of substrate III -48, III-52 .......................................................... 208 vii 3.4.3 General procedure of screening and optimization of ipso -halocyclization of substrate III-48 and III -52 ........................................................................ 209 3.4.4 Procedure of synthesis and ipso -halocyclization of substrate III-54 ......... 214 3.4.5 Synthesis and ipso -cyclization of substrate III-61 .................................... 216 3.4.6 Synthesis and ipso -cyclization of substrate III-72 .................................... 219 3.5 X -ray crystallography data .............................................................................. 224 3.5.1 X-ray crystallography data of III-53 .......................................................... 224 3.5.2 X-ray crystal structure data of III-55 ......................................................... 228 3.5.3 X-ray crystallography data of III-82 .......................................................... 231 3.5.4 X-ray crystallography data of III-57 .......................................................... 236 3.5.5 X-ray crystallography data of III-72 .......................................................... 240 3.5.6 X-ray crystallography data of III-81 .......................................................... 244 REFERENCES ..................................................................................................... 248 CHAPT ER FOUR XtalFluor -E¨ Mediated Proto -functionalization of N-vinyl Amides: Access to N-acetyl N,O -acetals ................................................................................... 252 4.1 Introduction ..................................................................................................... 252 4.2 Results and discussion .................................................................................. 262 4.2.1 Optimization for intermolecular hydroalkoxylation of enamide ................ 262 4.2.2 The scope for intermolecular hydroalkoxylation of enamides ................... 263 4.2.3 Mechanistic studies .................................................................................. 265 4.2.4 HBF 4 catalyzed hydroalkoxylation ............................................................ 270 4.2.5 Study of intramolecular hydroalkoxylation ................................................ 272 4.2.6 Attempts of constructing C -N/C -C bond mediated by XtalFl uor -E¨ .......... 273 4.2.7 Summary ................................................................................................. 274 4.3 Experimental section ...................................................................................... 275 4.3.1 General information ................................................................................. 275 4.3.2 General procedure A for screening and optimization ............................... 275 4.3.3 Analytical data for products ...................................................................... 276 4.3.4 General procedure for synthesis of unsaturated amides and analytical data .......................................................................................................... 287 4.4 Acknowledgement .......................................................................................... 297 REFERENCES ..................................................................................................... 298 viii LIST OF TABLES Table 1. 1 The study of TFE -HFIP cosolvent system ..................................................... 19 Table 1. 2 The study of other solvents ........................................................................... 20 Table 1. 3 Electrophilic chlorine source study ................................................................ 21 Table 1. 4 The study of additives ................................................................................... 22 Table 1. 5 The study of catalyst ..................................................................................... 23 Table 2 .1 Screening of electrophilic halogen source ................................................... 114 Table 2 .2 Screening of solvent .................................................................................... 116 Table 2 .3 Catalyst loading study ................................................................................. 117 Table 2 .4 Temperature study for different substrates ................................................. 118 Table 2 .5 Variations from standard condition .............................................................. 120 Table 2 .6 Substrate scope using TFE as solvent ........................................................ 122 Table 2 .7 Substrate scope using HFIP as solvent ...................................................... 123 Table 2 .8 Substrate scope using TFE -DCM as solvent at Ð30 ¡C .............................. 124 Table 2 .9 Kinetic resolution of racemic allyl amides via dichlorination ........................ 127 Table 2 .10 Screen variations from standard condition to improve dr .......................... 129 Table 3 .1 Halogen screening for substrate III-48 ........................................................ 191 Table 3 .2 Optimization of reaction conditions for substrate III-52 ................................ 192 Table 3 .3 Catalyst screen for substrate III-54 .............................................................. 194 Table 3 .4 Evaluation of ( R)-VANOL -hydrogen phosphate ........................................... 196 Table 3 .5 Halogen screening for substrate III-61 ........................................................ 198 Table 3 .6 Optimization of reaction conditions for substrate III-61 ................................ 200 ix Table 3 .7 Screen of different electrophilic halogen reagent for III-72 .......................... 203 Table 3 .8 Catalyst screening for III-72......................................................................... 204 Table 3 .9 Evaluation of chiral ligand with different Lewis acid .................................... 205 Table 4 .1 Reaction condition optimization ................................................................... 263 Table 4 .2 Substrates scope ......................................................................................... 265 Table 4 .3 Control experiments with increasing loadings of XtalFluor -E¨ ..................... 266 Table 4 .4 Control experiments of nucleophiles with different nucelophilicity and acidity ......................................................................................................................... 267 Table 4 .5 Comparison of yields between XtalFluor -E¨ and HBF 4¥OEt 2 as catalyst ..... 271 Table 4 .6 Intramolecular cyclization mediated by XtalFluor -E¨ ................................... 272 x LIST OF FIGURES Figure 1.1 The 1H NMR of substrate I-76 before and after recrystalization ................... 17 Figure 2.1 a) plot of ee of recovered starting material vs conversion as a function of S; b) plot of ee of product vs conversion as a function of S .......................... 102 Figure 2. 2 Stoichiometric NMR studies of substrate -catalyst mixtures in CF 3CH2OH at ambient temperature and 0.02 M concentratio n of substrate and catalystÉÉÉÉ.16 5 Figure 4.1 19F NMR spectrum of a) XtalFluor -E¨; b) XtalFluor -E¨ + 1 equiv MeOH; c) XtalFluor -E¨ + 2 equiv MeOH; d) XtalFluor -E¨ + 4 equiv MeOH; e) XtalFluor -E¨ + 5 equiv MeOH; f) XtalFluor -E¨ + 10 equiv MeOH ( ! 63.21 was from standard compound benzotrifluoride 1 equiv.) ........................... 269 xi LIST OF SCHEMES Scheme 1. 1 Desymmetrization of dienes ........................................................................ 2 Scheme 1.2 Desymmetrization of diynes ........................................................................ 3 Scheme 1.3 Desymmetrization of anhydrides ................................................................. 4 Scheme 1.4 Desymmetrization of meso -diol ................................................................... 4 Scheme 1.5 Desymmetrization via alkylation and Michael addition ................................ 5 Scheme 1.6 Desymmetrization via alkylation ................................................................. 6 Scheme 1.7 Two types of desymmetrization via halofunctionalization ........................... 7 Scheme 1.8 The first enantioselective halocyclization with practical ee and Titanium complex catalyzed iodocylization ...................................................................... 8 Scheme 1.9 Desymmetrization of cyclohexadiene via bromo -lactonization .................... 9 Scheme 1.10 HenneckÕs work of organocatalyzed enantioselective desymmetrization ......................................................................................................... 10 Scheme 1.11 YeungÕs work of organocatalyzed enantio selective desymmetrization ... 11 Scheme 1.12 Desymmetrization of cyclopropyl carb oaldehyde by 1,3 -dichlorination through umploung aldehyde iminium activation ............................................................. 12 Scheme 1.13 Our groupÕs previous work ...................................................................... 14 Scheme 1.14 First snapshot of desymmetrization of diene amide ............................... 15 Scheme 1.1 5 Optimal conditions for substrate I-76 ...................................................... 24 Scheme 1.16 Initial test of three different optimal conditions ........................................ 25 Scheme 1.17 Substrate scope using TFE -HFIP (v/v 7:3) as solvent ............................ 27 Scheme 1.18 Substrate scope using TFE -DCM (v/v 7:3) as solvent ............................ 29 xii Scheme 1.19 The substrate scope .............................................................................. 31 Scheme 1.20 Derivatization of product s........................................................................ 33 Scheme 1.21 Other failed derivatizations ...................................................................... 35 Scheme 1.22 Synthesis of aryl substituted diene .......................................................... 36 Scheme 1.23 Mitsunobu strategy to access aryl substituted dienes ............................. 37 Scheme 1. 24 Reductive amination strategy to access aryl substituted dienes ............ 37 Scheme 1. 25 SN2 strategy to access to aryl substituted diene .................................... 38 Scheme 1. 26 Reduction of oxime to access aryl substituted dienes ............................. 39 Scheme 1. 27 Synthesis of aliphatic substituted diene .................................................. 40 Scheme 1.2 8 Synthesis of bis(aryl) -amides .................................................................. 41 Scheme 1.2 9 Synthesis of bis(alkyl) -amides ................................................................. 43 Scheme 2.1 Catalytic kinetic resolution ....................................................................... 101 Scheme 2.2 Early landmark studies in kinetic resolution of alkene ............................. 105 Scheme 2.3 a) Cobalt -salen catalyzed HKR; b) Mechanism of HKR .......................... 106 Scheme 2 .4 (DHQD) 2AQN catalyzed alcoholysis of meso UNCA .............................. 107 Scheme 2 .5 DKR of lactone II-15 catalyzed by a thiourea -based bifunctional catalyst ....................................................................................................................... 108 Scheme 2 .6 Kinetic resolution of 2 -oxindole catalyzed by cinchona -alkaloid squaramide ................................................................................................................. 108 Scheme 2.7 Kinetic resolution of unsaturated amine and alcohols ............................. 110 Scheme 2.8 Access to propargylic amines by coupling of alkyne and aldimine .......... 111 Scheme 2 .9 Our groupÕs previous work and proposed work ....................................... 112 Scheme 2.10 Two distinct stereoselective steps leading to diastereomers ................. 126 Scheme 2.11 Kinetic resolution of II-82....................................................................... 129 xiii Scheme 3 .1 C-O bond forming ipso -cyclization .......................................................... 178 Scheme 3 .2 ipso -cyclization catalyzed by Iridium catalyst .......................................... 179 Scheme 3 .3 ipso -cyclization catalyzed by a Palladium catalyst .................................. 180 Scheme 3 .4 ipso -cyclization of an activated alkyne by single electron oxidation path ............................................................................................................................. 181 Scheme 3 .5 Silver catalyzed dearomatization of indole .............................................. 182 Scheme 3 .6 C-N bond forming ipso -cyclization ......................................................... 183 Scheme 3 .7 Types of dearomatization via halofunctionalization ................................. 184 Scheme 3 .8 Fluorocyclization of tryptamine and tryptophol ........................................ 185 Scheme 3 .9 Enantioselective ipso -chlorocyclization of indoles ................................... 186 Scheme 3 .10 LarockÕs ipso -iodocyclization ................................................................ 187 Scheme 3 .11 Electrophilic ipso -iodocyclization with para -activiting group ................. 188 Scheme 3 .12 Electrophilic ipso -iodocyclization without para -activiting group ............ 188 Scheme 3 .13 ipso -iodocyclization to access spiro -pyrimidine/coumarin .................... 189 Scheme 3 .14 Ipso -chlorocylization of O -linker Substrate ............................................ 193 Scheme 3 .15 ipso -bromocyclization of benzoyl protected N-tethered substrate ........ 196 Scheme 3 .16 ortho -directing group assisted nucleophilic substitution of propargylic alcohols ...................................................................................................................... 202 Scheme 3 .17 Evaluation of NBS with chiral dihydrogen phosphate ............................ 205 Scheme 3 .18 Reactions of other derivatives ............................................................... 206 Scheme 3 .19 Gold catalyzed ipso -cylclization ........................................................... 207 Scheme 3 .20 Other subs trates for ipso -halocyclization .............................................. 207 Scheme 4 .1 Catalytic intramolecular hydroalkoxylation .............................................. 253 Scheme 4 .2 TfOH catalyzed intermolecular hydroalkoxylation ................................... 253 xiv Scheme 4 .3 Intramolecular alkoxylation catalyzed by I 2 and PhSiH 3 .......................... 254 Scheme 4 .4 Access to N-acetyl -N,O-acetals via condensation of amide with aldehyde ..................................................................................................................... 255 Scheme 4 .5 Access to N-acetyl -N,O-acetals via activation of nitrile ........................... 256 Scheme 4 .6 Chiral phosphoric acid catalyzed addition of alcohol to imine ................. 256 Scheme 4 .7 Chiral phosphoric acid catalyzed oxyfluorination .................................... 257 Scheme 4 .8 Sulfur -based fluorinating reagent ............................................................ 258 Scheme 4 .9 XtalFluor -E¨ as deoxofluorinating reagent .............................................. 259 Scheme 4 .10 XtalFluor -E¨ mediated benzylation ....................................................... 260 Scheme 4 .11 XtalFluor -E¨ mediated aziridine opening ............................................... 261 Scheme 4 .12 Reaction scheme .................................................................................. 262 Scheme 4 .13 Proposed mechanism ........................................................................... 270 Scheme 4 .14 Other attempts of intramolecular cyclization ......................................... 273 Scheme 4 .15 Constructing C -N bond .......................................................................... 273 Scheme 4 .16 Attempts of constructing C -C bond ....................................................... 275 xv KEY TO ABBREVIATIONS [! ] specific rotation ! chemical shift † angstrom ACN acetonitrile AcOH acetic acid Ar aromatic BF3¥OEt 2 boron trifluoride diethyl ether BINOL 1,1Õ -Bi-2-naphthol Bz benzoyl cm centimeter CHCl3 chloroform d doublet DABCO 1,4 -diazabicyclo[2,2,2]octane DBDMH 1,3 -dibromo -5,5 -dimethylhydantoin DCDMH 1,3 -dichloro -5,5 -dimethylhy dantoin DCM dichloromethane DMAP 4-diaminopyridine DMF N,N -dimethylformamide (DHQ) 2AQN dihydroquinine(anthraquinone -1,4 -diyl) -diether (DHQ) 2PHAL dihydroquinine 1,4 -phthalazinediyl diether xvi (DHQD) 2PHAL dihydroquinidine 1,4 -phthalazinediyl diether (DHQD) 2Pyr dihydroquinidine -2,5 -diphenyl -4,6 -pyrimidinediyl diether ee enantiomeric excess Et3N triethylamine Et2O diethyl ether EtOAc ethyl acetate equiv equivalents g gram(s) h hour(s) HPLC high pressure liquid chromatography HRMS high resolution mass spectrometry Hz hertz iPr iso propyl J coupling constant m multiplet m-CPBA 3-chloroperoxybenzoic acid MeOH methanol min minutes mg milligram MHz megahertz mmol millimole m. p. melting point xvii M molar NBS N-bromosuccinimide NCP N-chlorophthalamide NCS N-chlorosuccinimide NaHCO 3 sodium bicarbonate NaOH sodium hydroxide Na2SO4 sodium sulfate Na2S2O3 sodium thiosulfate NMR nuclear magnetic resonance Ph phenyl q quartet s singlet Rf retention factor rt room temperature TBAF tetrabutylammonium fluoride TBS t-butyldimethylsilyl TCCA trichloroisocyanuric acid TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Ts tosyl UV ultraviolet -visible spectrosco 1 CHAPTER ONE Catalytic Enantioselective Desymmetrisation of Dienes via Chlorocyclization 1.1 !Introduction Desymmetrization of achiral or meso molecules is an important strategy to yield enantioenriched products. Normally people define desymmetrization as a transformation which conve rts an achiral or meso compound to an enantiomerically enriched chiral product by the destruction of a symmetry el ement. 1 The substrates for desymmetrization are wide, including but not limited to C 2-symmetric dienes, diynes, anhydrides, epoxides, aziridines, diols and dicarbonyl compounds. 1 Among various desymmetrization strategies, the desymmetrization of meso -dienes, not surprisingly, is one of the most widely investigated category considering the importance of olefin functionalization in organic synthesis. To name a few (Scheme 1.1), the Schreiber group reported desymmetrization of meso -dienes I-1 using Sharp less asymmetric epoxidation. 2-3 Landais used (DHQ) 2PYR as catalyst to desymmetrise silyl -substituted cyclohexadiene I-3 via dihydroxylation. 4 Belley used Sharpless asymmetric dihyd roxylation on substituted dienes I-5 to access enantio - enriched pentols I-6.5 Martin desymmetrized diene I-7 to get cyclo -propane -delta -lactone I-8 and I-9 via rhodium carboximide I-10 catalyzed enantioselective intramolecular cyclopropanation. 6 2 Scheme 1.1 Desymmetrization of dienes Similarly, desymmetrization of diynes has also been studied. For example, HelquistÕs group desymmetrized diynes I-11 via silver catalyzed intramolecular hydroamination OH(!)-DIPT, Ti(O iPr)4tBuOOH OOHOBn OBn OBn OBn 94%, 97% eeDesymmetrization of meso-dienes by epoxidation: Desymmetrization of cyclohexadiene by AD reaction: SiMe 2OHK2Os(OH) 4, K2CO3K3Fe(CN) 6, tBuOH/H 2OSiMe 2OHOHOH80%, 65% eeDesymmetrization of meso-dienes by dihydroxylation: OH0.3 mol% K 2OsO 2¥2H2OK3Fe(CN) 6, K2CO3HOOHOHOHOH70%, 98% eeDesymmetrization of meso-dienes by cyclopropanation: OON21 mol% Rh 2(5- S-MEPY)4CH2Cl2, reflux OOHHHOOHHH+73%, endo:exo =1:1.2, 92% ee(endo), 91% ee(exo )NOCO2MeHRhRhRh2(5- S-MEPY)4I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 I-10 (DHQ) 2PYR, 0 ¼C 2 mol% (DHQD) 2PHAL 3 (Scheme 1.2). This strategy can be applied to the synthesis of monomorine I. 7 Yamada incorporate d CO2 into bispropargylic alcohol I-13 to form chiral cyclic carbonates using catalytic silver acetate and chiral Schiff base ligand I-15.8 Fu used Rh(Tol -BINAP) to catalyze the cyclization of meso -diynes I-16 to generate cyclopentanones I-17 in excellent yield and ee.9 Scheme 1.2 Desymmetrization of diynes More recently, impressive advances have been seen in organocatalyzed enantioselective desymmetrization. Among these, cinchona -alkaloid derived catalysts play an important role, espec ially in desymmetrization of meso -anhydrides. A large body of work for desymmetrization via nucleophilic ring -opening of anhydrides by alcohols have been reported. 1 List et al . reported a novel textile supported cinchona alkaloid derived TBS TBS NH210 mol% Ag(Phen)OTf NTBS 95%PhPhOHCO2 (1.0 Mpa) 3 mol% AgOAc I-15 OOOPhPh98%, 92% eeNNNNI-11 I-12 I-13 I-14 I-15 RROHOMe 10 mol% [Rh(( R)Tol-BINAP)]BF 4OROMe Rup to 95% eeI-16 I-17 CH2Cl2, 10 ¼CCH3CN, 50 ¼C, 8 h 4 sulfonamide cataly st I-19 to desymmetrise anhydrides I-18 by metholysis (Scheme 1.3). 10 Hamersak et al used quinine or quinidine to catalyze the desymmetrization of anhydride I-21 to afford half ester I-22 by using benzyl alcohol (Scheme 1.3). 11 The products can be further derivatized into Rolipram. Scheme 1.3 Desymmetrization of anhydrides Besides anhydrides, meso -1,2 -diol s I-23 have been desymmetrized by NBS induced mono -oxidation using quinine -derived urea catalyst I-24 (Scheme 1.4). 12 This method furnish !-hydroxy ketone s I-25 in good yield and enantioselectivity. Scheme 1.4 Desymmetrization of meso -diol OOONHOMe NHSOOCF3CF310 equiv MeOH, MTBE, rt CO2MeCO2H99%, 93%eeOOOOONNOHOCH3OOCO2HCO2BnBnOH 69%, 95% eeI-18 I-19 I-20 I-21 I-22 I-19 ROHOHR10 mol% I-24 3 equiv N-bromophthalimide CHCl3/PhCl (10:1) 24 ¼C, 2-24 h ROOHRup to 94% yield up to 95% eeNNNHOCH3NHCF3CF3OI-24 I-23 I-25 5 Melchiorre used cinchona alkaloid based primary amine I-28 as catalyst in a highly selective !-alkylation of 4 -substituted cyclohexanones reaction (Scheme 1.5). 13 You and co-workers employed cinchonine derived urea catalyst I-31 for an intramolecular Michael addition between cyclohexadienone and a pendant biphenylsulfonyl methylene (Scheme 1.5). 14 Scheme 1.5 Desymmetrizatio n via alkylation and Michael addition Mukherjee developed an allylic alkylation reaction of prochiral 1,3 -dinitropropane I-33 using quinidine derived thiourea catalyst I-35 (Scheme 1.6). 15 The catalyst is a bifunctional catalyst which contains a Lewis basi c tertiary amine and a Br¿nsted acidic thiourea moiety. Similarly, he also developed an alkylative desymmetrization of prochiral cyclopentene -1,3 -diones I-37 by a quinine -based urea catalyst I-38 (Scheme 1.6). 16 On+NO2NO220 mol% I-28 40 mol% TFA ONO2NO2up to 94% yield up to 94% eeNNOCH3NH2I-28 ORSO2PhSO2PhRSO2PhSO2PhO10 mol% I-31 CH2Cl2, rt NNHNHNOF3CCF397% yield 91% eeI-31 I-26 I-29 I-30 I-32 Br23 W CFL, NaOAc toluene, 0 ¼CI-27 6 Scheme 1.6 Desymmetrization via alkylation Cinchona -alkaloid catalysts have been widely used in halofunctionalization recently as well. However, the use of halofunctionalization as a strategy to achieve desymmetrization is relatively underdeveloped. Based on literature reports, desymmetrization in volved halofunctionalization can be roughly divided into two types in terms of substrates (Scheme 1.7): 1) substrates that contain only one site for formation of halonium and two symmetrical nucleophilic sites that can be trapped by halonium ion; 17-21 2) s ubstrates that contain two symmetrical sites that can form halonium and only one site to be trapped by halonium. 17, 22 -24 NO2NO2CO2EtPhOBoc NO2NO2CO2EtPhCH2Cl24† MS, Ð10 ¼CNNNHNHSCF3+OOPh+MeNO 21.5 equiv Na 2CO3PhCF 3 (0.5 M) Ð10 ¼COOPhNMeO NHNOHNCF3CF3I-36 74%dr = 10:1 97% eeI-38 I-34 I-37 I-39 88%, 94% eeI-33 I-35 10 mol% I-35 I-38 7 Scheme 1.7 Two types of desymmetrization via halofunctionalization Enantioselective desymmetrization via h alofunctionalization was first reported in 1992 by TaguchiÕs group (Scheme 1.8). 19 They desymmerized prochiral diallyl(hydroxyl)acetic acids and C 2-symmetric diols through an iodolactonization process by usin g stoichiometric chiral Titanium (IV) complex based on a TADDOL derivativ e. Treatment of I-40 with Ti( iOPr) 4, pyridine, I 2 and TADDOL derived I-41 leads to cyclized trans - tetrahydrofuran derivative I-42 with 36% ee. The iodolactonization of symmetric diene I-44 with the same condition gave lactone I-45 with higher ee (67%). Th is was also the first example of an enantioselective halocyclization with practical ee. Later they reported Titanium TADDOL complex I-47 can induce highly enantioselective carbocyclization of 4 -pentenylmalonate I-46 (Scheme 1.8). 17 The high enantioselectivity was due to the strong coordination between the malonate substrate and the Titanium complex. NuNuNuX+type 1 type 2 X+X+ 8 Scheme 1.8 The first enantioselective halocyclization with practical ee and Titanium complex catalyzed iodocylization More recently several groups reported organocatalyzed desymmetrization using a halofunctionalization strategy (Scheme 1.9). Kan reported a catalytic desymmetrization of cyclohexadiene derivatives I-49 via asymmetric bromolactonization. 22 NBS was used as a brominating reagent and (DHQD) 2PHAL as catalyst. For most cyclohexadiene substrates, the ees were low to moderate (40% - 80% ee). Similarly, MarinÕs group reported a single example of desymmetrization of prochiral cyclodienoic acid I-51 by bromolactonizati on, although only 46% ee was achieved. 23 They applied a BINOL derived bifunctional catalyst I-52 which contains both acidic phenol and basic amidine. OHOHOOHIOOHI+36% ee64% (cis:trans = 1: 5.4) CO2HOHOIOHO67%65% eeOOPhMePhPhOHPhPhOHI-41 I-40 I-42 I-43 I-44 I-45 CO2BnCO2Bn1 equiv I-47 I-46 1.2 equiv I 21.2 equiv CuO CH2Cl2, Ð78 ¼C to 0 ¼CBnO 2CCO2BnIHI-48 OOMeMePhPhOPhPhOTi2I-47 1 equiv I-41 1 equiv Ti(O iPr)41 equiv pyridine 1.5 equiv I 2CH2Cl2, Ð78 ¼C to rt 1 equiv I-41 1 equiv Ti(O iPr)41 equiv pyridine 1.5 equiv I 2CH2Cl2, Ð78 ¼C to rt 96% 85% ee 9 Scheme 1.9 Desymmetrization of cyclohexadiene via bromo -lactonization Henneck et al. reported another desymmetrization approach of bromolactonization of dialkynoic acids I-54 catalyzed by (DHQD) 2PHAL (Scheme 1.10). 24 They proposed that the pyridazine unit of the catalyst can activate the carboxylic acid by hydrogen bonding. Besides, they r eported a haloetherification reaction of a symmetric diol I-56. The success of this reaction depends on the selective opening of the in situ -generated meso -halonium ions. The chiral counteranion of BINOL -phosphoric acid circumvents the erosion of enantiose lectivity caused by halonium olefin -to-olefin transfer. 25 HO2CORn1.2 equiv NBS CHCl3-Hexane (1 : 1) 10 mol% (DHQ) 2PHAL Ð40 ¼COOBrORnn = 1, 2 up to 93% eeI-49 I-50 CO2H1.2 equiv TBCO CH2Cl2/tol (1:1) Ð50 ¼C, 4 dI-51 OBrOI-53 72%, % eePhOHNNMe 2MeI-52 BrBrTBCO OBrBr10 mol% I-52 10 Scheme 1.10 HenneckÕs work of organocatalyzed enantioselective desymmetrization YeungÕs group reported bromocyclization of symmetric olefinic 1,3 -dicarbon yl compounds I-59 giving rise to functionalized dihydro furans (Scheme 1.11). 21 They used quinidine -derived -amino -thiocarbamate I-60 as the catalyst and NBS as the bromination source. Even though moderate to high ees were reported for most substrates, reactions were sluggis h and took 4 days to complete. They believe that the amino -thiocarbamate is a bifunctional catalyst: the Lewis basic sulfur can activate Br in NBS and the quinuclidine moiety in the catalyst can deprotonate the !-H of the carbonyl. Similar work from YeungÕ s group is the desymmetrization of trisubstituted alkenoic 1,3 -diols I-62 via bromoetherification using Lewis basic C 2-symmetric cyclic sulfide I-63 as catalyst (Scheme 1.11). 18 They believe that chiral cyclic sulfide can activate the NBS to give a chiral bromine species and the chiral bromine is then delivered to the olefin. MsOH can facilitate the formation of sulfide -Br species by protonation of the succinimide. Likewise, Yeun g developed a desymmetrization of diolefinic diols I-65 by enantioselective bromoetherification using quinidine -derived thiocarbamate catalyst I-66.26 They proposed OHOR1R2R21.2 equiv NBS 10 mol% (DHQD) 2PHAL OOR1R2R2BrR1 = CO 2Me, Aryl, CH 2OR, HR2 = H, Alkyl, Aryl up to 96% eeI-54 I-55 HOOHRRRRNOX20 mol% I-57 CH2Cl2, 0 ¼C2-12 h I-56 ORROHRRXI-58 60-89% up to 71% eeSiPh 3OOSiPh 3POONaI-57 CHCl3-Hexane (1 : 1) Ð30 ¼C, 15 h 11 that the acidic proton of the 1,3 -diol may interact with the quinuclidine nitrogen atom of the catalyst and an intramolecular hydrogen bond can help lock the substrate in a pseudo six -membered ring chair conformation. Scheme 1.11 YeungÕs work of organocatalyzed enantioselective desymmetrization Most of the reported enantioselective desymmetri zations which use halofunctionalization strategy involve the formation of a C -Br bond. The exception is that NHOOHRBrRÕOSArHN pseudo chair conformation PhPhOPhO20 mol% I-60 ,1.1 equiv NBS PhMe, Ð40 ¼C 4 days OPhBrPhPhONNOMe OSNHI-59 I-61 I-60 PhOH10 mol% I-63 ,1.2 equiv NBS 1 equiv MsOH CH2Cl2, Ð78 ¼C2 days OPhBrOHI-62 I-64 OH81%, dr =11.5:1, 71% eeOSOOOt-butyl t-butyl I-63 PhOH4† MS, CHCl 3/hexane (4:7) Ð60 ¼C, 12 hOBrPhHOHOBnBn90%88:12 dr86% eeNNOOSNHEtO OMe MeO I-65 I-67 I-66 10 mol% I-66 1.2 equiv NBP 89%, 96% ee 12 by Gilmour and coworkers who developed an iminium catalyzed 1,3 -dichlorination of cyclopropane carb oxa ldehyde I-68 (Scheme 1.12). 27 He used Macmill anÕs first -generation chiral imida zolidinone catalyst to activate cyclopropane carb oxaldehyde s. Collidine hydrochloride and perchlorinated quinone were used as nucleophilic and electrophilic chlorinating reagents, respectively. However, this method does not belong to olefin halofunctionali zation. Up to this time , catalytic enantioselective desymmetrization which involves olefin chloro -functionalization is absent. Scheme 1.12 Desymmetrization of cyclopropyl carboaldehyde by 1,3 -dichlorination through umploung aldehyde iminium activatio n In 2010 our group developed the chlorolactonization of 4 -substituted 4 -pentenoic acid I-70 (Scheme 1.13). This method was the first catalytic enantioselective chlorolactonization with synthetically useful ees. Since then we realized that (DHQD) 2PHAL can be a promising candidate for catalyzing other chlorofunctionalization reac tions. In 2011, our group reported a highly stereoselective chlorocyclization of unsaturated amides I-72 giving rise to the highly functionalized oxazine motif using (DHQD) 2PHAL as catalyst. 28 In that study dichlorodiphenylhydantoin (DCDPH) was found super ior to other electrophilic chlorine sources. More interestingly, we found RRCHONHCl20 mol% ClNRÕ2RRClClClClClClOrtClCHORRClNHNOBnHMeMeMe¥I-68 I-69 13 trifluoroethanol (TFE) as an optimal solvent after exhaustive solvent screening. TFE revealed its uniqueness, which has also been demonstrated in a later study, as a highly polar, pr otic, weak nucleophilic and noncoor dinating counteranion solvent. TFE greatly promoted the enantioselectivity of the reaction. The reaction scope is general in terms of the olefin substitution pattern. Both aliphatic and aromatic substituents are well tole rated. Based on this methodology our group developed a highly diastereoselective kinetic resolution of racemic olefinic amides I-74 via chlorocyclization. 29 We proposed that (DHQD) 2PHAL concomitantly differentiates the chirality of racemates as well as ind uces high face selectivity of the olefin. The Krel value for some substrates are up to 50 which is sufficient to get both substrate and product in pure enantioform. In the terms of mechanism, we proposed that the stereoinduction results from the protonated (DHQD) 2PHAL, which could be Br¿nsted acid catalys is or Lewis base assisted Br¿nsted acid catalysis (LBBA). 30 14 Scheme 1.13 Our groupÕs previous work Inspired by the work mentioned above, a symmetric diene skeleton with amide was designed as nucleophile. The strategy of chlorocyclization has been applied to bis -allylamide to afford highly functionalized oxazines with three contiguous stereo -centers RCO2H10 mol% (DHQD) 2PHAL 1.1 equiv DCDPH 1 equiv BnOH CHCl3:Hex (1:1) Ð40 ¼COORClup to 90% eeThe first example of catalytic enantioselective halolactonization: R2R1NHOAr1.1 equiv DCDPH 2 mol% (DHQD) 2PHAL TFE, Ð30 ¡C, 1- 2 h ONArR1R2ClNNOClClOPhPhDCDPH Chlorocyclization of unsaturated amides: 14 substrates , yield up to 99% ee up to 99%R1R2NHPhOracemate 0.55 equiv NCP 0.5 mol% (DHQD) 2PHAL CF3CH2OH (0.1M), 24 ¡C, 10-90 min ONR1R2PhCl+R1R2NHPhOKinetic resolution of unsaturated amides: 15 substrates selectivity generally up 50 NNONOMe NMeO O(DHQD) 2PHAL NNNOOClNCPI-70 I-71 I-72 I-73 I-74 I-75 15 and a remaining double bond which can be f urther derivatized. T he chirality of oxazine can be used to induce stereoinduction to the double bon d without external chiral catalysts. 1.2 !Results and discussion 1.2.1 ! Preliminary results Dr. Jaganathan first started this project. After the success with kinetic resolution of alkenoic amides with (DHQD) 2PHAL, desymmetrization of meso -alkenoic amides seemed like a reasonable possibility . Initially he employed the same condition s for the chlorocyclization of amides to the kinetic resolution of the meso compound I-76. In the presence of 10 mol% of (DHQD) 2PHAL and 1.1 equiv NCP, the reaction afforded the cyclized pr oduct in good diastereoselectivity (>9:1 dr) and enantioselectivity (89% ee) but with incomplete conversion (70%) and low isolated yield (30%) at room temperature after 30 min (Scheme 1.14). The absolute stereochemistry of the product was confirmed by X -ray crystallography. Encouraged by this result, we began optimization studies of reaction conditions. Scheme 1.14 First snapshot of desymmetrization of diene amide PhNHBz 1.1 equiv NCP 10 mol% (DHQD) 2PHAL ONPhPhPhCl>9:1 dr, 89% ee30% yield, 70% conversion PhI-76 I-77 PhNHBz 1.1 equiv NCP 10 mol% (DHQD) 2PHAL ONPhPhPhCl93% ee34% yield, 66% conversion PhI-76 I-77 ONPhPhPhClClOCH2CF3+12%I-78 TFE (0.04 M) 23 ¼C, 30 min TFE (0.04 M) 23 ¼C, 17 h 16 The reaction was first repeated with the same substrate and used the same condition of the first snapshot by Arvind (Scheme 1.14). Instead of 30 min the reaction time was increased to 17 h. However, the reaction was still not complete after 17 h and only reached 66% conversion (34% isola ted yield) with 93% ee. The major side -product is the TFE incorporated product I-78, which has also been observed in the kinetic resolution of alkenoic amide s. The TFE incorporated product is due to the excess electrophilic chlorine source in the reaction reacting with the cyclized product. Trifluoroethanol (TFE) is a nucleophilic solvent and excess amount of TFE in the reaction is prone to be trapped by chlorinium ion. Besides the TFE incorporated product, it was also found that the purity of substrate is an important factor and can erode the yield. Even though the substrate looks pure by NMR, some polymers or inorganic salts generated in the synthesis of the substrate can be separated by column chromatography only with difficulty (I will discuss the substr ate synthesis in a later part). As can be seen in Figure 1.1, spectrum a is the substrate I-76 after recrystalization, spectrum b is the substrate I-76 after purification through column chromatography, spectrum c is the impurity trace in b. Although spectr um b has almost all the correct peaks of the substrate (except for the NH hydrogen shifts), there is a broad peak in the aromatic region (6.75 ppm -7.75 ppm) which was initially neglected. Spectrum c shows the isolated material buried under the aromatic reg ion (6.75 ppm-7.75 ppm). The 1H NMR absorption of this fraction are too messy to characterize, they may be due to some polymer or inorganic salts. The very pure form of the substrate I-76 should be white flake s which c an be obtained from recrystallization. 17 Figure 1.1 The 1H NMR of substrate I-76 before and after recrystalization 1.2.2 ! Solvents study From the initial study, it was realized that the incomplete conversion was one of the biggest issue s. The reaction is not complete in TFE after an extended time. TFE proved to be superior to any other solvents in our previous study of chlorocyclization s as well as for the dichlorination of unsaturated amides in terms of enantioselectivity. However, the meso -diene substrate and the de symmetrized product have poor solu bility in TFE, which presumably leads to the incompletion of the reaction. An attempt was made to find an ideal solvent which can provide better soluability than TFE and meanwhile not deteriorate the enantioselectivity. We proposed that TFE can facilitate hydrogen bonding between catalyst and substrate or that its acidity can protonate the quinuclidine nitrogen of (DHQD) 2PHAL. 29 Based on this principle, an a b c 18 attempt was made to find an alternative solvent which was also proti c, acidic and highly polar. Another commonly used fluorinated solvent is HFIP (hexafluoro iso propanol). The reaction was investigated with HFIP instead of TFE while keeping the other conditions the same. Gratifyingly the reaction was much faster and was com plete within 2 h at room temperature. However, the increased the reaction rate resulted in sacrificed diastereoselectivity ( dr = 4.5:1) while the enantioselctivity was reduced somew hat (Table 1.1, entry 2). Aside from giving better solu bility, HFIP also in hibits the generation of a major sideproduct arising from TFE incorporation, therefore the yield is much higher (95%). Then the TFE -HFIP cosolvent system was explored trying to find a ratio that can give high yield as well as good selectivity (Table 1.1). By varying the TFE -HFIP ratio from 3:7 to 7:3, a clear trend was observed: the more HFIP that was used the reaction is faster but gives a lower dr; the more TFE the higher enantioselectivity but the lower yield (Table 1.1, entry 4, 6, 7). Another trend, as can be see n from Table 1.1 is that lowering the temperature from room temperature to "#10 ¼C greatly increases the ee (entry 3 and entry 8). But fu rther cooling to #30 ¼C did not make too much difference to the ee, although reaction was slower (entry 5 and entry 6). 19 Table 1.1 The study of TFE -HFIP cosolvent system Since TFE /HFIP co -solvent did not solve the problem, the investigation was extended to other solvents (see Table 1.2). Other non -protic and less polar solvents like dichloromethane and aceto nitrile, not surprisingly lead to poor results. There was no reaction at all using DCM as solvent at #30 ¼C. The reaction in MeCN at room temperature was very sluggish and the enantioselectivity dropped significantly (Table 1.2, entry 2). It turned out tha t TFE is essential and plays an important role. Then mixtures of TFE with other non -fluorinated solvents were examined . TFE -MeCN did not lead to a complete reaction after 22 h (Table1.2, entry 3), even though the ee and dr were good. The reaction was even slower in the more polar solvent combination of TFE -DMF, and the ee was just moderate. Finally, it was found that the TFE-DCM solvent system greatly increases the reaction rate, giving 91% yield, predominantely as a single diastereomer in 98% ee (Table1.2, entry 5). The substrate is more solu ble in DCM than in TFE alone. However, TFE is very crucial as well and did make a big difference (Ta ble 1.2, entry 1 and entry 5). PhNHOPhPh7.7 mol% (DHQD) 2PHAL solvent (0.05 M) ONPhClPhPhCl++ONPhClPhPhClOCH2CF3Cl+ (equiv) NCS (1.0) NCS (1.1) NCP (1.0) NCP (1.1) NCP (1.1) NCP (1.1) NCP (1.1) NCP (1.0) entry 12345678temp (¡C) rtrtrt-30-10-30-30-10solvent (ratio) TFEHFIPTFE-HFIP (3 : 7) TFE-HFIP (7 : 3) TFE-HFIP (1 : 1) TFE-HFIP (1 : 1) TFE-HFIP (6 : 4) TFE-HFIP (3 : 7) time (h) 18212173121719%yield ( I-77 )a61 (76) 9591 (100) 58 (71) 99 (100) 96 (100) 91 (100) 69 (70) %yield ( I-78 )a10--10----dr (I-77 )b> 20:1 4.5 : 14.5 : 1> 20:1 6 : 16 : 16.8 : 121 : 1%ee (I-77 )c9391919896979597a yield of isolated product is reported and conversion is in the parentheses; b dr was determined form 1H NMR; c ee was determined by chiral HPLC column. I-76 I-77 I-78 20 Table 1.2 The study of other solvents 1.2.3 ! Chlorine source study The TFE-incorp oration product I-78 (the major side product) was formed due to the excess of electrophilic chlorine source in the presence of TFE solvent. To get rid of this side product, the effect of adding different amount s of electrophilic chlorine reagent were studi ed. When 2 equiv of a Cl+ source (NCS or NCP) was used the reaction became messy and the expected product was not obtained (Table 1.3, entry 1 and 2). The major product was only the TFE incorporated product I-78. When only 1 equiv of NCP was used at #10 ¼C, the reaction proceeds to 70% comple tion (Table 1.3, entry 3). If just a little bit excess (1.3 equiv) of NCP was added in TFE -HFIP (3:7) solvent, the reaction was complete in 3 h and no TFE incorporated product was observed (Table 1.3, entry 4, although the dr was only 4:1. It is noteworthy that N-chlorophthalimide (NCP) was more reactive than N-chlorosuccinimide (NCS) and meanwhile gave higher yield, NCS lead to more TFE incorporated side product (Table 1.3, entries 6 and 7). Another electrophilic PhNHOPhPh7.7 mol% (DHQD) 2PHAL solvent ( 0.05 M) ONPhClPhPhCl+Cl+ (equiv) NCP (1.1) NCS (1.1) NCP (1.1) NCP (1.1) NCP (1.1) entry 12345temp (¡C) -30rt-30-30-30solvent (ratio) DCMMeCN TFE-MeCN (1 : 1) TFE-DMF (1 : 1) TFE-DCM (7 : 3) time (h) 242822483%yield ( I-77 )a032 (41) 68 (85) 59 (76) 91 (100) dr (I-77 )b-3.8 : 1> 20 : 1 10 : 1> 20 : 1 %ee (I-77 )c-47845198a yield of isolated product is reported and conversion is in the parentheses; b dr was determined form 1H NMR; c ee was determined by chiral HPLC column. I-76 I-77 21 chlori ne reagent DCDMH was more reactive and gave a complex mixture of products and only 15% of the desired product was isolated (Table1.3, entry 5). Table 1.3 Electrophilic chlorine source study 1.2.4 ! Additive study To understand other factors that affect the reaction outcome the effect of addition of some additives was studied (Table 1.4). These additives include base s, Lewis acid s, Br¿nsted acid s and Lewis base s. When 1 equiv NaHCO 3 was added to the reaction at #30 ¼C, the product was obtained in lower yield and with reduced ee and dr (Table 1.1, entry 6 and Table 1.4, entry 1). Stoichiometric amounts of a Lewis base (PPh 3) and a Br¿nsted acid (benzoic acid) both decreased the reaction rate significantly while not affecting the dr and ee that much (Table 1.4, entries 2 and 3) . Interestingly a catalytic amount of the Lewis acid Yt(OTf) 3 speeds up the reaction and improved the conversion within the same time frame from 71% to 95% (Table 1.1, entry 4 and Table 1.4, entr y 4). The c ombination of 0.1 equiv Yt(OTf) 3 with 1.1 equiv NCS can push the reaction to PhNHOPhPh7.7 mol% (DHQD) 2PHAL solvent ( 0.05 M) ONPhClPhPhCl++ONPhClPhPhClOCH2CF3Cl+ (equiv) NCS (2.0) NCP (2.0) NCP (1.0) NCP (1.3) DCDMH (1.0) NCP (1.1) NCS (1.1) entry 1234567temp (¡C) -10-10-10-10-30-30-30solvent (ratio) TFE-HFIP (7 : 3) TFE-HFIP (3 : 7) TFE-HFIP (3 : 7) TFE-HFIP (3 : 7) TFE-HFIP (1 : 1) TFE-HFIP (7 : 3) TFE-HFIP (7 : 3) time (h) 417193121724%yield ( I-77 )a0069 (70) 94 (100) 15 (100) 58 (71) 29 (67) %yield ( I-78 )a4417---1031dr (I-77 )b6.7 : 1d-21 : 14.4 :1---%ee (I-77 )c--9794-9898a yield of isolated product is reported and conversion is in the parentheses; b dr was determined form 1H NMR; c ee was determined by chiral HPLC column; d dr was for product I-78 .I-76 I-77 I-78 22 completetion within 17 h and afford the product in 90% yield, 19:1 dr and 98% ee (Table 1.4, entry 5). Under the latter reaction conditions, 7% of the TFE incorporated product was observed. However, other triflate salts such as AgOTf and Zn(OTf) 2 did not affect the reaction rate. It is still not clear how Yt(OTf) 3 speed s up the reaction. Adding molecular sieves in the reaction did not accelerate the reaction and some sta rting material was left after 24 h, albeit the yield and dr were high. Table 1.4 The study of additives 1.2.5 ! Screen of other conditions Last but not the least, we screened other organocatalysts. The r eaction with the qunidine derived thiourea catalyst A was slower than using (DHQD) 2PHAL and gave racemic products (Table 1.5, entry 1). The reaction did not proceed at all with the chiral Br¿nsted acid catalyst ( R)-TRIP (Table 1.5, entry 2). Running the reaction at lower concentration (0.025 M) of the substr ate gave 80% yield of I-77 in 94% ee while moderate dr (Table 1.5, entry 3). PhNHOPhPh7.7 mol% (DHQD) 2PHAL solvent ( 0.05 M) Ð30 ¼CONPhClPhPhCl+, additives Cl+ (equiv) NCP (1.1) NCP (1.1) NCP (1.1) NCP (1.1) NCS (1.1) NCS (1.1) NCS (1.1) NCS (1.1) entry 12345d678Additives (equiv) NaHCO3 (1.0) PPh3 (1.0) BzOH (1.0) Yt(OTf) 3 (0.1) Yt(OTf) 3 (0.1) AgOTf (0.1) Zn(OTf) 2 (0.1) 4A MS solvent (ratio) TFE-HFIP (1 : 1) TFE-HFIP (1 : 1) TFE-HFIP (1 : 1) TFE-HFIP (7 : 3) TFE-HFIP (7 : 3) TFE-HFIP (7 : 3) TFE-HFIP (7 : 3) TFE-HFIP (7 : 3) time (h) 1212171717242424%yield ( I-77 )a91 (100) 26 (38) 48 (53) 90 (95) 90 (100) 73 (88) 59 (70) 80 (82) dr (I-77 )b5.5 : 15.2 : 17.9 : 1> 20 : 1 19 : 116 : 1> 20 : 1 > 20 : 1 %ee (I-77 )c9395949998---a yield of isolated product is reported and conversion is in the parentheses; b dr was determined form 1H NMR; c ee was determined by chiral HPLC column; d 7% of I-78 was observed. I-76 I-77 23 Table 1.5 The study of catalyst 1.2.6 ! Summary of optimal condition After screening the solvent, temperature, catalyst and chlorine reagent, two comparable optimal conditions were identified (Scheme 1.15). When the meso -Diene substrate I-76 is exposed to 1.1 equiv NCP, 10 mol% (DHQD) 2PHAL with TFE -DCM (v/v 7:3) as solvent at #30 ¼C the cyclized product I-77 was obtained in 91% yield as single diastereomer in 98% ee (condition A ). Similar results can be achieved by using TFE -HFIP (v/v 7:3) and 10 mol% Yt(OTf) 3 as additive (condition B). However later stu dies of the substrate scope suggested that the effect of Yt(OTf) 3 is substrate dependent. For example, o-Me substituted phenyl d iene gave lower dr with Yt(OTf) 3 than without the PhNHOPhPh10 mol% catalyst solvent (0.05 M) ONPhClPhPh1.1 equiv NCP catalyst A(R)-TRIP (DHQD) 2PHAL entry 123dtemp (¡C) -30-30-30solvent (ratio) TFE-HFIP (1 : 1) tolueneTFE-HFIP (1 : 1) time (h) 174812%yield ( I-77 )a59 (60) 0 (0) 80 (100) dr (I-77 )b1 : 4-7 : 1%ee (I-77 )c2-94a yield of isolated product is reported and conversion is in the parentheses; b dr was determined form 1H NMR; c ee was determined by chiral HPLC column; d reaction concentration is 0.025 M. NNHNNHCF3CF3SOOPOOHiPriPriPriPriPriPrOMe A(R) -TRIPI-76 I-77 24 additive in TFE -HFIP (v/v 7:3). Interestingly for some substrates, the TFE -HFIP solvent system without any other additives gave better selectivities than TFE -DCM system. For most of the substrates both conditions were applied leading to the compar able results. This will be discuss ed in the substrate scope in later sections o f this chapter. Scheme 1.15 Optimal conditions for substrate I-76 1.3 Substrate scope 1.3.1 Initial application of optimal condition With optimal condition s in hand, other substrates bearing varied substituents on the phenyl ring were exposed to the re action conditions. First the o-Me phenyl diene substrate I-79 (Scheme 1.16) was tried . The c ombination of 10 mol% Yt(OTf) 3 as additive and TFE -HFIP (v/v 7:3) as solvent gave moderate yield and 94% ee but low dr (condition B) of the product I-80. Another optimal condition with TFE -DCM (v/v 7:3) as solvent gave higher yield but still low dr (condition A). Surprisingly the reaction was complete within 12 h PhNHOPhPh10 mol% (DHQD) 2PHAL TFE-DCM (v/v 7:3, 0.05 M) Ð30 ¼CONPhClPhPh1.1 equiv NCP 91%, dr >20:1, 98% eePhNHOPhPh10 mol% (DHQD) 2PHAL 10 mol% Yt(OTf) 3TFE-HFIP (v/v 7:3, 0.05 M) Ð30 ¼CONPhClPhPh1.1 equiv NCP 90%, dr = 19:1, 98% eeI-76 I-77 I-76 I-77 condition A: condition B: 25 without Yt(OTf) 3 as additive and gave much better dr with comparable yield and ee in TFE-HFIP (condition C). Scheme 1.16 Initial test of three different optimal conditions 1.3.2 Substrate scope To obtain the best result for each substrate, bot h solvent systems were tested. First the TFE -HFIP (v/v 7:3) solvent system was used. A number of aryl substituted diene amides were evaluated by exposing to 1.1 equiv NCP and 10 mol% (DHQD) 2PHAL at #30 ¼C in TFE -HFIP (Scheme 1.17). O-methyl substituted phenyl substrate I-79 reacted to give moderate yield with decent dr and ee. Electron -withdrawing substituents on phenyl ring like p-F I-82 and p-CF3 I-85 lead to a single diastereomeric product in high yield and excellent ee. Electron -rich phenyl substituents like p-OMe I-87 and p-Me I-81 substituents PhNHO10 mol% (DHQD) 2PHAL 10 mol% Yt(OTf) 3TFE-HFIP (v/v 7:3, 0.05 M) Ð30 ¼CONPhCl1.1 equiv NCP 74%, dr = 8.6:1, 94% eePhNHO10 mol% (DHQD) 2PHAL TFE-HFIP (v/v 7:3, 0.05 M) Ð30 ¼CONPhCl1.1 equiv NCP 75%, dr = 20:1, 95% eePhNHO10 mol% (DHQD) 2PHAL TFE-DCM (v/v 7:3, 0.05 M) Ð30 ¼CONPhCl1.1 equiv NCP 97%, dr =6:1, 93% eeI-79 I-80 I-79 I-80 I-79 I-80 condition B: condition C: condition A: 26 furnished poor stereoselectivity, g iving both poor dr and ee. For the less electron -rich m-MeO substituted phenyl substrate I-86, dr increased a little bit to 4:1 while the ee was high (97%). These data suggest that the intermediate in the reaction is likely a carbocatio n, which can be highly stabilized by an electron -donating group and therefore the face selectivity of nucleophilic capture by the amide is scrambled and hence the selectivity is eroded . Both m-Br and p-Br substituted phenyl substrates I-83 and I-84 provide good ee and dr, however the reactions are not complete in an extended time rang e probably due to the poor solu bility of substrates in TFE -HFIP. For the alkyl substituted substrate tert -butyl substituted diene I-88, the diastereoselectivity is good but ee is poor. 27 Scheme 1.17 Substrate scope using TFE -HFIP (v/v 7:3) as solven t To further improve the outcome of the reaction, the TFE-DCM (v/v 7:3) solvent system was evaluated by applying to the same substrates in addition to others (Scheme 1.18). An obvious drop in diastereoselectivity was observed for o-Me substituted phenyl substrate I-79 compared with the results in TFE -HFIP. A s imilar trend was also seen for the p-CF3 substituted phenyl substrate I-85 whose dr decreased from 20:1 to 8:1. The switch of solvent had minor effect on yield and dr of the p-Me substituted substrate I-81. RRNHBz 1.1 equiv. NCP 10 mol% (DHQD) 2PHAL TFE-HFIP (v/v 7:3, 0.05 M) Ð30 ¡CRNOClRPhNHBz NHBz NHBz NHBz NHBz NHBz F3CCF3FFBr 90% dr =19:1 98% ee75% dr =20:1 95% ee86%dr > 20:1 90% ee70% dr =1.6:1 47% ee87% dr > 20:1 96% eeNHBz BrBrNHBz 66%dr >20:1 41% eeNHBz OMe OMe Br63 % (63% conv.) dr= 1.3:1 24% eeMeO NHBz OMe 37% (47% conv.) dr >20:1 82 % ee70% (80% conv.) dr >20:1 96 % ee71%dr = 4:1 97% eea yield of isolated product is reported and conversion is in the parentheses; b dr was determined form 1H NMR; c ee was determined by chiral HPLC column I-76 I-79 I-81 I-82 I-83 I-84 I-85 I-86 I-87 I-88 I-76, I-79, I-81 -I-88 I-77, I-80, I-103 -I-108 28 The p-F substituted phenyl substrate I-82 gave quantitative yield and comparable selectivity except for a minor drop in ee. The b rominated phenyl substrates I-83 and I-84, in contrast to what was observed in TFE -HFIP, all afforded products in very good yields, drs and ees. The TFE-DCM solvent system did not lead to the full consumption of the p-MeO phenyl substrate I-87 after 24 h. The diastereoselectivity of m-MeO phenyl substrate I-86 could not be improved by using TFE -DCM as solvent but the yield increased significantly (71% to 92%) . In general, reactions are faster and cleaner in TFE -DCM solvent system presumably because solubili ty is better, so the reaction is faster and side products are suppressed. Disubstituted phenyl substrate, l ike 2,6 -dichlorinated phenyl substituted diene I-92 was tested but gave no discernable reaction. Naphthyl and heteroaromatic substituents are not com patible with this system. The furan substituted substrate I-94 gave only 36% conversion after 2 days. Thiophene substituted substrate I-100 was more reactive as compared to furan substituted I-94, leading to 82% conversion, but producing a complex mixture of products. Only a 26% yield of six -member ring products were obtained in poor dr and ee. 29 Scheme 1.18 Substrate scope using TFE -DCM (v/v 7:3) as solvent The tolerance of different substitution pattern s and electronic properties were tested , as feasible, since the synthesis of the meso -diene amides is not routine. A lkyl substituted dienes were examined . t-Butyl substituted I-88 failed to give high selectivity, its steric hindrance might be a reason. More general alkyl substituents such as n-butyl I-95 and cyclohexyl I-96 substituents have been evaluated. It turned out that they both gave excellent dr and ee in good yield. This result was within our expectation based on ArvindÕs RRNHBz 1.1 equiv. NCP 10 mol% (DHQD) 2PHAL TFE-DCM(7:3, 0.05 M) Ð30 ¡CRNOClRPhNHBz NHBz NHBz NHBz NHBz NHBz F3CCF3FFBr91% dr > 20:1 98% ee96%dr > 20:1 97% eeNHBz 93%dr > 20:1 90% eeBrBrNHBz 92 %dr = 7:1 97 % eewith (DHQ) 2PHAL OMe OMe NHBz 41 % dr = 2.8:1 56% eet-But-BuBrN.R.MeO NHBz OMe NHBz ClClClClNHBz 99%dr > 20:1 95 % eeClClNHBz FF99%dr > 20:1 96% ee97%dr =6:1 93% ee75% dr =1.6:1 (ee ND)88%dr =8:1 90% ee99% dr > 20:1 94% ee53% (74% conv.) dr =1.2:1 10% eeNHBz messy ONHBz O36% conv. a yield of isolated product is reported and conversion is in the parentheses; b dr was determined form 1H NMR; c ee was determined by chiral HPLC column. ND = none determined I-76 I-79 I-81 I-85 I-82 I-89 I-83 I-84 I-90 I-91 I-86 I-87 I-92 I-93 I-94 I-76 , I-79 , I-81 -I-94, I-100 I-74 , I-77 , I-103 -I-110, I-117 SNHBz S26% (82% conv.) dr = 4.4:1 23% eeI-100 30 work on the chlorocyclization of alkenoic amides where he reporte d aliphatic substituted substrates gave excellent enantioselectivity. 28 Another variable that can be tuned is the nature of the aryl amide (Scheme 1.19). p-MeO benzoyl and p-Br benzoyl protected amides I-97 and I-98 both gave excellent diastereoselectivity and enantioselectivity but not the acetyl protection group I-99 which led to complete loss of stereoinduction and poor yield. The complete loss of stereoinduction with the acetyl group might be due to the absence of " i nteraction between catalyst and substrate. Our previous reports of successful (DHQD) 2PHAL catalyzed chlorofunctionalization of unsaturated amides, include chlorocyclization, kinetic resolution and dichlorination, all used benzoyl type protection group. The specific preference of the amide might suggest that there is a " interaction existing between catalyst and substrate which can direct the nucleophilic trap of a chlorenium from a specific face. However, at this stage we donÕt have any evidence to support this assumption. Scheme 1.19 shows the complete substrate scope. 31 Scheme 1.19 The substrate scope NHBz NHBz NHBz NHBz F3CCF3FFBr86%a, dr > 20 : 1, 90% ee70%a, dr = 1.6 : 1, 47% ee87%a, dr > 20 : 1, 96% ee96%, dr > 20 : 1, 97% eeNHBz 93%, dr > 20 : 1, 90% eeBrBrNHBz 66%a, dr > 20 : 1, 41% eeNHBz 92%b ,dr = 7 : 1, 97 % eeOMe OMe NHBz 41%, dr = 2.8 : 1, 56% eet-But-BuBr63%, dr = 1.3 : 1, 24% eeMeO NHBz OMe NHBz 99%, dr > 20 : 1, 95 % eeClClNHBz FF99%, dr > 20:1, 96% eeNHBz 88%, dr > 20 : 1, > 99.9% eeNHBz 67%, dr > 20 : 1, 98% eeNHOOMe 77%, dr > 20 : 1, 95% eeNHOBr66%, dr > 20 : 1, > 99.9 % eeNHO53%, dr = 2 : 1, 3% eeR1R1NH1.1 equiv NCP 10 mol% (DHQD) 2PHAL TFE-DCM (7:3, 0.05M) Ð30 ¡CR1NOClR1NHBz NHBz 91% , dr > 20 : 1, 98% ee75%a, dr = 20 : 1, 95% eea TFE : HFIP (v/v, 7 : 3, 0.05 M) as solvent; b (DHQ) 2PHAL was used as catalyst. R2R2OI-76 I-90 I-89 I-79 I-84 I-86 I-81 I-85 I-88 I-82 I-91 I-95 I-83 I-87 I-96 I-97 I-98 I-99 I-77, I-80, I-103-I-117 I-76 , I-79 , I-81 -I-99 32 1.4 ! Derivatization of oxazine products To demonstrate the application of this methodology, further functionalization of the oxazine products were performed (Scheme 1.20). One of the merits of this desymmetrization method is that we can access oxazine bearing a double bond. Functionalization of olefins is one of the most well studied and important transformations. Since this methodology provides a highly stereoselective access to oxazine ring s, new chiral centers can be introduced onto the neighboring double bond in the absence of an external chiral catalyst. After an exhaustive screen, it was foun d that subjecting the oxazine product (98% ee, dr > 2 0:1) to Upjohn dihydroxylation conditions affording the diol product I-118 in 86% yield with more than 20:1 dr. More importantly, the dr of diol I-118 was not eroded. The double bond could be epoxidized by using m-CPBA and expoxide product I-119 was obtain ed with a slight decrease in dr in 67% yield. The absolute stereochemistry of diol and expoxide was determined by X -ray crystallography. The oxazine product can be hydrolyzed in HCl to afford the corresponding amino alcohol I-120 in quantitative yield but with diminished dr. 33 Scheme 1.20 Derivatization of product s ONPhPhClPh3.4 mol% OsO 4 ,1 equiv NMO, acetone/ t-BuOH/H 2O (18:1:1, 0.025 M), r.t, 1 h ONPhPhClPh98% eedr > 20 :1 86%dr >20:1 OHOHI-77 I-118 Dihydroxylation ONPhPhClPh98% eedr > 20 :1 2 equiv m-CPBA ONPhPhClPh67% dr = 16 :1 OEpoxidation: I-77 I-119 DCM (0.5 M) rt, 4 h PhNOPhPh1) 1.5 M HCl 105 ¼C, 30 h2) p-BrBzCl Ph98%dr =13 :1 98 % eedr >20:1 PhHydrolysis:ClOHClHNOBrI-77 I-120 34 Other transformations have been attempted including dihalogenation, chloroetherification, cyclopropanation, aziridination and hydroxyamination (Scheme 1.21). However, most of those transformations failed. The double bond next to the oxazine ring is unreactive for these reactions. Starting material was recovered for most of the transformations. Notably dichlorination developed by our group using DCDMH and LiCl in the absence of (DHQD) 2PHAL failed to give the desired product. 31 Likewise chloroetherification in the presence of (DHQD) 2PHAL did not induce any reaction as well. Dichlorination using PCl 5 gave the dichloride product I-134 in 1:1 dr. 35 Scheme 1.21 Other failed derivatizations 2 equiv DCDMH MeOH-MCN (3:7) Ð30 ¼C10 mol% (DHQD) 2PHAL N.R2 equiv DCDMH 100 equiv LiCl TFE, Ð30 ¼CN.R.chloro-etherification: aziridination: 1.2 equivN2CO2Et5 mol% Rh 2(OAc) 4DCM, rt N.R.dihalogenation: NOPhFFSO2Cl2CHCl3, Ð30 ¼CN.R.PhNOPhPhClPhNOPhPhClPhNOPhPhClCl2 equiv PCl 5CHCl3,65 ¼C, 12 hPhNOPhPhClPhNOPhPhClClCldr = 1:1 dr >20:1 98% eehydroxyamination: N.RPhNOPhPhCl1.25 equiv chloramine-T 1% OsO4 cyclopropanation: N.RPhNOPhPhCl2 equiv Et 2Zn2 equiv CH 2I2t-BuOH, 60 ¼C, 13 hDCM, 24 h I-77 I-77 I-77 I-77 I-77 I-77 I-105 I-134 36 1.5 Substrate synthesis The biggest challenge encountered in this project was the synthesis of bis -allylamide substrates. The symmetrical meso alkenyl amides have not been reported before, nor have the meso alkenyl amines been previously synthesized. It was desired to find a short and high yielding route to access the se substrate s. After exhaustive attempts, a four -step sequence was found to access the aryl substituted substrates, although with low yield overall (Scheme 1.22). First, the dienone s I-121 #I-133 were synthesized by adol reaction of acetone and the corresponding benzaldehyde in more than 90% yield for most substrates. The d ienone was subjected to excess LiHMDS followed by excess benzoyl chloride to give an imine. No purification was needed for the imine intermediate which tend to decompose on a column of silica gel . The imine was reduced with NaBH 4 to deliver the final product. The yield for the last three step s is between 10 - 30%. Scheme 1.22 Synthesis of aryl substituted diene s It is worth to summarize some of the failed routes. One path utilized the Mitsunobu reaction. We reduced the dieone I-125 to the secondary alcohol I-135 , but several conditions for the Mitsunobu reaction did not work. The combination of PPh 3, DIAD and phthalimide fail ed to give any conversion. While DPPA with DBU can transform the secondary alcohol to azide I-136 , nBu3P could not reduce the azide. Also it was hard to O+RCHO10 % aq. NaOHRRO>95% yield 1) 2.5 equiv LiHMDS, THF, Ð78 ¡C to rt; 10-30% RRNHBz (R = aryl) I-121 -I-133 I-76,I-79, I-81 -I-99 H2O, EtOH, rt 2) 3 equiv BzCl, Ð78 ¡C to rt; 3) 3 equiv NaBH 4, MeOH, 0 ¼C to rt 37 selectively reduce the azide in the presense of double bonds using other reduction methods, for example hydrogenation. Scheme 1.23 Mitsunobu strategy to access aryl substituted diene s Reductive amination is another commonly used strategy to transform ketones to amines. We attempted to use Ti(O iPr) 4 to induce amination. Ammonia/EtOH solution could not yiel d the imine product I-137 ; after adding NaBH 4 in one pot alcohol was obtained. Consisitent bubbling of ammonia gas followed by refluxing for 24 h only give partial conversion and most of the ketone was recovered. Scheme 1.24 Reductive amination strategy to access aryl substituted diene s Route1: O2 equiv NaBH 4MeOH OH1 equiv PPh 31 equiv DIAD 1 equiv phthalimide THF N.R.Route 2: OH1) 1.2 equiv DPPA 1.2 equiv DBU toluene 0 ¡C to rt 2) 1.5 equiv nBu3P THF-H 2O (4:1) 0¡C to rt N3I-125 I-135 I-135 I-136 Route 3: O1) 1.2 equiv Ti(O iPr)45 equiv NH 3 in EtOH 2) 2 equiv NaBH 4 1.2 equiv Ti(O iPr)4Bubble NH 3 gas in DCM-MeOH for 2 h then reflux with NH 3 ballon for 24 h NHpartially transformed ketone left OHI-125 I-135 I-137 38 We also used the strategy that convert s the secondary alcohol to a goo d leaving group and then reacting with a nitrogen nucleophile via a n SN2 pathway (Scheme 1.25). The secondary alcohol could be easily protected to give the methyl sulfonyl chloride I-138. However, when sodium azide was used as nucleophile, the sequence of S N2 followed by [3,3] sigmatropic rearrangement of azide occurred to yield I-139. Scheme 1.25 SN2 strategy to access to aryl substituted diene s There are reports of oxime synthesis from ketone and subsequent reduction of the oxime to amine. 32-33 The preparation of oxime I-140 from dienone I-125 was achieved in moderate yields. However varied methods for the reduction of the oxime failed, leading to the recovery of the oxime in most cases (Scheme 1.26). Route 4: OH1.2 equiv MsCl 1.2 equiv Et 3NDCM, 0¡C to r.t. OMs 2 equiv NaN 3DMF N3I-135 I-138 I-139 39 Scheme 1.26 Reduction of oxime to access aryl substituted diene s For the aliphatic substituted diene substrates, the four steps sequence using LiHMDS did not work. The Mitsunobu reaction was used to install the nitrogen group (Scheme 1.27). Starting from the corresponding alkyne I-142, an a ldol reaction afforded the meso -propargyl alcohol ( I-101, I -102 ). Reduction of the triple bond with Red -Al¨ gave exclusively the E bis -allyl alcohol I-143 which was ready for Mitsunobu reaction. The resulting phthalimide I-145 was removed by hydrazine hydrate and the resulted amine was protected with benzoyl chloride. However, the reduction step with Red -Al always gave the over -reduced product which could not be s eparated from the diene product. Route 5: O1.5 equiv NH 2OH¥HCl1 equiv Na 2SO4EtOH, reflux, 2 h NHO66 %Amberlyst-15 3 equiv LiCl 3 equiv NaBH 4THF, rt then reflux, 12 h NH2recover oxime 2 equiv Zn, 2 equiv NH 4ClMeOH, reflux, 24 h recover oxime 2 equiv LAH THF, 0¡ C, then reflux recover oxime 2 equiv Zn, AcOH EtOH, reflux, 24 h recover oxime 3 equiv DIBAL THF, 0¡C to rt recover oxime I-125 I-140 I-141 40 Scheme 1.27 Synthesis of aliphatic substituted diene s 1.6 Summary A useful and efficient desymmetrization of meso -diene amides via catalytic enantioselective chlorocyclization has been successfully developed . Many aryl and alkyl substituted dienes substrates are well tolerated. The reaction can furnish a highly functionalized oxazine with good yield and excellent enantioselectivity and diastereoselectivity. 1.7 Experimental section 1.7.1 General information All reagen ts were purchased from commercial sources and were used without purification. (DHQD) 2PHAL and N-chlorophthalimide were purchased from Aldrich. R1 equiv n-BuLi 0.5 equiv ethyl formate THF, Ð78 ¡C to rt RROH10 equiv Red-Al, THF, 0 ¼C to rt OHRR98%75%(R = cyclohexyl n-butyl) 1.1 equiv PPh 31.1 equiv phthalimide 1.1 equiv DIAD NRRI-145 OO1) 5 equiv NH 2NH2¥H2O, MeOH; 2) conc. HCl; 45%RRNHBz OHRR+THF, 0 ¼C to rt I-101 , I-102 I-142 I-143 I-144 54%I-95 , I-96 3) 1.1 equiv BzCl, 1.1 equiv Et 3N, DCM 41 Trifluoroethanol and hexafluoro -iso propanol were purchased from Combi -Blocks. TLC analyses were performed on sili ca gel plates (pre -coated on glass; 0.20 mm thickness with fluorescent indicator UV254) and were visualized by UV or charred in KMnO 4 stains. 1H and 13C NMR spectra were collected on 500 MHz NMR spectrometers (Agilent) using CDCl3. Chemical shifts are repo rted in parts per million (ppm) and are referenced to residual solvent peaks. For HRMS (ESI) analysis, a Water 2795 (Alliance HT) instrument was used and referenced against Polyethylene Glycol (PEG -400-600). Flash silica gel (32 -63 $ m, Silicycle 60 †) was used for column chromatography. All known compounds were characterized by 1H and 13C NMR and are in complete agreement with samples reported elsewhere. All new compounds were characterized by 1H and 13CNMR, HRMS, and melting point (where appropriate). Enan tiomeric excesses were determined using chiral HPLC (instrument: HP series 1100, Agilent 1260 infinity). 1.7.2 General procedure for synthesis of substrates Scheme 1.2 8 Synthesis of bis(aryl) -amides ROH2 equiv. 1 equiv. acetone 3 equiv. NaOH (10% aqueous solution) EtOH (1M), rt ORR11) 2.5 equiv. LiHMDS(1M in THF), THF Ð78 ¡C to rt NHBz RR22) 3 equiv. BzCl. Ð78 ¡C to rt 3) 2 equiv. NaBH 4, MeOH, 0 ¡C to rt 42 General procedure A : Dienone was synthesized according to reported literature. 34 To a solution of t he corresponding benzaldehyde ( 2 equiv) and acetone (1 equiv) in the sol vent of Ethanol (1M), 6M NaOH ( 2 M) was added dropwise (approximately 2 drops/sec to avoi d formation of side products). The reaction mixture warmed up rapidly forming a cloudy suspension. The mixture was allowed to stir at room temperature for another hour. The reaction was neutralized with the addition of HCl (concentrated), followed by extraction with dichlormethane. The combined organic extracts w ere washed with brine, dried over sodium sulfate, and finally subjected to purification by silica gel flash column chromatography or by recrystallization. The corresponding dienone was dissolved in freshly distilled THF (0.5 M) a nd stirred at #78 ¡C for 10 min. LiHMDS (1 M in THF) was added dropwise to the solution under Ar balloon. The reaction mixture was gradually warmed to room temperature and stirred for further 4 hr. T he reaction was cooled down to Ð78 ¡C and benzoyl chlori de was added in one portion. After strirring at room temperature for 2 hr, the reaction was quenched by addition of saturated ammonium chloride solution. The reaction was extracted with EtOAc and the combined organic layers were dried with Na 2SO4 and the s olvent was removed under reduced pressure. The residue was dissolved in MeOH and NaBH 4 was added at 0 ¡C. The reaction was gradually warmed to room temperature and stirred for 8 hr. Once the reaction was complete, H 2O was added to quench the reaction. The reaction was extracted with EtOAc and the combined organics were dried with Na 2SO4 and filtered. The solvent was removed under reduced pressure to afford the crude product. The product was purified with silica column chromatography using EtOAc/Hex as eluen t. 43 Scheme 1.2 9 Synthesis of bis(alkyl) -amides General procedure B : To a round bottom flask under Ar atmosphere add cyclohexylacetylene (13.9 mmol, 1,5 g) and freshly distilled THF (20 mL) was added, then n-BuLi solution in hexane (2.5 M, 15.2 mmol, 6.1 mL) was added dropwise to the alkyne solution at Ð78 ¼C. After stirring for 5 min, ethyl formate (6.95 mmol, 515 mg) was added in one portion at Ð78 ¼C. The reaction was then gradually warmed up to room tempe rature. After reaction was complete, saturated NH 4Cl solution (20 mL) was added to work up the reaction. The organics were separated and washed with DCM for three times. The combined organics were dried with Na 2SO4 and the solvent were removed under reduce d pressure. The propargyl alcohol product was purified in a flash column to afford 98% yield. R1 equiv n-BuLi 0.5 equiv ethyl formate THF, Ð78 ¡C to rt RROH10 equiv Red-Al, THF, 0 ¼C to rt OHRR98%75%(R = cyclohexyl) 1.1 equiv PPh 31.1 equiv phthalimide 1.1 equiv DIAD NRR54%OO1) 5 equiv NH 2NH2¥H2O, MeOH; 2) conc. HCl; 45%RRNHBz OHRR+THF, 0 ¼C to rt 3) 1.1 equiv BzCl, 1.1 equiv Et 3N, DCM 44 The propargylic alcohol was then reduced by Red -Al¨. To a solution of propargylic alcohol (6.9 mmol) in freshly distilled THF (50 mL) was added Red -Al¨ (42 mmol, 70% in toluene) and then the solution was stirred at room temperature for 12 hr. To quench the reaction, saturated Rochelle salt solution was added carefully and then the resulting mixture was stirred for 1h until two clear layers were seen. The mixture w as extracted with EtOAc three times, and the combined extracts were dried over Na 2SO4. The combined organic layers were concentrated under reduced pressure to afford crude residue, which was purified by chromatography on silica gel with EtOAc/Hexane as elu ent (75% yield). The allyl alcohol (4.67 mmol, 1 equiv) was dissolved in distilled THF (25 mL). Triphenylphosphine (5.14 mmol, 1.1 equiv), phthalimide (5.14 mmol, 1.1 equiv) and DIAD (5.14 mmol, 1.1 equiv) were added subsequently to the reaction mixture at 0 ¼C. After the reaction was complete, water was added to quench the reaction. The organic layers were separates and dried over the Na 2SO4. The solvent was removed under reduced pressure to afford the crude product. The product was purified by column chro matography on silica gel with 3% EtOAc/Hexane as eluent. 1.7.3 Analytical data for dienones: General procedure A with benzaldehyde (5.4 mmol) gave 90% yield of the pure product as yellow needle shaped crystals, mp. 111 ¼C. 1H NMR (500 MHz, CDCl 3) % 7.73 (2H, d, J = 15.6 Hz), 7.61 -7.60 (4H, m), 7.41 -7.60 (6H, m), 7.07 (2H, d, J = 16.2 Hz). OI-121 45 13C NMR (125 MHz, CDCl 3) % 188.9, 143.3, 134.8, 130.5, 129.0, 128.4, 125.4 ppm. General procedure A with m-anisaldehyde (5.4 mmol) gave 55% yield of the pure product as yellow oil. 1H NMR (500 MHz, CDCl 3) % 7.71 (2H, d, J = 16.0 Hz), 7.34 (2H, t, J = 8.0 Hz), 7.20 -7.24 (2H, m), 7.12 -7.16 (2H, m), 7.07 (2H, d, J = 15.5 Hz), 6.97 (2H, dd, J = 8.0 Hz, 2.5 Hz), 3.86 (6H, s). 13C NMR (125 MHz, CDCl 3) % 188.9, 159.9, 143.3, 136.2, 130.0, 125.7, 121.1, 116.4, 113.2, 55.4. General procedure A with p-anisaldehyde (5.4 mmol) gave 62% yield of the pure product as yellow solid, mp. 120 ¼C. 1H NMR (500 MHz, CDCl 3) % 7.70 (2H, d, J = 15.5 Hz), 7.54 -7.60 (4H, m), 6.91 -6.98 (6H, m), 3.85 (6H, s). 13C NMR (125 MHz, CDCl 3) % 188.8, 161.5, 142.6, 130.1, 127.6, 123.5, 114.4, 55.4. OOMe OMe I-122 OMeO OMe I-123 OI-124 46 General procedure A with o-tolualdehyde (5.4 mmol) gave 83% yield of the pure product as yellow solid, mp. 70 ¼C. 1H NMR (500 MHz, CDCl 3) % 8.05 (2H, d, J = 16.0 Hz), 7.64 -7.68 (2H, m), 7.29 -7.34 (2H, m), 7.22 -7.27 (2H, m), 7.00 (2H, d, J = 15.5 Hz), 2.49 (6H, s). 13C NMR (125 MHz, CDCl 3) % 188.9, 140.9, 138.2, 133.8, 130.9, 130.2, 126.7, 126.4, 126.4, 19.9. General procedure A with p-tolualdehyde (5.4 mmol) gave 73% yield of the pure product as yellow solid, mp. 166 ¼C. 1H NMR (500 MHz, CDCl 3) % 7.72 (2H, d, J = 16.0 Hz), 7.52 (4H, d, J = 8.5 Hz), 7.22 (4H, d, J = 8.5 Hz), 7.05 (2H, d, J = 15.5 Hz) 2.39 (6H , s). 13C NMR (125 MHz, CDCl 3) % 189.1, 143.2, 141.0, 132.1, 129.7, 128.4, 124.6, 21.5 ppm. General procedure A with o-fluorobenzaldehyde (5.4 mmol) gave 49% yield of the pure product as yellow solid, mp. 68 ¼C. 1H NMR (500 MHz, CDCl 3) % 7.87 (2H, d, J = 16.0 Hz), 7.61 -7.67 (2H, m), 7.35 -7.42 (2H, m), 7.10 -7.23 (6H, m). OI-125 OFFI-126 47 13C NMR (125 MHz, CDCl 3) 189.0, 162.6 (d, 1JC,F = 252.4 Hz.), 136.1 (d, 4JC,F = 2.9 Hz.), 131.9 (d, 3JC,F = 8.5 Hz.), 129.3 (d, 4JC,F = 2.8 Hz.), 127.6 (d, 3JC,F = 6.6 Hz.), 124.5 (d, 3JC,F = 3.9 Hz.), 122.8 (d, 2JC,F = 11.4 Hz.), 116.3 (d, 2JC,F = 21.9 Hz.). General procedure A with p-bromo benzaldehyde (5.4 mmol) gave 97% yield of the pure product as yellow solid, mp. 205 ¼C. 1H NMR (500 MHz, CDCl 3) % 7.67 (2H, d, J = 15.5 Hz), 7.55 (4H, d, J = 8.0 Hz), 7.47 (4H, d, J = 8.0 Hz), 7.05 (2H, d, J = 16.0 Hz). 13C NMR (125 MHz, CDCl 3) % 188.3, 142.2, 133.6, 132.2, 129.7, 125.7, 124.9. General procedure A with m-bromo benzaldehyde (5.4 mmol) gave 85% yield of the pure pro duct as yellow solid, mp. 93 -97 ¼C. 1H NMR (500 MHz, CDCl 3) % 7.78 (t, J = 1.9 Hz, 2H), 7.66 (dd, J = 15.9, 2.0 Hz, 2H), 7.54 (t, J = 7.6 Hz, 3H), 7.35 Ð 7.24 (m, 3H), 7.06 (dd, J = 15.9, 2.0 Hz, 2H). 13C NMR (125 MHz, CDCl 3) % 188.13, 141.89, 136.75, 133.34, 130.88, 130.49, 127.16, 126.34, 123.11. OBrBrI-127 OBrBrI-128 OClClI-129 48 General procedure A with p-chlorp benzaldehyde (5.4 mmol) gave 98% yield of the pure product as yellow solid, mp. 170 ¼C. 1H NMR (500 MHz, CDCl 3) % 7.73 (2H, d, J = 16.0 Hz), 7.61 (4H, d, J = 8.5 Hz), 7.45 (4H, d, J = 9.0 Hz), 7.09 (2H, d, J = 15.5 Hz). 13C NMR (125 MHz, CDCl 3) % 188.3, 142.1, 136.5, 133.2, 129.5, 129.3, 129.2, 125.7. General procedure A with 3 -furaldehdye (5.4 mmol) gave 95% yield of the pure product as yellow crystal, mp. 89 -94¼C. 1H NMR (500 MHz, CDCl 3) % 7.73 (dd, J = 1.5, 0.8 Hz, 2H), 7.63 (d, J = 15.7 Hz, 2H), 7.51 Ð 7.39 (m, 2H), 6.77 (d, J = 15.8 Hz, 2H), 6.67 (dd, J = 1.9, 0.8 Hz , 2H). 13C NMR (126 MHz, CDCl 3) % 188.55, 145.27, 144.49, 133.09, 125.30, 123.10, 107.40. General procedure A with 2 -naphthaldehyde (5.4 mmol) gave 27% yield of the pure product as yellow solid, 113 ¼C. 1H NMR (500 MHz, CDCl 3) % 8.66 (2H, d, J = 16.0 Hz), 8.29 (2H, d, J = 9.0 Hz), 7.87 -7.98 (6H, m), 7.51 -7.65 (6H, m), 7.25 (2H, d, J = 14.5 Hz). 13C NMR (125 MHz, CDCl 3) % 188.6, 140.4, 133.7, 132.2, 131.7, 130.8, 128.8, 128.1, 127.0, 126.3, 125.5, 125.2, 123.4. OI-130 OOOI-131 49 General procedure A with 4 -tert -butylbenzaldehyde (5.4 mmol) gave 50% yield of the pure product as yellow solid 1H NMR (500 MHz, CDCl 3) % 7.71 (d, J = 15.9 Hz, 2H), 7.55 (d, J = 8.4 Hz, 4H), 7.42 (d, J = 8.4 Hz, 4H), 7.04 (d, J = 15.9 Hz, 2H), 1.32 (s, 18H). 13C NMR (126 MHz, CDCl 3) % 189.12, 154.08, 143.07, 132.08, 128.25, 125.94, 124.77, 34.95, 31.17. General procedure A with 4 -(trifluoromethyl)benzaldehyde gave 34% yield of the pure product as yellow solid, mp.135 -140 ¼C. 1H NMR (500 MHz, CDCl 3) % 7.75 (d, J = 15.9 Hz, 2H), 7.75 Ð 7.66 (m, 8H), 7.15 (d, J = 15.9 Hz, 2H). 13C NMR (126 MHz, CDCl 3) % 188.08, 141.92, 137.94, 132.06 (d, JC-F = 32.6 Hz), 128.52, 127.17, 125.96 (q, JC-F=3.8 Hz), 124.86. General procedure A with 4 -fluorobenzaldehyde gave 95% yield of the pure product as yellow solid, mp.124 -128 ¼C. Ot-But-BuI-132 OCF3F3CI-133 OFFI-145 50 1H NMR (500 MHz, CDCl 3) % 7.72 (d, J = 15.9 Hz, 2H), 7.67 Ð 7.56 (m, 4H), 7.17 Ð 7.07 (m, 4H), 7.00 (d, J = 15.9 Hz, 2H). 13C NMR (126 MHz, CDCl 3) % 188.45, 164.0 5 (d, JC-F = 252.0 Hz), 142.10, 130.97 (d, JC-F = 3.3 Hz), 130.28 (d, JC-F = 8.5 Hz), 125.06 (d, JC-F = 2.4 Hz), 116.17 (d, JC-F = 21.9 Hz). 1.7.4 Analytical data for substrates General procedure A with dienone I-121 (2.00 g, 8.54 mmol) gave I-76 in 30% yield. white snowflake solids; M.P.: 203 -205 ¡C Rf: 0.54 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.86 (d, J = 7.8 Hz, 2H), 7.57 Ð 7.49 (m, 1H), 7.46 (d, J = 7.5 Hz, 2H), 7.40 (d, J = 7.0 Hz, 4H), 7.33 (t, J = 7.5 Hz, 4H), 7.26 (td, J = 7.3, 1.3 Hz, 2H), 6.67 (d, J = 16.0 Hz, 2H), 6.45 (d, J = 8.4 Hz, 1H), 6.36 (dd, J = 16.0, 6.1 Hz, 2H), 5.70 Ð 5.56 (m, 1H). 13C NMR (125 MHz, CDCl 3) ! 166.5, 136.4, 134.4, 131.8, 131.7, 128.7, 128.6, 128.0, 127.9, 127.0, 126.5, 52.8 HRMS analysis (ESI) : calculated for (M+H): C 24H21ClNO 374.1312; found: 374.1346. General procedure A with dienone I-124 (1.30 g, 5 mmol) gave I-79 in 19% yield white solids; M.P.: 145 -150 ¡C NHBz I-76 NHBz I-79 51 Rf: 0.22 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.82 (d, J = 6.9 Hz, 2H), 7.52 Ð 7.49 (m, 1H), 7.46 Ð 7.43 (m, 4H), 7.15 (ddd, J = 8.6, 5.2, 3.7 Hz, 6H), 6.89 (d, J = 1.5 Hz, 2H), 6.31 (d, J = 8.3 Hz, 1H), 6.21 (dd, J = 15.8, 6.1 Hz, 2H), 5.67 Ð 5.62 (m, 1H), 2.33 (s, 1H). 13C NMR (125 MHz, CDCl 3) ! 166.54, 135.6 2, 134.54, 131.63, 130.33, 129.87, 129.49, 128.67, 127.78, 126.95, 126.12, 125.73, 53.42, 19.85. HRMS analysis (ESI): calculated for (M+H): C 26H25NO 368.2014; found: 368.2014. General procedure A with dienone I-125 (1.50 g, 5.7 mmol) gave I-81 in 16% yield white solids; M.P. :165 -175 ¡C Rf: 0.14 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.83 (dt, J = 7.2, 1.4 Hz, 2H), 7.54 Ð 7.40 (m, 3H), 7.28 (d, J = 7.8 Hz, 4H), 7.11 (d, J = 7.8 Hz, 4H), 6.61 (d, J = 15.8 Hz, 2H), 6.36 Ð 6.24 (m, 3H), 5.59 (q, J = 7.5, 6.8 Hz, 1H), 2.32 (s, 6H). 13C NMR (125 MHz, CDCl 3) % 166.44, 137.71, 134.45, 133.66, 131.57, 129.30, 128.62, 127.13, 127.03, 126.48, 126.44, 52.81, 21.23. HRMS analysis (ESI): calculated for (M -H): C 26H24NO 366.1858; found: 366.1853. General procedure A with dienone I-133 (1.00 g, 2.7 mmol) gave I-85 in 9% yield NHBz I-81 NHBz F3CCF3I-85 52 white solids; M.P.: 156 -162 ¡C Rf: 0.14 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.84 (d, J = 7.0 Hz, 2H), 7.57 Ð 7.50 (m, 5H), 7.49 Ð 7.42 (m, 6H), 6.71 Ð 6.67 (m, 2H), 6.43 (dd, J = 16.0, 6.1 Hz, 2H), 6.38 (d, J = 8.3 Hz, 1H), 5.68 Ð 5.63 (m, 1H). 13C NMR (125 MHz, CDCl 3) % 166.55, 139.65, 133.97, 131.94, 130.86, 130.23, 129.95, 129.70, 128.75 , 127.01, 126.73, 125.66, 125.63, 125.60, 125.57, 52.73. HRMS analysis (ESI): calculated for (M+H): C 26H20NOF 6 476.1449; found: 476.1451 General procedure A with dienone I-145 (2.00g, 7.40 mmol) gave I-82 in 10% yield. white solids; M.P.: 148 -152 ¡C Rf: 0.12 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.83 Ð 7.81 (m, 2H), 7.56 Ð 7.41 (m, 3H), 7.36 (ddd, J = 8.5, 5.1, 2.2 Hz, 4H), 7.00 (td, J = 8.7, 2.2 Hz, 4H), 6.62 (d, J = 15.9 Hz, 2H), 6.28 (s, 1H), 6.24 (ddd, J = 15.9, 6.2, 2.2 Hz, 2H), 5.58 (d, J = 7.4 Hz, 1H). 13C NMR (125 MHz, CDCl 3) % 166.44, 162.47 (d, J = 247.4 Hz), 134.22, 132.48 (d, J = 3.4 Hz), 131.75, 130.75, 128.67, 128.08 (d, J = 8.1 Hz), 127.66 (d, J = 2.2 Hz), 126.98, 115.55 (d, J = 21.6 Hz), 52.80 . HRMS analysis (ESI): calculated for (M+H): C 24H20NOF 2 376.1513; found: 376.1507 NHBz FFI-82 53 General procedure A with dienone I-128 (1.10 g, 2.8 mmol) gave I-83 in 8% yield white solids; M.P.: 120 -125 ¡C Rf: 0.20 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.83 (d, J = 7.5 Hz, 2H), 7.57 Ð 7.48 (m, 3H), 7.44 (t, J = 7.6 Hz, 2H), 7.36 (dd, J = 7.8, 1.9 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 7.17 (t, J = 7.8 Hz, 2H), 6.57 (d, J = 15.9 Hz, 2H), 6.37 (d, J = 8.3 Hz, 1H), 6.31 (dd, J = 15.9, 6.1 Hz, 2H), 5.60 (q, J = 6.8 Hz, 1H). 13C NMR (125 MHz, CDCl 3) % 166.51, 138.39, 134.06, 131.84, 130.82, 130.64, 130.14, 129.33, 129.25, 128.70, 127.01, 125.30, 122.80, 52.66. HRMS analysis (ESI): calculated for (M -H): C 24H18NOBr 2 493.9755; found: 493.9740 General procedure A with dienone I-127 (1.44 g, 2.55 mmol) gave I-84 in 9.5% yield. white solids; M.P.: 180 -186 ¡C Rf: 0.13 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.85 Ð 7.77 (m, 2H), 7.56 Ð 7.47 (m, 1H), 7.47 Ð 7.36 (m, 6H), 7.27 Ð 7.18 (m, 4H), 6.58 (d, J = 16.0 Hz, 2H), 6.30 (dd, J = 15.8, 6.3 Hz, 3H), 5.57 (q, J = 6.8 Hz, 1H). NHBz BrBrI-83 NHBz BrBrI-84 54 13C NMR (125 MHz, CDCl 3) % 166.47, 135.20, 134.11, 131.81, 131.74, 130.86, 128.69, 128.53, 128.05, 126.99, 121.79, 52.77. HRMS analysis (ESI): calculated for (M -H): C 24H18NOBr 2 493.9755; found: 493.9752 General procedure B with (3E,6E)-2,2,8,8 -tetramethylnona -3,6 -dien -5-ol (630 mg, 3.2 mmol) gave 31% yield of I-88 in 3 steps. Rf: 0.70 (20% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.83 Ð 7.75 (m, 2H), 7.54 Ð 7.40 (m, 3H), 6.17 Ð 6.10 (m, 1H), 5.66 (dd, J = 15.7, 2H), 5.39 (dd, J = 15.7, 5.8 Hz, 2H), 5.19 (ddt, J = 10.0, 5.8, 1.4 Hz, 1H), 1.01 (s, 18H). 13C NMR (125 MHz, CDCl 3) % 166.50, 143.02, 131.35, 128.52, 126.94, 126.88, 12 4.13, 51.81, 32.94, 29.57. HRMS analysis (ESI): calculated for (M+H): C 20H30NO 300.2327; found: 300.2342 General procedure A with dienone I-122 (1.89 g, 6.42 mmol) gave I-86 in 23% yield white solids; M.P.: 110 -115 ¡C Rf: 0.17 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.85 Ð 7.79 (m, 2H), 7.53 Ð 7.48 (m, 1H), 7.47 Ð 7.41 (m, 2H), 7.24 Ð 7.18 (m, 2H), 6.98 (dt, J = 7.8, 1.2 Hz, 2H), 6.92 (dd, J = 2.6, 1.6 Hz, 2H), NHBz I-88 NHBz MeO OMe I-86 55 6.80 (ddd, J = 8.2, 2.6, 0.9 Hz, 2H), 6.63 (dd, J = 15.9, 1.4 Hz, 2H), 6.33 (dd, J = 16.0, 6.1 Hz, 3H), 5.65 Ð 5.56 (m, 1H), 3.79 (s, 6H). 13C NMR (125 MHz, CDCl 3) % 166.44, 159.81, 137.82, 134.32, 131.79, 131.70, 129.61, 128.67, 128.30, 127.00, 119.17, 113.71, 111.73, 109.98, 55.26, 52.68. HRMS analysis (ESI): calculated for (M+Na): C 26H25NO3Na 422.1732; found: 422.1734 General procedure A with bis(4 -methoxybenzylidene)acetone (6.0 mmol) gave I-87 in 10% yield. white solids; M.P.: 157 -161 ¡C Rf: 0.25 (30 % EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) 1H NMR (500 MHz, Chloroform -d) % 7.85 Ð 7.78 (m, 2H), 7.54 Ð 7.39 (m, 3H), 7.35 Ð 7.25 (m, 4H), 6.91 Ð 6.77 (m, 4H), 6.59 (dd, J = 15.9, 1.4 Hz, 2H), 6.29 (d, J = 8.3 Hz, 1H), 6.19 (dd, J = 15.9, 6.1 Hz, 2H), 5.61 Ð 5.49 (m, 1H), 3.79 (s, 6H). 13C NMR (125 MHz, CDCl 3) % 166.37, 159.36 , 134.46, 131.59, 131.14, 129.20, 128.62, 127.72, 126.98, 125.99, 113.98, 55.29, 52.89. HRMS analysis (ESI): calculated for (M+H): C 26H26NO3 400.1913; found: 400.1908. General procedure A with dienone I-129 (1.08 g, 3.56 mmol) gave I-90 in 7% yield white solids; M.P.: 152 -162 ¡C NHBz MeO OMe I-87 NHBz ClClI-90 56 Rf: 0.33 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.83 (d, J = 7.0 Hz, 1H), 7.54 Ð 7.49 (m, 1H), 7.47 Ð 7.40 (m, 2H), 7.32 Ð 7.24 (m, 9H), 6.59 (dd, J = 15.9, 1.5 Hz, 2H), 6.38 (d, J = 8.3 Hz, 1H), 6.28 (dd, J = 15.9, 6.1 Hz, 2H), 5.58 (dddd, J = 8.0, 6.2, 4.6, 1.5 Hz, 1H). 13C NMR (125 MHz, CDCl 3) % 166.48, 134.77, 134.13, 133.61, 131.80, 130.76, 128.79, 128.68, 128.44, 127.74, 127.01, 52.78. HRMS analysis (ESI): calculated for (M+H): C 22H20Cl2NO 408.0922; fou nd: 408.0918 General procedure A with dienone I-126 (0.83 g, 3.07 mmol) gave I-89 in 15% yield. white solids; M.P. 155 -158 ¡C Rf: 0.59 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.87 Ð 7.78 (m, 2H), 7.54 Ð 7.48 (m, 1H), 7.45 (ddd, J = 8.9, 7.1, 1.6 Hz, 4H), 7.24 Ð 7.16 (m, 2H), 7.14 Ð 7.04 (m, 3H), 6.80 (dd, J = 16.1, 1.4 Hz, 2H), 6.45 (dd, J = 16.1, 6.0 Hz, 2H), 6.33 (d, J = 8.3 Hz, 1H), 5.68 Ð 5.59 (m, 1H). 13C NMR (125 MHz, CDCl 3) % 166.63, % 160.31 (d, J = 249.8 Hz), 134.30, 131. 70, 130.61 (d, J = 5.3 Hz), 129.18 (d, J = 8.3 Hz), 128.65, 127.80 (d, J = 3.6 Hz), 127.08, 124.52 (d, J = 3.2 Hz), 124.25, 124.15 (d, J = 3.4 Hz), 115.80 (d, J = 22.1 Hz), 53.41. HRMS analysis (ESI): calculated for (M+Na): C 24H19F2NONa 398.1332; found: 39 8.1336 NHBz FFI-89 NHBz t-butyl t-butyl I-91 57 General procedure A with dienone I-132 (800 mg, 2.3 mmol) gave I-91 in 14.4% yield. Rf: 0.28 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.84 Ð 7.78 (m, 2H), 7.54 Ð 7.37 (m, 3H), 7.33 (s, 8H), 6.63 (dd, J = 15.9, 1.5 Hz, 2H), 6.34 Ð 6.24 (m, 3H), 5.63 Ð 5.57 (m, 1H), 1.29 (s, 18H). 13C NMR (125 MHz, CDCl 3) % 166.39, 151.01, 134.48, 133.64, 131.60, 131.51, 128.63, 127.34, 126.96, 126.23, 125.53, 52.72, 34.59, 31.26. HRMS analysis (ESI): calculated for (M+Na ): C 32H37NONa 474.2773; found: 474.2778 General procedure A with I-130 (1.59 g, 7.4 mmol) gave I-94 in 10.3% yield yellow solid; Melting point: 135 -142 ¼C Rf: 0.45 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.81 (dd, J = 7.7, 1.6 Hz, 2H), 7.55 Ð 7.45 (m, 1H), 7.47 Ð 7.27 (m, 5H), 6.55 Ð 6.43 (m, 4H), 6.36 (d, J = 8.3 Hz, 1H), 6.02 (dd, J = 15.8, 6.0 Hz, 2H), 5.49 (dt, J = 7.8, 5.9 Hz, 1H). 13C NMR (126 MHz, CDCl 3) % 166.42, 143.65, 140.87, 134.30, 131.67, 128.62, 127.61, 127.03, 123.43, 121.61, 107.44, 107.44, 52.66. HRMS analysis (ESI): calculated for (M -H): C 20H16NO3 318.1130; found: 318.1118 OONHBz I-94 NHBz I-92 ClClClCl 58 General procedure A of 1,5 -bis(2,6 -dichlorophenyl)penta -1,4 -dien -3-one (2.20 g, 5.9 mmol) gave I-89 in 30% yield. white solid; Melting point: 145 -150 ¼C 1H NMR (500 MHz, CDCl 3) % 7.83 (dd, J = 7.5, 1.6 Hz, 2H), 7.56 Ð 7.39 (m, 3H), 7.30 (d, J = 8.1 Hz, 4H), 7.09 (t, J = 8.1 Hz, 2H), 6.76 (dd, J = 16.4, 1.5 Hz, 2H), 6.43 (dd, J = 16.3, 5.6 Hz, 2H), 6.32 (d, J = 8.5 Hz, 1H), 5.82 Ð 5.71 (m, 1H). 13C NMR (126 MHz, CDCl 3) % 166.70, 136.02, 134.44, 133.98, 131.69, 128.70, 128.43, 128.41, 127.01, 126.00, 125.29, 52.87. HRMS analysis (ESI): calculated for (M -H): C 24H16NOCl 4 473.9986; found: 473.9980 General proced ure A with 1,5 -bis(thiophene -2-yl)1,4 -pentadien -3-one (2.2 g, 8.9 mmol) gave I-100 in 10% yield. yellow solid; Melting point: 160 -163 ¼C 1H NMR (500 MHz, CDCl 3) % 7.89 Ð 7.73 (m, 2H), 7.58 Ð 7.33 (m, 3H), 7.16 (dt, J = 4.8, 0.9 Hz, 2H), 7.02 Ð 6.85 (m, 4H), 6.86 Ð 6.67 (m, 2H), 6.27 (d, J = 8.3 Hz, 1H), 6.13 (dd, J = 15.8, 6.1 Hz, 2H), 5.67 Ð 5.44 (m, 1H). 13C NMR (126 MHz, CDCl 3) % 166.39, 141.35, 134.19, 131.74, 128.66, 127.46, 127.20, 127.01, 126.40, 125.32, 124.66 , 52.47. HRMS analysis (ESI): calculated for (M -H): C 20H16NOS 2 350.0673; found: 350.0670. SNHBz SI-100 59 General procedure B: C yclohexyl acetylene (1.5 g, 13.9 mmol) was used to yield the propargyl alcohol (1.7g, 99% yield). Rf: 0.67 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 5.13 (dt, J = 7.2, 1.9 Hz, 1H), 2.46 Ð 2.37 (m, 2H), 2.09 Ð 1.98 (m, 1H), 1.85 Ð 1.75 (m, 4H), 1.73 Ð 1.65 (m, 4H), 1.55 Ð 1.39 (m, 4H), 1.38 Ð 1.19 (m, 8H). 13C NMR (125 MHz, CDCl 3) % 88.9, 78.2, 52.6, 32.3, 28.9, 25.8, 24.8 General procedure B: C ycloacetylene (1.5 g, 13.9 mmol) was used to yield allyl alcohol 1.16g (75% yield for two steps). Allyl alcohol (1.16 g 4.67 mmol) was subjected to Mitsunobu reaction to obtain phthalimide (950 mg, 54% yield). Phthalimide (950 mg, 2. 52 mmol) was hydrolyzed and protected to furnish final product (400 mg, 45% yield). This compound could not be purified from a side product. Rf: 0.58 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.76 (dd, J = 9.7, 7.8 Hz, 2H), 7.52 Ð 7.38 (m, 4H), 6.03 (d, J = 8.5 Hz, 1H), 5.94 (d, J = 8.6 Hz, 0.27H), 5.58 (dd, J = 15.5, 6.5 Hz, 2.27H), 5.42 (dd, J = 15.6, 5.7 Hz, 2H), 5.35 (dd, J = 15.6, 6.2 Hz, 0.27H), 5.15 (q, J = 6.5 Hz, 1H), 4.61 Ð OHI-101 NHBz I-96 60 4.50 (m, 0.27H), 1.94 (dddd, J = 14.5, 11.0, 6.5, 3.1 Hz, 2H), 1.75 Ð 1.50 (m, 15H), 1.35 Ð 0.93 (m, 13H). 13C NMR (125 MHz, CDCl 3) % 166.19, 138.03, 137.68, 134.87, 131.35, 131.27, 128.53, 127.47, 126.92, 126.85, 126.61, 52.29, 51.55, 40.40, 37.58, 33.39, 33.33, 32.91, 32.89, 32.84, 26.65, 26.36, 26.15, 26.04. HRMS analysis (ESI): calculated for (M+H): C 24H34NO 352.2640; found: 352.2661 General procedure B: 1 -Hexyne (1.5 g, 18.26 mmol) was used to yield propargyl alcohol (1.6g, 91% yield). Rf: 0.67 (20% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 5.10 (dq, J = 7.1, 2.1 Hz, 1H), 2.24 (td, J = 7.1, 2.0 Hz, 4H), 2.12 Ð 2.05 (m, 1H), 1.55 Ð 1.46 (m, 4H), 1.46 Ð 1.34 (m, 4H), 0.92 (t, J = 7.2 Hz, 6H). 13C NMR (125 MHz, CDCl 3) % 85.12, 78.01, 52.57, 30.41, 21.93, 18.41, 13.5 9. General procedure B: 1 -Hexyne (1.5 g, 18.26mmol) was used to yield allyl alcohol (1.0 g, 61% yield for two steps). Allyl alcohol (940 mg, 4.79 mmol) was sub jected to Mitsunobu reaction to obtain phthalimide (620 mg, 40% yield). Phthalimide (310 mg, 0.953 mmol) was hydrolyzed and protected to furnish final product (180 mg, 63% yield). OHI-102 NHBz I-95 61 This compound could not be purified from a side product. Rf: 0.58 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.83 Ð 7.74 (m, 5H), 7.53 Ð 7.41 (m, 7H), 6.08 (d, J = 8.2 Hz, 1H), 5.98 (d, J = 8.5 Hz, 0.87H), 5.68 (ddtd, J = 15.4, 8.5, 6.7, 1.3 Hz, 3.87H), 5.51 (ddt, J = 15.4, 5.8, 1.4 Hz, 2H), 5.43 (ddt, J = 15.4, 6.4, 1.5 Hz, 0.87H), 5.22 Ð 5.13 (m, 1H), 4.65 Ð 4.56 (m, 0.87H), 2.06 (qd, J = 6.9, 4.7 Hz, 7H), 1.66 Ð 1.53 (m, 3H), 1.44 Ð 1.20 (m, 21H), 0.90 (td, J = 6.7, 6.1, 2.1 Hz, 14H). 13C NMR (125 MHz, CDCl 3) % 166.54, 166.23, 134.98, 134.78, 132.46, 131.99, 131.34, 131.25, 129.97, 128.93, 128.50, 128.49, 126 .91, 126.85, 52.45, 51.40, 35.50, 32.00, 31.99, 31.76, 31.34, 31.28, 29.13, 25.85, 22.59, 22.23, 22.20, 14.07, 13.93. HRMS analysis (ESI): calculated for (M+H): C 20H30NO 300.2327; found: 300.2346 General procedure A with dienone I-121 (1.00 g, 4.3 mmol) gave I-97 in 10% yield. white solids; M.P.: 188 -193 ¡C Rf: 0.39 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.80 (d, J = 8.8 Hz, 2H), 7.41 Ð 7.35 (m, 5H), 7.34 Ð 7.26 (m, 5H), 7.27 Ð 7.21 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.64 (dd, J = 16.0, 1.4 Hz, 2H), 6.38 Ð 6.26 (m, 3H), 5.65 Ð 5.56 (m, 1H), 3.83 (s, 3H). NHOOMe I-97 62 13C NMR (125 MHz, CDCl 3) % 165.96, 162.29, 136.44, 131.67, 128.84, 128.59, 128.24, 127.84, 126.58, 126.53, 113.80, 55.43, 52.68. HRMS analysis (ESI): calculated for (M+H): C25H24NO2 370.1807; found: 370.1812 General procedure A with dienone I-121 (1.40 g, 6 mmol) gave I-98 in 15% yield. white solids; M.P.: 215 -220 ¡C Rf: 0.65 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.69 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.42 Ð 7.35 (m, 4H), 7.35 Ð 7.27 (m, 4H), 7.25 (d, J = 7.6 Hz, 2H), 6.65 (dd, J = 16.0, 1.4 Hz, 2H), 6.32 (dd, J = 15.9, 6.1 Hz, 2H), 6.27 (d, J = 8.2 Hz, 1H), 5.63 Ð 5.54 (m, 1H). 13C NMR (125 MHz, CDCl 3) % 165.47, 136.27, 133.15, 132.08, 131.88, 128.64, 128.63, 127.99, 127.72, 126.54, 126.38, 52.98. HRMS analysis (ESI): calculated for (M+H): C 24H21BrNO 418.0807; found: 418.0791 General procedure A with dienone I-121 (1.93 g, 8 mmol) gave I-99 in 5% yield. white solids; M.P.: 172 -176 ¡C Rf: 0.43 (30% EtOAc in Hexane, UV) NHOBrI-98 PhHNPhOI-99 63 1H NMR (500 MHz, CDCl 3) % 7.40 Ð 7.35 (m, 4H), 7.31 (dd, J = 8.5, 6.8 Hz, 4H), 7.27 Ð 7.21 (m, 2H), 6.57 (dd, J = 16.0, 1.4 Hz, 2H), 6.25 (dd, J = 16.0, 6.0 Hz, 2H), 5.69 (d, J = 8.5 Hz, 1H), 5.51 Ð 5.35 (m, 1H), 2.43 (hep t, J = 6.9 Hz, 1H), 1.21 (d, J = 6.9 Hz, 6H) 13C NMR (125 MHz, CDCl 3) % 175.92, 136.48, 131.43, 131.43, 128.60, 128.30, 127.83, 126.50, 77.29, 77.04, 76.78, 51.95, 35.85, 19.71 HRMS analysis (ESI): calculated for (M -H): C 21H22NO 304.1701; found: 304.1695 1.7.5 General procedure for desymmetrisation General procedure C : D iene substrate ( I-76, I -79, I -81-I-99) (0.1 mmol, 1 equiv) was dissolved in TFE/DCM (1 mL, 7:3, v/v), followed by adding (DHQD) 2PHAL (0.01 mmol, 0.1 equiv) as catalyst. After the reaction m ixture was stirred at -30 ¡C for 5 min, NCP (0.11 mmol, 1.1 equiv) was added. Reaction was stirred at -30 ¡C until completion, evident by TLC. M ost of the solvent was r emoved under reduced pressure, and 1 0% aq. Na 2SO3 (1 mL) and DCM were added to dissolve the residue. Aqueous layers wer e extracted with DCM (3X) . The combined organics were dried over Na 2SO4. After filtration, the solvent was removed under reduced pressure to deliver the crude product. T he crude product was purified via the column chromatogra phy with silica gel using EtOAc in hexane as eluent. General procedure D : D iene substrate ( I-76, I -79, I -81-I-99) (0.1 mmol, 1 equiv) was dissolved in TFE/HFIP (1 mL, 7:3, v/v), followed by adding (DHQD) 2PHAL (0.01 mmol, 0.1 equiv) as catalyst. After the reaction mixture was stirred at -30 ¡C for 5 min, NCP (0.11 mmol, 1.1 equiv) was added in one portion. The r eaction was stirred at -30 ¡C until completion as evident from TLC. M ost of the solvent was remov ed under reduced 64 pressure, and 10% aq. Na 2SO3 (1 mL) and DCM were added to dissolve the residue. Aqueous layers wer e extracted with DCM (3X) . The combined organics were dried over Na2SO4. After filtration, the solvent was removed under reduced pressure to deliver the crude product. T he crude product was purified via column chromatography with silica gel using EtOAc in hexane as eluent. 1.7.6 Analytical data for desymmetrisation products Procedure C with I-76 (136 mg, 0.4 mmol) gave I-77 (121.00 mg, 81%) . Rf: 0.54 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.14 Ð 8.07 (m, 2H), 7.51 Ð 7.19 (m, 13H), 6.69 (d, J = 15.7 Hz, 1H), 6.43 (dd, J = 15.8, 5.6 Hz, 1H), 5.47 (d, J = 6.1 Hz, 1H), 4.51 (t, J = 4.9 Hz, 1H), 4.43 Ð 4.36 (m, 1H). 13C NMR (125 MHz, CDCl3) % 154.42, 137.74, 136.75, 133.38, 132.58, 131.12, 128.95, 128.88, 128.53, 128.24, 127.69, 127.60, 127.11, 126.67, 126.23, 79.16, 58.29, 54.84. HRMS analysis (ESI): calculated for (M+H): C 24H21ClNO 374.1312; found: 374.1346. Resolution of enantiomers: Daicel Chiralpak IA, 5% IPA -Hex, 1 mL/min; 254 nm, RT1 = 8.76 min, RT2 = 9.84 min. ["]D20 = +29.5¡ ( C 1.0, CH 2Cl2, ee = 98 %) X-ray crystallography: ONPhClPhPhI-77 65 Procedure D with I-79 (18.4 mg, 0.05 mmol) gave I-80 (15.10 mg, 75%) . Rf: 0.53 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 8.13 Ð 8.03 (m, 2H), 7.52 Ð 7.37 (m, 4H), 7.34 Ð 7.20 (m, 4H), 7.19 Ð 7.10 (m, 3H), 6.95 (dd, J = 15.5, 1.5 Hz, 1H), 6.26 (dd, J = 15.6, 5.6 Hz, 1H), 5.75 (d, J = 5.4 Hz, 1H), 4.56 (s, 1H), 4.39 (dd, J = 5.4, 3.9 Hz , 1H), 2.42 (s, 3H), 2.34 (s, 3H). 13C NMR (125 MHz, CDCl 3) % 154.70, 136.20, 135.98, 135.63, 135.19, 132.67, 131.50, 131.07, 130.94, 130.18, 128.81, 128.77, 128.23, 127.56, 127.55, 126.70, 126.09, 126.05, 125.78, 76.86, 57.23, 54.65, 19.92, 19.22. HRMS a nalysis (ESI): calculated for (M+H): C 26H25ClNO 402.1625; found: 402.1648. ONClPhI-80 66 Resolution of enantiomers: Daicel Chiralpak IA, 5% IPA -Hex, 1 mL/min; 254 nm, RT1 = 5.4 min, RT2 = 7.9 min. ["]D20 = +33.9¡ (C 1.0, CH 2Cl2, ee = 95 %) Procedure D with I-81 (0.05 mmol, 18.4 mg) gave I-103 (14.07 mg, 70%). Rf: 0.79 (30% EtOAc in Hexane, UV) For major diastereomer: 1H NMR (500 MHz, CDCl 3) % 8.14 Ð 8.02 (m, 2H), 7.53 Ð 7.37 (m, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.28 Ð 7.17 (m, 6H), 7.11 (d, J = 7.8 Hz, 2H), 6.63 (dd, J = 15.8, 1.4 Hz, 1H), 6.38 (dd, J = 15.8, 5.6 Hz, 1H), 5.40 (d, J = 6.3 Hz, 1H), 4.50 (ddd, J = 5.7, 4.1, 1.5 Hz, 1H), 4.37 (dd, J = 6.3, 4.1 Hz, 1H), 2.36 (s, 3H), 2.32 (s, 3H). 13C NMR (125 MHz, CDCl 3) % 154.52, 138.85, 137.50 , 134.76, 133.97, 133.23, 132.63, 131.05, 129.51, 129.20, 128.19, 127.59, 126.56, 126.23, 126.04, 78.99, 58.43, 55.06, 21.23, 21.21. HRMS analysis (ESI): calculated for (M+H): C 26H25ClNO 402.1625; found: 402.1648. Resolution of enantiomers: Daicel Chiralpa k OD -H, 5% IPA -Hex, 0.5 mL/min; 280 nm, RT1 = 10.0 min, RT2 = 11.4 min. ["]D20 = +8.6¡ (C 0.4, CH 2Cl2, ee = 47 %) NOClI-103 67 Procedure D with I-85 (19.02 mg, 0.04 mmol) gave I-104 (17.54 mg, 86%). Rf: 0.43 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.09 (dd, J = 8.2, 3.5 Hz, 2H), 7.69 (dd, J = 8.4, 3.4 Hz, 2H), 7.50 (dddd, J = 29.0, 24.7, 8.4, 4.5 Hz, 9H), 6.73 (dd, J = 15.9, 3.5 Hz, 1H), 6.54 (dt, J = 15.9, 4.6 Hz, 1H), 5.47 (dd, J = 6.7, 3.6 Hz, 1H), 4.54 (t, J = 4.6 Hz, 1H), 4.39 (dt, J = 7.8, 3.8 Hz, 1H). 13C NMR (125 MHz, CDCl 3) % 154.38, 141.24, 139.99, 132.55, 132.06, 131.45, 131.17, 129.73, 129.47, 129.26, 128.36, 127.57, 126.87, 126.83, 125.92(q), 125.52(q), 125.21, 78.30, 57.52, 54.99. HRMS analysis (ESI): calculated for (M+H): C 26H19ClF6NO 510.1059; found: 510.1074 Resolution of enantiomers: Daicel Chiralpak IA, 5% IPA - Hex, 1 mL/min; 254 nm, RT1 = 6.5 min, RT2 = 9.4 min. ["]D20 = +13.8¡ (C 1.0, CH 2Cl2, ee = 90 %) F3CNOClCF3I-104 FNOClFI-105 68 Procedure D with I-82 (19 mg, 0.0506 mmol) gave I-105 (18.04 mg, 87%) . Rf: 0.48 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.09 Ð 8.04 (m, 2H), 7.52 Ð 7.46 (m, 1H), 7.46 Ð 7.28 (m, 6H), 7.10 (t, J = 8.4 Hz, 2H), 7.00 (t, J = 8.5 Hz, 2H), 6.63 (d, J = 15.7 Hz, 1H), 6.37 (dd, J = 15.8, 5.5 Hz, 1H), 5. 38 (d, J = 6.8 Hz, 1H), 4.55 Ð 4.49 (m, 1H), 4.34 (dd, J = 6.8, 4.4 Hz, 1H). 13C NMR (125 MHz, CDCl 3) % 163.94, 163.40, 161.97, 161.44, 154.49, 133.36, 133.33, 132.83, 132.80, 132.57, 132.34, 131.26, 128.33, 128.29, 128.26, 128.25, 128.18, 127.57, 126.46, 126.44, 115.97, 115.80, 115.56, 115.38, 78.23, 58.16, 55.28. HRMS analysis (ESI): calculated for (M+H): C 24H19ClNOF 2 410.1123; found: 410.1129 Resolution of enantiomers: Daicel Chiralpak IA, 5% IPA - Hex, 1 mL/min; 254 nm, RT1 = 9.2 min, RT2 = 13.4 min. ["]D20 = +25.5¡ (C 1.0, CDCl 3, ee = 95%) Procedure C with I-83 (12 mg, 0.024 mmol) gave I-106 (12.25 mg, 96%) . Rf: 0.53 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.10 Ð 8.04 (m, 2H), 7.57 (d, J = 1.8 Hz, 1H), 7.55 Ð 7.47 (m, 3H), 7.43 (dd, J = 8.2 , 6.9 Hz, 2H), 7.37 Ð 7.26 (m, 4H), 7.17 (t, J = 7.8 Hz, 1H), 6.62 (dd, J = 15.8, 1.5 Hz, 1H), 6.46 Ð 6.40 (m, 1H), 5.39 Ð 5.24 (m, 1H), 4.55 Ð 4.51 (m, 1H), 4.35 (dd, J = 6.6, 4.3 Hz, 1H). NOPhClBrBrI-106 69 13C NMR (125 MHz, CDCl 3) % 154.36, 139.67, 138.75, 132.37, 132.20, 132.16, 131.33, 130.62, 130.43, 130.07, 129.47, 128.32, 128.25, 127.59, 125.38, 125.11, 122.97, 122.75, 78.19, 57.67, 54.94. HRMS analysis (ESI): calculated for (M+H): C 24H19ClNOBr 2 529.9522; found: 529.9539 Resolution of enantiomers: Daicel Chiralpak AD-H, 5% IPA - Hex, 1 mL/min; 254 nm, RT1 = 9.3 min, RT2 = 10.6 min. ["]D20 = +8.1¡ (C 1.0, CH 2Cl2, ee = 97 %) Procedure C with I-84 (12 mg, 0.024 mmol) gave I-107 (11.87 mg, 93%) . Rf: 0.49 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.06 (dt, J = 8.5, 1.3 Hz, 2H), 7.56 Ð 7.51 (m, 2H), 7.52 Ð 7.46 (m, 1H), 7.46 Ð 7.37 (m, 4H), 7.25 (ddd, J = 21.2, 8.3, 1.1 Hz, 4H), 6.61 (d, J = 15.8 Hz, 1H), 6.45 Ð 6.31 (m, 1H), 5.36 (d, J = 6.6 Hz, 1H), 4.50 (dt, J = 5.5, 2.8 Hz, 1H), 4.33 (ddd, J = 6.6, 4.3, 1. 1 Hz, 1H). 13C NMR (125 MHz, CDCl 3) % 154.41, 136.50, 135.55, 132.60, 132.22, 132.05, 131.66, 131.32, 128.31, 128.21, 128.10, 127.56, 127.49, 123.14, 121.60, 78.32, 57.78, 55.12. HRMS analysis (ESI): calculated for (M+H): C 24H19ClNOBr 2 529.9522; found: 529 .9521 Resolution of enantiomers: Daicel Chiralpak IA, 5% IPA - Hex, 1 mL/min; 254 nm, RT1 = 10.4 min, RT2 = 13.8 min ["]D20 = +20.0¡ (C 1.0, CH 2Cl2, ee = 90 %) NOPhClBrBrI-107 70 Procedure C with I-86 (19 mg, 0.048 mmol) gave I-108 (19.16 mg, 92%) . Rf: 0.46 (20% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.10 (dt, J = 7.1, 1.4 Hz, 2H), 7.51 Ð 7.45 (m, 1H), 7.42 (dd, J = 8.3, 6.8 Hz, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.27 Ð 7.18 (m, 1H), 7.02 (dt, J = 7.7, 1.2 Hz, 1H), 6.99 Ð 6.85 (m, 4H), 6.79 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H), 6.66 (dd, J = 15.8, 1.5 Hz, 1H), 6.42 (dd, J = 15.8, 5.5 Hz, 1H), 5.44 (d, J = 5.8 Hz, 1H), 4.50 (ddd, J = 5.6, 4.0, 1.5 Hz, 1H), 4.40 (dd, J = 5.8, 4.1 Hz, 1H), 3.79 (d, J = 5.6 Hz, 6H). 13C NMR (125 MHz, CDCl 3) % 159.92, 159.75, 154.36, 139.31, 138.21, 133.23, 132.55, 131.12, 130.01, 129.50, 128.24, 127.59, 127.51, 119.31, 118.34, 114.12, 113.45, 112.02, 111.86, 79.12, 58.17, 55.32, 55.25, 54.72. HRMS analysis (ESI): calculated for (M+H): C 26H25ClNO 3 434.1523; found: 434.1518 Resolution of enanti omers: Daicel Chiralpak AD -H, 3% IPA - Hex, 1 mL/min; 250 nm, major diastereomer: RT1 = 24.8 min, RT2 = 27.3 min ["]D20 = -18.1¡ ( C 1.0, CH 2Cl2, ee = 97 %) Procedure C with I-90 (20 mg, 0.05 mmol) gave I-109 (21.92 mg, 99%) . NOOMe MeO PhClI-108 ClNOClPhClI-109 71 Rf: 0.67 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.09 Ð 8.03 (m, 2H), 7.53 Ð 7.45 (m, 1H), 7.45 Ð 7.25 (m, 10H), 6.62 (dd, J = 15.8, 1.5 Hz, 1H), 6.42 (dd, J = 15.8, 5.5 Hz, 1H), 5.38 (d, J = 6.7 Hz, 1H), 4.51 (td, J = 4.3, 2.2 Hz, 1H), 4.33 (dd, J = 6.7, 4.3 Hz, 1H). 13C NM R (125 MHz, CDCl 3) % 154.43, 135.97, 135.10, 134.97, 133.42, 132.53, 132.24, 131.31, 129.10, 128.71, 128.30, 127.88, 127.81, 127.56, 127.36, 78.26, 57.89, 55.13. HRMS analysis (ESI): calculated for (M+H): C 24H19Cl3NO 442.0532; found: 442.0552 Resolution of enantiomers: Daicel Chiralpak IA, 5% IPA -Hex, 1 mL/min; 254 nm, RT1 = 9.5 min, RT2 = 12.4 min ["]D20 = +23.2¼ (C 1.0, CH 2Cl2, ee = 94.7 %) Procedure C with I-89 (36 mg, 0.1 mmol) gave I-110 (40.57 mg, 99%) . Rf: 0.57 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.14 Ð 8.08 (m, 2H), 7.50 (tq, J = 6.6, 1.7 Hz, 2H), 7.47 Ð 7.35 (m, 3H), 7.31 (td, J = 7.6, 1.7 Hz, 1H), 7.23 Ð 7.05 (m, 4H), 7.02 (ddd, J = 10.7, 8.2, 1.2 Hz, 1H), 6.89 (d, J = 15.9 Hz, 1H), 6.48 (dd, J = 15.9, 5.4 Hz, 1H), 5.80 (d, J = 5.0 Hz, 1H), 4.55 (t, J = 4.4 Hz, 1H), 4.50 Ð 4.43 (m, 1H). 13C NMR (125 MHz, CDCl 3) % 161.29, 160.58, 159.30, 158.61, 154.17, 132.42, 131.21, 130.80, 130.73, 129.82, 129.77, 129.00, 128.93, 128.27, 127.86, 127.83, 127.62, 127.58, NOClPhFFI-110 72 125.89, 125.87, 125.11, 125. 01, 124.78, 124.75, 124.60, 124.50, 124.09, 124.06, 116.07, 115.91, 115.82, 115.64, 74.84, 74.82, 56.39, 56.37, 54.67. HRMS analysis (ESI): calculated for (M+H): C 24H19ClNOF 2 410.1123; found: 410.1150 Resolution of enantiomers: Daicel Chiralpak IA, 5% IPA -Hex, 1mL/min; 254 nm, RT1 = 6.4 min, RT2 = 8.9 min ["]D20 = +39.7¡ (C 1.0, CH 2Cl2, ee = 96 %) Procedure C with I-91 (22.6 mg, 0.05 mmol) gave I-111 (9.96 mg, 41%) . Rf: 0.89 (30% EtOAc in Hexane, UV) Major diasteromer: 1H NMR (500 MHz, CDCl 3) % 8.13 Ð 8.04 (m, 2H), 7.51 Ð 7.30 (m, 9H), 7.26 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 15.9 Hz, 1H), 6.39 (dd, J = 15.8, 5.5 Hz, 1H), 5.43 (d, J = 6.0 Hz, 1H), 4.53 Ð 4.49 (m, 1H), 4.38 (dd, J = 6.0, 4.1 Hz, 1H), 1.30 (d, J = 8.2 Hz, 18H). 13C NMR (125 MHz, CDCl3) % 166.63, 161.31, 159.32, 134.30, 131.70, 130.63, 130.58, 129.21, 129.14, 128.65, 127.81, 127.78, 127.08, 124.53, 124.51, 124.25, 124.16, 124.13, 115.89, 115.71, 53.41. HRMS analysis (ESI): calculated for (M+H): C 32H37ClNO 486.2564; found: 486.2571 Resolution of enantiomers: Daicel Chiralpak IA, 1% IPA -Hex, 1 mL/min; 254 nm, RT1 = 8.2 min, RT2 = 9.1 min NOClPhI-111 73 Procedure C with I-96 (28 mg, 0.08 mmol) gave I-112 (27.17 mg, 88%) . Rf: 0.89 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.03 Ð 7.85 (m, 2H), 7.51 Ð 7.30 (m, 3H), 5.61 (qd, J = 15.5, 5.7 Hz, 2H), 4.35 (t, J = 5.0 Hz, 1H), 4.22 (dd, J = 7.9, 4.6 Hz, 1H), 4.08 (dd, J = 7.9, 4.4 Hz, 1H), 2.02 (dq, J = 5.0, 2.7, 2.0 Hz, 1H), 1.89 Ð 1.49 (m, 11H), 1.44 (qd, J = 12.5, 3.5 Hz, 1H ), 1.36 Ð 1.04 (m, 9H). 13C NMR (125 MHz, CDCl 3) % 154.41, 141.03, 133.07, 130.74, 128.09, 127.39, 124.52, 79.69, 77.22, 56.53, 54.90, 40.63, 38.95, 32.87, 32.80, 29.35, 26.29, 26.25, 26.22, 26.18, 26.04, 25.78. HRMS analysis (ESI): calculated for (M+H): C 24H33ClNO 386.2251; found: 386.2263 Resolution of enantiomers: Daicel Chiralpak IA, 1% IPA -Hex, 1 mL/min; 254 nm, RT1 = 5.6 min, RT2 = 11.7 min ["]D20 = +91¼ (C 1.0, CH 2Cl2, ee = 100 %) Procedure C with I-95 (30 mg, 0.1 mmol) gave I-113 (22.37 mg, 67%) . NOClPhI-112 NOClI-113 74 Rf: 0.64 (15% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.99 Ð 7.90 (m, 2H), 7.51 Ð 7.30 (m, 3H), 5.80 Ð 5.55 (m, 2H), 4.38 Ð 4.35 (m, 1H), 4.28 (td, J = 8.3, 3.2 Hz, 1H), 4.04 (dd, J = 7.9, 4.6 Hz, 1H), 2.13 Ð 2.05 (m, 2H), 1.96 Ð 1.86 (m, 1H), 1.76 Ð 1.56 (m, 2H), 1.51 Ð 1.22 (m, 7H), 0.94 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 154.29, 135.40, 133.02, 130.74, 128.06, 127.38, 126.75, 76.06, 57.29, 56 .54, 32.61, 32.17, 31.24, 26.85, 22.49, 22.24, 13.99, 13.93. HRMS analysis (ESI): calculated for (M+H): C 20H29ClNO 334.1938; found: 334.1942 Resolution of enantiomers: Daicel Chiralpak IA, 1% IPA -Hex, 1 mL/min; 254 nm, RT1 = 4.6 min, RT2 = 5.8 min ["]D20 = +83.1¼ (C 1.0, CH 2Cl2, ee = 98 %) Procedure C with I-97 (37 mg, 0.1 mmol) gave I-114 (31.10 mg, 77%) . Rf: 0.77 (30% EtOAc in Hexane, UV) White solids, M.P.=148 -152 ¡C 1H NMR (500 MHz, CDCl 3) % 8.08 Ð 8.02 (m, 2H), 7.45 Ð 7.28 (m, 10H), 7.26 Ð 7.20 (m, 1H), 6.95 Ð 6.89 (m, 2H), 6.68 (dd, J = 15.8, 1.5 Hz, 1H), 6.43 (dd, J = 15.8, 5.6 Hz, 1H), ONPhClPhOMe I-114 75 5.44 (d, J = 6.1 Hz, 1H), 4.48 (ddd, J = 5.6, 4.1, 1.6 Hz, 1H), 4.39 (dd, J = 6.2, 4.1 Hz, 1H), 3.85 (s , 3H). 13C NMR (125 MHz, CDCl 3) % 162.01, 154.23, 137.84, 136.80, 133.31, 129.28, 128.90, 128.84, 128.52, 127.64, 127.29, 126.67, 126.28, 125.04, 113.51, 79.02, 58.41, 55.41, 54.86. HRMS analysis (ESI): calculated for (M+H): C 25H23ClNO 2 404.1417; found: 404.1457 Resolution of enantiomers: Daicel Chiralpak IA, 15% IPA -Hex, 1 mL/min; 250 nm, RT1 = 16.3 min, RT2 = 19.7 min ["]D20 = +2.8¡ (C 1.0, CH 2Cl2, ee = 95 %) Procedure C with I-98 (21 mg, 0.05 mmol) gave I-115 (14.94 mg, 66%) . Rf: 0.74 (30% EtOAc in Hexane, UV) White solids, M.P.= 128 -134 ¼C 1H NMR (500 MHz, CDCl 3) % 7.96 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.45 Ð 7.37 (m, 5H), 7.34 Ð 7.26 (m, 4H), 7.27 Ð 7.19 (m, 1H), 6.66 (dd, J = 15.8, 1.4 Hz, 1H), 6.40 (dd, J = 15.8, 5.6 Hz, 1H), 5.46 (d, J = 5.8 Hz, 1H), 4.47 (ddd, J = 5.6, 4.0, 1.5 Hz, 1H), 4.39 (dd, J = 5.9, 4.0 Hz, 1H). ONPhClPhBrI-115 76 13C NMR (125 MHz, CDCl 3) % 153.64, 137.56, 136.64, 133.43, 131.48, 131.45, 129.21, 129.04, 128.94, 128.55, 127.76, 126.91, 126.66, 126.12, 125.86, 79.35, 58.10, 54.75. HRMS analysis (ESI): calculated for (M+H): C 24H20ClBrNO 452.0417; found: 452.0415 Resolution of enantiomers: Daicel Chiralpak IA, 5% IPA -Hex, 1 mL/min; 250 nm, RT1 = 12.7 min, RT2 = 17.1 min ["]D20 = +4.8¡ (C 1.0, CH 2Cl2, ee = 100 %) Procedure C with I-99 (30.5 mg, 0.1 mmol) gave I-116 (18.01 mg, 53%) . colorless oil Rf: major diastereomer: 0.74; minor diastereomer: 0.82 (30% EtOAc in Hexane, UV) For the major diastereomer: 1H NMR (500 MHz, CDCl 3) % 7.39 (dtd, J = 8.6, 6.5, 4.9 Hz, 5H), 7.33 Ð 7.26 (m, 4H), 7.23 Ð 7.20 (m, 1H), 6.60 Ð 6.53 (m, 1H), 6.39 Ð 6.30 (m, 1H), 5.23 (d, J = 5.8 Hz, 1H), 4.26 (dq, J = 5.9, 4.0 Hz, 2H), 2.67 (p, J = 6.9 Hz, 1H), 1.29 (dd, J = 6.9, 2.9 Hz, 6H). 13C NMR (126 MHz, CDCl 3) % 163 .57, 138.00, 136.77, 133.14, 128.85, 128.78, 128.51, 127.64, 127.30, 126.63, 126.17, 78.68, 58.48, 53.99, 34.48, 20.11, 20.01. HRMS analysis (ESI): calculated for (M -H): C 21H21ClNO 338.1312; found: 338.129 Resolution of enantiomers: Daicel Chiralpak IA, 15 % IPA -Hex, 1 mL/min; 250 nm, RT1 = 5.27 min, RT2 = 7.50 min ONPhClPhI-116 77 Procedure C with I-100 (0.06 mmol, 21 mg) gave I-117 as diastereomers mixture (6.02 mg, 26%) . pale yellow oil Rf: 0.77 (30% EtOAc in Hexane, UV) For the major diastereomer: 1H NMR (500 MHz, CDCl 3) % 8.08 Ð 8.02 (m, 2H), 7.51 Ð 7.38 (m, 3H), 7.36 (dd, J = 5.0, 1.2 Hz, 1H), 7.16 (dt, J = 5.2, 0.9 Hz, 1H), 7.12 (dt, J = 3.6, 1.1 Hz, 1H), 7.03 (dd, J = 5.0, 3.6 Hz, 1H), 7.00 Ð 6.92 (m, 2H), 6.86 Ð 6.78 (m, 1H), 6.29 (dd, J = 15.6, 5.3 Hz, 1H), 5.65 ( dd, J = 6.6, 0.9 Hz, 1H), 4.61 (ddd, J = 5.6, 4.3, 1.7 Hz, 1H), 4.40 (dd, J = 6.6, 4.3 Hz, 1H). 13C NMR (126 MHz, CDCl 3) % 154.09, 141.80, 140.47, 132.39, 131.18, 128.23, 127.60, 127.39, 127.14, 126.76, 126.24, 126.21, 126.14, 126.13, 124.47, 75.36, 58.11, 55.18. HRMS analysis (ESI): calculated for (M+H): C 20H17NOS 2Cl 386.0440; found: 386.0435. Resolution of enantiomers: Daicel Chiralpak AD -H, 5% IPA -Hex, 1 mL/min; 254 nm, RT1 = 12.6 min, RT2 = 14.2 min Procedure C with I-87 (17 mg, 0.042 mmol) gave I-146 (9.66 mg, 53%). NOPhSSClI-117 I-146 ONPhClOMe MeO 78 colorless oil, Rf: 0.67 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.12 Ð 8.04 (m, 2H), 7.55 Ð 7.39 (m, 3H), 7.39 Ð 7.33 (m, 2H), 7.32 Ð 7.27 (m, 2H), 6.96 Ð 6.90 (m, 2H), 6.89 Ð 6.82 (m, 2H), 6.66 Ð 6.57 (m, 1H), 6.33 (dd, J = 15.8, 5.7 Hz, 1H), 5.39 (d, J = 6.7 Hz, 1H), 4.54 (ddd, J = 5.7, 4.2, 1.5 Hz, 1H), 4.37 (dd , J = 6.7, 4.2 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H). 13C NMR (126 MHz, CDCl 3) % 159.97, 159.26, 154.57, 132.88, 132.64, 131.03, 129.72, 129.55, 128.19, 127.85, 127.71, 127.58, 124.76, 114.16, 113.91, 78.60, 58.59, 55.39, 55.33, 55.30. HRMS analysis (ESI): calculated for (M+H): C 26H25NO3Cl 434.1523; found: 434.1509. Resolution of enantiomers: Daicel Chiralpak IA, 5% IPA -Hex, 1 mL/min; 254 nm, RT1 = 16.2 min, RT2 = 22.2 min 1.7.7 Derivatization of oxazine product The oxazine substrate I-77 (0.048 mmol, 16 mg) was dissolved in a mixture of acetone (1.8 mL), t-BuOH (0.1 mL) and H 2O (0.1 mL). To the colorless solution was added OsO 4 (0.0165 mmol, 4.2 mg), followed by NMO (0.053 mmol, 6.2 mg) at room temperature. The reaction turned to brown. A fter the completion, solvent was removed and passed the residue thru a flash column to afford 16.8 mg white solid as product. Rf: 0.51 (30% EtOAc in Hexane, UV) ONPhPhClPh3.4 mol% OsO 4 ,1 equiv NMO, acetone/ t-BuOH/H 2O (18:1:1, 0.025 M), r.t, 1 h ONPhPhClPh98% eedr > 20 :1 86%dr >20:1 OHOHI-77 I-118 79 Brown solids, M.P.=142 -150 ¼C 1H NMR (500 MHz, CDCl3) % 8.16 Ð 8.11 (m, 2H), 7.58 Ð 7.51 (m, 1H ), 7.48 (dd, J = 8.3, 6.8 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H), 7.39 Ð 7.31 (m, 5H), 7.30 Ð 7.25 (m, 1H), 7.24 Ð 7.20 (m, 2H), 5.78 (s, 1H), 5.44 (s, 1H), 4.74 Ð 4.66 (m, 1H), 4.03 (ddd, J = 9.0, 6.7, 2.0 Hz, 1H), 3.73 (s, 1H), 3.64 (dd, J = 9.2, 3.0 Hz, 1H), 2.03 Ð 1.92 (br, 1H) . 13C NMR (125 MHz, CDCl 3) % 154.08, 141.57, 138.27, 132.31, 131.32, 129.12, 128.71, 128.37, 128.32, 127.50, 126.27, 124.77, 81.39, 74.60, 72.72, 56.18, 51.81. HRMS analysis (ESI): calculated for (M+H): C 24H23ClNO 3 408.1366; found: 408.1391 The absolute stereochemistry was determined by X -ray crystallography: The oxazine substrate I-77 (0.1 mmol, 38 mg) was dissolve in DCM (2 mL), followed by adding m-CPBA (77% wt, 0.2 mmol, 44 mg). The reaction was stirred at r oom temperature for 4 h. Then add water to the reaction and separate the organic portion. The ONPhPhClPh98% eedr > 20 :1 2 equiv m-CPBA ONPhPhClPh67% dr = 16 :1 I-77 I-119 ODCM (0.5 M) r.t, 4 h 80 organic portion was dried over Na 2SO4 and remove the solvent under reduced pressure. The crude residue was purified through a silica gel column (10% EtOAc in hexa ne as eluent) and afforded 26 mg product as colorless wax. The absolute stereochemistry was determined by X -ray crystallography. Rf: 0.78 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 8.17 Ð 8.07 (m, 2H), 7.55 Ð 7.31 (m, 11H), 7.30 Ð 7.25 (m, 2H), 5.75 (d, J = 2.1 Hz, 1H), 4.61 (dd, J = 3.2, 2.2 Hz, 1H), 3.99 (d, J = 1.9 Hz, 1H), 3.58 (dd, J = 5.5, 3.1 Hz, 1H), 3.29 (dd, J = 5.5, 2.0 Hz, 1H). 13C NMR (125 MHz, CDCl 3) % 154.31, 138.06, 136.96, 132.40, 131.25, 129.18, 128.87, 128.41, 128.23, 128.20, 127.59, 125.84, 124.88, 80.52, 62.74, 57.87, 55.69, 51.87. HRMS analysis (ESI): calculated for (M+H): C 24H21ClNO 2 390.1261; found: 390.1273 The absolute stereochemistry was determined by X -ray crystallography: 81 Hydrolysisi of oxazine was done following reported literature with I-77 (34 mg, 0.091 mmol). 28 Rf: 0.65 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.03 Ð 7.97 (m, 2H), 7.56 Ð 7.49 (m, 5H), 7.40 Ð 7.24 (m, 7H), 6.65 (dd, J = 15.8, 1.3 Hz, 1H), 6.48 (d, J = 9.2 Hz, 1H), 6.28 (dd, J = 15.8, 6.2 Hz, 1H), 6.18 (d, J = 7.8 Hz, 1H), 5.62 (ddt, J = 9.5, 6.2, 1.8 Hz, 1H), 4.66 (dd, J = 7.8, 2.0 Hz, 1H). 13C NMR (125 MHz, CDCl 3) % 165.48, 164.90, 136.61, 133.32, 132.97, 131.83, 129.73, 129.03, 128.68, 128.65, 128.63, 128.45, 128.15, 127.69, 126.64, 75.98, 66.63, 51.24. HRMS analysis (ESI): calculated for (M -H): C 24H20NO2ClBr 468.0366; found: 468.0366. !PhNOPhPh1) 1.5 M HCl 105 ¼C, 30 h2) p-BrBzCl Ph98%dr =13 :1 98 % eedr >20:1 PhClOHClHNOBrI-77 I-120 82 1.8 X -ray crystal structure data 1.8.1 X -ray crystal structure for I -77 !Experimental Single colourless chunk -shaped crystals of ( BB817B ) were used as received. A suitable crystal (0.30 & 0.22 & 0.12) mm3 was selected and mounted on a nylon loop with paratone oil on a Bruker APEX -II CCD diffractometer. The crystal was kept at T = 173(2) K during data collection. Using Olex2 (Dolomanov et al., 2009), the structure was solved with the XT (Sheldrick, 2015) st ructure solution program, using the Intrinsic Phasing solution method. The model was refined with version of XL (Sheldrick, 2008) using Least Squares minimisation "!Crystal Data !C24H20ClNO, !Mr = 373.86, orthorhombic, P2 12121 (No. 19), a = 9.3060(8) †, b =!9.6574(9) †, c = 21.8911(19) †,!"!#!#!#!$!#!90$%!V = 1967.4(3) †3, T = 173(2) K, Z = 4, Z' = 1, µ&MoK "'!= 0.207, 14580 reflections measured, 3615 unique ( Rint = 0.0335) which were used in all calculations. The final wR2 was 0.0784 (all data) and R1 was 0.0332 (I > 2(I)). 83 Crystal data and structure refinement Compound BB817B Formula C24H20ClNO Dcalc. / g cm -3 1.262 µ(mm-1!!0.207 Formula Weight 373.86 Colour colourless Shape chunk Size/mm 3 0.30 & 0.22 & 0.12 T/K 173(2) Crystal System orthorhombic Flack Parameter 0.02(3) Hooft Parameter 0.04(3) Space Group P212121 a/† 9.3060(8) b/† 9.6574(9) c/† 21.8911(19) "($!!90 #($!!90 $($!!90 V/† 3 1967.4(3) Z 4 Z' 1 Wavelength/† 0.710730 Radiation type MoK "!!%!"# ($!!)"*+)! !%!$% ($!!,-"./.! !Measured Refl. 14580 Independent Refl. 3615 Reflections Used 3255 Rint 0.0335 Parameters 244 Restraints 0 Largest Peak 0.161 Deepest Hole -0.165 GooF 1.059 wR2 (all data) 0.0784 wR2 0.0749 R1 (all data) 0.0384 ! 84 The Model has Chirality at C1 (Chiral SPGR) R Verify; The Model has Chirality at C2 (Chiral SPGR) S Verify; The Model has Chirality at C3 (Chiral SPGR) R Verify: 85 Packing diagram of BB817B: !! Citations 1.COSMO -V1.61 - Software for the CCD Detector Systems for Determining Data Collection Parameters, Bruker axs, Madison, WI (2000). 2. O.V. Dolomanov and L.J. Bourhis and R.J. Gildea and J.A.K. Howard and H. Puschmann, Olex2: A complete structure s olution, refinement and analysis program, J. Appl. Cryst. , (2009), 42, 339 -341. 3. Sheldrick, G.M., A short history of ShelX, Acta Cryst. , (2008), A64 , 339 -341. 86 Software for the Integration of CCD Detector System Bruker Analytical X -ray Systems, 4. Bruker axs, Madison, WI (after 2013) 1.8.2 X -ray crystal structure for I -118 !Experimental. Single colourless needle -shaped crystals of ( BB717D ) were used as received. A suitable crystal (0.34 & 0.08 & 0.06) mm3 was selected and mounted on a nylon loop with paraton e oil on a Bruker APEX -II CCD diffractometer. The crystal was kept at T = 173(2) K during data collection. Using Olex2 (Dolomanov et al., 2009), the structure was solved with the ShelXT (Sheldrick, 2015) structure solution program, using the Intrinsic Phasing solution method. The model was refined with version of XL (Sheldrick, 2008) using Least Squares minimisation. Crystal Data. C24H22ClNO3, Mr = 407.87, monoclinic, P21 (No. 4), a = 10 .39310(10) †, b = 9.62820(10) †, c = 20.5187(2) †,!#!=!98.2450(10) ¡,!"!=!$!= 90¡%!V = 2032.02(4) †3, T = 173(2) K, Z = 4, Z' = 2, !µ(CuK ") = 1.869, 27382 reflections measured, 7691 unique ( Rint = 0.0470) which were used in all calculations. The final wR2 was 0.0732 (all data) and R1 was 0.0306 (I > 2(I)). 87 Crystal data and structure refinement Compound BB717D Formula C24H22ClNO 3 Dcalc. / g cm -3 1.333 µ/mm -1 1.869 Formula Weight 407.87 Colour colourless Shape needle Size/mm 3 0.34 & 0.08 & 0.06 T/K 173(2) Crystal System monoclinic Flack Parameter 0.018(6) Hooft Parameter 0.010(7) Space Group P21 a/† 10.39310(10) b/† 9.62820(10) c/† 20.5187(2) "($!!90 #($!!98.2450(10) $($!!90 V/† 3 2032.02(4) Z 4 Z' 2 Wavelength/† 1.541838 Radiation type CuK "!!%!"# ($!!4.298 %!$% ($!!72.150 Measured Refl. 27382 Independent Refl. 7691 Reflections Used 7125 Rint 0.0470 Parameters 539 Restraints 1 Largest Peak 0.159 Deepest Hole -0.186 GooF 1.027 wR2 (all data) 0.0732 wR2 0.0710 R1 (all data) 0.0346 R1 0.0306 88 The following are 50% thermal ellipsoidal drawings of the molecule in the asymmetric cell with various amount of labeling: !The Model has Chirality at C1A (Chiral SPGR) S Verify; The Model has Chirality at C2A (Chiral SPGR) S Verify; The Model has Chirality at C3A (Chiral SPGR) R Verify; The Model has Chirality at C4A (Chiral SPGR) S Verify; The Model has Chirality at C5A (Chiral SPGR) R Verify: !The Model has Chirality at C1B (Chiral SPGR) S Verify; The Model has Chirality at C2B (Chiral SPGR) S Verify; The Model has Chirality at C3B (Chiral SPGR) R Verify; The Model has Chirality at C4B (Chiral SPGR) S Verify; The Model has Chirality at C5B (Chir al 89 SPGR) R Verify: !!The following hydrogen bonding interactions with a maximum D -D distance of 3.1 † and a minimum angle of 110 ¡ are present in BB717D : O1A ÐO1B: 2.668 †, O2A ÐO1A: 2.673 †, O1B ÐO2B: 2.685 †, O2B ÐO2A_ 1: 2.718 †: ! 90 Packing diagram of BB71 7D: !!!Citations 1.COSMO -V1.61 - Software for the CCD Detector Systems for Determining Data Collection Parameters, Bruker axs, Madison, WI (2000). 2.O.V. Dolomanov and L.J. Bourhis and R.J. Gildea and J.A.K. Howard and H. Puschmann, Olex2: A complete structure solution, refinement and analysis program, J. Appl. Cryst. , (2009), 42, 339 -341. 3. Sheldrick, G.M., A short history of ShelX, Acta Cryst. , (2 008), A64 , 339 -341. 4. Sheldrick, G.M., ShelXT -Integrated space -group and crystal -structure determination, 91 Acta Cryst. , (2015), A71 , 3-8. 5. Software for the Integration of CCD Detector System Bruker Analytical X -ray Systems, Bruker axs, Madison, WI (after 2013). 1.8. 3 X-ray crystal structure for I -119 !Experimental. Single colourless needle -shaped crystals of ( BB717A ) were used as received. A suitable crystal (0.22 & 0.10 & 0.08) mm3 was selected and mounted on a nylon loop with paratone oil on a Bruker APEX -II CCD diffractometer. The crystal was kept at T = 173(2) K during data collection. Using Olex2 (Dolomanov et al., 2009), the structure was solved with the XT (Sheldrick, 2015) st ructure solution program, using the Intrinsic Phasing solution method. The model was refined with version of XL (Sheldrick, 2008) using Least Squares minimisation. Crystal Data. !C24H20ClNO2, Mr = 389.86, orthorhombic, P212121 (No. 19), a = 10.0607(3) †, b = 10.4054(3) †, c = 19.2999(5) †, "!=!#!=!$!= /0$%!V = 2020.42(10) †3, T = 173(2) K, Z = 4, Z' = 1, !µ(CuK ")!= 1.820, 12613 reflections measured, 3804 unique (Rint = 0.0423) which were used in all calculations. The final wR2 was 0.0793 (all data) and R1 was 0.0323 (I > 2(I)). 92 Crystal data and structure refinement Compound BB717A Formula C24H20ClNO 2 Dcalc. / g cm -3 1.282 µ(mm-1!!1.820 Formula Weight 389.86 Colour colourless Shape needle Size/mm 3 0.22 & 0.10 & 0.08 T/K 173(2) Crystal System orthorhombic Flack Parameter 0.041(10) Hooft Parameter 0.031(10) Space Group P212121 a/† 10.0607(3) b/† 10.4054(3) c/† 19.2999(5) "($!!90 #($!!90 $($!!90 V/† 3 2020.42(10) Z 4 Z' 1 Wavelength/† 1.541838 Radiation type CuK "!!%min /¡!!4.582 %max /¡!!69.898 Measured Refl. 12613 Independent Refl. 3804 Reflections Used 3403 Rint 0.0423 Parameters 253 Restraints 0 Largest Peak 0.154 Deepest Hole -0.193 GooF 1.029 wR2 (all data) 0.0793 wR2 0.0761 R1 (all data) 0.0385 R1 0.0323 93 The following are 50% thermal ellipsoidal drawings of the molecule in the asymmetric cell with various amount of labeling: The Model has Chirality at C2 (Chiral SPGR) R Verify; The Model has Chirality at C3 (Chiral SPGR) S Verify; The Model has Chirality at C4 (Chiral SPGR) R Verify; The Model has Chirality at C5 (Chiral SPGR) S Verify; The Model has Chirality at C6 (Chiral SPGR) S Verify: !!Packing diagram of BB717A: 94 !!!Citations 1.COSMO -V1.61 - Software for the CCD Detector Systems for Determining Data Collection Parameters, Bruker axs, Madison, WI (2000). 2. O.V. Dolomanov and L.J. Bourhis and R.J. Gildea and J.A.K. Howard and H. Puschmann, Olex2: A complete structure solution, r efinement and analysis program, J. Appl. Cryst. , (2009), 42, 339 -341. 3. Sheldrick, G.M., A short history of ShelX, Acta Cryst. , (2008), A64 , 339 -341. 4. Software for the Integration of CCD Detector System Bruker Analytical X -ray Systems, Bruker axs, Madison, WI (after 2013). 95 REFERENCES 96 REFERENCES 1. Borissov, A.; Davies, T. Q.; Ellis, S. R.; Fleming, T. A.; Richardson, M. S. W.; Dixon, D. J., Organocatalytic enantioselective desymmetrisation. Chemical Society Reviews 2016, 45 (20), 5474 -5540. 2. Schreiber, S. L.; Schreiber, T. S.; Smith, D. B., Reactions that proceed with a combination of enantiotopic group and diastereotopic face selectivity can deliver products with very high enantiomeric excess: experimental support of a m athematical model. Journal of the American Chemical Society 1987, 109 (5), 1525 -1529. 3. Smith, D. 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Sakakura, A.; Sakuma, M.; Ishihara, K., Chiral Lewis Base -Assisted Br¿nsted Acid (LBBA) -Catalyzed Enantioselective Cyclization of 2 -Geranylphenols. Organic Letters 2011, 13 (12), 3130 -3133. 31. 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. 32. Bruenker, H. -G.; Adam, W., Diastereoselective and Regioselective Singlet Oxygen Ene Oxyf unctionalization (Schenck Reaction): Photooxygenation of Allylic Amines and Their Acyl Derivatives. Journal of the American Chemical Society 1995, 117 (14), 3976 -3982. 33. Hyster, T. K.; Rovis, T., Pyridine synthesis from oximes and alkynesviarhodium(iii) catalysis: Cp* and Cpt provide complementary selectivity. Chemical Communications 2011, 47 (43), 11846 -11848. 99 34. Ashtekar, K. D.; Ding, X.; Toma, E.; Sheng, W.; Gholami, H .; Rahn, C.; Reed, P.; Borhan, B., Mechanistically Inspired Route toward Hexahydro -2H-chromenes via Consecutive [4 + 2] Cycloadditions. Organic Letters 2016, 18 (16), 3976 -3979. 100 CHAPTER TWO Kinetic Resolution of Propargyl Amides in a Chlorocyclization Reaction 2.1 Introduction Kinetic resolution is the process of using a chiral reagent or chiral catalyst to promote the reaction of one enantiomer over the other , resulting in a mixture of resolved starting materi al and converted product (Scheme 2.1). It is an important strategy for access ing enantio enriched molecules , as an alternative to using the chiral pool or enantioselective synthesis. The chiral pool is using enantio -pure starting materis provided by nature, however this method is always limited to the range and the stereochemistry of available natural products. Therefore , kinetic resolution and enantioselective synthesis using chiral reagent s or chiral catalyst s play a critical role in or ganic synthesis. Kinetic resolution can be criticized for its inherent inelegance and poor atom economy because the maximum theoretical yield is 50%. On the other hand , if one can transform racemic starting materials to some other useful enantio -enriched products in the process of resolution, it would counterbalance this disadvantage to some degree. Many factors determine the efficiency and practicality of kinetic resolution. Jacobsen has highlighted several features of a practical and efficient kinetic res olution: 1 1!The s tarting material is readily accessible. 2!Products are obtained in quantitative yield or with minimal byproducts. 3!The chiral catalyst is inexpensive. 4!The resolved starting material and product are easily isolated. 5!The reaction can be proce ssed in large scale. 101 6!Reaction time must be short. Scheme 2.1 Catalytic kinetic resolution People usually use the selectivity factor (S or K rel ) to evaluate the efficiency of a kinetic resolution. In general, systems with Krel > 10 are useful . Krel is defined as the relative reaction rate of two enantiomers, so it is correlated with the energy difference of diastereomeric transition states (Scheme 2.1). S can also be defined using the formula of ee and conversion. The ee of the recovered substrate and converte d product varies as a function of conversion (Figure 2.1). As you can see from plot a below, even though the S is only 5, recovered starting material can also be obtained in more than 90% ee by controlling the conversion at 70%. In contrast, high selectivi ty factor is required if you want to get the converted product in high ee (see Figure 2.1 , plot b). S is an important factor to evaluate the efficacy of kinetic resolution in many of the reported kinetic resolution studies, howe ver, it is to some degree ov ersimplif ying the process of kinetic resolution for three reasons. First, the correlation between ee and conversion plotted in Figure 2.1 is based on the assumption that the reaction is first order with respect to the substrate. Second, the selectivity fac tor only accounts for the conversion of substrate and assume s that the reaction only lead s to one converted product, but some reported kinetic resolutions have side products and the isolated yield of the converted product is less than the conversion. Finally, a minor change in conversion will significantly affect the selectivity SRSS+reagent chiral catalyst +SS+PRracemic substrate S = K rel = K fast /Kslow = e !!G!/RT 102 factor. Jacobsen also mentioned that most S values reported in the literature are inaccurate. 1 Therefore simply using S is not an accurate, or at least not a comprehensive way to describe the efficacy of a kinetic resolution. The yield and ee of the converted product and resolved starting material are required . a) # $%&'()*+,-)*+..-/&'()*+,-)*0..-/ Figure 2.1 a) plot of ee of recovered starting material vs conversion as a fu nction of S; b) plot of ee of product vs conversion as a function of S 1. 103 Figure 2.1 (contÕd) b) $%#123#(*+,)*0..4-/123#(*+,)*+..4-/ Although it is hard to meet all the aforementioned criteria for a perfect kinetic resolution, many great examples have been reported that demonstrate the practical utility of this important synthetic strategy. One of the earliest examples is the landmark work of Sharpless for the kinetic resolution of allylic alcohol ( Scheme 2.2, a ).2 He used titanium alkoxide tartrate complex to epoxidize prochiral allylic alcohols. It was observed that the S enantiomer react s 104 times faster than the R enantiomer to give a 98:2 erythro to threo 104 product ratio when L -(+) -DIPT was used. If Ti(O -i-Pr) 4 is used alone, the threo product is predominant. He also showed that the resolution process can proceed under catalytic conditions by using 25 mol% titanium alkoxide tartrate complex but with an extended time range. This work repre sents the earliest non -enzymatic resolut ion usin g a synthetic catalyst. Since then alkenes have become the most studied category in kinetic resolution. Corey reported the kinetic resolution of allylic 4 -methoxybenzoate by asymmetric dihydroxylation using cinchona alkaloid catalyst II-5 (Scheme 2 .2, b ).3 Noyori reported the Ru-catalyzed oxidative kinetic resolution of benzylic alcohols. This method merits the high selectivity and quan titative yield for a variety of benzylic and allylic alcohols ( Scheme 2.2, c).4 Transition -metal -salen complexes ar e another class of privileged catalysts for hydrolytic kinetic resolution (HKR) of epoxides. HKR provides a good way to access chiral epoxides other than direct enantioselective epoxidation of olefins since racemic epoxides are readily synthesized from alk enes. Chiral salen complexes of Cr and Co can catalyze the opening of epoxides with a variety of nucleophiles, such as carboxylic acids, phenols, azides, and water. JacobsenÕs (salen) -Co catalyzed kinetic resolution of terminal epoxides results in high selectivity and generate the corresponding diols in excellent ee (Scheme 2.3, a ).5 The HKR is second -order for the catalyst, proceeding via simultaneous activation of epoxide and nucleophile. Surprisingly the high selectivity is no t caused by different binding constants between the two epoxide enantiomers with the catalyst, since they are comparable. The high selectivity arises from the pre ferential ring -opening process of one of the diastereomeric catalyst -epoxide adducts (Scheme 2 .3, b). The 105 active form of catalyst is (salen)Co(OH), which is generated after (salen)Co(OAc) or (salen)Co(Cl) is added to the epoxide. Scheme 2.2 Early landmark studies for thr kinetic resolution of alkene s. MeO OOMeO OO1 mol% II-5 K2CO3K3Fe(CN) 6K2OsO 4¥2H2OMeO OO+OHOHRRÕOHRRÕOHRRÕOH+OH2.5 mol% II-9 acetone OHO+46%97% eeKrel > 40 NHRuNTsII-9 Krel up to 138OtBuONNOMe Krel = 20 a.b.c.II-1 II-2 II-3 II-4 II-6 II-7 II-8 II-10 II-11 II-5 OTBHP Ti(O- i-Pr)4L-(+)-DIPT 106 Scheme 2.3 a) Cobalt -salen catalyzed HKR; b ) Mechanism of HKR . Since the time that Sharpless used cinchona alkaloid derivatives as catalysts in kinetic resolution during the 1980s, a number of other groups studying kinetic resolutions started using this type of catalyst. Deng reported cinchona alka loid catalyzed kinetic resolution of urethane protected 5-amino acid N -carboxyanhydride (UNCA) II-12 that leads to 5-amino acid derivatives II-13 and II-14 (Scheme 2.4 ).6 (DHQD) 2AQN catalyzed the alcoholysis of meso UNCA to generate the amino ester II-13 with S up to 170. This work NNt-But-But-But-BuCoOOOAc (R,R)-(Salen)Co(Ac) RO(R,R)-cat ROROHOHROROHOH++(S,S )-cat H2OH2OCoXOXOHCoOHX =Cl, OAc R+H2ORCoXORCoOHOH2RDSCoXORCoHOOH2H2OOHHORa.b. 107 indicates that small -molecule catalyzed kinetic resolution of carbonyl derivatives can be as efficient as the enzyme catalyzed process es. Scheme 2.4 (DHQD) 2AQN catalyzed alcoholysis of meso UNCA . More recently WangÕs group reported that the cinchona -alkaloid derived amine thiourea bifunctional catalyst II-17 can catalyze a highly enantioselective transesterification process to generate chiral biaryl products ( Scheme 2.5 ).7 Biaryl lactone II-15 can undergo dynamic kinetic resolution (DKR) by reacting with alcohol II-16. The synergistic activation of lactones and alcohols by the thiourea and amine , respectively , is crucial for achieving high yield and enantioselectivity. NOOOPhOO10 mol% (DHQD) 2AQN OOMe NHOOPhNOOOPhOO+OOONEtNOMe MeO NNOEt(DHQD) 2AQNII-12 II-13 II-14 0.55 equiv MeOH Et2O, 4† MS 108 Scheme 2.5 DKR of lactone II-15 catalyzed by a thiourea -based bifunctional catalyst . Scheme 2.6 Kinetic resolution of 2 -oxindole catalyzed by cinchona -alkaloid squaramide . OO+NO2BrOMe HO10 mol% II-17 rtOMe OOBrOHNO2NNHNHNSF3CCF3MeO OOR1R2SNHNHNHORchiral scaffold activation mode II-15 II-16 II-18 II-17 NBoc OCO2EtCO2MeMeO 2C2 mol% II-20 0.55 equiv PhCH 2Br 10% aq K2CO3CH2Cl2(0.1 M), rt NBoc OCO2EtCO2MeMeO 2CPhNNNHHNOOOCF3F3CBrII-19 II-21 II-20 109 Kinetic resolution of 2 -oxindole II-19 through an enolate alkylation process catalyzed by cinchona -alkaloid derived squaramide catalyst II-20 has been reported by ConnonÕs group ( Scheme 2.6 ).8 The S N2 reaction is taking place in a biphasic solvent system using a phase transfer catalyst, leading to a single diastereomer with S up to 261. This chapter describes kinetic resolution of propargyl amide s via chlorocyclization catalyzed by a cinchona -alkaloid catalyst. Kinetic resolution of propargyl or allyl amine s and propargyl alcohol s have been reported. Most of the kinetic resolutions of propargyl amines are throu gh N-acety lation process es. For example , CossyÕs group used N-acetyl -1,2 -bis -trifluoromethanesulfon -amidocyclo -hexane II-23 as a chiral acetylating reagent to react with primary propargyl amine II-22, affording acetamide II-24 with high selectivity (Scheme 2.7, a) .9 Siedel also reported the first small -molecule catalyzed kinetic resolution of racemic allylic amines by an acylati on reaction (Scheme 2. 7, b ). He utilized a dual catalyst system which contains a nucleophile catalyst PPY and a chiral hydrogen bon ding catalyst II-27. The nucleophilic catalyst and the acylating reagent generate an ion pair which can form hydrogen bond with the chiral catalyst, leading to a chiral ion pair. Fu reported a Rh -catalyzed kinetic resolution of 4 -alkynals II-29 (Scheme 2. 7, c ).10 Rh-(Tol -BINAP) complex catalyze the cyclization of 4 -alkynals leading to cyclopentenone product II-31. Similarly a Rh(I) -BINAP complex can catalyze the kinetic resolution of secondary propargylic alcohol II-32 by isomerization into 5,+-enones ( Scheme 2. 7, d ).11 The isomerization proceeds through 1,2 or 1,3 -hydrogen migration. 110 Scheme 2.7 Kinetic resolution of unsaturated amine s and alcohols . NH2+PhOOOPhPhPhHNOPh5 mol% PPY PhMe, Ð78 ¼CNNPPYNHHNHNSNHSF3CF3CCF3CF3R1NH2R20.5 equiv II-23 R1NHR2ONHNSSOOCF3OOCF3OS up to 197R2R1OMe HO5% [Rh(( R)-Tol-BINAP)]BF 4R2R1OMe HO+OR2R1OMe S up to 22ArOHR5% [Rh(( R)-BINAP)]OTf ArOHR+ArROS up to 11.5 P(Ph) 2P(Ph) 2(R)-BINAP NNORRNHNHRSOOPhchiral ion pair a.b.c.d.II-22 II-24 II-23 II-25 II-26 II-27 II-28 II-29 II-30 II-31 II-32 II-33 II-34 II-27 THFÐ20 ¼C, 12 hCH2Cl2, 25 ¼CCH2Cl2, 30 ¼C 111 Propargyl amines in pure enantio meric form are important and versatile building blocks in organic synthe sis. Conventional routes for the preparation of chiral propargylic amines include:1) nucleophilic 1,2 -addition to activated aldimines; 2) kinetic resolution of racemic propargyl amines. For route (1) a three -component coupling of an aldehyde, an alkyne and an amine catalyzed by a chiral catalyst is used to access to enantiopure propargylic amines (Scheme 2. 8).12-14 This method usually requires the activation of the C-H bond of terminal alkyne by a transition metal catalyst. As mentioned above, there are als o reported kinetic resolution s of propargylic amines employing chiral acylating reagent s.9 However , kinetic resolution of propargylic amines by halofunctionalization has not been reported yet. Scheme 2.8 Access to propargylic amines by coupling of alkyne and aldimine . In 2013 , our group reported the first example of kinetic resolution via chlorofunctionalization of olefin s (Scheme 2. 9).15 This was a captivating piece of work for several reasons. First , the C-Cl bond generated can be a functional handle for further functionalization . Second , the kinetic resolution leads to a product with three contiguous chiral centers. Thirdly , (DHQD) 2PHAL as a catalyst can not only show high olefin face selectivity with a chlorenium donor, but also effectively discriminate the chirality of propargylic amides. This proposed method for the kinetic resolution of propargylic amides was inspired by our previous work on organocatalytic enantioselective chlorocyclization R[M] R[M] NHR1R2RR1NHR2L** 112 of olefi nic amide s. Based on previous work it was proposed that propargylic amide s should be able to undergo similar kinetic res olution via chlorocyclization. Scheme 2.9 Our groupÕs previous work and proposed work 2.2 Results and Disscussion 2.2.1 Evaluate the efficiency of kinetic resolution Generally, people use Krel or S to evaluate the efficiency of a kinetic resolution. However as mentioned above, S usually is not an accurate and reliable value since minor variation on conversion can change the S by several folds. Therefore , it really depends on how accurate ly we measure the conversion of a reaction. During the development of this project, different ways to measure the conversion were attempted . Each of those methods has pros and cons. Crude 1HNMR was used to evaluate conversion by adding methyl ter t-butyl ether as internal standard , which is an easy and fast way to get the conversion. However , the error can be notable sometimes since MTBE is volatile. Besides, using methyl and t-butyl as standard , respectively , gave different integration of products. Alternatively, GC was used to determine conversion. This method R1R2NHOPh0.55 equiv NCP ONClR1R2PhR1R2NHOPh+S > 50 R2NHOPhR1ONR1R2PhClR2NHOPhR1+previous work:this work: II-35 II-36 II-37 0.5 mol% (DHQD) 2PHAL CF3CH2OH (0.1 M) 24 ¼C NCP(DHQD) 2PHAL 113 requires plotting a standard curve using a stock solution of different percentage products or substrates along with a high boiling point internal standard such as undecane. For the method to be accurate, each time you need to make a stock solution of crude and subject it to GC analysis, which is not an efficient way for high throughput screen ing . Another way is using the isolated yield of the recovered substrate to decide the conversion. This method is more straightforward, however , is not accurate when running small scale reaction s. During the project, for those conversions decided by isolated yield, reactio ns were carried out on 0.2 mmol 60.5 mmol scale . Recently , many that study kinetic resolution , use the following equation to calculate conversion: 16 ,7'8.9:;7' #)<=&> - % ??)@A-??)@A-B??)C- where eesm is ena ntiomeric excess of the recovered substrate and eep is the enantiomeric excess of product. In this case, conversion is only determined by ee which is measured by HPLC . To some degree, this helps to avoid the errors caused by direct measuring conversion. From now on , this conversion will be designated as CHPLC whe rever it appears . 2.2.2 Screening of the halogen source s I started screening the reaction by choosing a halogen source that results in less background reaction. Substrate II-39 was exposed to different types of electrophilic halogen source s in acetonitrile without adding catalyst. Reac tions were quenched after 15 min to evaluate the background reaction rate. The m ore reactive electrophilic chlorine reagent trichloro iso cyanuric acid (TCCA) resulted in complicated products and the reaction was done after 15 min. N-bromosuccinimide lead s to 66% conversion with both six -member ed ring an d five -membered ring regioisomer formation (84:16 ratio). Not 114 surprisingly the more electrophilic N-iodosuccinimide gave 99% conversion and endo/exo isomers in 1:1 ratio. Finally it was found that NCS ( N-chlorosuccinimide) gave no reaction even after 3 hours at room temperature. Therefore , NCS was chosen as the optimal halogen source for catalytic reactions. Table 2.1 Screening of e lectrophilic halogen source 2.2.3 Screen ing of solvents With NCS as an optimal electrophilic chlorine reagent in hand, substrate II-38 was used for screening solvent (Table 2.2) . Chlorinated solvent s includ ing dichloromethane, dichloroethane and chloroform gave low conversion and ee for the recovered substrate. The s electivity factor for all reactions was around 2. Acetonitrile and CHCl 3/hexane led to incomplete reactions, even after extended time. More polar p rot ic solvent iso -propanol still did not give full conversion , however they did increase the ee of the recovered substrate , the selectivity factor in iso -propanol went up to 9. This suggested that polar PhNHOC5H11Ph1.2 equiv. X +MeCN (0.1 M) 24 ¼C, 15 min ONPhXC5H11Ph+ONC5H11PhXPhEntry 1234aII-39 II-56 II-83 NNNOOOX +TCCANBS NISNCSconv. (%) 9566990rr (endo:exo) nd 84:1650:50!a No reaction after 3 h ClClClTCCANOOBrNBSNOOINISNOOClNCS 115 prot ic solvent s might be important for good enantiose lectivity. The m ore polar trifluoroethanol (TFE) increased the reaction rate and ee greatly , but le d to a 6% yield of the TFE incorporated side product II-72. Another fluorinated solvent hexafluoro -iso propanol (HFIP) avoid ed this sid e product and gave higher yield, however the enantioselectivity was lower, with S = 29, while S = 40 for TFE . Based on this, it was assumed that both good yield and enantioselectivity might be achieved through using different ratio s of TFE/HFIP co -solvent system. However , it turned out that ee was generally worse than TFE alone when HFIP was used as a cosolvent and the TFE incorporated product II-72 was always observed. Using other c o-solvent combination, i.e. TFE and other non -fluorinated solvent s like CHC l3 and DCM led to decreased enantioselectivity, with S around 20 (Scheme 2.10, entry 12 and 13). Finally, TFE, HFIP and TFE -DCM (7:3) were used respectively for substrate scope analysis . 116 Table 2.2 Screen ing of solvent 2.2.4 Catalyst Study Different loadings of catalyst were tried (Table 2.3) . Typically, 10 mol% (DHQD) 2PHAL was used as catalyst. When the catalyst loading was 2 mol% and 5 mol%, S was 25 and 27 respectively, which are lower than that of 10 mol% catalyst. Therefore , 10 mol% (DH QD) 2PHAL was used as the optimal loading . For large scale reactions, the catalyst can be recycled by column chromatography using MeOH/EtOAc as eluent. solventDCMDCECHCl3MeCN i-propanol CHCl3 : hexane (1:1) TFETFE : HFIP (1:1) TFE : HFIP (3:7) TFE : HFIP (1:9) HFIPCHCl3 : TFE (5:1) DCM : TFE (5:1) CH3CN : TFE (5:1) entry 1234567891011121314%conva (%yield)b14202011301452 (44) 51(44) 51(44) 52 (43) 51 (48) 37 (33) 44 (40) 24%ee (II-55 )c7572687772208080807278899080%ee ((S)-II-38 )c9101383249284847286515221PhNHBz 0.55 equiv. NCS 10 mol% (DHQD) 2PHAL solvent , r.t. ONPhPhCl+PhNHBz II-38 II-55 (S)-II-38 a conversion is based on GC yields of unreacted substrate using undecane as internal standard; b yield of isolated product is reported; c ee was determined by chiral HPLC. BzHN MeF3CH2COClPhII-72 117 Table 2.3 Catalyst loading study 2.2.5 Temperature Study Another important variable for screening is temperature. Low temperatures were tried for those substrates which gave low ee at room temperature, such as p-MeO phenyl and p-Me phenyl substrates II-41 and II-40 (Table 2 .4). When the temperature was decreased to #10 ¼C, the reaction rate for both substrates reduced greatly. p-MeO phenyl substrate II-41 only gave 42% conversion after 12 h in contrast of 50% conversion at room temperature after 1.5 h. Besides, the enantioselectivity was almost the same as that at room temperature in terms of S. For II-40, S was even worse at #10 ¼C than that at room temperature. For substrates that gave good enantioselectivity at room temperature, lowering the temperature had a drastic improvement in S. For example, S of phenyl substrate II-39 increased from 18 to 27 when temperature was decreased from room temperature to #10 ¼C. Further decreasing the temperature from #10 ¼C to #30 ¼C increased the S further, albeit using a different solvent. catalyst loading 2 mol% 5 mol% 10 mol% conversion%a505052ratio (II-55:II-72) b7:16:16:1ee (II-55) c818280ee (II-72) c888688ee (( S)-II-38) c828392PhNHBz 0.55 equiv NCS ONPhPhCl+PhNHBz +PhClOBzHN F3CII-38 II-55 (S)-II-38 II-72 (DHQD) 2PHAL CF3CH2OH (0.1 M) rt, 80 min a conversion is based on GC yields of unreacted substrate using undecane as internal standard; b ratio is based on 1H NMR; c ee is determined by chiral HPLC 118 Table 2.4 Temperature study for different substrates To get better solubility, TFE -DCM (v/v, 7:3) was used as solvent at #30 ¼C. Although reactions take longer time to complete, the enantioselectivity increased quite a bit. S for phenyl substrate II-39 can be up to 210, which is almost as efficient as an enzyme MeO n-pentyl NHPhOee % (( S)-II-41) ee % (II-59) temp (¼C) conv (%) S b23Ð10504220214101.82.2ee % (( S)-II-40) ee % (II-58) temp (¼C) conv (%) S b23Ð1055306325862911.5 4.8ee % (( S)-II-39) ee % (II-56) temp (¼C) conv (%) S b23Ð1056599199917018.527Ð30a5732222Ð30a52827618Ð30a519991210a TFE-DCM(V/V, 7:3) was used as solvent; b conversion was determined by recovered substrate. II-41 0.55 equiv NCS ONn-pentyl PhClMeO MeO n-pentyl NHPhO+II-59 (S)-II-41 10 mol% (DHQD) 2PHAL CF3CH2OH (0.1 M) Men-pentyl NHPhOII-40 0.55 equiv NCS ONn-pentyl PhClMeMen-pentyl NHPhO+II-58 (S)-II-40 10 mol% (DHQD) 2PHAL CF3CH2OH (0.1 M) n-pentyl NHPhOII-39 0.55 equiv NCS ONn-pentyl PhCln-pentyl NHPhO+II-56 (S)-II-39 10 mol% (DHQD) 2PHAL CF3CH2OH (0.1 M) 119 catalyzed kinetic resolution. But for p-MeO phenyl substrate II-41, S remains the same even at low temperature ( #30 ¼C). p-Me phenyl substrate II-40 had a slightly higher S at #30 ¼C as compared to room temperature. In summary, low temperature could help further increase the S of substrates that work well at room temperature, however, for those that gave poor enantioselectivity at room temperature, low temperature does not make a large difference. 2.2.6 Variations from standard condition Other variables including catalyst and halogen sources were also investigated (Table 2.5). It is noteworthy that other C 2-symmetric cinchona alkaloid catalysts like (DHQD) 2Pyr and (DHQD) 2AQN did not induce any enan tioselectivity and gave almost racemic products. Other halogenated succinimide, including NBS and NIS, gave no enantioselectivity as well. 120 Table 2.5 Variations from standard condition 2.2.7 Substrate s scope with TFE as solvent After screening different conditions, TFE turned out to be the best solvent in terms of enantioselectivity. Substrates bearing a range of sterically and electronically diverse functionalities were tried using TFE as solvent, NCS as chlorinating reagent and (DHQD) 2PHAL as catalyst at room temperature. The TFE incorporated product was observed for most substrates (between 5% to 10%). The ratio of cyclized product to TFE incorporated product was indicated for some substrates. As shown in Scheme 2.6, the ees of some TFE incorp orated products were as good as those of the cyclized products. The absolute stereochemistry of TFE incorporated product was not determined. However, based on indirect evidence based on the simple math of ee and conversion, it was PhNHBz 0.55 equiv. NCS 10 mol% (DHQD)2PHAL HFIP , r.t. ONPhPhCl+PhNHBz II-38 II-57 (S)-II-38 "standard" conditions entry 12345variaton from "standard" conditons none(DHQD) 2Pyr instead of (DHQD) 2PHAL (DHQD) 2AQN instead of (DHQD) 2PHAL NBS instead of NCS NIS instead of NCS %ee (II-57) a782720%ee (( S)-II-38) a862600a ee was determined by chiral HPLC NONNONNNH3COOCH3ONNNOCH3OOOH3CON(DHQD) 2Pyr (DHQD) 2AQN 121 hypothesized that the TFE incorporated product has the same stereochemistry as the cyclized product. Phenyl substituted alkynes with less bulky R 2 (R2 = pentyl, methyl) gave good enantioselectivity (Table 2.6, entries 1 and 2). Substrates with bulky R 2 groups, like t-butyl had slower reactions and poor enantioselectivity (Table 2.6, entry 11), leading to almost racemic cyclized product when conversion was 25% after 24 h. Besides alkyl substituents, aryl groups were also substituted for R 2, II-47 was produced with moderate enanti oselectivity (Table 2.6, entry 10). The electronic effect on R 1 was obvious and substituents on phenyl have a drastic effect on enantioselectivity. In general, electron rich phenyl and very electron poor aryls lead to lower ee, examples are p-MeO phenyl II-41 and p-NO2 phenyl II-45 (Table 2.6, entries 3 and 8). Reaction of II-45 is sluggish with NCS as the chlorinating reagent and only 20% conversion was obtained when the more reactive DCDMH was used. If there is a strong electron donating group at the meta position of phenyl, the ee was still good (Table 2.6, entry 4). Moderately electron rich substituents such as p-Me and o-Me phenyl gave moderate ee (Table 2.6, entries 5 and 6). However, alkyl substituted alkynes were not compatible with this system (Tabl e 2.6, entry 9). No enantioselectivity was observed for the alkyl substituted alkyne II-46. In terms of selectivity factor Krel , as shown in Table 2.6, those for phenyl substituted alkynes Krel were around 50, and for methyl substituted phenyls were slightly lower Krel (36 and 48). Surprisingly, the electron -with drawing F goup leads to a Krel of up to 65, while the p-NO2 substituted phenyl substrate was not resolved at all. Although Krel is not a n accurate parameter because of the reasons previously discussed, especially considering that side 122 products are formed, it still can be a straightforward reference to roughly compare the efficiency of a kinetic resolution. Table 2.6 Substrate scope using T FE as solvent 2.2.8 Substrate scope with HFIP as solvent Since the TFE incorporated product was always been observed when TFE was used as solvent, a polar, more acidic and non-nucleophilic alternative HFIP was tried (Table 2.7). The yield generally improved for most substrates, but the ee eroded slightly. Notably, p-CF3 phenyl substrate II-49 gave much higher enantioselectivity as compared to the similarly electron -deficient p-NO2 phenyl substrate II-45. Other aryl substituted substrates, such as 1 -naphthalenyl, gave moderate enantioselectivity. Besides benzoyl, other amine protecting groups, including p-F benzoyl and p-Me benzoyl also performed well. The 4 -F R2NHBz 0.55 equiv. NCS 10 mol % (DHQD) 2PHAL, TFE (0.1 M), rt ONR1R2PhCl+R2NHBz R1R1+BzHN R2F3CH2COClR1substrate II-38 II-39 II-41 II-42 II-40 II-43 II-44 II-45 II-46 II-47 II-48 entry 12345678g9e1011R1PhPh4-OMe-Ph 3-OMe-Ph 4-Me-Ph 2-Me-Ph 4-F-Ph 4-NO 2-Phpentyl PhPhR2methyl pentyl pentyl pentyl pentyl pentyl pentyl pentyl pentyl Pht-butyl %conv. a (%yield b)50 (42) 54 (45) 50 53 (41) 56 (48) 55 (48) 53 (43) 37 (15) 2049 (35) 25ee % (II-55-II-63) c80842184867485752407ee % (II-38-II-48) c8998209663979811252?a conversion was determined by recovered substrate yield; b yield of isolated cyclized product is reported; c ee was determined by chiral HPLC. d Krel was calculated using equation Krel =In[(1-c)(1-ee)]/ln[(1-c)(1+ee)], c is the conversion that determined by recoverd substrate e DCDMH was used instead of NCS, MeCN was used as solvent instead of TFE f yield in parenthesis was for TFE incorporated product g DCDMH was used instead of NCS Kreld515024853665215-ee % (II-72-II-76) f90 (5%) 83 (4%) -82 (9%) -77 (5%) 78 (3%) ----II-55-II-63 II-38-II-48 (S)-II-38-II-48 II-72-II-76 123 benzoyl protecting group II-51 gave lower ee, while the 4 -Me benzoyl protecting group II-52 gave better ee than benzoyl (Table 2.7, entries 2 and 12, entries 1 and 13). Table 2.7 Substrate scope using HFIP as solvent 2.2.9 Substrate scope with TFE-DCM as solvent at low temperature From temperature studies, it was realized that low temperature can increase the enantioselectivity for most substrates. As a result, the scope of the transformation at Ð30 ¡C using TFE -DCM (v/v, 7/3) as co -solvent was evaluated. DCM ca n facilitate the solubility of substrates. The general trend is consistent with the results at room temperature. Phenyl rings bearing electron -donating substituents (4 -OMe, 4 -Me, 2 -Me) led to a lower selectivity factor (Table 2.8, entries 3, 5 and 6). When R2 is some sterically R1R2NHR30.55 equiv. NCS 10 mol% (DHQD) 2PHAL HFIP ( 0.1 M), rt 0. 5 h to 8 hONR1ClR2R3+R1R2NHR3II-55-II-70 (S)-II-38-II-53 II-38-II-53 substrate II-38 II-39 II-41 II-42 II-40 II-43 II-44 II-45 II-49 II-50 II-46 II-51 II-52 II-47 II-53 entry 123456789101112131415R1PhPh4-OMe-Ph 3-OMe-Ph 4-Me-Ph 2-Me-Ph 4-F-Ph 4-NO2-Ph 4-CF 3-Ph1-Naphthalenyl pentyl PhPhPhPhR2methyl pentyl pentyl pentyl pentyl pentyl pentyl pentyl methyl methyl pentyl pentyl methyl PhCyR3BzBzBzBzBzBzBzBzBzBzBz4-F-Bz 4-Me-Bz BzBz%conv. a (%yield b)51 (48) 53 (51) 42 (40) 51 (51) 55 (52) 55 (51) 55 (50) 1437 (28) 55 (53) 2055 (53) 54 (40) 50 (40) 48 (43) ee% (II-55-II-70) c7780228638648026448278734467ee% (II-38-II-53) c8094198456829264266080975249a conversion was determined by recovered substrate yield; b yield of isolated cyclized product is reported; c ee was determined by chiral HPLC; d Krel was calculated using equation K rel =In[(1-c)(1-ee)]/ln[(1-c)(1+ee)], c is the conversion that is determined from recovered substrate. Kreld1839225412232961114355 124 demanding group, such as cyclohexyl and TBS protected silyl ether, Krel dropped. Besides, aryl substituent R2 (R2 = phenyl) was not well tolerated in this system (Table 2.8, entry 10). Both electron -deficient and electron -rich protecting groups of amine gave good enantioselectivity (Table 2.8, entries 8 and 13). The efficiency of the kinetic resolution greatly improved under low t emperature for most substrates. Krel were generally above 100 for substrates that only gave Krel up to 50 at room temperature in TFE. Substrate II-39 even gave Krel up to 210, which is comparable with enzyme catalyzed kinetic resolution. Table 2.8 Substra te scope using TFE -DCM as solvent at #30 ¡C 2.2.10 Large scale reaction Large scale kinetic resolutions were performed to evaluate its practicality. Substrate II-38 (0.84 g) was subjected to reaction conditions with TFE as solvent at ambient R2NHR30.55 equiv. NCS 10 mol% (DHQD) 2PHAL, TFE-DCM (v/v, 7:3, 0.1 M) -30 ¼CONR1R2R3Cl+R2NHR3R1R1substrate II-38 II-39 II-41 II-42 II-40 II-43 II-44 II-51 II-50 II-47 II-53 II-54 II-52 entry 12345678910111213R1PhPh4-OMe-Ph 3-OMe-Ph 4-Me-Ph 2-Me-Ph 4-F-Ph Phnaphthalenyl PhPhPhPhR2methyl pentyl pentyl pentyl pentyl pentyl pentyl pentyl methyl Phcyclohexyl propyl-OTBS methyl R3BzBzBzBzBzBzBzp-F-Bz BzBzBzBzp-Me-Bz %conv. a (%yield b)50 (42) 51 (46) 57 (49) 52 (40) 52 (45) 50 (38) 51 (47) 50 (44) 56 (49) 40 (33) 46 (42) 48 (36) 52 (40) ee % (II-55-II-71) c88.7912284769094907260779287ee % ((S)-II-38-II-54) c94.6993299.9828397929537677799a conversion was determined from recovered substrate yield; b yield of isolated cyclized product is reported; c ee was determined by chiral HPLC; d Krel was calculated using equation Krel =In[(1-c)(1-ee)]/ln[(1-c)(1+ee)], c is the conversion that is determined from recovered substrate. II-55-II-71 (S)-II-38-II-54 II-38-II-54 kreld1322102116 1828119 792551721116 125 temperature. Considering the high cost of catalyst on large scale, catalyst loading was decreased to 2 mol%. The chlorocyclized product II-55 was obtained in 68% ee and 45% of the substrate was recovered in 87% ee. Compared with the small -scale reaction, Krel dropped greatly ( Krel is from 51 to 14). Scheme 2.9 Large scale reaction 2.3 Kinetic resolution of racemic amides by dihalogenation After developing the kinetic resolution of unsaturated amides via intramolecular cyclization, it was of interest to assess whether kinetic resolution of unsaturated amides can be achieved by intermolecular halofunctionalization. The Borhan group recently developed a highly regio -, diastereo -, and enantioselective vicinal dichlorination of allyl amides using (DHQD) 2PHAL as catalyst. 17 This method represents an excellent catalyst - controlled stereo -discrimination process. Similarly, a successful kinetic resolution of racemic allyl amides requi res a series of highly catalyst -controlled processes (Scheme 2.10). First, the ca talyst should be able to discriminate between two enantiomers of allyl amides. Second, high face selectivity is required for olefin capture of electrophilic chlorine source, while potential olefin -to-olefin transfer can erode the stereochemical fidelity of the chlorenium intermediate. Third, the regioselectivity of chloride opening of chiral chlorenium ion will determine the dr and ee of the dichlori nated products . PhNHBz 0.55 equiv. NCS 2 mol% (DHQD) 2PHAL TFE (0.3 M) rtONPhClPh+PhNHBz 0.84 g49 % isolated yield 68 % ee45 % isolated yield 87 % eeII-38 II-55 (S)-II-38 Krel = 14 126 Scheme 2.10 Two distinct stereoselective steps leading to diastereomers . It has already been demonstrated that excellent catalyst control is possible in dichlo rination of allyl amides, 17 and thus the next step is to examine whether (DHQD) 2PHAL can efficiently resolve the two enantiomers of racemic allyl amides via dichlorinatio n. The alkyl substituted (Z)-olefin II-77 was subjected to the dichlorination condition, in which DCDMH and a large excess of LiCl was used as the electrophilic and nucleophilic chlorine source, respectively. However, the dichlorinated products were obtain ed in almost 1:1 dr. One of the diastereomers II-78 had much higher ee than II-79. The absolute stereochemistry of the diastereomer II-78 that had higher ee was confirmed by X -ray crystallography. This stereochemical outcome was consistent with the dichlorination of allyl amides which also lead to anti -dichlorination. The less reactive chlorine reagent NCS also gave 1:1 dr but good ee for the dichlorination p roduct. To determine if both enantiomers can be pushed to dichlorination or undergo dynamic kinetic NHOArracemic NHOArNHOArClNHOArClOArface selectivity OArClNHOArClCl++ClNHOArClClNHOArClClNHOArClClNHOArClCl++regioselectivity anti-opening ClNHOArClClNHOArClCl+NHOArClClNHOArClCl+ 127 resolution by adding 1.1 equiv NCS, however 33% of the starting material in almost pure enantiomeric form remained unreacted, suggesting a big difference fo r the reaction rate between the two enantiomers. Table 2.9 Kinetic resolution of racemic allyl amides via dichlorination Next the focus shifted to improving the diastereoselectivity of the reaction. Various conditions including changes in concentration, chloride source and catalyst were screened. The concentration of the reaction did not have an influence on dr. Other electrophilic chlorine sources like NCP gave 1:1 dr as well. The basic additive Na 2CO3 did not improve dr. Other cinchona alkaloid dimer ca talysts including (DHQD) 2Pyr and (DHQD) 2AQN gave 1:1 dr as well and proved sluggish in promoting the reaction. Quinidine derived thiocarbamate catalyst II-80 gave chloro -cyclization product II-81 instead of dichlorination product. When 100 equiv KCl was used as the nucleophilic chloride source, no dichlorination product was observed and instead the 5 -member ring NHO0.55 equiv Cl +100 equiv LiCl 5 mol% (DHQD) 2PHAL TFE (0.2 M), Ð30 ¼C, 4hHNp-NO 2-phenyl OClClII-77 +HNp-NO 2-phenyl OClCl(R, R, R)-II-78 +II-79 NHp-NO 2-phenyl ONO2Yield( II-78 and II-79) % a534467dr (II-78:II-79) b1.1:11.2:11.1:1ee (II-78) % c8810086ee (II-79)% c476042ee ( II-77 recover) % c1006597Cl+DCDMH NCSNCSda yield of isolated product is reported; b dr is determined from crude 1H NMR; c ee was determined by chiral HPLC; d 1.1 equiv NCS was used. II-77 Yield( II-77 recover) % a364024 128 product II-81 was obtained. Since (DHQD) 2PHAL can effectively resolve aryl substituted allyl amides via chlorocyclization, 15 the phenyl substituted substrate II-82 was subjected to dichlorination condition, however complicated products were obtained. So far the catalytic system that has been developed is not capable of kinetic resolution of racemic amides through dichlorination. 129 Table 2.10 Screen variations from standard condition to improve dr Scheme 2.11 Kinetic resolution of II-82 2.4 Summary We have developed an efficient and practical kinetic resolution of propargyl amides via chlorocyclization using (DHQD) 2PHAL as the catalyst. Krel s were generally >20 and reached up to 210. This catalytic system is tolerated with various aryl substituted Yield( II-78 and II-79) % a44464842504837c46112123cdr (II-78:II-79) b1.2:11.2:11.3:11.2:11.2:11.2:1!1.1:11.3:11.2:1!variations from standard condition none0.1 M TFE instead of 0.2 M 0.4 M TFE instead of 0.2 M NCP instead of NCS 10 equiv LiCl instead of 100 equiv add 1 equiv Na 2CO3100 equiv KCl instead of LiCl 10 mol% (DHQD) 2PHAL instead of 5 mol%, rt 10 mol% (DHQD) 2Pyr instead of (DHQD) 2PHAL, rt 10 mol% (DHQD) 2AQN instead of (DHQD) 2PHAL, rt 10 mol II-80 instead of (DHQD) 2PHAL a yield of isolated products is reported; b dr is determined from crude 1H NMR; c yield was for cyclized product II-81 .NONNHPhSOMe ONClNO2NHO0.55 equiv Cl +100 equiv LiCl 5 mol% (DHQD) 2PHAL TFE (0.2 M), Ð30 ¼C, 4hHNp-NO 2-phenyl OClClII-77 +HNp-NO 2-phenyl OClCl(R, R, R)-II-78 +II-79 NHp-NO 2-phenyl ONO2II-77 II-81 II-80 NHp-NO 2-phenyl O1.1 equiv. DCDMH 100 equiv. LiCl 10 mol% (DHQD) 2PHAL TFE (0.2 M), Ð20 ¼C Phmessy II-82 130 propargyl amides. Electronic and steric modification of the aryl substituents have drastic impact on the Krel . However, this kinetic resolution is not compatible with alkyl substituted propargyl amides. Kinetic resolution of allyl amides via intermolecular dichlori nation was also evaluated. After exhaustive screening, the downside of poor dr of dichlorination products could not be circumvented. 2.5 Acknowledgement Thanks are due to Mr. Mengke Fan who worked as an undergraduate research assistant in the lab during th e duration of this project. He helped with the synthesis of substrates and executed many experiments. 2.6 Experimental Section 2.6.1 General Information All reagents were purchased from commercial sources and were used without purification. (DHQD) 2PHAL and N-chlorosuccinimide were purchased from Aldrich. Trifluoroethanol and hexafluo ro-iso propanol were purchased from Combi -Blocks. TLC analyses were performed on silica gel plates (pre -coated on glass; 0.20 mm thickness with fluorescent indicator UV25 4) and were visualized by UV or charred in KMnO 4 stains. 1H and 13C NMR spectra were collected on 500 MHz NMR spectrometers (Agilent) using CDCl 3. Chemical shifts are reported in parts per million (ppm) and are referenced to residual solvent peaks. For HRM S (ESI) analysis, a Water 2795 (Alliance HT) instrument was used and referenced against Polyethylene Glycol (PEG -400-600). Flash silica gel (32 -63 $ m, Silicycle 60 †) was used for column chromatography. All known compounds were characterized by 1H and 13C 131 NMR and are in complete agreement with samples reported elsewhere. All new compounds were characterized by 1H and 13C NMR, HRMS, and melting point (where appropriate). Enantiomeric excesses were determined using chiral HPLC (instrument: HP series 1100, Agi lent 1260 infinity). 2.6.2 General Procedure for Screening and Optimization of Kinetic Resolution A 5 mL vial equipped with a magnetic stir bar was charged with the substrate (0.2 mmol, 1 equiv) and catalyst (0.1 equiv). The mixture was dissolved in the a ppropriate solvent (0.1M) and was stirred at designated temperature for 5 min. N-chlorosuccinimide was then added to the reaction mixture and the reaction was stirred at the designated temperature until completion. The reaction was then quenched with saturated Na 2SO3 and extracted with dichloromethane. The combined organics were dried over anhydrous Na2SO4 and filtered. Conversions were decided by GC analysis or 1H NMR. Pure products and unreacted substrate were isolate d by column chromatography on silica gel as stationary phase (EtOAc/Hexanes gradient). 2.6.3 Analytical data for cyclized products: colorless gum , Rf: 0.85 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.99 (d, J = 7 Hz, 2H), 7.78 (d, J = 7 Hz, 2 H), 7.49 - 7.39 (m, 6H), 4.40 (q, J = 7 Hz, 1H), 1.57 (d, J = 6.5 Hz, 3H). NOClPhII-55 132 13C NMR (125 MHz, CDCl 3) ! 151.3, 143.3, 131.6, 131.4, 131.2, 129.3, 128.3, 128.2, 128.1, 127.4, 113.2, 54.5, 22.4 HRMS analysis (ESI): calculated for (M+H): C 17H14ClNO 284.0842; found: 284.0857 Resolution of enantiomers: Daicel Chiralpak AD -H, 1% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 8.6 min, RT2 = 10.7 min. ["]D20 = $27.8 ( C 1.0, CH 2Cl2, ee = 89%) The structure and absolute stereochemistry was confirmed by X -ray crystallography: colorless oil , Rf: 0.81 (30% EtOAc in Hexane, UV) NOClPhII-56 133 1H NMR (500 MHz, CDCl 3) ! 7.99 (d, J = 7.5 Hz, 2H), 7.78 (d, J = 7.5 Hz, 2H), 7.49 - 7.39 (m, 6H), 4.39 (dd, J = 4 Hz, 2.5 Hz, 1H), 1.95 - 1.85 (m, 2H), 1.58 - 1.32 (m, 6H), 0.93 (t, J = 7 Hz, 3H). 13C NMR (125 MHz, CDCl 3) ! 163.9, 161.9, 151.3, 143.2, 131.4, 131.2, 130.4, 130.3, 128.3, 127.4, 115.3, 58.5, 34.9, 31.7, 23.9, 22.6, 14.1 HRMS analysis (ESI): calculated for (M+H): C 21H22ClNO 340.1468; found: 340.1484 Resolution of enantiomers: Daicel Chiralpak AD -H, 1% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 8.07 min, RT2 = 8.75 min. ["]D20 = $31.5 ( C 1.0, CH 2Cl2, ee = 91%) colorless oil, Rf: 0.77 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.95 (d, J = 7 Hz, 2H), 7.48 - 7.25 (m, 7H), 4.47 (dd, J = 4 Hz, 2 Hz, 1H), 2.41 (s, 3H), 1.98 - 1.89 (m, 2H), 1.64 Ð 1.45 (m, 2H), 1.42 - 1.36 (m, 4H), 0.93 (t, J = 7 Hz, 3H). 13C NMR (125 MHz, CDCl 3) ! 171.2, 151.3, 145.3, 137.4, 131.4, 131.0, 130.4, 130.1, 129.7, 128.2, 127.5, 125.7, 113.0, 57.8, 34.8, 31.8, 23.9, 22.7, 19.5, 14.1 HRMS analysis (ESI): calculated for (M+H): C 22H24ClNO 354.1625; found: 354.1638 Resolution of enantiomers: Daicel Chiralpak IA, 1% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 7.57 min, RT2 = 9.6 min. ["]D20 = $12.0 ( C 1.0, CH 2Cl2, ee = 90%) NOClPhII-57 134 colorless oil, Rf: 0.88 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.98 (d, J = 7.5 Hz, 2H), 7.65 (d, J = 7.5 Hz, 2H), 7.48 - 7.38 (m, 3H), 7.25 (d, J = 7.5 Hz, 2H), 4.36 (dd, J = 4 Hz, 2 Hz, 1H), 2.39 (s, 3H), 1.92 - 1.82 (m, 2H), 1.57 Ð 1.42 (m, 2H), 1.37 - 1.29 (m, 4H), 0.88 (t, J = 7 Hz, 3H). 13C NMR (125 MHz, CDCl 3) ! 151.5, 144.1, 139.4, 131.5, 131.1, 128.8, 128.3, 128.2, 127.5, 111.4, 58.6, 35.0, 31.8, 23.9, 22.6, 21.5, 14.1 HRMS analysis (ESI): calculated for (M+H): C 22H25ClNO 354.1625; found: 354.1640 Resolution of enantiomers: Daicel Chiralpak AD -H, 1% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 8.4 min, RT2 = 10.0 min. ["]D20 = $17.0 (C 1.0, CH 2Cl2, ee = 76%) colorless oil, Rf: 0.80 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.97 (d, J = 7.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.48 - 7.38 (m, 3H), 6.96 (d, J = 8.5 Hz, 2H), 4.35 (dd, J = 4 Hz, 2 Hz, 1H), 3.84 (s, 3H), 1.95 - 1.79 (m, 2H), 1.57 Ð 1.40 (m, 2H), 1.35 - 1.30 (m, 4H), 0.88 (t, J = 7 Hz, 3H). NOClPhII-58 NOClPhII-59 MeO 135 13C NMR (125 MHz, CDCl 3) ! 160.1, 151.5, 143.8, 131.6, 131.1, 129.7, 128.3, 127.4, 124.1, 113.5, 110.8, 58.6, 55.3, 35.0, 31.8, 23.9, 22.6, 14.1 HRMS analysis (ESI): calculated for (M+H): C 22H25ClNO 2 370.1574; found: 370. 1590 Resolution of enantiomers: Daicel Chiralpak AD -H, 1% IPA - Hex , 0.5 mL/min; 254 nm, RT1 = 10.3 min, RT2 = 11.4 min. ["]D20 = +0.6 (C 1.0, CH 2Cl2, ee =7%) colorless oil, Rf: 0.76 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.97 (d, J = 7.5 Hz, 2H), 7.47 - 7.29 (m, 6H), 6.95 (m, 1H), 4.36 (dd, J = 4 Hz, 2 Hz, 1H), 3.84 (s, 3H), 1.94 - 1.81 (m, 2H), 1.57 Ð 1.40 (m, 2H), 1.35 - 1.30 (m, 4H), 0.88 (t, J = 7 Hz, 3H). 13C NMR (125 MHz, CDCl 3) ! 159.2, 151.4, 143.9, 132.9, 131.4, 131.2, 129.2, 128.3, 127.5, 120.7, 114.9, 114.0, 112.2, 58.7, 55.4, 35.0, 31.8, 23.9, 22.6, 14.2 HRMS analysis (ESI): calculated for (M+H): C 22H25ClNO 2 370.1574; found: 370.1604 Resolution of enantiomers: Daicel Chiralpak IA, 100 % Hex, 0.2 mL/min; 254 nm, RT1 = 23.77 min, RT2 = 25.94 min. ["]D20 = $10.5 ( C 1.0, CH 2Cl2, ee = 8 4%) NOClPhII-60 OMe 136 colorless oil, Rf: 0.77 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 8.03 (d, J = 10 Hz, 2H), 7.81 (dd, J = 1.5 Hz, 8 Hz, 2H), 7.49 Ð 7.32 (m, 11H), 5.36 (s, 1H) 13C NMR (125 MHz, CDCl 3) ! 151.7, 143.6, 141.2, 131.5, 131.4, 131.2, 129.6, 128.8, 128.4, 128.3, 128.2, 127.9, 127.7, 111.6, 58.7, 63.1 HRMS analysis (ESI): calculated for (M+H): C 22H16ClNO 346.0999; found: 346.1011 Resolution of enantiomers: Daicel Chiralpak AD -H, 2 % IPA -Hex, 0.5 mL/min; 254 nm, RT1 = 11.38 min, RT2 = 15.9 min. ["]D20 = $28.5 ( C 1.0, CH 2Cl2, ee = 60%) colorless oil, Rf: 0.77 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.96 (d, J = 7 Hz, 2H), 7.75 (dd, J = 4 Hz, 5.5 Hz, 2H), 7.48 Ð 7.38 (m, 3H), 7.12 (t, J = 10 Hz, 2H), 4.36 (dd, J = 4.5 Hz, 2 Hz, 1H), 1.96 - 1.81 (m, 2H), 1.57 Ð 1.40 (m, 2H), 1.35 - 1.30 (m, 4H), 0.88 (t, J = 7 Hz, 3H). 13C NMR (125 MHz, CDCl 3) ! 163.9, 161. 9, 151.3, 143.2, 131.2, 130.3, 129.7, 128.3, 127.8, 115.3, 111.9, 58.6, 34.9, 31.7, 23.9, 22.6, 14.1 HRMS analysis (ESI): calculated for (M+H): C 21H21ClFNO 358.1374; found: 358.1390 PhNOPhClPhII-61 NOClPhII-62 F 137 Resolution of enantiomers: Daicel Chiralpak AD -H, 1 % IPA -Hex, 0.5 mL/min; 254 nm, RT1 = 8.37 min, RT2 = 9.72 min. ["]D20 = $6.3 ( C 1.0, CH 2Cl2, ee = 94%) colorless oil, Rf: 0.81 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 8.28 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.5 Hz, 3H), 7.50 Ð 7.40 (m, 4H), 4.38 (dd, J = 4.5 Hz, 2 Hz, 1H), 1.98 - 1.80 (m, 2H), 1.57 Ð 1.40 (m, 2H), 1.35 - 1.30 (m, 4H), 0.88 (t, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 150.9, 147.8, 142.2, 137.7, 131.4, 129.1, 128.8, 128.4, 127.4, 123.5, 115 .2, 58.6, 34.9, 31.7, 23.9, 22.6, 14.1 HRMS analysis (ESI): calculated for (M+H): C 21H21ClN 2O3 385.1319; found: 385.1337 Resolution of enantiomers: Daicel Chiralpak AD -H, 1 % IPA -Hex, 1 mL/min; 254 nm, RT1 = 6.35 min, RT2 = 8.07 min. ["]D20 = 6.2 ( C 1.0, CH 2Cl2, ee = 75%) colorless oil , Rf: 0.8 6 (30% EtOAc in Hexane, UV) NOClPhII-63 O2NONPhClO2NII-83 138 1H NMR (500 MHz, CDCl 3) % 8.40 Ð 8.25 (m, 2H), 8.09 Ð 7.95 (m, 4H), 7.68 Ð 7.40 (m, 3H), 5.25 (dd, J = 7.5, 3.3 Hz, 1H), 2.31 Ð 2.11 (m, 1H), 1.99 (dddd, J = 13.8, 10.4, 7.5, 5.1 Hz, 1H), 1.52 Ð 1.20 (m, 6H), 1.00 Ð 0.78 (m, 3H). 13C NMR (126 MHz, CDCl 3) % 160.87, 156.44, 146.44, 141.13, 132.39, 128.79, 128.17, 127.92, 125.72, 123.50, 107.61, 72.21, 31.78, 31.55, 24.51, 22.51, 14.04. HRMS analysis (ESI): cal culated for (M+H): C 21H21ClN 2O3 385.1319; found: 385.13 29 colorless oil, Rf: 0.85 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.86 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 9 Hz, 2H), 7.45 - 7.40 (m, 3H), 7.20 (d, J = 8.5 Hz, 2H), 4.37 (q, J = 7 Hz, 1H), 2.39 (s, 3H), 1.55 (d, J = 7 Hz, 3H). 13C NMR (125 MHz, CDCl 3) ! 151.4, 143.3, 141.5, 131.7, 129.3, 129.0, 128.7, 128.3, 128.1, 127.4, 113.3, 54.5, 22.4, 21.5 HRMS analysis (ESI): calculated for (M+H): C 18H17ClNO 298.0999; found: 298.1006 Res olution of enantiomers: Daicel Chiralpak IA, 3% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 8.6 min, RT2 = 11.0 min. ["]D20 = $23.7 ( C 1.0, CH 2Cl2, ee = 87%) NOClII-66 139 colorless oil, Rf: 0.85 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.98 (dd, J = 5 Hz, 3.5 Hz, 2H), 7.74 (dd, J = 8 Hz, 4 Hz, 2H), 7.46 - 7.39 (m, 3H), 7.07 (t, J = 8.5 Hz, 2H), 4.35 (q, J = 4 Hz, 2 Hz, 1H), 1.92 - 1.82 (m, 2H), 1.58 - 1.30 (m, 6H), 0.88 (t, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 165.7, 150.6, 144.0 137.7, 131.6, 1 29.7, 129.6, 129.4, 128.2, 128.1, 115.4, 58.5, 34.9, 31.7, 23.9, 22.6, 14.1 HRMS analysis (ESI): calculated for (M+H): C 21H21ClFNO 358.1374; found: 358.1389 Resolution of enantiomers: Daicel Chiralpak IA, 0.1% IPA -Hex, 0.3 mL/min; 254 nm, RT1 = 20.0 min, R T2 = 23.5 min. ["]D20 = $29.6 ( C 1.0, CH 2Cl2, ee = 88 %) colorless oil, Rf: 0.89 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.02 Ð 7.79 (m, 4H), 7.70 (d, J = 8.2 Hz, 2H), 7.60 Ð 7.33 (m, 3H), 4.40 (q, J = 6.7 Hz, 1H), 1.57 (d, J = 6.8 Hz, 3H). II-67 NOClFNOClPhII-68 F3C 140 13C NMR (125 MHz, CDCl 3) % 150.91, 142.13, 135.03, 135.02, 131.33, 131.12, 128.60, 128.36, 127.37, 125.14 ( q, JC-F = 3.7 Hz), 125.11, 114.90, 54.47, 22.31. HRMS analysis (ESI): calculated for (M+H): C 18H13ClF3NO 352.0740; found: 352.0728 Resolution of enantiomers: Daicel Chiralpak AD -H, 1% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 8.2 min, RT2 = 9.0 min. ["]D20 = $26.0 (C 1.0, CH 2Cl2, ee = 64 %) Rf: 0.77 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.97 - 7.88 (m, 5H), 7.65 (d, J = 7 Hz, 1H), 7.55 - 7.50 (m, 3H), 7.43 - 7.31 (m, 3H), 4.51 (q, J = 7 Hz, 1H), 1.66 (d, J = 7 Hz, 3H). 13C NMR (125 MHz, CDCl 3) ! 151.2, 143.6, 133.7, 131.4, 131.2, 130.9, 130.2, 129.1, 128.7, 128.6, 128.3, 127.6, 126.9, 126.2, 125.2, 125.1, 115.8, 54.0, 22.8 HRMS analysis (ESI): calculated for (M+H): C 21H16ClNO 334.0999; found: 334.1016 Resolution of enantiomers: Daicel Chiralpak AD -H, 1% IPA - Hex, 1 mL/min; 254 nm, RT1 = 4.6 min, RT2 = 5.6 min. ["]D20 = $37.9 ( C 1.0, CH 2Cl2, ee = 72%) NOClPhII-69 NOClPhII-70 141 colorless oil, Rf: 0.78 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 8.0 (d, J = 7 Hz, 2H), 7.77 (d, J = 7 Hz, 2H), 7.49 - 7.38 (m, 6H), 4.24 (d, J = 3.5 Hz, 1H), 1.98 -1.59 (m, 7H), 1.35 -1.10 (m, 4 H) 13C NMR (125 MHz, CDCl 3) ! 151.5, 144.6, 131.8, 131.4, 129.3, 1 28.3, 128.1, 127.5, 111.1, 63.6, 42.2, 29.3, 26.9, 26.6, 26.4, 26.2 HRMS analysis (ESI): calculated for (M+H): C 22H22ClNO 352.1468; found: 352.1486 Resolution of enantiomers: Daicel Chiralpak AD -H, 1% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 8.5 min, RT2 = 9.7 min. ["]D20 = $24.0 ( C 1.0, CH 2Cl2, ee = 77%) colorless oil, Rf: 0.87 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.98 (dt, J = 7.3, 1.4 Hz, 2H), 7.84 Ð 7.68 (m, 2H), 7.57 Ð 7.32 (m, 6H), 4.41 (dd, J = 6.4, 3.9 Hz, 1H), 3.68 (t, J = 6.5 Hz, 2H), 2.08 Ð 1.59 (m, 4H), 0.87 (s, 9H), 0.03 (s, 6H). 13C NMR (125 MHz, CDCl 3) % 151.50, 144.15, 131.63, 131.36, 131.15, 129.34, 128.26, 128.13, 127.45, 111.75, 63.04, 58.31, 31.35, 27.65, 25.98, 18.36, -5.24, -5.25. HRMS analysis (ESI): calcula ted for (M+H): C 25H33ClNO 2Si 442.1969; found: 442.1974 Resolution of enantiomers: Daicel Chiralpak IA, 0.1% IPA - Hex, 1 mL/min; 254 nm, RT1 = 5.1 min, RT2 = 6.0 min. ["]D20 = $33.2 (C 1.0, CH 2Cl2, ee = 92 %) II-71 ONPhClOTBS 142 colorless oil, Rf: 0.82 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.10 Ð 7.91 (m, 2H), 7.84 Ð 7.66 (m, 2H), 7.55 Ð 7.32 (m, 6H), 4.07 (s, 1H), 1.11 (s, 9H). 13C NMR (126 MHz, CDCl 3) % 152.16, 145.92, 132.01, 131.27, 131.09, 129.40, 128.60, 128.41, 128.20, 127.68, 110.15, 68.79, 39.49, 26.54. HRMS analysis (ESI): calculated for (M+H): C 20H21ClNO 326.1312 ; found: 326.1316 colorless oil, Rf: 0.85 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.96 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 7.5 Hz, 2H), 7.50 - 7.38 (m, 6H), 4.45 (q, J = 7 Hz, 1H), 1.57 (d, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 151.5, 144.8, 132.7, 131.4, 131.2, 129.5, 128.7, 128.3, 128.1, 127.4, 104.0, 56.0, 23.0 HRMS analysis (ESI): calculated for (M+H): C 17H15NOBr 328.0337 ; found: 328.0346 Resolution of enantiomers: Daicel Chiralpak AD -H, 1% IPA - Hex, 1 mL/min; 254 nm, RT1 = 4.3 min, RT2 = 5.1 min. ["]D20 = +3.3 (C 1.0, CH 2Cl2, ee = 3 %) NOClPhII-72 NOBrPhII-73 143 1H NMR (500 MHz, CDCl 3) % 7.80 Ð 7.74 (m, 2H), 7.53 Ð 7.46 (m, 3H), 7.47 Ð 7.34 (m, 5H), 6.32 (d, J = 8.1 Hz, 1H), 5.79 (dq, J = 8.1, 6.8 Hz, 1H), % 4.27 (dq, J = 11.9, 8.6 Hz, 1H), 3.84 (dq, J = 11.8, 8.4 Hz, 1H), 1.46 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl 3) % 166.53, 14 8.81, 134.44, 131.61, 130.98, 130.75, 129.70, 129.66, 128.63, 128.44, 126.95, 124.31, 66.5 (q, JC-F =34.78) 44.59, 18.86. HRMS analysis (ESI): calculated for (M -H): C 19H16NO2ClF3 382.0822; found: 382.0820 major diastereomer ((R,R,R )-II-78): 1H NMR (500 MHz, CDCl 3) % 8.29 (d, J = 8.7 Hz, 2H), 7.97 Ð 7.82 (m, 2H), 6.59 (d, J = 8.4 Hz, 1H), 4.58 (ddd, J = 8.4, 6.7, 4.6 Hz, 1H), 4.39 (t, J = 4.8 Hz, 1H), 4.11 (dt, J = 8.2, 4.9 Hz, 1H), 2.00 Ð 1.84 (m, 2H), 1.42 (d, J = 6.7 Hz, 3H), 1.10 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl 3) % 164.74, 149.75, 139.54, 128.18, 123.93, 68.09, 64.99, 48.97, 29.01, 16.06, 10.68. HRMS analysis (ESI): calculated for (M+H): C 13H17N2O3Cl2 319.0616 ; found: 319.0623 HNClF3CH2COOII-72 HNONO2ClClII-78 , II-79 144 Resolution of enantiomers: Daicel Chiralpak OJ -H, 10% IPA - Hex, 1 mL/min; 254 nm, RT1 = 27.8 min, RT2 = 34.8 min. minor diastereomer (II-79): 1H NMR (500 MHz, Chloroform -d) % 8.29 (d, J = 8.7 Hz, 2H), 7.97 Ð 7.82 (m, 2H), 6.59 (d, J = 8.4 Hz, 1H), 4.58 (ddd, J = 8.4, 6.7, 4.6 Hz, 1H), 4.39 (t, J = 4.8 Hz, 1H), 4.11 (dt, J = 8.2, 4.9 Hz, 1H), 2.00 Ð 1.84 (m, 2H), 1.42 (d, J = 6.7 Hz, 3H), 1.10 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, cdcl 3) % 164.74, 149.72, 139.76, 128.17, 123.95, 69.23, 65.87, 48.00, 28.73, 20.12, 11.04. HRMS analysis (ESI): calcu lated for (M+H): C 13H17N2O3Cl2 319.0616 ; found: 319.0625 Resolution of enantiomers: Daicel Chiralpak OJ -H, 1 5% IPA - Hex, 1 mL/min; 254 nm, RT1 = 18.1 min, RT2 = 27.9 min. X-ray crystallography structure of the major diastereomer (( R,R,R )-II-78): 145 2.6.4 General procedure for synthesis of substrates: General pathway A: General pathway B: General procedure for Mitsunobu reaction : To a solution of 3 -butyn -2-ol (2 .0 g, 28.5 mmol), pthalimide (8.2 g, 31.4 mmol) and triphenylphosphine (4.6 g, 31.4 mmol) in freshly distilled tetrahydrofuran was added dropwise di -iso propyl azodicarboxylate (6.3 g, 31.4 mmol) at 0 ¼C. Then the reaction mixture was stirred at room temperature for 3 h. Solvent was removed and the residue was triturated with ether to precipitate out OHPhThNH (1.1 equiv.) PPh3 (1.1 equiv.) DIAD (1.3 equiv.) THF, 0 ¡C to rt NOOArI ( 1.0 equiv.) CuI ( 2.0 mol%) Pd(PPh 3)2Cl2 (1.0 mol%) Et3NNOOArNH2NH2¥H2O (6.0 equiv.) MeOH, 50 ¡C ArNH2RClO( 1.1 equiv.) Et3N ( 1.1 equiv) DCM, 0 ¡C to rt ArHNORII-84 n-pentyl OHPhThNH (1.1 equiv.) PPh3 (1.1 equiv.) DIAD (1.3 equiv.) THF, 0 ¡C to rt n-pentyl NOOArI ( 1.0 equiv.) CuI ( 2.0 mol%) Pd(PPh 3)2Cl2 (1.0 mol%) Et3Nn-pentyl NH2NH2NH2¥H2O (6.0 equiv.) MeOH, 50 ¡C n-pentyl BzHN ClO( 1.1 equiv.) Et3N ( 1.1 equiv) DCM, 0 ¡C to rt n-pentyl ArNHBz 99%II-85 II-86 146 triphenylphosphine oxide. The white solid was filtered off and the filtrate was concentrated and purified on silica gel (15% EtOAc in hexane) to give 4.8 g of II-84 as white solid (85% yield). General procedure for Sonogashira coupling : CuI (2 mol%) an d Pd(PPh 3)2Cl2 (1 mol%) were added to an oven -dried round bottom flask equipped with a stir bar. Anhydrous Et 3N (0.4 M) was added and flush with Argon. Propargyl phthalimide (1equiv) and corresponding aryl iodide (1 equiv) were then added into the reaction mixture. The reaction was stirred at room temperature for 8 h. After the reaction was complete, Et 3N was removed under reduced pressure . The crude residue was purified by silica column chromatography. General procedure for cleavage of phthalimide: To a so lution of phthalimide (3 mmol, 1equiv) in EtOH (15 mL) was added hydrazine hydrate (18 mmol, 6 equiv) dropwise. The resulting mixture was stirred at 60 ¼C for 3 h. The formed white precipitate was then filtered through a thin layer of celite, washed with E t2O and the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography over silica gel to afford the propargyl amine. General procedure for protection of amine: Propargyl amine (1 equiv) was dissolved in fresh ly distilled dichloromethane at 0 ¼C. Et 3N (1.1 equiv) was added to the solution dropwise , followed by addition of benzoyl chloride (1 equiv) in one portion. After the reaction was complete , water was added to the reaction mixture. The organic layer was separated and dr ied over Na 2SO4. The crude residue , obtained after removal of solvent was purified by column chromatography with silica gel. 147 General pathway C: Procedure for the synthesis of propargyl alcohol: To a solution of phenyl acetylene (6 mmol, 1 equiv) in anhydrous THF (24 mL) at $78 ¼C was added a solution of n-BuLi (2.5 M in THF, 6 mmol, 2.4 mL) dropwise. After stirring at the same temperature for 15 min, the corresponding aldehyde (6 mmol, 1 equiv) was added and was stirred for 1 h before saturated NH 4Cl (30 mL) was added. The organic layer was separated and the aqueous phase was extracted twice with EtOAc (2X20 mL). The combined organic layers were dried over anhydrous Na 2SO4, filtered and concentrated. The crude was purified by column chromatography over silica gel to afford propargyl alcohol. From propargyl alcohol to amide , the procedure is same as the path A and path B sequence: Mitsunobu reaction, cleavage of phthalimide and protection of amine. 2.6 .5. Analytical data for kinetic resolution substrates and intermediates: PhROHPh+RO 1.1 equiv n-BuLi THF, !78 ¼C to rt 1.1 equiv PPh 31.1 equiv DIAD PhRNOO6 equiv NH 2-NH 2¥H2OPhRNH21 equiv Et 3N1 equiv BzCl PhRNHBz DCM, 0 ¼C to rt EtOH, 60 ¼C 1.1 equiv phthalimide THF, 0 ¼C to rt NOOII-84 148 II-84 was synthesized through general procedure for Mits unobu reaction with 3-butyn -2-ol (2.00 g, 28.50 mmol) in 85% yield. Rf: 0.57 (30% EtOAc in Hexane, UV) white solids; M.P.: 80 ¡C -85 ¡C 1H NMR (500 MHz, CDCl 3) % 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 5.20 (qd, J = 7.2, 2.5 Hz, 1H), 2.33 (d, J = 2.5 Hz, 1H), 1.70 (d, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl 3) % 166.88, 134.13, 131.83, 123.44, 81.08, 71. 19, 36.85, 20.06. HRMS analysis (ESI): calculated for (M+H): C 12H10NO2 200.0712; found: 200.0712 II-85 was synthesized through general procedure for Mits unobu reaction with 1 -octyn -2-ol(1.00g, 7.92 mmol) in 85% yield. yellow oil, Rf: 0.69 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.87 (dd, J = 5.4, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.0 Hz, 2H), 5.03 (td, J = 8.0, 2.5 Hz, 1H), 2.36 (d, J = 2.5 Hz, 1H), 2.17 Ð 1.98 (m, 2H), 1.39 Ð 1.24 (m, 6H), 0.92 Ð 0.82 (m, 3H). 13C NMR (126 MHz, CDCl3) % 167.07, 134.12, 131.75, 123.45, 80.35, 71.78, 41.50, 33.31, 30.97, 25.91, 22.42, 13.95. HRMS analysis (ESI): calculated for (M+H): C 16H18NO2 256.1338; found: 256.1350 n-pentyl NOOII-85 149 II-86 was synthesized from II-85 (1.60 g, 4.83 mmol) through g enera l procedure of cleavage of phtha limide and protection gave 55% yield in two steps as colorless oil. Rf: 0.6 3 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.81 Ð 7.70 (m, 2H), 7.41 (dt, J = 41.0, 7.4 Hz, 3H), 6.61 (d, J = 9.2 Hz, 1H), 4.92 (tdd, J = 8.3, 6.3, 2.4 Hz, 1H), 2.27 (d, J = 2.4 Hz, 1H), 1.83 Ð 1.61 (m, 2H), 1.45 (dp, J = 10.7, 3.5 Hz, 2H), 1.28 (dq, J = 7.1, 3.3 Hz, 4H), 0.90 Ð 0.78 (m, 3H). 13C NMR (126 MHz, CDCl3) % 166.50, 134.00, 131.64, 128.52, 127.10, 83.32, 71.27, 41.85, 35.72 , 31.28, 25.32, 22.50, 14.00. HRMS analysis (ESI): calculated for (M+H): C 15H20NO 230.1545; found: 230.1559 II-87 was synthesized though general pathway C with cyclohexyl carboxaldehyde (6 mmol) in 71% yield. yellow oil, Rf: 0.75 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 7.42 (dq, J = 5.9, 2.1 Hz, 2H), 7.34 Ð 7.23 (m, 3H), 4.36 (td, J = 6.0, 2.1 Hz, 1H), 1.97 Ð 1.83 (m, 2H), 1.81 Ð 1.70 (m, 3H), 1.73 Ð 1.56 (m, 1H), 1.31 Ð 1.05 (m, 5H). 13C NMR (126 MHz, CDCl3) % 131.68, 128.32, 128.26, 122.72, 109.99, 89.18, 67.72, 44.32, 28.65, 28.20, 26.39, 25.92, 25.90. II-86 NHBz PhOHII-87 150 II-88 was synthesized though general pathway C with benzaldehyde (5 mmol) in 99% yield. yellow oil, Rf: 0.68 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 7.64 (dd, J = 7.2, 1.8 Hz, 2H), 7.55 Ð 7.26 (m, 8H), 5.71 (d, J = 6.2 Hz, 1H), 2.37 Ð 2.26 (m, 1H). 13C NMR (126 MHz, CDCl3) % 140.61, 131.75, 128.69, 128.62, 128.47, 128.31, 126.74, 122.38, 88.65, 86.68, 65.14. II-38 was synthesized through path A. II-84 was subjected to the Sonagashira coupling condition with iodobenzene (2.1 mmol) to afford corresponding phthalimide in 100% yield. Then phthalimide was cleaved and protected with benzoyl group according general procedure, leading to 78% yield of II-38 in two steps as white solids; M.P.: 115 ¡C -120 ¡C. Rf: 0.78 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.85 Ð 7.72 (m, 2H), 7.54 Ð 7.44 (m, 1H), 7.41 (ddd, J = 8.7, 5.1, 2.7 Hz, 4H), 7.34 Ð 7.24 (m, 3H), 6.53 (d, J = 8.1 Hz, 1H), 5.26 (dq, J = 8.0, 6.8 Hz, 1H), 1.58 (d, J = 6.8 Hz, 3H). OHII-88 PhNHBz II-38 151 13C NMR (125 MHz, CDCl 3) ! 166.2, 134.1, 131.7, 131.6, 128.6, 128.4, 128.3, 127.0, 122.5, 89.3, 82.6, 38.2, 22.7 HRMS analysis (ESI): calculated for (M+H): C 17H15NO 250.1232; found: 250.1239 Resolution of enan tiomers: Daicel Chiralpak AD -H, 15% IPA - Hex, 1.0 mL/min; 254 nm, RT1 = 5.2 min, RT2 = 6.1 min. ["]D20 = $42.4 (C 1.0, CH 2Cl2, ee = 95%) II-39 was synthesized with II-86 (2 mmol) through path B, Sonagashira coupling gave 90% yield as white solids; white solids; M.P.: 84 ¡C - 92 ¡C Rf: 0.72 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.80 (d, J = 7 Hz, 2H), 7.49 -7.38 (m, 5H), 7.28 - 7.26 (m, 3H), 6.57 (d, J = 7 Hz, 1H), 5.19 (dd, J = 7 Hz, 1H), 1.86 -1.80 (m, 2H), 1.55 -1.52 (m, 2H), 1.34 -1.29 (m, 4H), 0.87 (t, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 166.4, 134.2, 131.8, 131.6, 128.5, 128.3, 127.1, 122.7, 88.6, 83.2, 45.2, 36.1, 31.4, 25.5, 22.6, 14.0 HRMS analysis (ESI): calculat ed for (M+H): C 21H23NO 306.1858; found: 306.1878 Resolution of enantiomers: Daicel Chiralpak AD -H, 15% IPA - Hex, 1.0 mL/min; 254 nm, RT1 = 5.5 min, RT2 = 5.9 min. ["]D20 = $33.6 ( C 1.0, CH 2Cl2, ee = 99%) PhNHBz II-39 152 II-40 was synthesized with II-86 (0.87 mmol) through path B, Sonagashira coupling gave 86% yield as white solids; M.P.: 83 ¡C - 87 ¡C Rf: 0.73 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.78 (d, J = 7 Hz, 2H), 7.51 -7.41 (m, 3H), 7.30 (d, J = 7 Hz, 2H), 7.09 (d, J = 7 Hz, 2H), 6.31 (d, J = 7 Hz, 1H), 5.17 (dd, J = 7 Hz, 1H), 2.32 (s, 3H), 1.82 (m, 2H), 1.56 -1.54 (m, 2H), 1.35 -1.23 (m, 4H), 0.88 (t, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 166.2, 138.5, 134.2, 131.6, 129.0, 128.6, 127.0, 119.5, 87.8, 83.4, 42.6, 36.2, 31.4, 25.4, 22.5, 21 .5, 14.0 HRMS analysis (ESI): calculated for (M+H): C 22H25NO 320.2014; found: 320.2027 Resolution of enantiomers: Daicel Chiralpak IA, 10% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 14.3 min, RT2 = 15.6 min. ["]D20 = $27.9 ( C 1.0, CH 2Cl2, ee = 82%) II-43 was synthesized with II-86 (2.0 mmol) through path B, Sonagashira coupling gave 85% yield as white solids; M.P.: 68 ¡C - 71 ¡C Rf: 0.69 (30% EtOAc in Hexane, UV) NHBz II-40 NHBz II-43 153 1H NMR (500 MHz, CDCl 3) ! 7.78 (d, J = 7 Hz, 2H), 7.52 -7.37 (m, 4H), 7.23 - 7.18 (m, 2H), 7. 17 - 7.09 (m, 1H), 6.30 (d, J = 7 Hz, 1H), 5.21 (dd, J = 7 Hz, 1H), 2.41 (s, 3H), 1.89 -1.82 (m, 2H), 1.58 -1.54 (m, 2H), 1.35 -1.32 (m, 4H), 0.88 (t, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 166.3, 140.2, 132.0, 131.6, 129.4, 128.6, 128.4, 127.0, 125.5, 122.4, 92.4, 82.2, 42.8, 36.2, 31.4, 25.5, 22.6, 20.8, 14.0 HRMS analysis (ESI): calculated for (M+H): C 22H25NO 320.2014; found: 320.2036 Resolution of enantiomers: Daicel Chiralpak AD -H, 15% IPA - Hex, 1 mL/min; 254 nm, RT1 = 5.0 min, RT2 = 5.4 min. ["]D20 = $25.7 ( C 1.0, CH 2Cl2, ee = 83%) II-41 was synthesized with II-86 (0.74 mmol) through path B, Sonagashira coupling gave 95% yield as white solids; M.P.: 69 ¡C - 73 ¡C Rf: 0.60 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.78 (d, J = 7 Hz, 2H), 7.48 (t, J = 7 Hz, 1H), 7.42 (t, J = 7 Hz, 2H), 7.34 (d, J = 7 Hz, 2H), 6.81 (d, J = 7Hz, 2H), 6.31 (d, J = 7 Hz, 1H), 5.15 (dd, J = 7 Hz, 1H), 3.79 (s, 3H), 1.84 -1.80 (m, 2H), 1.55 -1.52(m, 2H), 1.35 -1.32 (m, 4H), 0.88 (t, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 166.2, 159.6, 134.2, 133.2, 131.6, 128.6, 127.0, 114.7, 113.9, 87.1, 83.2, 55.3, 42.6, 36.2, 31.4, 25.4, 22.5, 14.0 HRMS analysis (ESI): calculated for (M+H): C 22H25NO2 336.1964; found: 336.1980 NHBz II-41 MeO 154 Resolution of enantiomers: Daicel Chiralpak IA, 5% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 33.5 min, RT2 = 37.2 min. ["]D20 = $3.5¡ (C 1.0, CH 2Cl2, ee = 20 %) II-42 was synthesized with II-86 (0.74 mmol) through path B, Sonagashira coupling gave 99% yield white solids; M.P.: 69 ¡C - 73 ¡C Rf: 0.60 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.79 (d, J = 7.5 Hz, 2H), 7.48 Ð 7.40 (m, 3H), 7.18 (t, J = 8 Hz, 1H), 7.00 (d, J = 8 Hz, 1H), 6.86 (s, 1H), 6.45 (d, J = 8 Hz, 1H), 5.17 (dd, J = 7 Hz, 8 Hz, 1H), 3.79 (s, 3H), 1.86 -1.80 (m, 2H), 1.55 -1.52(m, 2H), 1.34 -1.30 (m, 4H), 0.88 (t, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 166.3, 159.3, 134.2, 131.6, 129.4, 128.6, 127.0, 124.3, 123.6, 116.6, 114.9, 88.4, 83.2, 55.3, 42.5, 36.2, 31.6, 31.3, 25.5, 22.5, 14.0 HRMS analysis (ESI): calculated for (M+H): C 17H14ClNO 336.1964; found: 336.1975 Resolution of enantiomers: Daicel Chiralpak AD -H, 15% IPA - Hex, 1 m L/min; 280 nm, RT1 = 6.7 min, RT2 = 7.8 min. ["]D20 = $30.4 ( C 1.0, CH 2Cl2, ee = 99%) NHBz II-42 MeO 155 II-53 was synthesized through path C with II-87 (1.56 mmol) in 53% yield for 3 steps. white solids; M.P.: 145 ¡C - 152 ¡C Rf: 0.61 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.79 (d, J = 9 Hz, 2H), 7.51 - 7.48 (m, 1H), 7.44 - 7.41 (m, 4H), 7.29 - 7.27 (m, 3H), 6.37 (d, J = 9 Hz, 1H), 5.09 (dd, J = 6 Hz, 2.5 Hz, 1H), 1.92 -1.66 (m, 7H), 1.28 -1.21 (m, 4H), 13C NMR (125 MHz, CDCl 3) ! 166.4, 134.3, 131.8, 131. 7, 128.6, 128.3, 127.0, 122.7, 87.4, 84.1, 47.5, 42.8, 29.5, 28.5, 26.3, 26.0, 25.9 HRMS analysis (ESI): calculated for (M+H): C 22H23NO 318.1858; found: 318.1876 Resolution of enantiomers: Daicel Chiralpak AD -H, 10% IPA - Hex, 1 mL/min; 2 28 nm, RT1 = 8.2 m in, RT2 = 9.0 min. ["]D20 = $19.4 ( C 1.0, CH 2Cl2, ee = 67%) II-45 was synthesized with II-86 (1.3 mmol) through path B, Sonagashira coupling gave product as white solids in 66% yield. white solids; M.P.: 120 ¡C - 125 ¡C Rf: 0.60 (30% EtOAc in Hexane, UV) NHBz II-53 NHBz II-45 O2N 156 1H NMR (500 MHz, CDCl 3) ! 8.15 (d, J = 8.5 Hz, 2H), 7.79 - 7.77 (d, J = 9 Hz, 2H), 7.56 - 7.49 (m, 3H), 7.44 (t, J = 8 Hz, 2H), 6.27 (d, J = 8.5 Hz, 1H), 5.20 (dd, J = 7 Hz, 8.5 Hz, 1H), 1.88 -1.83 (m, 2H), 1.55 Ð 1.50 (m, 2H), 1.39 -1.33 (m, 4H), 0.88 (t , J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 166.4, 147.1, 133.9, 132.5, 131.9, 129.6, 128.7, 128.5, 127.0, 123.5, 94.1, 81.4, 42.4, 35.8, 31.3, 25.5, 22.5, 14.0 HRMS analysis (ESI): calculated for (M+H): C 21H22N2O3 351.1709; found: 351.1720 Resolution of e nantiomers: Daicel Chiralpak AD -H, 15% IPA - Hex, 1 mL/min; 254 nm, RT1 = 11.2 min, RT2 = 12.9 min. ["]D20 = $3.0¡ ( C 1.0, CH 2Cl2, ee = 11%) II-44 was synthesized with II-86 (0.74 mmol) through path B, Sonagashira coupling gave 99% yield product as white solids; M.P.: 80 ¡C - 86 ¡C. Rf: 0.60 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.78 (d, J = 7 Hz, 2H), 7.44 - 7.37 (m, 4H), 6.98 (t, J = 7 Hz, 2H), 6.32 (d, J = 7 Hz, 1H), 5.15 (dd, J = 7 Hz, 1H), 1.84 - 1.81 (m, 2H), 1.55 - 1.51 (m, 2H), 1.35 -1.32 (m, 4H), 0.88 (t, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 166.3, 134.1, 133.6, 131.7, 128.6, 127.0, 118.7, 115.6, 115.5, 88.3, 82.2, 42.5, 36.1, 31.3, 25.5, 22.5, 14.0 HRMS analysis (ESI) : calculated for (M+H): C 21H22FNO 324.1764; found: 324.1787 NHBz II-44 F 157 Resolution of enantiomers: Daicel Chiralpak AD -H, 15% IPA - Hex, 1 mL/min; 254 nm, RT1 = 6.09 min, RT2 = 6.4 min. ["]D20 = $30.4 ( C 1.0, CH 2Cl2, ee = 9 7%) II-52 was synthesized through path A with II-84 (7.03 mmol), propargyl amine was protected with p-tolu oylchloride according general procedure, leading to 75% yield of II-52 as white solids; M.P.: 92 ¡C - 100 ¡C Rf: 0.53 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.71 (d, J = 7.5 Hz, 2H), 7.44 - 7.43 (m, 2H), 7.32 -7.26 (m, 5H), 6.35 (d, J = 8 Hz, 1H), 5.27 (dd, J = 8 Hz, 6.5 Hz, 1H), 2.40 (s, 3H), 1.60 (d, J = 6.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 166.2, 131.8, 131.2, 130.2, 129.2, 129.1, 128.4, 128.3, 127.0, 89.4, 82.5, 3 8.1, 22.8, 21.5 HRMS analysis (ESI): calculated for (M+H): C 18H17NO 264.1388; found: 264.1404 Resolution of enantiomers: Daicel Chiralpak IA, 10% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 19.0 min, RT2 = 24.0 min. ["]D20 = $24.9 (C 1.0, CH 2Cl2, ee = 9 9%) HNII-52 O 158 II-47 was synthesized through path C with II-88 (4.88 mmol). II-88 was subjected to Mitsunobu reaction to afford phthalimide in 50% yield. Phthalimide was cleaved and protected with benzoyl group to get 44% yield of II-47 in two steps. white solids; M.P.: 164 ¡C - 171 ¡C Rf: 0.64 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.80 (d, J = 7.5 Hz, 2H), 7.64 (d, J = 7Hz, 2H), 7.50 - 7.37 (m, 7H), 7.34 - 7.31 (m, 4H), 6.63 (d, J = 8.5 Hz, 1H), 6.47 (d, J = 8 Hz, 1H) 13C NMR (125 MHz, CDCl 3) ! 166.3, 139.0, 133.8, 131.9, 130.2, 128.8, 128.6, 128.5, 128.4, 128.2, 127.2, 127.1, 122.4, 86.9, 85.1, 45.6 HRMS analysis (ESI): calculated for (M+H): C 22H17NO 312.1388; found: 312.1408 Resolution of enantiomers: Daicel Chiralpak IA, 15% IPA - Hex, 1 mL/mi n; 254 nm, RT1 = 8.6 min, RT2 = 10.8 min. ["]D20 = $2.9 (C 1.0, CH 2Cl2, ee = 82 %) II-50 was synthesized through path A with II-84 (3.92 mmol) , Sonagashira coupling with 1-iodonapthalene gave 70% yield of phthalimde, then pthalimide cleavage and protection gave 21% yield of II-50 for two steps. white solids; M.P.: 114 ¡C - 120 ¡C PhNHBz II-47 PhNHBz II-50 159 Rf: 0.47 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 8.27 (d, J = 8.5 Hz, 1H), 7.83 - 7.80 (m, 4H), 7.65 (d, J = 6.5 Hz, 1H), 7.56 - 7.38 (m, 6H), 6.44 (d, J = 7 Hz, 1H), 5.41 (q, J = 7.5 Hz, 1H), 1.72 (d, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 166.3, 134.1, 133.3, 133.1, 131.7, 130.7, 128.9, 128.6, 128.3, 127. 0, 126.9, 126.7, 126.4, 126.0, 125.2, 94.2, 80.7, 38.5, 22.9 HRMS analysis (ESI): calculated for (M+H): C 21H17NO 300.1388; found: 300.1397 Resolution of enantiomers: Daicel Chiralpak AD -H, 1 5% IPA - Hex, 1 mL/min; 254 nm, RT1 = 5.7 min, RT2 = 7.1 pDpDmin. ["]D20 = $30.1 ( C 1.0, CH 2Cl2, ee = 95%) II-49 was synthesized through path A with II-84 (5.02 mmol), Sonagashira coupling with 1-iodo -4-(trifluoromethyl)benzene (5.02 mmol) gave 64% yield of phathalimde, then phthalimide cleavage and protection gave 45% yield of II-49 for two steps. white solids; M.P.: 141 ¡C - 150 ¡C Rf: 0.58 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.78 (d, J = 8.5 Hz, 2H), 7.54 - 7.48 (m, 5H), 7.42 (t, J = 8 Hz, 2H), 6.41 (d, J = 8 Hz, 1H), 5.27 (q, J = 7.5 Hz, 1H), 1.58 (d, J = 7 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 166.3, 133.9, 132.0, 131.8, 128.6, 127.0, 125.2, 91.9, 81.2, 38.0, 22.5 NHBz II-49 F3C 160 HRMS analysis (ESI): calculated for (M+H): C 18H14F3NO 318.1106; found: 318.1113 Resolution of enantiomers: Daicel Chiralpak IA, 10% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 16.3 min, RT2 = 18.0 min. ["]D20 = $13.3 (C 1.0, CH 2Cl2, ee = 42 %) II-51 was s ynthe sized through path B with II-85 (1.5 mmol). Propargyl amine was protected with p-F-benzoylchloride in 81% yield. Then Sonagashira coupling of protected propargyl amine with iodobenzene gave II-51 in 91% yield. yellow solids; M.P.: 65 ¡C - 70 ¡C Rf: 0.49 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.80 (dt , J = 6 Hz, 2H), 7.40 (m, 2H), 7.30 - 7.27 (m, 3H), 7.08 (t, J = 9 Hz, 2H), 6.40 (d, J = 8.5 Hz, 1H), 5.15 (q, J = 7.5 Hz, 1H), 1.86 -1.78 (m, 2H), 1.56 -1.50 (m, 2H), 1.34 -1.30 (m, 4H), 0.88 (t, J = 7.5 Hz, 3H) 13C NMR (125 MHz, CDCl 3) ! 165.8, 165.3, 163.8 , 131.8, 130.4, 129.4, 129.3, 128.3, 122.6, 115.7, 115.5, 88.4, 83.4, 42.7, 36.2, 31.3, 25.5, 22.5, 14.0 HRMS analysis (ESI): calculated for (M+H): C 21H22FNO 324.1764; found: 324.1778 Resolution of enantiomers: Daicel Chiralpak AD -H, 15% IPA - Hex, 1 mL/mi n; 254 nm, RT1 = 5.1 min, RT2 = 5.8 min. ["]D20 = $24.3 (C 1.0, CH 2Cl2, ee = 87 %) HNII-51 OF 161 II-46 was synthesized starting with 1 -heptyne (5.2 mmol). Procedure is same as path C. white solids; M.P.: 36 ¡C - 41 ¡C Rf: 0.80 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.81 Ð 7.68 (m, 2H), 7.56 Ð 7.35 (m, 3H), 6.17 (d, J = 8.8 Hz, 1H), 4.89 (dtd, J = 8.1, 5.8, 2.8 Hz, 1H), 2.16 (tdd, J = 7.1, 2.2, 1.0 Hz, 2H), 1.79 Ð 1.59 (m, 2H), 1.53 Ð 1.38 (m, 4H), 1.37 Ð 1.21 (m, 8H), 0.93 Ð 0.81 (m, 6H). 13C NMR (125 M Hz, CDCl 3) % 166.17, 134.37, 131.50, 128.54, 126.92, 83.89, 79.27, 42.35, 36.35, 31.36, 31.04, 28.37, 25.39, 22.55, 22.18, 18.62, 14.01, 13.99. HRMS analysis (ESI): calculated for (M -H): C 20H28NO 298.2171; found: 298.2173 II-89 was synthesized according to the reported literature. 18 1.2 equiv n-BuLi 1.2 equiv hexanal THF, !78 ¼C to rt OH1.1 equiv PPh3 1.1 equiv DIAD 1.1 equiv phthalimide THF, 0 ¼C to rt NOONH2-NH 2rìH2OMeOH NH21 equiv BzCl 1 equiv Et 3NDCM, 0 ¼C to rt NHBz 77% two steps 27% two steps II-46 HOOH1 equiv TBSCl 2 equiv NaH THF, 0 ¼C to rt HOOTBS 86%2 equiv Py SO3,4 equiv Et 3NDMSO (1 M) DCM (0.2 M) 0 ¼C to rt OOTBS 83%II-89 NHBz OTBS II-54 162 II-54 was synthesized through procedure C with II-89 (3.4 mmol), phthalimide was obatained in 56% yield for 2 steps; II-54 was obtained in 60% yield for two steps. yellow solids; M.P.: 4 5 ¡C - 52 ¡C Rf: 0.70 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.82 Ð 7.74 (m, 2H), 7.51 Ð 7.35 (m, 5H), 7.28 (dd, J = 5.3, 2.0 Hz, 3H), 6.66 (d, J = 8.3 Hz, 1H), 5.24 (dt, J = 8.2, 6.6 Hz, 1H), 3.78 Ð 3.56 (m, 2H), 2.03 Ð 1.62 (m, 4H), 0.88 (d, J = 8.7 Hz, 9H), 0.10 Ð -0.04 (m, 6H). 13C NMR (125 MHz, CDCl 3) % 166.33, 134.21, 131.76, 131.66, 131.62, 128.57, 128.34, 128.26, 128.21, 127.04, 122.64, 88.33, 83.38, 62.70, 42.21, 32.75, 29.01, 25.98, 25.95, 25.92, 18.39, -5.20, -5.27. HRMS analysis (ESI ): calculated for (M -H): C 25H32NO2Si 406.2202; found: 406.2212 Resolution of enantiomers: Daicel Chiralpak AD -H, 5% IPA - Hex, 1 mL/min; 254 nm, RT1 = 6.2 min, RT2 = 6.8 min. ["]D20 = $25.8 (C 1.0, CH 2Cl2, ee = 77 %) II-48 was synthesized through path C with pivaldehyde (6 mmol) . 1) 5 equiv NH 2-NH 2rìH2OMeOH Ph1.2 equiv n-BuLi 1.2 equiv pivaldehyde Ð78 ¼C to rt PhOH1.1 equiv PPh 31.1 equiv DIAD 1.1 equiv phthalimide THF, 0 ¼C to rt PhNOO69% two steps 2) 1 equiv BzCl 1 equiv Et 3N DCM, 0¼ to rt PhNHBz 44% two steps II-48 163 white s olids; M.P.: 80 - 82 ¡C Rf: 0.69 (30% EtOAc in Hexane) 1H NMR (500 MHz, Chloroform -d) % 7.85 Ð 7.72 (m, 2H), 7.53 Ð 7.38 (m, 5H), 7.28 (dd, J = 5.1, 1.9 Hz, 3H), 6.27 (d, J = 9.6 Hz, 1H), 5.07 (d, J = 9.6 Hz, 1H), 1.11 (s, 9H). 13C NMR (126 MHz, cdcl 3) % 166.65, 134.43, 131.72, 131.67, 128.66, 128.29, 128.27, 127.00, 122.77, 87.48, 83.89, 51.31, 36.35, 26.14. HRMS analysis (ESI): calculated for (M+H): C 20H22NO 292.1701; found: 292.1707 Path D : II-91 was synthesized according to our groupsÕ previous work. 19 II-91(1.2 g, 4.8 mmol) was dissolved in EtOAc ( 30 mL). To the solution was added LindlarÕs catalyst (200 mg). The reaction mixture was degassed for 3 times under vacuum and then stirred under H2 balloon for 12 h. After the reaction was complete, filter the catalyst thru celite and remove solvent to afford the crude. Purify the compound through flash column chromatography (silica gel, 15% EtOAc in Hexane) to get final product as white solid (90% yield). OH1.5 equiv. PPh 31.5 equiv. DIAD 1.5 equiv. phthalimide THF, r.t NOO3 equiv. NH 2-NH 2rìH2OMeOH, 50 ¼C NH21 equiv p-NO 2-benzoylchloride 1.1 equiv. Et 3NCH2Cl2, 0 ¼C to r.t. HNOp-NO 2-phenyl Lindlar's cat. H2, EtOAc HNOp-NO 2-phenyl 83%55% two steps 90%II-90 II-91 II-77 164 Rf =0.55 (30% EtOAc in Hexane) white solid; M.P. = 47 - 51¡C 1H NMR (500 MHz, CDCl 3) % 8.23 (d, J = 8.8 Hz, 2H), 7 .89 (d, J = 8.8 Hz, 2H), 6.23 (d, J = 7.5 Hz, 1H), 5.57 Ð 5.47 (m, 1H), 5.30 (tt, J = 10.5, 1.6 Hz, 1H), 4.97 (dddd, J = 8.8, 7.6, 6.6, 1.1 Hz, 1H), 2.16 (td, J = 7.5, 1.6 Hz, 2H), 1.30 (d, J = 6.7 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, cdcl 3) % 164.41, 149.39, 140.41, 134.59, 129.69, 128.13, 123.68, 43.70, 21.76, 21.09, 14.18. HRMS analysis (ESI): calculated for (M+H): C 13H17N2O3 249.1239; found: 249.1245 Resolution of enantiomers: Daicel Chiralpak OJ-H, 15% IPA - Hex, 0.5 mL/min; 254 nm, RT1 = 21.1 min, RT2 = 25.8 min. 2.7 1H NMR study In order to elucidate the nature that catalyst can differentiate two enantiomers of substrate and therefore lead to different reaction rate, we did solvent -suppression 1H NMR in trifluoroethanol which is the reaction solvent. Enantio pure (R) - and (S) - substrate 1a were mixed with stoichiometric amount of (DHQD) 2PHAL in trifluoroethanol. The methyl proton shows slig htly different chemical shift. This observation indicates that diff erent binding affinity between enantiomers and catalyst lead to different reaction rate. II-77 NHONO2 165 Figure 2. 2 Stoichiometric NMR studies of substrate -catalyst mixtures in CF 3CH2OH at ambient temperature and 0.02 M concentration of substrate and catalyst. 2.8 X -ray crystallography structure data 2.8.1 X-ray crystal structure data of II -55 166 #Experimental. #Single colourless needle -shaped crystals of ( BB614a ) were used as supplied. A suitable crystal (0.54 & 0.08 & 0.06 mm 3) was selected and mounted on a nylon loop wit h paratone oil on a Bruker APEX -II CCD diffractometer. The crystal was kept at T = 173(2) K during data collection. Using Olex2 (Dolomanov et al., 2009), the structure was solved with the ShelXS (Sheldrick, 2008) structure solution program, using the Direc t Methods solution method. The model was refined with version 2013 -4 of XL (Sheldrick, 2008) using Least Squares minimisation. Crystal Data. C17H14ClNO, Mr = 283.74, orthorhombic, P2 12121 (No. 19), a = 4.5922(3) †, b = 10.4221(5) †, c = 29.1253(13) #†D#"#=###=#$#= 90 ¡,#V = 1393.95(13) † 3, T = 173(2) #K, Z = 4, Z' = 1.000, µ#(CuK ")#= 2.369, 13565 reflections measured, 2712 unique ( Rint = 0.0823) which were used in all calculations. The final wR2 was 0.0978 (all data) and R1 was 0.0410 (I > 2(I)). 167 Crystal data and structure refinement Compound BB614a CCDC n/a Formula C17H14ClNO Dcalc. / g cm -3 1.352 µ/mm -1 2.369 Formula Weight 283.74 Colour colourless Shape needle Max Size/mm 0.54 Mid Size/mm 0.08 Min Size/mm 0.06 T/K 173(2) Crystal System orthorhombic Space Group P212121 a/† 4.5922(3) b/† 10.4221(5) c/† 29.1253(13) "EF#90 #EF#90 $EF#90 V/† 3 1393.95(13) Z 4 Z' 1.000 %GHI EF#3.034 %GJK EF#72.147 Measured Refl. 13565 Independent Refl. 2712 Reflections Used 2246 Rint 0.0823 Parameters 182 Restraints 0 Largest Peak 0.174 Deepest Hole -0.174 GooF 1.027 wR2 (all data) 0.0978 wR2 0.0915 R1 (all data) 0.0553 R1 0.0410 168 ## 169 #The Model has Chirality at C1 ............. R 170 2.8.2 X -ray crystal structure data of II -79 Experimental. Single colourless needle -shaped crystals of ( bb1015b ) were used as received. A suitable crystal (0.49 & 0.09 & 0.04) was selected and mounted on a nylon loop with paratone oil on a Bruker APEX -II CCD diffractometer. The crystal was kept at T = 173(2) K during data collection. Using Olex2 (Dolomanov et al., 2009 ), the structure was solved with the ShelXS (Sheldrick, 2008) structure solution program, using the Direct Methods solution method. The model was refined with version 2014/6 of XL (Sheldrick, 2008) using Least Squares minimisation. Crystal Data. !C26H32Cl4N4O6, Mr = 638.35, orthorhombic, P2 12121 (No. 19), a = 12.9069(2) †, b = 13.3255(2) †, c = 18.0382(3) †,!" =!#!= $ =!90¡, V = 3102.41(8) †3, T = 173(2) K, Z = 4, Z' = 1 %!µ(CuK ")!= 3.847, 22480 re flections measured, 5929 unique (Rint = 0.0436) which were used in all calculations. The final wR2 was 0.0763 (all data) and R1 was 0.0317 (I > 2(I)). 171 Crystal data and structure refinement Compound bb1015b Formula C26H32Cl4N4O6 Dcalc. / g cm -3 1.367 /mm -1 3.847 Formula Weight 638.35 Colour colourless Shape needle Max Size/mm 0.49 Mid Size/mm 0.09 Min Size/mm 0.04 T/K 173(2) Crystal System orthorhombic Flack Parameter 0.005(7) Hooft Parameter -0.001(8) Space Group P212121 a/† 12.9069(2) b/† 13.3255(2) c/† 18.0382(3) "($!!90 #($!!90 $($!!90 V/† 3 3102.41(8) Z 4 Z' 1 %!"# ($!!4.125 %!$% ($!!72.367 Measured Refl. 22480 Independent Refl. 5929 Reflections Used 5413 Rint 0.0436 Parameters 365 Restraints 0 Largest Peak 0.255 Deepest Hole -0.219 GooF 1.028 wR2 (all data) 0.0763 wR2 0.0736 R1 (all data) 0.0369 R1 0.0317 ! 172 !Figure 1: !Figure 2: !!Figure 3: The Model has Chirality at C3A (Chiral SPGR) R Verify; The Model has Chirality at C4A (Chiral SPGR) R Verify; The Model has Chirality at C5A (Chiral SPGR) R Verify 173 !Figure 4: !!Figure 5: The Model has Chirality at C3B (Chiral SPGR) R Verify; The Model has Chirality at C4B (Chiral SPGR) R Verify; The Model has Chirality at C5B (Chiral SPGR) R Verify !Figure 6: The following hydroge n bonding interactions with a maximum D -D distance of 174 2.9 † and a minimum angle of 120 ¡ are present in BB1015b : N1B -O1A(1) =2.808 †, N1A -O1B =2.857 †. !!Figure 7: Packing diagram of BB1015b. 175 REFERENCES 176 REFERENCES 1. 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Nakamura, S.; Ohara, M.; Nakamura, Y.; Shibata, N.; Toru, T., Copper -Catalyzed Enantioselective Three -Component Synthesis of Optically Active Propargylamines from Aldehydes, Amines, and Aliphatic Alkynes. Chemistry Ð A European Journal 2010, 16 (8), 2360-2362. 13. Wei, C.; Li, C. -J., A Highly Efficient Three -Component Coupling of Aldehyde, Alkyne, and Amines via C ' H Activation Catalyzed by Gold in Water. Journal of the American Chemical Society 2003, 125 (32), 9584 -9585. 14. Gommermann, N.; Koradin, C.; P olborn, K.; Knochel, P., Eine enantioselektive, Kupfer(I) -katalysierte Drei -Komponenten -Reaktion zur Synthese von Propargylaminen. Angewandte Chemie 2003, 115 (46), 5941 -5944. 15. Jaganathan, A.; Staples, R. J.; Borhan, B., Kinetic Resolution of Unsaturat ed Amides in a Chlorocyclization Reaction: Concomitant Enantiomer Differentiation and Face Selective Alkene Chlorination by a Single Catalyst. Journal of the American Chemical Society 2013, 135 (39), 14806 -14813. 16. Klauber, E. G.; Mittal, N.; Shah, T. K .; Seidel, D., A Dual -Catalysis/Anion -Binding Approach to the Kinetic Resolution of Allylic Amines. Organic Letters 2011, 13 (9), 2464 -2467. 17. Soltanzadeh, B.; Jaganathan, A.; Yi, Y.; Yi, H.; Staples, R. J.; Borhan, B., Highly Regio - and Enantioselectiv e Vicinal Dihalogenation of Allyl Amides. Journal of the American Chemical Society 2017, 139 (6), 2132 -2135. 18. Moragas, T.; Liffey, R. M.; Regentov⁄, D.; Ward, J. -P. S.; Dutton, J.; Lewis, W.; Churcher, I.; Walton, L.; Souto, J. A.; Stockman, R. A., Sigmatropic Rearrangement of Vinyl Aziridines: Expedient Synthesis of Cyclic Sulfoximines from Chiral Sulfinimines. Angewandte Chemie International Edition 2016, 55 (34), 10047 -10051. 19. Jaganathan, A.; Garzan, A.; Whitehead, D. C.; Staples, R. J.; Borhan, B., A Catalytic Asymmetric Chlorocyclization of Unsaturated Amides. Angewandte Chemie International Edition 2011, 50 (11), 2593 -2596. 178 CHAPTER THREE !"#$%&'()*+,)&%! !"#$ -.&)(+/+)01&$0(#!$(!2(#3$%,+$!&!240%&)!560%( -2*#$*% ! 3.1 Introduction Dearomative ipso -cyclization of arene compounds is an important transformation in organic synthesis and has been widely used in the total synthesis of natural products. 1 Intramolecular ipso -cyclization reactions enable the construction of a spiro -centre in a straightforward way, which can overall efficiently transform easily accessible molecules to more complicated structures. 2 However enantioselective processes are rare, especially catalytic ones. The two major challenges in developing enantioselective dearomative ipso -cyclization are: 1) the high energy barrier encountered in dearomatization processes; 2) the competitive ortho -cyclization process. In 2008, the first enantioselective oxidative dearomatization of phenols III-1 to synthesize a chiral spirolactone using chiral hypervalent iodine reagent III-2 was reported by KitaÕs group (Scheme 3.1). 3 Nucleophilic attack on an int ermediate which was formed via ligand exchange afford quinone variants in up to 86% ee. Scheme 3.1 C-O bond forming ipso -cyclization . OHRCO2HIIOOAc OAc OROOOIPhXRÕNuup to 86% eeIII-1 III-2 III-3 179 More recently transition -metal catalyzed dearomative ipso -cyclizations are emerging. In 2010, YouÕs group reported a highly enantioselective synthesis of spiroindolenines via Ir-catalyzed asymmetric allylic alkylation reaction (Scheme 3.2). 4 An electrophilic "-allyl -iridium intermediate was generated when the Iridium catalyst was subjected to allyl carbonate substrate III-4 and indole functioned as a good carbon nucleophile. The BINOL derived phosphoramidite ligand III -5 furnished excellent ee and dr. Similarly, they developed the first Ir -catalyzed intramolecular asymmetric allylic dearomatization of phenols III-7.5 Spir ocyclohexenone derivatives III-9 were obtained up to 97% ee. Scheme 3.2 ipso -cyclization catalyzed by Iridium catalyst . HamadaÕs group and BuchwaldÕs group developed palladium catalyzed dearomatization of phenols (Scheme 3.3). 6-7 Hamada dearomatized phenols III-10 using Pd-catalyzed intramolecular ipso -Friedel -Crafts allylic alkylation. They demonstrated a single example of catalytic asymmetric synthesis of spiro[4,5]cyclohexadienones III-12 NHNROOOMe 2 mol% Ir(cod)Cl 24 mol% III-5 2 equiv Cs 2CO3CH2Cl2, reflux NRNup to 98% yield up to 97% eeup to 99:1 drOHNROOMe O2 mol% Ir(cod)Cl 24 mol% III-8 2 equiv Li 2CO3THF, 50 ¼C RNOup to 95% yield up to 97% eeOOPNOOPNArArIII-4 III-6 III-5 III-7 III-9 III-8 180 with 89% ee. BuchwaldÕs group dearomati zed phenol III-13 using palladium catalyzed C -arylation. The reaction proceeds through reductive elimination of a palladacycle intermediate. Applying chiral phosphine ligands III-14 enables a practical asymmetric catalytic process with up to 91% ee, albeit only 2 examples of asymmetric version. Scheme 3.3 ipso -cyclization catalyzed by a Palladium catalyst . Zhang reported a copper catalyzed oxidative ipso -cylization of an activated alkyne to synthesize azaspiro[4,5]trienones III-17 with silanes through selective activation of Si -H and C -H bond (Scheme 3.4, a). 8 They proposed that the reaction proceeds via a radical mechanism. Hence it would be difficult to develop an asymmetric version under this system. Very similarly WangÕs group reported a metal -free synthesis of sulfonated azaspiro[4,5]trienones III-19 through oxidative spirocyclization of arylpropioamides III-18 CH3HOCO2t-BuCO2t-BuOCO2Me5 mol% Pd(dba) 26 mol% III-11 1 equiv Li 2CO3OBuO 2CCO2Bu80%9:1 dr89% eeOHBr4 mol% Pd(OAc) 216 mol% H 2O12 mol% III-14 O99% yield 91% eePNMe 2t-BuPhNHHNOOPPh2Ph2PIII-10 III-11 III-12 III-13 III-14 III-15 OHBrPdLpalladacycle CH3CN, 10 ¼C1.5 equiv K 2CO3dioxane (0.2 M) 80 ¼C, 16 h 181 with sulfonylhydrazides (Scheme 3.4, b). 9 The reaction proceeds through single electron oxidation of sulfonyl hydrazide mediated by I 2O5. Scheme 3.4 ipso -cyclization of an activated alkyne by single electron oxidation path . Unsworth Õs group reported a silver catalyzed dearomatization of indole to synthesize spirocyclic indolenines (Scheme 3.5). 10 Activation of the alkyne with "-acidi c Ag(I) catalyst promotes spirocyclization via nucleophilic attack by the indole at the 3 -position. They have not demonstrated an asymmetric version yet. NOPh+HSiPh 35 mol% CuI 7 equiv TBHP t-BuOH, 130 ¼C ONOPhSiPh 367%NOSiPh 3Ph¥Ph3SirìNPhSiPh 3O¥TBHP + Cu It-BuO rì + Cu II(OH) Ph3SiH oxidation NO+PhSOONHNH21 equiv I 2O53 equiv TBHP 1,4-dioxane, 80 ¼C NOSO2PhPh¥NPhSO2PhO¥a.b.SOOPhPhSOONHNH2I2O5oxidation 89%III-16 III-17 PhNOPhSO2PhOIII-18 III-19 182 Scheme 3.5 Silver catalyzed dearomatization of indole . Another type of ipso -cyclization involves C -N bond formation instead of C -C bond formation: oxidation of arenes to a carbocation in advance of trapping by an NH - nucleophile. For example, an oxidative cyclization of phenolic alkylsulfonamides III-22 mediated by hypervalent io dine reagent to form spiro -pyrrolidine III-23 has been reported (Scheme 3.6, a). 11 Contrary to this method, phenol could behave like a nucleophile in a redox neutral environment. More recently a conceptually simple method of C -N bond forming dearomatizatio n has been reported by BowerÕs group (Scheme 3.6, b). 12 The process involves a S EAr-like attack of the aromatic moiety onto the activated tosyloxyammonium intermediate which is in situ generated upon deprotection of Boc with TFA. NHR4OR1R2R310 mol% AgNO 3Ag2OCH2Cl2 (0.1 M) 24 hNHR3R4OR1R2dr = 1:1 up to 98% yield NHOHPhAgIIII-20 III-21 183 Scheme 3.6 C-N bond forming ipso -cyclization . We have witnessed a large body of research focused on the catalytic asymmetric halofunctionalization of alkenes in the last few years, however catalytic asymmetric dearomatizations through halofunctionalization are still underdeveloped. 13 There are generally two ways to realize dearomatization via halofunctionalization. In the first class, electrophilic halogenation occurs at a substituted aromatic ring, like phenol and indole, then a stabilized dearomatized product is ge nerated directly (Scheme 3.7, a) or halonium intermediate is trapped by a tethered nucleophile (Scheme 3.7, b). In the second class, electrophilic halogenation occurs at an alkyne or alkene moiety to yield the halonium HONHSOORPhI(OAc) 2TFA, rt ORNup to 96% yield ONipso -cyclization aIII-22 III-23 OHR1NR2TsO Boc R32 equiv TFA TFE (0.1 M) 0 ¼C to rt, 24-48 h NHR1R2OR3RNOTs HHipso -cyclization up to 91% yield bIII-24 III-25 184 intermediate which is subsequently tr apped intramolecularly by an aromatic ring at the ipso position (Scheme 3.7, c). So far, to the best of our knowledge, examples that fall into the second class are all racemic. Scheme 3.7 Types of dearomatization via halofunctionalization . As opposed o f the second type of reaction, many catalytic asymmetric dearomatization reactions initiated by electrophilic halogenation on arenes have been reported. In 2011, GouverneurÕs group reported the first organocatalyzed asymmetric fluorocyclization through dea romatization of indoles III-26 (Scheme 3.8). 14 Two sets of conditions with stoichiometric and catalytic amounts of (DHQ) 2PHAL, respectively, lead to fluorocyclization of tryptamine or tryptophol derivatives with moderate to high ee. ORÕRX+ORXNuORXOHRX+ORXa.b.NHNuX+NNuXNHNuXc.RÕ 185 Electrophilic fluorine sources Selectfluor and NFSI were utilized . Like many other organocatalytic asymmetric halofunctionalization reactions, the major conceptual difficulty of this reaction is that the in situ generated transient chiral N -F cinchona spec ies is similarly reactive or less reactive with respect to the achiral fluorinating reagent. Similarly an analogous bromine cyclization of tryptamine derivative III-28 was later reported by Xie (Scheme 3.8). 15 They used the DABCO derived bromine reagent III-29 as bromine source and chiral phosphoric acid as catalyst. Scheme 3.8 Fluorocyclization of tryptamine and tryptophol . NXHR1R2NR1R2XFHA: 1.2 equiv Selectfluor 1.2 equiv (DHQ) 2PHAL 1.2 equiv NaHCO 3acetone, Ð78 ¼C B: 1.2 equiv NFSI 0.2 equiv (DHQ) 2PHAL 6 equiv K 2CO3acetone, Ð78 ¼C X = O, NTs, NCOMe NCO2Bn, NBoc up to 90% yield 92% eeNSO2PhSO2PhFNFSI NNClF2BF 4Selectfluor NNHPGÕ NPGÕ NPG BrH1.3 equiv III-29 10 mol% 8H-( R)-TRIP up to 99% eeRPGRNNF3CCF3BrBrClOOiPriPriPriPriPriPrPOOHIII-26 III-27 III-28 III-30 III-29 4 equiv NaHCO 3toluene, 0 ¼C 186 YouÕs group developed a highly enantioselective chlorocyclization of indole derived benzamides III -31 and III-33 using (DHQD) 2PHAL as catalyst (Scheme 3.9). 16-17 By using different substrates, both spiro -cyclization and fused ring products were obtained in high ee, respectively. They proposed a catalytic model in which the phthalazine nitrogen forms a hydrogen bond with benzamide NH to increase the nucleophilicity of the amide group and the quinuclidine nitrogen can activate the chlorenium to provide a chiral enviro nment. Scheme 3.9 Enantioselective ipso -chlorocyclization of indoles . Unlike a lot of asymmetric examples of dearomatization that are initiated by halogenation of arenes, asymmetric version of the dearomatization by halogenation of tethered alkynes and a lkenes remains underdeveloped (Scheme 3.7, c). So far most reported examples of this type of reaction are racemic. The earliest work of this area dates back to 2005, when Larock reported a straightforward route to spiro[4,5]trienones via intramolecular ips o-halocyclization of simple methoxy -substituted -4-aryl -1-alkynes (Scheme 3.10). 18 This reaction shows that the linkage of amine, ether and CH 2 were well tolerated. ICl or I 2 proved to be an efficient electrophile to give the iodonium intermediate, AcNHNOR3R1R2+DCDPH 10 mol% (DHQD) 2PHAL CHCl3, Ð30 ¼CAcNR1ONR3ClR2up to 96% eeTsNNH+DCDMH 1 mol% (DHQD) 2PHAL CF3CH2OH, rt OR1TsNNOR1Clup to 99% eeIII-31 III-32 III-33 III-34 187 which ca n undergo intramolecular ipso -attack by the electron -rich aromatic ring. The methyl group of methoxy can be removed through nucleophilic displacement by the base. This work represents a general model for future work on ipso -halocyclization initiated by halogenation of alkynes or alkenes. Scheme 3.10 LarockÕs ipso -iodocyclization . In 2008, Li re ported an electrophilic ipso -iodocyclization of N-(4-methylphenyl)propiolamides to access 4 -methyleneazaspiro[4,5]trienes (Scheme 3.11a) .19 The major difference of this work in comparison to LarockÕs system is using para -methyl as the activating group instead of para -methoxy substituent . Similarly , the same group then reported the ipso -cyclization of N-(4-methoxylphenyl)propiolamide III-39 through an electrophile exchange process (Scheme 3.11b) .20 Electrophilic fluoride reagent III -41 or Selectfluor can react with CuX (X= Br, I, SCN) to generate electrophilic cation X +, which reacts with an alkyne to initiate the ipso -cyclization. Besides the alkoxy or alkyl activa ting group at the para -position of phenyl group, non -activated substrates OMe XYPhI2 or ICl NaHCO3 or NaOMe CH2Cl2, Ð78 ¼CYXOPhIX = O, NH, NTf, NCOMe, CH 2Y = CH 2, COup to 100% yield OMe NPhTfI+OMe NPhITfNu-ONTfIPhMeNu-III-35 III-36 188 have also been studied by LiÕs group (Scheme 3.12). 21 In the presence of a suitable nucleophile like AcOH or trifluroethanol, the cationic allyl intermediate can be captured by AcO Ð or CF 3CH2OÐ anion, respectively. The yields ranged from moderate to good, however the dr were generally between 1:1 to 2:1. Scheme 3.11 Electrophilic ipso -iodocyclization with para -activ ating group . Scheme 3.12 Electrophilic ipso -iodocyclization without para -activ ating group . NROI2 or ICl NIROMeCN, then H 2OÐ25 ¼C to rt up to 100% yield ZROMeO 1.5 equiv F 3 equiv CuX OZIROMeCN, 90 ¼C up to 93% yield Z = NRÕ, O X = I, Br, SCN R = aryl, alkyl F+CuXX+CuFNFBF4F=NNClF2BF4 a.b.III-37 III-38 III-39 III-40 III-41 Selectfluor ZRÕOAcOZIRÕORRZ = NMe, O NRÕIORHOAc NRÕIOCF3CH2O/AcO NISHOAc or CF 3CH2OHrtor CF 3CH2OHRup to 98% yield up to 3:1 drIII-42 III-43 189 Majumdar and coworkers used the ipso -iodocyclization strategy to synthesize spiro -coumarin, quinolone and pyrimidine heterocyclic compounds (Scheme 3.13). They used I2 as the electrophilic iodine source and N aHCO 3 as the base, which is similar to LarockÕs conditions. 18 Scheme 3.13 ipso -iodocyclization to access spiro -pyrimidine/coumarin . Although a lot of high yielding examples of dearomatization through halofunctionalization have been reported, the lack of catalytic enantioselective versions is still the downside of this area. Possible reasons why developing highly efficient asymmetric dearomatization via halofunctionalization is challenging are 1) the competitive background reactions or side reactions overr ide the catalytic reactions due to the highly reactive electrophilic halogenating reagent; 2) the mechanism of catalytic asymmetric dearomatizations through halofunctionalization are not well understood, which prevents rational design of highly efficient c atalytic systems. 13 Inspired by recent success of asymmetric chlorofunctionalizations of olefins developed in the Borhan labs, NNOONOPhR1R1R24 equiv I 23 equiv NaHCO 31.5 equiv MeOH MeCN, rt NNNOOOPhIMeO R1R1R2XNORPhO4 equiv I 23 equiv NaHCO 31.5 equiv MeOH MeCN, rt XMeO NIOROPh to 88% yield up to 92% yield III-44 III-45 III-46 III-47 190 an effort was undertaken to develop catalytic asymmetric dearomatization via halofunctionalization. 22-24 This chapter will depict the efforts towards the catalytic asymmetric ipso -halocyclization of 4 -aryl -1-alkyne derivatives. 3.2 Results and discussion 3.2.1 Screen the halogen source with N-(4-methoxyphenyl) -4-methyl -N-(3-phenylprop -2-yn-1-yl)benzenesulfonamide The initial evaluations of various halogenating reagents in racemic non -catalytic reaction s employed LarockÕs substrate III -48 (Table 3.1). Halo genated -succinimides, halogenated hydantoin s and halogenated isocyanuric acid s were screened. Reactions were run at room tem perature. TCCA and N-halo succinimide species gave high conversion and yield after 3 h. Among the various electrophilic halogen reagents, NIS and TCCA gave ~90% yields within 3 h. However, DCDMH led to sluggish reaction and only gave 16% conversion after 3 h, although in a very clean reaction. Hence, DCDMH might be a good choice for catalytic reactions in terms of its slow background reaction. 191 Table 3.1 Halogen screening for substrate III-48 3.2.2 Asymmetric ipso -halocyclization of N-(4-methoxy -2-methylphenyl) -4-methyl -N-(3-phenylprop -2-yn-1-yl)benzenesulfonamide The asymmetric reaction with N-tethered propargyl substrate III-52 was evaluated . DCDMH and TCCA were used for screening cinchona alkaloid dimer catalysts (Table 3.2). TCCA was more reactive as compared to DCDMH, and reactions were done within half an hour in acetonitrile . However, complicated mixtures products were obtained and the yield was low. Reaction s were not complete with DCDMH even after 27 h. (DHQD) 2AQN, (DHQD) 2Pyr and (DHQD) 2PHAL all gave racemic products. OCH3NTsPh2 equiv X +2 equiv NaHCO 3MeCN, rt aNTsPhOconversion (%) b757095951690yield (%) b247070901586X+Br2I2NBS NISDCDMH TCCAa reactions are quenched after 3 h; b conversions and yield were determined based on crude 1H NMR using MTBE as internal standard III-48 X=Cl, III-49 X=Br, III-50 X=I, III-51 III-49 -III-51 X 192 Table 3.2 Optimization of reaction conditions for substrate III-52 OCH3NTsPh2 equiv X +10 mol% catalyst 2 equiv NaHCO 3MeCN, rt NTsClPhOconversion (%) a685469761001001000yield (%) b553722554444370catalyst none(DHQ) 2AQN (DHQD) 2Pyr(DHQD) 2PHAL DABCO (DHQ) 2AQN (DHQD) 2Pyr(DHQD) 2Pyra conversions were determined from crude 1H NMR; b yields were determined from isolated products; c ee were determined from chiral HPLC. entry 12345678ee (%) c !223!82!ClDCDMH DCDMH DCDMH DCDMH TCCATCCATCCANCStime (h) 127272440.50.524III-52 III-53 193 3.2.3 Asymmetric ipso -halocy clization with 2 -bromo - 4-methoxy - 1-((3 -phenylprop -2-yn-1-yl) oxy) benzene Scheme 3.14 Ipso -chloro cylization of O -linker Substrate In addition to the N-tethered propargyl substrate s, the O -tethered substrate III-54 has also been evaluated which contains an ortho -Br substituent on the benzene ring to install a prechiral center . Intramolecular chlorocyclization with TCCA as electrophilic chlorine source and DABCO as Lewis base catalyst leads to a major product III-55 in 65% yield (Scheme 3.14 ). The product was characterized by X -ray crystallography. The proposed mechanism is that the benzene ring undergo es chlori ne substitution at the ortho -position to the methoxy and chlorenium is formed on the propargyl group which lead to ipso -cyclization . The generated trienone II is converted to the chlore nium III which is trapped by the anion of isocyanuric acid. Different cinchona alkaloid derived catalysts were screened for the asymmetric reaction of III-54 (Table 3.3). Both monomer and dimer hydroquinine or hydroquinidine derived catalysts induced no noticeable enantioselectivity , OPhBrOCH32 equiv TCCA 10 % DABCO, NaHCO 3MeCN, rt OClPhO65%BrNHNHNOOOClClOPhBrOClClBrClOOClPhBrClOOClPhNNNOOOClClClelectrophilic chlorination III-54 III-55 IIIIII 194 also led to low yields. The best result was obtained from (DHQ) 2AQN as catalyst, which gave 75% yield and 7% ee. In consideration of the practicality and poor enantioselectivity of the product, O -tethered propargyl substrates were not further investigate d. Table 3.3 Catalyst screen for substrate III-54 OPhBrOMe 2 equiv TCCA 2 equiv NaHCO 310 mol% catalyst MeCN, rt 2 h -18 h BrClClNHNHNOOOOOClPhentry 12345678catalyst III-95 III-96 III-97 III-98 III-99 (DHQD) 2PHAL (DHQ) 2AQN hydroquinidine yield % (III-55) a2534253844447525ee % (III-55) b335< 2 < 2 373a yield was determined by isolated product; b ee was determined by chiral HPLC. POOPIII-95 NNOOIII-96 NNOONIII-97 NOHNSFFMeO NIII-98 NOHNSMeO NNO2III-99 NONONOCH3NH3COOO(DHQ) 2AQNIII-54 III-55 195 3.2.4 Use of Br ¯nsted acid ( R)-VANOL hydrogenphosphate as catalyst The discouraging results from using cinchona alkaloid based catalysts might indicate that a Lewis -base is not a suitable catalyst for this reaction. Instead, a Br¿nsted acid catalyst was tried since there is precedence of Br ¿nsted acid -catalyzed halofunctionalization in the literature. For example, DenmarkÕs group reported the bromocycloetherification catalyzed by chiral Br¿nsted acid TRIP. 25 Hennecke and coworkers also reported the haloetherification catalyzed by the sodium salt of VAPOL phosphoric acid and other BINOL derived phosphoric acids. 26 Thanks to the generosity of Prof. WulffÕs lab, ( R)-VANOL hydrogen phosphate III -58 was used as a Br¿nsted acid catalyst representative . The tosyl protected N -linked substrate III-52 was treated with N -bromosuccinimide and ( R)-VANOL hydrogen phosphate ( Table 3.4), however the enantioselectivity and yield were poor for the expected product III-56. The major product was indeed dibrominated methyl product III-57. Different solvents and catalyst loadings were screened. Dichloromethane and chloroform gave the best enantioselectivity, leading to only 15% ee, and the yields were generally poor. I n addition, reactions were not complete when 1 equiv of NBS was used, which was ascribed to the formation of the dibrominated product III-57. When 3 equiv of NBS were applied, the reaction was finished within 3 h in DCM. In addition to the tosyl protected substrate, the benzoyl protected substrate III-59 was evaluated in the presence of DBDMH and ( R)-VANOL hydrogen phosphate in MeCN (Scheme 3.15), however only racemic product III-60 was obtained. 196 Table 3.4 Evaluation of ( R)-VANOL -hydrogen phosphate Scheme 3.15 ipso -bromocyclization of benzoyl protected N-tethered substrate OCH3NTsPh1 equiv NBS (R)-VANOL hydrogen phosphate III-58 rt, solvent NTsBrPhOconversion (%) aNDND10010075645675yield (III-56)(%) a492917261110145solventMeCN MeCN tolueneCH2Cl2CH2Cl2CH2Cl2benzene CHCl3a conversions and yield were determined from GC ; b ee were determined from chiral HPLC; c 2 equiv NaHCO 3 was added; d 3 equiv NBS was used instead of 1 equiv. entry 12c3d4d5678ee (III-56)(%) b3331533314equiv of cat. 0.10.10.30.30.10.050.10.1time (h) 2218348482424+NTsBrPhOCHBr 2OOPhPhPOOH(R)-VANOL hydrogen phosphate III-52 III-56 III-57 III-58 OCH3NBzPh1 equiv DBDMH 8 mol% ( R)-VANOL hydrogen phosphate MeCN, rt, 10 min NBzBrPhO100% conversion, 50% yield, 2% eeIII-59 III-60 197 3.2.5 Asymmetric ipso -halocy clization with N-(4-methoxy -2-methylphenyl) -3-phenyl -N-tosylpropiolamide The failure of achieving any enantioselectivity by using Lewis base and Br¿nsted acids made us re -examine the interaction s of the catalysts with the substrate . Based on previous studies in the BorhanÕs group on the enantioselective Lewis base catalyzed chlorocyclization and dichlorination reactions, all the successful examples ar e either amides, carboxylic acids or carbamates. In general, for Br¿nsted acid catalys is in the literature, these catalysts function through hydrogen binding with the subst rates. So maybe the lack of hydrogen bond acceptor on the substrate III-52 prohibits the delivery of enantioselective delivery from the Br¿nsted acid catalyst. This would suggest the need for substrates to be modified if we want to continue to apply Lewis base or Br¿nsted acid catalysts. To this end, the methylene next to the tr iple bond was replaced with a carbonyl, depicted as III-61, which indeed has precedence in literature. 19-21 There are reported non -asymmetric electrophilic ipso -cyclization using similar substrates. 20 The screening commenced with different halogen sources using acetonitrile as solvent at room temperature (Table 3.5). The electrophilic iodine sources NIS and ICl furnished good yield when 2 equiv of NaHCO 3 were added. Chlorenium reagents like NCS, DCDMH and chloramine -T were less reactive leading to sluggish reactions. The bromine containing reagent NBS gave poor yield. 198 Table 3.5 Halogen screening for substrate III-61 With optimal halogen reagents ICl and NIS in hand, our continued effort was focused on asymmetric catalysis (Table 3.6). In general, the presence of NaHCO 3 as a base can improve the yield (Table 3.6, entries 2, 4, 5 15, 16). When monomeric cinchona alkaloid catalysts quinine and quinidine were used, no enantioselectivity was induced at room temperature or even when the temperature was lower ed to #30¡C (Table 3.6, entries 2 to 6). Reactions were sluggish at #30"¡C and could not be brought to completion even after an extended time frame . Cinchona alkaloid dimer catalysts (DHQD) 2PHAL and (DHQD) 2Pyr furnished racemic products as well (Table 3.6, entries 8, 9, 10, 12 and 13) . The combination of (DHQD) 2PHAL and highly polar protic solvent TFE, which normally gave good ee for the labÕs chloro functionalization chemistry led to racemic product (Table NTsOPhOMe NXPhOTsO1 equiv X +MeCN (0.1 M) rt, 24 h conversion (%) a100100100381006235yield (%) a4480c95c521c300X+NISNISbIClbNCSNBS DCDMH Chloramine-T a conversion and yield were decided by crude 1H NMR using methyl- t-butyl ether as internal standard; b 2 equiv NaHCO 3 were added; c yields were determined by isolated product through column chromatography. III-61 III-62 -III-64 X=Cl, III-62 X=Br, III-63 X=I, III-64 199 3.6, entry 9), albeit with good yield . Other quinin e or quinidine derived monomeric catalysts, such as thiocarbamate III-65 and ester III-67 induced no enantioselectivity (Table 3.6, entries 7 and 16). Chiral Br¿nsted acid (R)-VANOL hydrogen phosphate and thiourea III -66 gave poor yield and no enantioselec tivity was obtained (Table 3.6, entries 11, 14 and 15). Reaction with chlorenium reagent NCS catalyzed by (DHQD) 2PHAL in TFE led to good yield and improved ee (Table 3.6, entry 12) . So far this substrate failed to give any practical enantioselectivity with the catalysts we have tested. NBS induced bromo -ipso cyclization, catalyzed by (DHQD) 2PHAL, and gave racemic product in moderate yield (Table 3.6, entry 17). 200 Table 3.6 Optimization of reaction conditions for substrate III-61 NTsOPhOMe NXPhOTsO2 equiv X +MeCN (0.1 M) 2 equiv NaHCO 310 mol% catalyst conversion (%) a8062601001001001001001008056100100100100100100yield (%) b7356407580414374804036784836949468XICl (1 equiv) NISNISeNISNISNISe NISNISeNISd,eNISe NCSf,eNCSd,eDCDMH NISgIClNISNBS d,ea conversions were decided by crude 1H NMR using methyl- t-butyl ether as internal standard; ; b yields were determined by isolated product through column chromatography; c ee were determined by chiral HPLC column d TFE was used as solvent instead of MeCN; e no NaHCO3 was added; f DCM was used as solvent instead of MeCN. g CHCl3 was used as solvent catalyst (DHQD) 2PHAL quininequininequininequininequinidineIII-65 (DHQD) 2Pyr(DHQD) 2PHAL (DHQD) 2PHAL (R)-VANOL PA ((DHQD) 2PHAL (DHQD) 2PHAL III-66 III-66 III-67 (DHQD) 2PHAL ee (%) c20000000212600010NNONHSPhOMe III-65 temp. (¼C) 23Ð30Ð3023Ð10Ð10Ð10232323 2323232323Ð3023NNNHNHSOMe III-66 CF3F3CNNOOOMe III-67 Clentry 12345678910 11121314151617III-61 III-62 -III-64 X=Cl, III-62 X=Br, III-63 X=I, III-64 201 3.2. 6 Asymmetric ipso -halocy clization with N-(2-hydroxyphenyl) -N-methyl -3-phenylpropiolamide After exhaustive search for the asymmetric ipso -halocyclization of N-tethered para -activating phenyl substrate III -61, we realized that this reaction might not be compatible with our g roupÕs catalytic system. I got some inspiration from recent work from SchneiderÕs group (Scheme 3.16, a). 27 They reported an ortho -directing group assisted nucle ophili c substitution of propargylic alcohols III-68 catalyzed by chiral phosphoric acid III-71. Based on the mechanism, o-hydroxy group of III-68 helps to form highly reactive o-quinone methides, which are readily attacked by enamides III-69. More importantly a chiral phosphoric acid helps bring quinone and enamides close together and subjects the cyclization step to a chiral environment by hydrogen binding. Inspired by this catalytic model, I designed a new ortho -activating substrate III-72, which could be interacting with Br¿nsted acid through hydrogen binding with carbonyl and hydroxyl groups (Sc heme 3.16, b), which presumably direct ipso -cyclization in a chiral pocket. 202 Scheme 3.16 ortho -directing group assisted nucle ophili c substitution of propargylic alcohols The investigation began with the substrate III-72 with halogen screening using (S)-VANOL phosphoric acid III-75 (Table 3. 7). Reactions were conducted under SchneiderÕs condition , using dichloromethane as solvent at room temperature. Not surprisingly, electrophilic iodine sources, such as I 2, ICl and NIS were more reactive than bromine and chlorine reagents in terms of yield, although in poor ee. Chlorinated hydantoin species (DCDMH, DCDPH) and NCS resulted mostly in the recovery of starting materials recovery. No enantioselectivity was obtained under conditions with different halonium reagent. OHOHR+XAcHN 5 mol% III-71 CH2Cl2, rt ORXHNHX = CH 2, O, SAcyields up to 83% dr up to 98:2,er up to 99:1OOPOOHORNAc HHBA*ONOPhHBA*proposed model abHIII-72 III-68 III-69 III-70 III-71 203 Table 3.7 Screen of different electrophilic halogen reagent for III-72 Next, I screened other chiral phosphoric acids using NIS, which turned out to be the optimal halogen reagent in the study above (Table 3.8). ( R)-BINOL phosphoric acid incre ased the ee to 6% as compared with ( S)-VANOL phosphoric acid (2% ee). Lowering the temperature from rt to Ð20 ¼C further increased the ee to 12%. Switching solvent from DCM to toluene further increased ee to 16%. Adding Lewis acids such as Zn(OTf) 2 increased the yield but had minor effect on ee. More sterically hindered ( R)-t-butyl VANOL phosphoric acid III-78 at Ð20 ¼C gave comparable ee as the ( R)-BINOL phosphoric acid. BINOL derived thio -phosphoramide III-80 gave 3% ee at Ð30 ¼C in toluene. Last, but not least, 30% ee was obtained when ( R)-TRIP III -79 was used as catalyst at Ð30 ¼C. The major side product observed in this reaction was the aromatic electrophilic iodination product III -76. NHOOPh10 mol% ( S)-VANOL phosphoric acid III-75 1.5 equiv X +DCM, rt NOOPhXyield % a648401403372ee % b00!2!22time(h) 48348482084X+I2IClDCDMH DCDPH NCSNBS NISa yields were determined from isolated product; b ee were determined from chiral HPLC. NNOORRClClR = Me, DCDMH R = Ph, DPDMH III-72 III-73 ,III-74 OOPhPhPOOHIII-75 X=Br, III-73 X=I, III-74 204 Table 3.8 Catalyst screening for III-72 The strategy of using the combination of metal and chiral ligand was also examined. (Table 3.9). I assumed that chiral ligands like VANOL, VANOL phosphoric acid and tartaric acid along with Lewis acid can have some cooperative chiral control. However different Lewis acids such as Pd(OAc) 2, Ti(O iPr) 4 and Yb(OTf) 3 combined with chiral ligands gave no enantioselectivity. Other halogen sources such as NBS were also evaluated using ( R)-TRIP as catalyst. III-73 was obtained in 40% yield and 8% ee (Scheme 3.17). NHOOPh10 mol% catalyst 1.5 equiv NIS NOOPhINHOOPhI+condition yield %aee % b(R)-BINOL phophoric acid III-77 , DCM (0.1M), rt 686(R)-BINOL phophoric acid III-77, DCM (0.1M), Zn(OTf) 2, rt 864(R)-BINOL phophoric acid III-77 , DCM (0.1M), !20 ¼C8512(R)-t-butyl VANOL phophoric acid III-78 , DCM(0.1M), !20 ¼C53125 mol% ( R)-TRIP III-79 , toluene (0.1M), !30 ¼C4930a yields were determined from isolated product; b ee were determined from chiral HPLC PhPhOOPOOHt-butyl t-butyl OOPOOHR-BINOL PA R-t -butyl VANOL PA OOPOOHiPriPriPriPriPriPr(R)-TRIP 5 mol% III-80 , toluene (0.1 M), !30 ¼C423OOPSNHTfiPriPriPriPriPriPrIII-80 (R)-BINOL phophoric acid III-77, toluene (0.1M), !30 ¼C!16III-72 III-74 III-76 III-77 III-78 III-79 205 Table 3.9 Evaluation of chiral ligand with different Lewis acid Scheme 3.17 Evaluation of NBS with chiral dihydrogen phosphate It is noteworthy to point out that if phenol was protected with methyl, no ipso -cyclized product was observed (Scheme 3.18). The maj or product was III -81, which might be due to the generated iodonium being trapped by H 2O when the reaction was worked up. Same product was observed when acetic acid and H 2O were used. However, when glacial acetic acid was used alone as solvent, ipso -cyclized product III-82 was obtained in moderate yield. Another interesting observation was that when the N was not protected ( III -83), no reaction occurs using chiral phosphoric acid as the catalyst. NOPhOH10 mol% catalyst dichloromethane ( 0.1 M) 1.5 equiv. NIS r.t. NIPhOOcatalyst yield %ee %Pd(OAc) 2, (S)-VANOL phosphoric acid 642Pd(OAc) 2, (S)-t-butyl-VANOL 370Ti(O iPr)4, (R)-t-butyl-VANOL 430Yb(OTf) 3!H2O, (D)-tartaric acid 8000"III-72 III-74 NOPhHO5 mol% ( R)-TRIP 1.5 eq. NBS tol(0.1M ). -30 ¡C 24 hNOBrOPhIII-73 40 %8% eeIII-72 206 Scheme 3.18 Reactions of other derivatives 3.3 Summ ary and future work We attempted to achieve enantioselective ipso -cyclization mediated by electrophilic halogen sources. We have tested different catalytic systems including Lewis base and Br¿nsted acid catalysts, however none of them could deliver practic al ee. We also tried to modify the skeleton of substrates to tune its hydrogen -bonding affinity with catalysts, for example substrate III-72 which was supposed to have good hydrogen binding affinity with chiral hydrogen phosphate catalyst furnished 30% ee. For the future work, to achieve good enantioselectivity we could try other organocatalysts or some organometal catalysts. For example, we could modify substrate to III-84, which contains a triple bond that can be activated by gold catalyst with a chiral ligand (Scheme PhON1.5 equiv NIS MeCN (0.1 M) NPhIOOOO1.5 equiv NIS, HOAc: H 2O (v/v, 6:4) PhON1.5 equiv NIS HOAc OOAc OMe NOIPhPhOHNO1.5 equiv NIS NR(S)-VANOL phosphoric acid DCM, rt 64%III-72 III-81 III-72 III-82 III-83 207 3.19). There are a large body of work with chiral gold catalysis. For instance, Toste reported gold -TRIP as a tight ion pair to catalyze the enantioselective construction of C -O/C-N bond. 28-29 YouÕs group recently reported a gold catalyzed dearomatization of naphthols to construct spirocarbocylces, however they have not demonstrated asymmetric version yet. 29 Scheme 3.19 Gold catalyzed ipso -cylclization Another future endeavor could be using the double bond as a halenium acceptor instead of triple bond. Based on our groupÕs previous study, most successful examples of Lewis base catalyzed enantioselctive halofunctionalization is with olefinic amides. Besides N-linked, C and O-linked substrates can also be candidates (Scheme 3.20). Indeed N-linker itself is also a chiral center which could have different conformation of states due to the restricted rotation of the C -N bond. I surmise the possibility that different conformation of the substrate could scramble the cyclization, which is the ena ntio -determing step. Scheme 3.20 Other substrates for ipso -halocyclization NHOAuL* NHOAuL* NOIII-84 III-85 III-86 NHOOHOOOHOOIII-87 III-88 III-89 208 3.4 Experimental section 3.4.1 General information NBS was used after recrystallization from 90 -95 ¼C water. NIS was recrystallized from dioxane/CCl 4. DCDMH was used after recrystallization from CHCl 3 and then sublimation. Other halogen reagents were purchased from commercial sources without purification. TLC analyses were performed on silica gel plates (pre -coated on glass; 0.20 mm thickness with fluorescent indicator UV254 ) and were visualized by UV or charred in KMnO 4 stains. 1H and 13C NMR spectra were collected on 500 MHz NMR spectrometers (Agilent) using CDCl 3. Chemical shifts are reported in parts per million (ppm) and are referenced to residual solvent peaks. For HRMS (ESI) analysis, a Water 2795 (Alliance HT) instrument was used and referenced against Polyethylene Glycol (PEG -400-600). Flash silica gel (32 -63 $ m, Silicycle 60 †) was used for column chromatography. All known compounds were characterized by 1H and 13C N MR and are in complete agreement with samples reported elsewhere. All new compounds were characterized by 1H and 13C NMR, HRMS, and melting point (where appropriate). Enantiomeric excesses were determined using chiral HPLC (instrument: HP series 1100, Agil ent 1260 infinity). 3.4.2 Synthesis of substrate III -48, III -52 4-Methoxy -2-methylaniline (2.74 g, 20.0 mmol, 1.0 eq uiv ) was added to an oven -dried round bottom flask charged with Ar. Freshly distilled CH 2Cl2 100 mL was added into flask. NH2OCH3CH31 equiv TsCl, Et 3NCH2Cl2, 0 ¼C to rt HNOCH3CH3TsIII-91 209 The solution was stirred in an ice bath for 5 min followed by addition of distilled Et 3N (3.47 g, 34.3 mmol, 1.7 eq uiv ). Tosylchloride (3.8 g, 20.0 mmol, 1.0 eq uiv ) was added. The solution mixture was stirred for 2 h in an ice bath. The reaction was quench ed with water. The organic layer was extracted with CH 2Cl2 (3&30 mL). The organic layer was separated and dried over Na 2SO4. The solvent was removed under reduced pressure to afford the crude product. Recrystalization of the crude product with EtOAc/hexane afford ed III-91 as a white solid in 75% yield. Melting point: 69 ,-72 ,. 1H NMR (500 MHz, CDCl 3), % 7.79 (d, 2H, J = 5.0 Hz), % 7.30 (d, 2H, J = 10.0 Hz), % 6.79 (d, 1H, J = 10.0 Hz), % 6.71 (d, 1H, J = 5.0 Hz), % 6.64 (dd, 1H, J = 5.0 Hz, 10.0 Hz), % 3.78 (s, 1H), % 2.44 (s, 3H), % 1.88 (s, 3H). 13C NMR (125 MHz, CDCl 3), % 158.28, 143.57, 136.78, 135.41, 129.50, 128.03, 127.21, 126.89,116.00, 111.78. 3-Phenyl -2-propyn -1-ol (396 mg, 3.3 mmol, 1 eq uiv ), triphenylphosphine (944 mg , 3.6 mmol, 1.1 eq uiv ) and freshly distilled THF (16 mL) were added to a round bottom flask, followed by compound III -91 (1.0 g, 3.6 mmol, 1.1 eq uiv ) and the mixture was stirred at the 0 , for 10 min. DIAD (728 mg, 3.6 mmol, 1.1 eq uiv ) was added into the mixture. The reaction was stirred at 0 , and gradually warmed to room temperature. After 2 h, the reaction was worked up with water (40 mL). The mixture was e xtract ed with EtOAc and the organic layer was dried with anhydrous Na 2SO4. The solids were f ilter ed and the HNOCH3CH3TsPhOH+1.1 equiv PPh 31.1 equiv DIAD THF, 0 ¼C to rt OCH3NTsPhH3CIII-91 III-52 210 solvent was removed under reduced pressure to afford a yellowish oil. The product was purified with column chromatography to yield III -52 as a colorless oil 668 mg (50% yield) . 1H NMR (500 MHz, CDCl 3) % 2.41 (s, 6 H), % 3.78 (s, 3H), % 4.36 (d, 2 H, J = 17.5 Hz), % 4.78 (d, 2H, J = 17.5 Hz), % 6.57 (dd, 1H, J = 3 Hz, 9 Hz), % 6.81 (d, 1H, J = 3 Hz), % 7.18 (dd, 2H, J = 1.5 Hz, 8 Hz), % 7.24 -7.29 (m, 5H), % 7.69 (d, 2H, J = 7.5 Hz ) . 13C NMR (125 MHz, CDCl 3), % 18.55, 21.43, 42.17, 55.21, 83.48, 85.15, 111.45, 116.11, 122.38, 128.09, 128.13, 128.31, 129.27, 129.72, 130.63, 131.35, 136.64, 141.21, 143.40, 159.36. HRMS (ESI) (m/z): [M+H] + calculated for [ C 24H24NO3S]+: 406.1477, found: 406.1478. 71% yield of III-48 was obtained using procedure abo ve, color less oil, R f = 0.62 (30% EtOAc in Hexane, UV) 1H NMR (500MHz, CDCl 3) % 7.59 (d, 2H, J = 8 Hz), % 7.24 -7.27(m, 3H), % 7.15 -7.20 (m, 6H), % 6.80 (d, 2H, J = 9 Hz), % 4.61 (s, 2H), % 3.78 (s, 3H), % 2.36 (s, 3H). 13C NMR (125 MHz, CDCl 3), % 21.49, 42.31, 55.39, 83.78, 85.47, 114.16, 122.41, 128.13, 128.16, 128.39, 129.21, 130.11, 131.46, 132.24, 136.09, 143.38, 159.31. HRMS (ESI) (m/z): [M+H] + calculated for [ C 23H22NO3S]+: 392.1320, found: 393.1322. OCH3NTsPhIII-48 211 3.4.3 General procedure of screening and optimization of ipso -halocyclization of substrate III-48 and III -52 Substrate III-52 (30 mg, 0.074 mmol, 1 eq uiv ) was dissolved in dr y solvent (1 mL) . The appropriat e catalyst (0.0074 mmol, 0.1 equiv) and the halogen source (0.074 mmol, 1 eq uiv ) were added. The reaction was stirred at the room temperature for the stated time , and work ed up with saturated Na 2S2O3. The organic layer was extracted with EtOAc and dried over anhydrous Na 2SO4. T he solvent was removed under t he reduced pressure to yield a wax like solid . X = Cl (III -53): 1H NMR (500 MHz, CDCl 3), % 2.01 (s, 3H ), % 2.44 (s, 3H ), % 4.46 (d, 1H, J = 15 Hz), % 4.58 (d, 1H, J = 15 Hz), % 6.05 (s, 1H), % 6.14 (dd, 1H, J = 10 Hz, 5 Hz), % 6.50 (d, 1H, J = 10 Hz), % 7.00 (d, 2H, J = 5 Hz), % 7.22 -7.33 (m, 5H), % 7.72 (d, 2H, J = 5 Hz) ; 13C NMR (125 MHz, CDCl 3), % 19.11, 21.58, 57.01, 75.05, 127.03, 127.67, 128.38, 128.51, 129.04, 129.26, 129.32, 129.77, 129.89, 135.16, 136.24, 144.35, 145.77, 156.75, 184.78. HRMS (ESI) (m/z): [M+H] + calculated for [C 23H21NO3SCl] +: 426.0931, found : 426.0927. The structure was further verified by X -ray crystallography : OCH3NTsPhH3CX+, catalyst solvent NXPhTsOIII-52 X=Cl, III-53 X=Br, III-56 X= I, III-92 212 Resolution of enantiomers: Daicel Chiralpak OD -H, 20% IPA/Hex, 1 mL/min; 2 54 nm, RT1= 10.6 min, RT2 = 15.2 min . X = Br (III -56): White solids, melting point: 170 -172 ,. 1H NMR (500 MHz, CDCl 3) % 2.01 (s, 3 H), % 2.44 (s, 3H), % 4.49 (d, 1H, J = 14 Hz), % 4.62 (d, 1H, J = 14 Hz), % 6.03 (s, 1H), % 6.13 (dd, 1H, J = 9.5 Hz, 2 Hz), % 6.49 (d, 1H, J = 10 Hz), % 6.83 (d, 2H, J = 8 Hz) % 7.22 -7.33 (m, 5H), % 7.72 (d, 2H, J = 8 Hz); 13C NMR (125 MHz, CDCl 3) % 19.14, 21.60, 59.09, 75.51, 116.49, 127.68, 128.35, 128.54, 129.23, 129.34, 129.79, 129.87, 130.04, 136.30, 138.50, 144.34, 145.56, 156.63, 184.77. HRMS (ESI) (m/z): [M+H] + calculated for [ C 23H21NO3SBr] +: 470.0426, found: 470.0397. Resolution of enantiomers: Daicel Chiralpak OD -H, 20% IPA/Hex, 1 mL/min; 2 54 nm, RT1= 10.3 min, RT2 = 14.8 min . X = I (III -92): White solids, melting point:190 -192 ,. 213 1H NMR (500 MHz, CDCl 3) % 2.01 (s, 3H), % 3.44 (s, 3H ), % 4.46 (d, 1H, J = 13 Hz ), % 4.61 ( d, 1H, J = 13 Hz), % 6.01 (s, 1H ), % 6.11 (dd, 1H, J =10 Hz, 2 Hz), % 6.46 (d, 1H, J = 10 Hz), % 6.90 ( d, 1H, J =8 Hz), % 7.25 -7.33 (m, 5H), % 7.72 (d, 2H, J = 8 Hz) . 13C NMR (125 MHz, CDCl 3) % 19.19, 21.60, 63.11, 75.54, 90.79, 127.66, 128.33, 128.60, 129.11, 129.33, 129.73, 129.79, 131.97, 136.38, 144.30, 144.75, 145.53, 156.68, 184.78. HRMS (ESI) (m/z): [M+H] + calculated for [ C 23H21NO3SI] +: 518.0287, found: 518.028 4. Resolution of enantiomers: Daicel Chiralpak OD -H, 15% IPA/Hex, 1 mL/min; 2 54 nm, RT1=22 min, RT2 = 36 min . X = Cl (III -49): 1H NMR (500 MHz, CDCl 3) % 7.75 (d, J = 8.3 Hz, 2H), 7.38 Ð 7.21 (m, 5H), 6.72 (d, J = 10.0 Hz, 2H), 6.15 (d, J = 10.0 Hz, 2H), 4.52 (s, 2H), 2.47 (s, 3H). 13C NMR (125 MHz, CDCl 3) % 184.34, 146.71, 144.49, 142.61, 135.81, 134.90, 129.83, 129.25, 129.11, 128.31, 127.91, 127.28, 72.28, 56.48, 21.64. HRMS (ESI) (m/z): [M+H] + calculated for [C 22H19NO3SCl]+: 412.0774 , found : 412.0764 . X = Br (III -50): 1H NMR (500 MHz, CDCl 3) % 7.75 (d, J = 8.3 Hz, 2H), 7.41 Ð 7.21 (m, 5H), 7.05 Ð 6.93 (m, 2H), 6.71 (d, J = 10.0 Hz, 2H), 6.14 (d, J = 10.1 Hz, 2H), 4.57 (s, 2H), 2.47 (s, 3H). 13C NMR (125 MHz, CDCl 3) % 184.28, 146.50, 144.47, 138.19, 135.85, 130.12, 129.83, 129.80, 129.23, 129.12, 128.26, 127.90, 116.63, 72.70, 58.51, 21.64. HRMS (ESI) (m/z): [M+H] + calculated for [C 22H19NO3SBr] +: 456.0269, found : 456.0266. NXPhTsO 214 X = I (III -51) : 1H NMR (500 MHz, CDCl 3) % 7.75 (d, J = 8.3 Hz, 2H), 7.43 Ð 7.21 (m, 5H), 7.00 Ð 6.89 (m, 2H), 6.69 (d, J = 10.0 Hz, 2H), 6.12 (d, J = 10.0 Hz, 2H), 4.56 (s, 2H), 2.47 (s, 3H). 13C NMR (125 MHz, CDCl 3) % 184.32, 146.50, 144.42, 144.33, 135.89, 132.07, 129.81, 129.65, 129.20, 129.19, 128.24, 1 27.90, 91.09, 72.68, 62.46, 21.64. HRMS (ESI) (m/z): [M+H] + calculated for [C 22H19NO3SI]+: 504.0130 , found : 504.0090 . 3.4.4 P rocedure of synthesis and ipso -halocyclization of substrate III-54 2-Bromo -4-methoxyphenol (950 mg, 4.7 mmol, 1 equiv ) and K 2CO3 (0.68 g, 4.9 mmol, 1 eq uiv ) was dissolved in distilled DMF (25 mL) , followed by adding phenyl propargyl bromide (1000 mg, 5.13 mmol, 1.1 equiv) . The reaction mixture was refluxed at 120 , for 1.5 h. The reaction was quenched with H 2O, and the mixture was extract ed with ethyl acetate. The organic layer was dried with anhydrous Na 2SO4. The solvent was removed under the reduced pressure to afford crude residue, which was then purified in column chromatography to yield III-54 as yellow oil in 81% yield . (This compound is stable on bench for more than 5 years!) Rf = 0.76 (30% EtOAc in Hex, UV) 1H NMR (500 MHz, CDCl 3 ) % 7.40 (dd, J = 7.6, 1.9 Hz, 2H), 7.34 Ð 7.25 (m, 3H), 7.16 Ð 7.05 (m, 2H), 6.81 (dd, J = 9.0, 3.0 Hz, 1H), 4.91 (s, 2H), 3.75 (s, 3H). OHBrOCH3PhBr+ 1 equiv K 2CO3DMF, 120 ¼C OBrOCH3PhIII-54 215 13C NMR (125 MHz, CDCl 3) % 154.93, 148.54, 131.77, 128.69, 128.29, 122.23, 118.77, 116.70, 113.71, 113.47, 87.58, 83.76, 58.91, 55.87. Compound III-54 (100.0 mg, 0. 3 mmol, 1 eq uiv ) was dissolved in acetonitrile (1 mL) . NaHCO 3 (50.4 mg, 0. 6 mmol, 2 eq uiv ) was added into the solution, followed by DABCO (33.7 mg, 0.0 3 mmol, 0.1 eq uiv ), and TCCA ( 139.4 mg, 0. 6 mmol, 2 eq uiv ). The reaction was s tirr ed at room temperature for the statetd time , the reaction was worked up with saturated Na 2S2O3. The mixture was e xtract ed with EtOAc and dr ied over the anhydrous Na2SO4, and the solvent was removed under reduced pressure to get a viscous yellow oil 105 mg (66% yield) . 1H NMR (500 MHz, CDCl 3), % 4.60 (d, 1H, J = 12.5 Hz), % 4.84 (d, 1H, J = 12.5 Hz), % 6.02 (s, 1H), % 6.87 (s, 1H), % 7.40 -7.41 (m, 5H). 13C NMR (125 MHz, CDCl 3), % 65.37, 77.63, 82.99, 90.86, 128.86, 128.93, 129.82, 129.92, 130.26, 130.85, 135.30, 145.58, 147.09, 148.45, 148.87, 176.82. The structure was verified by X -ray crystallography. OBrOCH3Ph2 equiv TCCA, 10 mol% DABCO 2 equiv NaHCO 3MeCN, rt ClClOONNNOOOClPhBrIII-54 III-55 216 Resolution of enantiomers: Daicel Chiralpak AD-H, 20% IPA/Hex, 1 mL/min; 2 50 nm, RT1= 9.9 min, RT2 = 10.2 min . 3.4.5 Synthesis and ipso -cyclization of substrate III -61 III-61 was synthesized with III-91 (1000 mg, 3.43 mmol) according to the reported procedure. 30 1.15g III-61 was obtained as yellow glue (81% yield). Rf =0.37 (UV, 30% EtOAc / Hex) 1H NMR (500 MHz, Chloroform -d) % 8.08 Ð 7.95 (m, 2H), 7.40 Ð 7.30 (m, 3H), 7.29 Ð 7.19 (m, 2H), 7.11 Ð 7.02 (m, 3H), 6.95 Ð 6.86 (m, 1H), 6.82 (dd, J = 8.7, 2.9 Hz, 1H), 3.87 (d, J = 0.9 Hz, 3H), 2.48 (s, 3H), 2.40 (s, 3H). 13C NMR (126 MHz, cdcl 3) % 160.66, 152.88, 145.31, 140.92, 13 5.69, 132.98, 131.31, 130.81, 129.46, 129.41, 128.45, 127.21, 119.25, 116.18, 112.20, 93.15, 81.64, 55.54, 21.75, 18.75. HNOCH3CH3TsPhOH+1.0 equiv DCC 0.1 equiv DMAP CH2Cl2 (0.2M) OCH3NTsPhH3COOIII-91 III-61 217 HRMS (ESI) (m/z): [M+H] + calculated for [ C 24H22NO4S]+: 420.1270 , found: 420.1273 . X = Cl (III -62): 1H NMR (500 MHz, CDCl 3) % 8.06 Ð 7.97 (m, 2H), 7.47 Ð 7.30 (m, 5H), 7.24 Ð 7.15 (m, 2H), 6.50 (d, J = 0.9 Hz, 2H), 6.35 Ð 6.25 (m, 1H), 2.46 (s, 3H), 1.96 (d, J = 1.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) % 184.26, 162.83, 152.26, 151.47, 146.27, 142.07, 135.03, 132.77, 131.36, 130.93, 129.84, 128.86, 128.79, 127.72, 127.67, 127.38, 71.29, 21.79, 18.21. HRMS (ESI) (m/z): [M+H] + calculated for [ C 23H19NO4SCl]+: 440.0723 , found: 440.0717 . Resolution of enantiomers: Daicel Chiralpak AD-H, 20% IPA/Hex, 1 mL/min; 2 50 nm, RT1= 13.7 min, RT2 = 15.2 min . X = Br (III -63): 1H NMR (500 MHz, Chloroform -d) % 8.10 Ð 7.96 (m, 2H), 7.50 Ð 7.29 (m, 5H), 7.21 Ð 7.10 (m, 2H), 6.50 (s, 2H), 6.30 (d, J = 1.7 Hz, 1H), 2.48 (s, 3H), 2.00 (d, J = 1.4 Hz, 3H). 13C NMR (126 MHz, cdcl 3) % 184.22, 163.37, 156.05, 151.32, 146.23, 141.81, 135.05, 132.71, 131.25, 130.83, 129.84, 128.85, 128.80, 128.73, 127.55, 118.41, 72.96, 21.81, 18.26. HRMS (ESI) (m/z): [M+H] + calculated for [ C 23H19NO4SBr]+: 484.0218 , found: 484.0237 . Resolution of enantiomers: Daicel Chir alpak IA, 20% IPA/Hex, 1 mL/min; 2 54 nm, RT1= 13.9 min, RT2 = 16.4 min . NXPhTsOO 218 X = I (III -64): 1H NMR (500 MHz, CDCl 3) % 8.03 (d, J = 8.4 Hz, 2H), 7.46 Ð 7.29 (m, 5H), 7.13 Ð 6.94 (m, 2H), 6.56 Ð 6.40 (m, 2H), 6.26 (t, J = 1.5 Hz, 1H), 2.47 (s, 3H), 2.00 (d, J = 1.4 Hz, 3H). 13C NMR (126 MHz, CDCl 3) % 184.26, 164.92, 162.40, 151.41, 146.16, 141.81, 135.06, 132.49, 130.99, 130.67, 130.59, 129.83, 128.88, 128.75, 127.41, 96.22, 74.96, 21.81, 18.31. HRMS (ESI) (m/z): [M+H] + calculated for [ C 23H19NO4SI]+: 532.0079 , found: 532.0091 . Resolution of enantiomers: Daicel Chiralpak IA, 20% IPA/Hex, 1 mL/min; 2 50 nm, RT1= 17.3 min, RT2 = 20.7 min . 219 3.4.6 Synthesis and ipso -cyclization of substrate III -72 III-93 was synthesizd according to reported procedure 31: Na (2.3 g, 100 mmol) was slowly added to MeOH (40 mL) . Once the evolution of H 2 gas had ceased, anisidine (2.46 g, 20 mmol) was added and the resulting hot solution was poured into a suspension of paraformaldehyde (840 mg, 28 mmol) in MeOH. The mixture was st irred at rt for 5 h and NaBH 4 (700 mg, 20 mmol) was added. The solution was heated under reflux and hydrolyzed with 1 M KOH solution (20 mL). Most of the MeOH was removed under reduced pressure and DCM was added to the residue. The organic layer was separa ted and the solvent was removed under reduced pressure to afford the crude. The crude was purified by column chromatography in silica gel with 15% EtOAc in Hexane as eluent. 820 mg of III-93 as white solid was obtained (30% yield). 1H NMR (500 MHz, CDCl 3) % 6.92 (td, J = 7.6, 1.4 Hz, 1H), 6.79 (dd, J = 8.0, 1.3 Hz, 1H), 6.69 (td, J = 7.7, 1.5 Hz, 1H), 6.62 (dd, J = 7.8, 1.5 Hz, 1H), 4.25 (s, 1H), 3.86 (s, 3H), 2.88 (s, 3H). 13C NMR (126 MHz, CDCl3) % 146.88, 139.38, 121.34, 116.28, 109.31, 109.21, 55.39, 30.39. NH2O 1) 5 equiv Na 1.4 equiv paraformaldehyde MeOH 2) NaBH 4NHOIII-93 220 III-94 was synthesized with III-93 (1.1 g, 8.02 mmol) followed the same procedure as III -61 described above. Ginger color solid was obtained in 83% yield . 1H NMR (500 MHz, Chloroform -d) % 7.39 (ddt, J = 9.2, 8.0, 1.4 Hz, 1H), 7.31 (ddt, J = 8.1, 6.1, 1.6 Hz, 2H), 7.26 Ð 7.16 (m, 2H), 7.10 (dt, J = 8.4, 1.6 Hz, 2H), 7.05 Ð 6.98 (m, 2H), 3.94 Ð 3.76 (m, 3H), 3.30 (d, J = 1.6 Hz, 3H). 13C NMR (126 MHz, cdcl 3) % 155.82, 155.12, 132.43, 132.42, 131.75, 129.76, 128.54, 128.27, 120.57, 120.56, 11 1.86, 89.28, 82.64, 55.68, 35.22. HRMS (ESI) (m/z): [M+H] + calculated for [ C 17H16NO2]+: 266.1181 , found: 266.1194 . To a solution of III-94 (770 mg, 2.9 mmol) in distilled dichloremethane (10 mL) was added a solution of BBr 3 (11.6 mmol, 1 M in DCM) at room temperature. The mixture was protected with Ar balloon. After completion, the reaction was quenched the reaction with H2O to hydrolize excess BBr 3 and boron complexes. The organic layer was extracted with dichloromethane. The solvent was removed under reduced pressure to give crude residue. The crude was purified with column chromatography (silica gel, 15% to 25% NHO+PhOHO1 equiv DCC 0.1 equiv DMAP CH2Cl2, 0 ¼C to rt NOOPh83%III-93 III-94 NOOPh4 equiv BBr 3CH2Cl2, rt NOHOPhIII-94 III-72 221 EtOAc /hexane) to give colorless crystals III-72 in 59% yield. M.P. = 108 -113 ¼C. R f = 0.24 (UV, 30% EtOAc in Hexane) amide cis/trans isomer mixture: 1H NMR (500 MHz, CDCl 3) % 7.65 Ð 7.60 (m, 1H), 7.51 Ð 7.39 (m, 1H), 7.36 Ð 7.29 (m, 1H), 7.29 Ð 7.13 (m, 5H), 7.13 Ð 6.93 (m, 6H), 6.83 (d, J = 12.8 Hz, 1H), 3.76 (s, 2H), 3.36 (s, 3H). 13C NMR (126 MHz, CDCl 3) % 156.09, 155.39, 153.44, 151.31, 13 2.63, 132.62, 130.60, 130.13, 129.94, 129.68, 129.26, 129.09, 128.62, 128.16, 125.51, 121.21, 120.08, 120.07, 119.85, 117.72, 93.48, 91.72, 82.07, 81.51, 40.26, 35.64. HRMS (ESI) (m/z): [M+H] + calculated for [ C 16H14NO2]+: 252.1025 , found: 252.1028 . The structure has been confirmed by X -ray crystallography: NOIPhOIII-74 222 brownish oil, R f = 0.12 ( UV, 30% EtOAc in Hexane) 1H NMR (500 MHz, CDCl3) % 7.44 Ð 7.30 (m, 3H), 7.23 Ð 7.13 (m, 2H), 6.93 (ddd, J = 9.9, 6.0, 1.7 Hz, 1H), 6.51 (dd, J = 9.4, 5.9 Hz, 1H), 6.19 Ð 6.07 (m, 2H), 2.84 (s, 3H). 13C NMR (126 MHz, CDCl3) % 194.36, 168.80, 157.28, 141.98, 136.94, 131.97, 129.78, 128.42, 127.65, 127.55, 127.10, 97.85, 77.90 , 27.54. HRMS (ESI) (m/z): [M+H] + calculated for [ C 16H13NO2I]+: 377.9991 , found: 378.0006 . Resolution of enantiomers: Daicel Chiralpak AD-H, 10% IPA/Hex, 1 mL/min; 2 50 nm, RT1= 18.4 min, RT2 = 22.2 min . 1H NMR (500 MHz, Chloroform -d) % 7.43 Ð 7.28 (m, 5H), 7.02 (ddd, J = 9.9, 6.0, 1.7 Hz, 1H), 6.56 (ddd, J = 9.4, 6.0, 0.8 Hz, 1H), 6.21 (dt, J = 9.9, 0.9 Hz, 1H), 6.14 (ddd, J = 9.4, 1.7, 0.9 Hz, 1H), 2.83 (s, 3H). 13C NMR (126 MHz, cdcl 3) % 194.35, 167.20, 150.88, 141.94, 137.20, 130.26, 129.94, 128.51, 127.68, 127.54, 127.21, 119.58, 75.23, 29.61. HRMS (ESI) (m/z): [M+H] + calculated for [ C 16H12NO2Br]+: 330.0130 , found: 330.0135 . Resolution of enantiomers: Daicel Chiralpak AD-H, 10% IPA/Hex, 1 mL/min; 2 50 nm, RT1= 16.2 min, RT2 = 19.1 min . NOOPhBrIII-73 NPhIOOOIII-81 223 dia stereomers mixture s: 1H NMR (500 MHz, Chloroform -d) % 7.77 Ð 7.67 (m, 2H), 7.58 Ð 7.40 (m, 4H), 7.41 Ð 7.25 (m, 6H), 7.17 (ddd, J = 8.3, 7.5, 1.7 Hz, 1H), 7.05 (td, J = 7.6, 1.3 Hz, 1H), 6.92 (ddd, J = 7.4, 5.7, 1.5 Hz, 2H), 6.81 (dd, J = 8.3, 1.3 Hz, 1H), 6.67 (td, J = 7.6, 1.2 Hz, 1H), 5.95 (s, 1H), 5.8 5 (s, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 3.25 (d, J = 5.2 Hz, 6H). 13C NMR (126 MHz, cdcl 3) % 190.96, 188.72, 166.06, 164.71, 154.86, 154.63, 133.44, 133.37, 133.29, 130.91, 130.90, 130.39, 130.30, 130.03, 129.08, 128.78, 128.75, 128.50, 128.42, 128.37, 121. 33, 112.13, 112.04, 55.82, 55.20, 37.84, 37.52, 28.60, 26.72. The structure was confirmed by X -ray crystallography: dia stereomers mixture s (ratio= 5:4) OAc OMe NOIPhIII-82 224 1H NMR (500 MHz, CDCl 3) % 7.46 Ð 7.28 (m, 7H), 7.26 Ð 7.12 (m, 2H), 6.15 (ddd, J = 9.8, 3.9, 1.4 Hz, 1H), 6.09 (ddd, J = 9.8, 3.4, 1.5 Hz, 1H), 5.81 (td, J = 4.0, 1.1 Hz, 1H), 5.57 (td, J = 3.7, 1.4 Hz, 1H), 5.48 (ddd, J = 18.1, 9.8, 1.2 Hz, 2H), 5.18 (dd, J = 4.2, 1.4 Hz, 1H), 5.12 (dd, J = 4.0, 1.5 Hz, 1H), 3.54 (d, J = 4.7 Hz, 5H), 2.86 (s, 3H), 2.78 (s, 3H), 2.07 (s, 3H), 1.93 (s, 2H). X-ray crystallography: 3.5 X -ray crystallography data 3.5.1 X -ray crystallography data of III-53 The following are 50% thermal ellipsoidal drawings of the molecule in the asymmetric cell with vario us amount of labeling: 225 This is a drawing of the packing along the a -axis: Crystal data and structure refinement for bb104 Identification code bb104 Empirical formula C23 H20 Cl N O3 S Formula weight 425.91 Temperature 173(2) K Wavelength 1.54178 † Crystal system Monoclinic Space group P 21/c Unit cell dimensions a = 13.1210(2) † " = 90¡. b = 17.7164(3) † # = 110.5720(10)¡ c = 9.7092(2) † $ = 90¡ Volume 2113.05(6) † 3 Z 4 Density (calculated) 1.339 Mg/m 3 Absorption coefficient 2.721 mm -1 226 F(000) 888 Crystal size 0.12 x 0.12 x 0.09 mm 3 Theta range for data collection 4.38 to 67.71¡. Index ranges -15<=h<=15, -21<=k<=20, -10<=l<=11 Reflections collected 12122 Independent reflections 3666 [R(int) = 0.0309] Completeness to theta = 67.71¡ 95.7 % Absorption correction Semi -empirical from equivalents Max. and min. transmission 0.7840 and 0.7325 Refinement method Full -matrix least -squares on F 2 Data / restraints / parameters 3666 / 0 / 264 Goodness -of-fit on F 2 1.135 Final R indices [I>2sigma(I)] R1 = 0.0479, wR2 = 0.1389 R indices (all data) R1 = 0.0569, wR2 = 0.1448 Largest diff. peak and hole 1.014 and -0.367 e.† -3 Experimental Section: A colorless needle crystal with dimensions 0.12 x 0.12 x 0.09 mm was mounted on a Nylon loop using very small amount of paratone oil. Data were collected using a Bruker CCD (charge coupled device) based diffractometer equipped with an Oxford Cryostream low -temperature apparatus operating at 173 K. Data were measured using omega and phi scans of 0.5¡ per frame for 30 s. The total number of images was based on results from the program COSMO 1 where redundancy was expected to be 4.0 and completeness to 0.83 † to 100%. Cell parameters were retrieved using APEX II software 2 and refined using SAINT on all observed reflect ions. Data reduction was performed using the SAINT software 3 which corrects for Lp. Scaling and absorption corrections were applied using SADABS 4 multi -scan technique, supplied by George Sheldrick. The structures are solved by the direct method using the S HELXS -97 and refined by least squares method on F 2, SHELXL - 97, 227 which are incorporated in SHELXTL -PC V 6.10. 5 The structure was solved in the space group P2 1/c (# 14 ). All non -hydrogen atoms are refined anisotropi cally. Hydrogens were calculated by geomet rical methods and refined as a riding model. The crystal used for the diffraction study showed no decompo sition during data collection. All drawings are done at 50% ellipsoids. Citation s: 1. COSMO V1.61, Software for the CCD Detector Systems for Determining Data Collection Parameters. Bruker Analytical X -ray Systems, Madison, WI (2009). 2. APEX2 V2010.11 -3. Software for the CCD Detector System ; Bruker Analytical X -ray Systems, Madison, WI (2010). 3. SAINT V 7.68A Software for the Integration of CC D Detector System Bruker Analytical X -ray Systems, Madison, WI (2010). 4. SADABS V2008/2 Program for absorption corrections using Bruker -AXS CCD based on the method of Robert Blessing ; Blessing, R.H. Acta Cryst. A51, 1995, 33 -38. 5. Sheldrick, G.M. "A sho rt history of SHELX". Acta Cryst . A64 , 2008, 112 -122. 228 3.5.2 X -ray crystallography data of III-55 The following are 50% thermal ellipsoidal drawings of the molecule in the asymmetric cell with various amount of labeling : This is a drawing of the packin g along the a -axis : 229 Crystal data and st ructure refinement Identification code bb105_0m Empirical formula C19 H12 Br Cl6 N3 O5 Formula weight 654.93 Temperature 173(2) K Wavelength 1.54178 † Crystal system Monoclinic Space group P 21/c Unit cell dimensions a = 15.67910(10) † " = 90¡. b = 10.46970(10) † # = 116.7272(1)¡. c = 16.93680(10) † $ = 90¡. Volume 2483.22(3) † 3 Z 4 Density (calculated) 1.752 Mg/m 3 Absorption coefficient 8.536 mm -1 F(000) 1296 Crystal size 0.19 x 0.11 x 0.09 mm 3 Theta rang e for data collection 5.14 to 67.94¡. Index ranges -18<=h<=17, -12<=k<=11, -20<=l<=20 Reflections collected 18304 Independent reflections 4480 [R(int) = 0.0264] Completeness to theta = 67.94¡ 99.0 % Absorption correction Semi -empirical from equivalents Max . and min. transmission 0.5272 and 0.2982 Refinement method Full -matrix least -squares on F 2 Data / restraints / parameters 4480 / 17 / 377 Goodness -of-fit on F 2 0.986 Final R indices [I>2sigma(I)] R1 = 0.0355, wR2 = 0.0938 R indices (all data) R1 = 0.0389, wR2 = 0.0968 Largest diff. peak and hole 0.899 and -1.018 e.† -3 Experimental: A colorless block crystal with dimensions 0.19 x 0.11 x 0.09 mm was mounted on a Nylon loop using very small amount of paratone oil. 230 Data were collected using a Bruker CCD (charge coupled device) based diffractometer equipped with an Oxford Cryostream low -temperature apparatus operating at 173 K. Data were measured using omega and phi scans of 0.5¡ per frame for 30 s. The total number of images was based on results from the program COSMO 1 where redundancy was expected to be 4.0 and compl eteness of 100% out to 0.83 †. Cell parameters were retrieved using APEX II software 2 and refined using SAINT on all observed reflections. Data reduction was performed using the SAINT software 3 which corrects for Lp. Scaling and absorption corrections were applied using SADABS 4 multi -scan technique, supplied by George Sheldrick. The structures are solved by the direct method using the SHELXS -97 program and refined by least squares method on F 2, SHELXL - 97, which are incorporated in SHELXTL -PC V 6.10. 5 The structure was solved in the space group P2 1/c (# 14). All non -hydrogen ato ms are refined anisotropically. Hydrogen atoms were found by difference Fourier methods and refined isotropically. The crystal used for the diffraction study showed no decompo sition during data collection. All drawings are done at 50% ellipsoids. Citations: 1. COSMO V1.61, Software for the CCD Detector Systems for Determining Data Collection Parameters. Bruker Analytical X-ray Systems, Madison, WI (2009). 2. APEX2 V2010.11 -3. Software for the CCD Detector System ; Bruker Analytical X -ray Systems, Madison, WI (2010). 3. SAINT V 7.68A Software for the Integration of CCD Detector System Bruker Analytical X -ray Systems, Madison , WI (2010). 231 4. SADABS V2.008/2 Program for absorption corrections using Bruker -AXS CCD based on the method of Robert Blessing; Blessing, R.H. Acta Cryst. A51, 1995, 33-38. 5. Sheldrick, G.M. "A short history of SHELX". Acta Cryst . A64 , 2008, 112 -122. 3.5. 3 X-ray crystallography data of III-82 The Model has Chirality at C1A (Polar SPGR) R Verify: The Model has Chirali ty at C7A (Polar SPGR) R Verify: The Model has Chirality at C1B (Polar SPGR) S Verify; The Model has Chirali ty at C7B (Polar SPGR) S V erify : ! 232 This is a drawing of the packing diagram : 233 Crystal data and st ructure refinement Compound BB315b Formula C19H18INO 4 Dcalc. / g cm -3 1.634 µ(mm-1!!1.768 Formula Weight 451.24 Colour colourless Shape chunk Max Size/mm 0.30 Mid Size/mm 0.20 Min Size/mm 0.18 T/K 173(2) Crystal System orthorhombic Flack Parameter -0.036(12) Hooft Parameter -0.027(12) Space Group Pna2 1 a/† 14.7594(7) b/† 15.5768(8) c/† 15.9589(8) "($!!90 #($!!90 $($!!90 V/† 3 3669.0(3) Z 8 Z' 2 %!"# ($!!1.827 %!$% ($!!25.379 Measured Refl. 29546 Independent Refl. 6736 Reflections Used 5996 Rint 0.0423 Parameters 457 Restraints 1 Largest Peak 1.199 Deepest Hole -0.395 GooF 1.057 wR2 (all data) 0.0841 wR2 0.0801 R1 (all data) 0.0396 R1 0.0342 234 Experimental Single crystals of C 23H17NO2Br2 were crystallized from [Chloroform] . A suitable crystal was selected and mounted on a nylon loop using Paratone Oil. The crystal was kept at 173.15 K during data collection. Data were collected using a Bruker APEX -II CCD (charge coupled device) based diffractometer equipped with an Oxford Cryostream low -temperature apparatus operating at 173 K. Data were me asured using omega and phi scans of 0.5¡per frame for 30 s. The total number of images was based on results from the program COSMO, 1 where redundancy was expected to be 4.0 and completeness to 0.83 † to 100%. Cell parameters were retrieved using APEX II so ftware=2 0 (I)] R1 = 0.0340, wR 2 = 0.0825 Final R indexes [all data] R1 = 0.0464, wR 2 = 0.0882 Largest diff. peak/hole / e † -3 1.53/ -0.73 Experimental Single crystals of C 46H34Br6N2O6S2 (III-57) were crystallized from DCM. A suitable crystal was selected and mounted on a nylon loop using Paratone Oil. The crystal was kept at 173.15 K during data collection. Data were collected using a Bruker APEX -II CCD (charge coupled device) based diffractometer equipped with an Oxford Cryostream low -temperature apparatus operating at 173 K. Data were measured using omega and phi scans of 0.5¡per frame for 30 s. The total number of images was based on results from the program COSMO, 1 where red undancy was expected to be 4.0 and completeness to 0.83 † to 100%. Cell parameters were retrieved using APEX II software 20:1 up to 86% yield up to 98% eePhOOPhPOOHNNClF2BF 4Selectfluor (R,R)-PhDAP IV-24 IV-25 258 Scheme 4.8 Sulfur -based fluorinating reagent s. XtalFluor -E¨ consists of a sulfur nitrogen double bond with a highly electron deficient sulfur atom, bearing two electronegative fluorine atoms. Indeed, this polarized bond is the key feature for its reactivity of activat ing oxygenated organic compounds towards substi tution reactions. In 2009 LÕHeureux and coworkers found that XtalFluor -E¨ is capable of performing deoxofluorinations of hydroxyls and carbonyls when promoted by an exogenous fluoride source (Scheme 4.9). 21 It is noteworthy that XtalFluor -E¨ alone cannot p erform deoxofluorination of carbonyls, whereas alcohols can be transformed to alkyl fluorides, albeit sluggishly. Mechanistically, XtalFluor -E¨ is an electrophile that leads to a reactive dialkylaminodifluorosulfane intermediate. 22 Since the reaction mixtu re is absent of fluoride, exogenous fluoride is required. In this context, XtalFluor -E¨ combined with other nucleophilic halogen sources have also been used for halogenation of primary alcohols (Scheme 4.9). 23 More recently Paquin and coworkers reported the eliminative deoxofluorination of cyclohexanone derivatives IV-26 using XtalFluor -E¨ (Scheme 4.9). 24 In this context, the ketone would get converted to fluoroalkoxy -N,N-diethylaminodifluorosulfane IV-27, whic h then undergo E 2 triggered by Et 3N. NSF3DAST NSF3MeO MeO Deoxo-Fluor NSF2BF4NOSF2BF4XtalFluor-E XtalFluor-M NSOOFPyFluor 259 Scheme 4.9 XtalFluor -E¨ as deoxofluorinating reagent . XtalFluor -E¨ has also been used for activation of hydroxyl, carboxylic acid 25 or carbonyl for further transformations. The commonality of these transformations is the activation of the oxygen with XtalFluor -E¨ into a good leaving group for the subsequent displacement reaction. PaquinÕs group reported a transition metal and Lewis acid -free Friedel -Crafts benzylation of aren es activated by XtalFluor -E¨ (Scheme 4.10). 26 Benzylic alcohol IV-29 reacts with XtalFluor -E¨ to generate an alkoxy -N,N-diethylaminodifluorosulfane, and ionization provides a stabilized ROHROHORRO1.5 equiv XtalFluor-E ¨1.5 equiv 3HF ¥TEA CH2Cl2RFRFORRFFROHNSBF4FFROSFFHNHFRF+SOFN+HFmechanism: ROHRX1.5 equiv XtalFluor-E ¨Et4N+X-X = I, Br or Cl deoxofluorination: halogenation:eliminative deoxofluorination: XOR3 equiv XtalFluor-E 3 equiv Et 3NrìHFDMA, rt, 16 h XFRXOFSEt2NFFREt3NE2IV-26 IV-28 IV-27 260 carbocation which is ready for electrophilic substitution. Similarly, they reported XtalFluor -E¨ promoted allylation of benzyl alcohol afterwards. 27 Scheme 4.10 XtalFluor -E¨ mediated benzylation . Moreover, XtalFuor -E¨ has been extensively used to activate aziridines for fluoride opening of the ring (Scheme 4.11). 28 Bicyclic compound IV-31 was treated with XtalFuor -E¨ to afford fluorinated ester containing an imidazolidinone ring system. They believed that the sulfonami de group activates the aziridine through neighboring group participation. Partially negatively polarized O of the sulfonamide attacks the S of XtalFuor -E¨ to form adduct IV-32 with the concomitant generation of a fluoride anion. Fluoride leads to nucleophilic aziridine ring opening intermediate IV-33, which then undergoes intramolecular acylation of N giving rise to bicyclic imidazolidinone product IV-35.!!ROH1.1 equiv XtalFluor-E 5 equiv p-xylene RArOHEt2NSF 2ArOSFFNEt 2! H+ArHHAr2-HArAr2OSFFNEt 2IV-29 IV-30 CH2Cl2-HFIP (9:1) rt, 4h 261 Scheme 4.11 XtalFluor -E¨ mediated aziridine opening . Looking deeply into the literature about XtalFluor -E¨ activation, in most cases, it has been used as reagent, however XtalFluor -E¨ as catalyst has rarely been reported. Here we developed a practical, straightforwar d synthesis of N-acetyl -N,O -acetals catalyzed by XtalFluor -E¨ (Scheme 4.12). We surmised addition of alcohol to XtalFluor -E¨ generates protons that can initiate the protonation of enamides. The protonated enamide can be intercepted by the excess nucleophil e to yield N,O -acetal products. SOONCO2EtBocHN NF2SSOONSNBocHN CO2EtFFSOONSNBocHN CO2EtFHSOONSNHNCO2EtFHFFOOtBuTsN NHHHOFCO2EtH2OTsN HHCO2EtNHBoc 4 equiv XtalFluor-E ¨nmTsN NHFHHOCO2Etmnmechanism IV-31 IV-35 IV-35 IV-32 IV-33 IV-31 IV-34 1,4-dioxane, heat 10 min 262 Scheme 4.12 XtalFluor -E¨ catalyzed hydroalkoxylation of enamides. 4.2 Results and discussion 4.2.1 Optimization for intermolecular hydroalkoxylation of enamide We commenced our study with phenyl substituted enamide IV-36. Our initial attempt of using stoichiometric amount of XtalFluor -E¨ with excess MeOH (10 equiv) renders quantatitive yield of hydromethoxylation product (Table 4.1, entry 1). However, the reaction became slower when only 10% XtalFluor -E¨ was applied, and led to lower yield (Table 4.1, entry 2). This might be due to the attenuated activity of the in situ generated proton in methanol, thus we resorted to aprotic solvents. A variety of aprotic solvents have been screened. Reaction is sluggish in toluene, and much faster in dichloromethane, chloroform, dichloroethane and nitromethane, albeit with 5% substrates remaining after extended time. Ultimately it was found that DCM -MeOH (1:1, v:v) co -solvent system furnished 98% yield in 8 h. Another aminodifluorosulfin ium tetrafluoroborates salt XtalFluor -M¨ also gave 86% yield, albeit with lower reaction rate. In case of alcohols with low molecular weight, the excess amount is not an issue since the remaining alcohol can be evaporated. It is noteworthy that reaction wa s sluggish when acids such as TFA were used as the catalyst instead of XtalFluor -E¨. NHXtalFluor-E ¨ (10-20 mol%) NuHORNHORNuNONONuNu = ROH, RSH 263 Table 4.1 Reaction condition optimization 4.2.2 The scope for intermolecular hydroalkoxylation of enamides To demonstrate the generality of the reaction, a handful of enamide substrates were synthesized and subjected to the reaction condition (Table 4.2). Gratifyingly, the reaction resulted in the corresponding N,O or N,S-acetals with nearly quantitative yield for most of the substrates. The electronic and steric influence of the aryl group on the reactivity of the enamide was screened, with minimal effect on the yield and efficiency of the reaction. Nevertheless, the p-methoxy benzoyl group generally gave bette r results. The transformation was equally effective with aliphatic enamides, delivering high yield of the N,O-acetal products. The reaction is not limited to secondary enamides, as cyclic -tertiary enamides resulted in products with excellent yield. Further more, the cyclic nature of the enamide did not diminish the reaction outcome. With regard to the nature of the protic nucleophile, PhONH XtalFluor-E ¨ (10 mol%) PhONHOMe entry solvent time (h) conversion (yield) aMeOH (10 equiv) 2345678MeOH 4888% (57%) Toluene 2274% (66%) 1095% (89%) CHCl3CH2Cl21093% (83%) Nitromethane 1095% (85%) ClCH2CH2Cl1095% (85%) Acetonitrile 2285% (68%) 9c3697% (86%) aYields were estimated by 1H NMR analysis of the crude reaction mixture. bOne equivalent of XtalFluor-E ¨ was used cXtalFluor-M ¨ (10 mol%) was used instead of XtalFluor-E ¨. dMeOH:DCM (1:1 v:v, 0.1 M) was used. e 20% mol TFA was used instead of XtalFluor-E ¨.CH2Cl210d8100% (>98%) CH2Cl21bMeOH 3699% (>98%) 11d,eCH2Cl23850%IV-36 IV-54 264 light alcohols can be used to successfully give the corresponding N,O-acetal products. Thiols also yield N,S-acetals with exc ellent yields ( IV-59, IV-60). The thiol mediated reactions typically proceed faster as compared to alcohols as nucleophiles. The reaction can also be performed on a large scale without deterioration in efficiency ( IV-55, trans ). The stereoisomerism of the starting enamide ( cis or trans ) had minimal effect on the reaction. Of note is the incompatibility of the methodology with bulky nucleophiles. As illustrated in Table 2, hydroalkoxylation of enamide with n-propyl alcohol results in high yield of IV-57, however the reaction is less efficient with iso -propyl alcohol ( IV-58). The reaction of enamide with tert -butyl alcohol failed to give any product. Substrate IV-51 is unreactive under this condition, which might be due to the steric hindrance of two meth yl groups on enamide. When the enamide is substituted by phenyl group, no reaction occurred as well ( IV-52 and IV-53). 265 Table 4.2 Substrates scope . 4.2.3 Mechanistic studies To propose a reasonable mechanism, we conducted a few control experiments. As reported by Paquin and coworkers, alcohols can react with XtalFluor -E¨ to give a non -reversible adduct. 22, 27 In our optimized reaction condition, catalytic XtalFluor -E¨ is exposed to protic nucleophiles in large excess. As a result, the R1ONHR2 XtalFluor-E ¨ (20 mol%) NuHDCMR1ONHR2ORMeO ONHORMeO ONHSRNHOOMe NHOOMe FNHOOMe MeO OHNOMe OHNOMe OHNOMe NOORNOOMe NOOMe IV-55 , R = Me, 98% (cis) IV-55 , R = Me, 85%(trans) cIV-56 , R = Et, 95% (cis) IV-57 , R = n-Pr, 80% (cis) IV-58 , R = i-Pr, 40% (cis) IV-59 , R = n-Pr, 98% (trans) IV-60 ,R = n-Bu, 85% (trans) IV-54 , 98% (trans) 95% (cis) MeNHOOMe IV-62 , 98%IV-63 , 91% (cis) 72% (trans) IV-64 , 60% (cis) IV-68 , 100%a (71%) IV-67 , 83%IV-65 , 86%IV-70 , R = Me, 94% IV-71 , R = Et, 98% IV-69 , 98%(trans) bIV-66 , 98%MeO ONHOMe IV-61 , 98% (cis )a yield was determined by 1H NMR using methyl- tert -butyl ether as internal standard; the rest of the reported yields were based on isolated products. b HFIP/MeOH(v/v, 9:1) was used as solvent. c reaction was performed at 1.0 mmol scale. NHOMeO NHOMeO PhIV-51 N.R.IV-52 N.R.NHOPhIV-53 N.R.PhIV-36 -IV-53 IV-54 -IV-71 266 formation of the p utative adduct and its implication on the reaction progress is obscured by the presence of excess nucleophile. To circumvent this issue, the reaction of IV-46 was conducted in the presence of only one equivalent of methanol and the loading of XtalFluor -E¨ was varied. As illustrated in Table 4.3 the yield of N,O-acetal product IV-66 decreases as XtalFluor -E¨ loading increases. At a 1:1 ratio of methanol:XtalFluor -E¨, no desired product was detected based on 1H NMR analysis albeit with all substrate consumed . The complete disappearance of the enamide IV-46 in the reaction with methanol and XtalFluor -E¨ (1 equiv each) is illustrative of the fact that the protonation of the enamaide most likely is taking place under this condition, however in the absence of free methanol the protonated enamide undergoes deleterious side reactions. This set of experiments does suggest the fo rmation of an adduct such as I, depicted in Scheme 4.13 (dashed box). Table 4.3 Control experiments with increasing loadings of XtalFluor -E¨. NOXtalFluor-E ¨MeOH (1.0 equiv) DCM, rt NOOentry XtalFluor-E (equiv) yield a12345b0.190%0.269%0.540%1.00%1.00%a Yield was estimated by 1HNMR analysis of the crude reaction mixture. b After 2 hours another 5 equivalents of methanol was added. IV-66 IV-46 267 Table 4.4 Control experiments of nucleophiles with different nucelophilicity and acidity . Since the nucleophile acts as the proton source in this reaction, we designed experiments to investigate the contribution of nucleophilicity as well as the acidity of the protic nucleophiles on the course of the reaction. As illustrated in Table 4.4 , compa ring reactions of the enamide IV-37 revealed that the reaction with sulfur -based nucleophiles is faster than oxygen -based nucleophiles (compare entries 1 and 2, Table 4.4 ). On the other hand, the acidity of the protic nucleophile proved to have minimal eff ect on the reaction progress i.e., benzoic acid, despite its higher acid ity, was an incompetent reagent. This can be interpreted by the weaker nucleophilicity of benzoic acid that prevents adduct formation with XtalFluor -E¨. This hypothesis is in accordanc e with the reported data that adduct formation of carboxylic acids with XtalFluor -E¨ requires the presence of a base. 25 The increased nucleophilicity of thiobenzoic acid in comparison resulted in the fast consumption of substrate and formation of the corre sponding product was observed. NHXtalFluor-E ¨ (10 mol%) NuH (10 equiv) OPhNHOPhNua Yield was estimated by 1H NMR analysis of the crude reaction mixture. b ~ 65% starting material was recovered. DCMentry 1234bNuHMeOH EtSH PhCOSH PhCOOH time (h) 1210.348yield (%) a>95 >95 >95 0IV-37 268 We also conducted NMR study to further understand the mechanism. Upon addition of methanol to a solution of XtalFluor -E¨ in d3-acetonitrile, substantial changes in the 19F NMR of the mixture were observed. XtalFluor -E¨ has two peaks in the 19F NMR that correspond to the fluorine atoms on the sulfur (12.9 ppm) and the tetrafluoroborate anion ( Ð151.6 ppm). Addition of one equivalent of methanol resulted in the disappearance of the peak at 12 ppm concomitant with the appearance of multiple peaks in the 50 Ð60 ppm range. Addition of two equivalents of methanol simplified the spectrum into a single peak at 54 ppm (see Figure 4.1 for NMR traces). This newly emerged peak did not undergo any further changes upon increasing the eq uivalents of methanol (up to 10 equivalents). These results further suggest the formation of the putative adduct I. Our experimental and NMR data, along with observations and mechanistic suggestions that have appeared in the literature, lead us to the mec hanistic proposal depicted in Scheme 4.13. We surmised that addition of an alcohol to XtalFluor -E¨ provides a catalytic proton source as the initial step of the reaction. The protonated enamide can be intercepted by the excess nucleophile to yield the protonated N,O-acetal product. This protonated N,O-acetal product can act as proton source to activate another enamide. Put ative complexes (shown in the dashed box, Scheme 4.13) can potentially collapse to generate tetrafluoroboric acid (HBF 4) and subsequently this acid can protonate the enamide. This suggest that HBF 4 itself should be able to catalyze this reaction. Indeed, w e find the latter statement is true (Table 4.5). 269 Figure 4. 1. 19F NMR spectrum of a) XtalFluor -E¨; b) XtalFluor -E¨ + 1 equiv MeOH; c) XtalFluor -E¨ + 2 equiv MeOH; d) XtalFluor -E¨ + 4 equiv MeOH; e) XtalFluor -E¨ + 5 equiv MeOH; f) XtalFluor -E¨ + 10 equiv MeOH (!#63.21 was from standard compound benzotrifluoride 1 equiv.) . 270 Scheme 4.13 Proposed mechanism 4.2.4 HBF 4 catalyzed hydroalkoxylation Based on our proposed mechanism, we believe that HBF 4, putatively generated from XtalFluor -E¨ and alcohol, is the species that catalyzes the reaction. To verify this, HBF 4¥OEt 2 (20 mol%) was used as the catalyst instead of XtalFluor -E¨ with different substrates. We observed comparable results to those obtained with XtalFluor -E¨. Most reactions with HBF 4OEt 2 proceeded faster than XtalFluor -E¨ catalyzed reactions. However, for some substrates yields are a bit lower than with XtalFluor -E¨ as catalysts since products are prone to decomposition under strong acidic condition s. RNHORNHORNHOXRHBF4BF4RXHNSBF4FFNSBF4FFXRHNSBF4FFXRHorNSHBF 4FFXR+X = O or S RNHOXRHBF 4+RXH12IIIIII 271 Table 4.5 Comparison of yields between XtalFluor -E¨ and HBF 4¥OEt 2 as catalys t. R1ONHR220 mol% catalyst DCM-MeOH (v/v 1:1) rt, 1h R1ONHR2OMe MeO ONHOMe MeNHOOMe NHOOMe MeO NHOOMe NHOOMe FOHNOMe NOOMe NOOMe OHNOMe ONHMeO OXtalFluor-E ¨ aHBF 4¥OEt 2 asubstrate entry 198982919839870495985609968675794988988398383109864cis cis cis cis trans cis a isolated yield of N,O-acetal products nBu 272 4.2.5 Study of intramolecular hydroalkoxylation In addition to the intermolecular hydroalkoxylation, intramolecular hydroalkoxylation has also been evaluated ( Table 4.6 ). Unsaturated amide IV-72 was subjected to catalytic amount of XtalFluor -E¨ in DCM at ambient temperature, after 20 h only 4% conversion was observed. However, when stoichiometric amount of XtalFluor -E¨ was used, 80% yield of lactam product was obtained a fter 24 h. For primary alcohol substrate IV-74, cyclized product bearing a tetrahydrofuran ring was obtained in 94% yield when 10 mol% XtalFluor -E¨ was used. The external alcohol reagent MeOH seems not to affect the reaction outcome. Other unsaturated amid e IV-76 and allyl amine IV-77 did not give desired cyclized products even in the presence of stoichiometric amount of XtalFluor -E¨. Table 4.6 Intramolecular cyclization mediated by XtalFluor -E¨ MeO NHOPhXtalFluor-E ¨(x mol%) DCM, rt MeO NPhOentry conversion a (yield) b124%100% (80%) XtalFluor-E 10 mol% 100 mol% MeO OHXtalFluor-E ¨(10 mol%) DCM, rt MeO OMeOH (x equiv) entry conversion a (yield) b12100% (93%) 100% (94%) a yield was estimated by 1H NMR analysis of the crude reaction mixture. b isolated yield. 100MeOH (equiv) time (hours) 186IV-72 IV-73 IV-74 IV-75 273 Scheme 4.14 Other attempts for intramolecular cyclization . 4.2.6 Attempts of constructing C -N/C -C bond mediated by XtalFluor -E¨ As an extension of the C -O/S bond formation, we next endeavored to build C -N bonds with chemistry mediated by XtalFluor -E¨. Substrate IV-38 was treated with excess n-butylamine in DCM w ith 20 mol% XtalFluor -E¨, however no reaction occurred. We ascribed this to the fact that the generated acid would protonate the amine first, and thus there is no more acid to activate the enamide for further reaction. Scheme 4.15 Attempts at c onstructi ng a C-N bond . Besides constructing a C -heteroatom bond, we also attempted to construct more challenging C -C bond using XtalFluor -E¨ as catalyst. We chose a strong nucleophile, allyltributylsilane, which usually reacts with a variety of cationic carbon ele ctrophiles and is used with Lewis acids. Different Lewis acids and solvent combinations have been tested, however, either benzamide formed as a result of substrate decomposition or no reaction occurred. NHPh O1 equiv. XtalFluor-E DCM (0.1M) cat. MeOH r.t., 23 h 90% substrate recovered 1 equiv. Xtalfluor-E DCM (0.1M) r.t., 3 days NHTs39% converison, messy products IV-76 IV-77 ONHODCM (0.1M) rt, 12 h 20 mol% XtalFluor-E NH2N.R.10 equiv. IV-38 274 Scheme 4.16 Attempts at constructing a C-C bond . 4.2.7 Summary We developed a mild and simple method for the generation of protons from the reaction of XtalFluor -E¨ with a protic solvent. Reaction of enamides under the prescribed conditions lead to the protofunctionalization of olefins, yielding N,O -acet als or N,S -acetals. The N,O /N,S -acetal products can be accessed in nearly quantatitive yield in most cases, often without need for further purification. XtalFluor -E¨ is commercially available and the water -soluble side product can be removed easily. Constr ucting C -N or C -C bonds using XtalFluor -E¨ could be our future endeavors. Also, combining XtalFluor -E¨ with other chiral catalysts to construct C -O bond enantioselectively is also our interest. MeO ONH20 mol% XtalFluor-E 5 equiv. TMSOTf HFIP-DCM(1:1, 0.1M), rt 2h20 mol% XtalFluor-E 1 equiv. KF DCM( 0.1M), rt 2hN.R.20 mol% XtalFluor-E 1 equiv. KF HFIP( 0.1M), rt 2hN.R.MeO ONH220 mol% XtalFluor-E 1 equiv. MeOH DCM( 0.1M), rt 36 hMeO ONHO90%(nBu) 3Sn4 equiv. 4 equiv. (nBu) 3Sn(nBu) 3Sn4 equiv. (nBu) 3Sn4 equiv. IV-38 275 4.3 Experimental section 4.3.1 General information All reagents were purchased from commercial sources and were used without purification. XtalFluor -E¨ and N-vinylcaprolactam were purchased from Aldrich. N-vinyl -2-pyrrolidone was purchased from Combi -Blocks. TLC analyses were performed on silica gel plate s (pre -coated on glass; 0.20 mm thickness with fluorescent indicator UV254) and were visualized by UV or charred in PMA stains. 1H and 13C NMR spectra were collected on 500 MHz NMR spectrometers (Agilent) using CDCl 3. Chemical shifts are reported in parts per million (ppm) and are referenced to residual solvent peaks. Flash silica gel (32 -63 $ m, Silicycle 60 †) was used for column chromatography. All known compounds were characterized by 1H and 13C NMR and are in complete agreement with samples reported els ewhere. All new compounds were characterized by 1H and 13C NMR, HRMS, and melting point (where appropriate). 4.3.2 General p rocedure A for screening and optimization A 5 mL vial equipped with a magnetic stir bar was charged with the substrate (0.1 mmol, 1 equiv.) and XtalFluor -E¨ (20 mol%). The mixture was dissolved with freshly distilled dichloromethane (0.5 mL) and alcohol (0.5 mL). The vial was flushed with argon and sealed. The reaction was stirred at ambient temperature for 1 -24 h. The reaction was then quenched with saturated Na 2SO3 and extracted with dichloromethane. The combined organics were dried over anhydrous Na 2SO4 and filtered. Conversions were calculated by 1H NMR. Pure product was isolated by column chromatography on silica gel 276 or aluminum o xide (activated, neutral) as stationary phase (EtOAc in Hexanes as gradient). 4.3.3 Analytical data for products General procedure A was used with 19.1 mg (0.1 mmol) of IV-38 yielding 21.8 mg (98 %) of IV-55; 19.1 mg (0.1 mmol) of IV-39 yielding 19 mg ( 85%) of IV-55. white solids; M.P.: 66 - 70 ¼C ; Rf: 0.23 (30% EtOAc in Hexane, UV) . 1H NMR (500 MHz, CDCl 3) ! 7.74 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 9 Hz, 2H), 6.17 (d, J = 9.5 Hz, 1H), 5.24 (tt, J = 5 Hz, 13 Hz, 1H), 3.83 (s, 3H), 3.37 (s, 3H), 1.76 (m, 1H), 1.63 (m, 1H), 0.96 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl 3) ! 167.2, 162.5, 128.8, 126.2, 113.8, 82.7, 56.0, 55.4, 28.8, 9.2 . HRMS analysis (ESI): calculated for (M+Na): C 12H17NO3Na 246.11 06; found: 246.1113 General procedure A was used with 19.1 mg (0.1 mmol) of IV-38 yielding 22.5 mg (95 %) of IV-56 as a clear oil. ONHONHO 20 mol% Xtalfluoro-E ¨ MeOH:DCM(1:1) (0.1 M) rtOOIV-38 orIV-55 ONHOIV-39 IV-38 ONHONHO 20 mol% XtalFluoro-E ¨EtOH:DCM (1:1) (0.1 M) rt, 24 h OOIV-56 277 Rf: 0.33 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.76 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 9 Hz, 2H), 6.2 (d, J = 9 Hz, 1H), 5.36 (m 1H), 3.86 (s, 3H), 3.70 (m, 1H), 3.57 (m, 1H), 1.78 (m, 1H), 1.66 (m, 1H), 1.20 (t, J = 7 Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl 3) ! 166.8, 162.4, 128.8, 126.2, 113.8, 81.2, 63.8, 55.4, 29.1, 15.2, 9.3 . HRMS analysis (E SI): calculated for (M+Na): C 13H19NO3Na 260.1263; found: 260.1270 General procedure A was used with 19.1 mg (0.1 mmol) of IV-38 yielding 20 mg (80 %) of IV-57 as a clear oil. Rf: 0.29 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) ! 7.74 (d, J = 9 Hz, 2H), 6.92 (d, J = 9 Hz, 2H), 6.17 (d, J = 9 Hz, 1H), 5.34 (m, 1H), 3.85 (s, 3H), 3.59 (m, 1H), 3.47 (m, 1H), 1.79 (m, 1H), 1.71 -1.56 (m, 3H), 0.99 (t, J = 7.5 Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl 3) ! 166.7, 162.4, 128.8, 126.3, 113.8, 81.4, 70.2, 55.4, 29.1, 22.9, 10.6, 9.4 HRMS analysis (ESI): calculated for (M+Na): C 14H21NO3Na 274.1419; found: 274.1425 20 mol% Xtalfluoro-E ¨ONHONHOn-PrOH:DCM (1:1) (0.1 M) rt, 28 h OOIV-38 IV-57 278 General procedure A was used with 19.1 mg (0.1 mmol) of IV-38 yielding 20 mg (40 %) of IV-58 as a clear oil. Rf: 0.41 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.73 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.19 (d, J = 9.4 Hz, 1H), 5.43 Ð 5.35 (m, 1H), 3.87 (dt, J = 12.3, 6.1 Hz, 1H), 3.83 (s, 3H), 1.75 Ð 1.66 (m, 1H), 1.67 Ð 1.58 (m, 1H), 1.19 (d, J = 6.0 Hz, 3H), 1.13 (d, J = 6.2 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 166.57, 162.38, 128.77, 126.36, 113.82, 79.32, 69.22, 55.45, 29.48, 23.52, 21.70, 9.45. HRMS analysis (ESI): calculated for (M+Na): C 14H21NO3Na 274.1419; found: 274.1420 General procedure A was used with 19.1 mg (0.1 mmol) of IV-39 yielding 29 mg (98%) of IV-59 as a wax. Rf: 0.43 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.73 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.12 (d, J = 9.8 Hz, 1H), 5.30 (ddd, J = 9.8, 7.3, 6.3 Hz, 1H), 3.83 (s, 3H), 2.64 (ddd, J = 12.7, 8.0, 20 mol% Xtalfluoro-E ¨ONHONHOi-PrOH:DCM (1:1) (0.1 M) rt, 9 h OOIV-38 IV-58 ONHONHS 20 mol% XtalFluoro-E ¨n-PrSH:DCM (1:1) (0.1 M) rt, 2 h OOIV-39 IV-59 279 6.0 Hz, 1H), 2.46 (ddd, J = 12.8, 8.2, 6.9 Hz, 1H), 1.86 Ð 1.69 (m, 2H), 1.69 Ð 1.52 ( m, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 166.20, 162.35, 128.71, 126.19, 113.82, 56.00, 55.44, 32.80, 29.59, 23.11, 13.53, 10.86. HRMS analysis (ESI): calculated for (M+Na): C 14H21NO2SNa 290.1191; found: 290.1197 General procedure A was used with 19.1 mg (0.1 mmol) of IV-39 yielding 20 mg (85 %) of IV-60 as a white solid. white solids; M.P.: 75 - 80 ¼C Rf: 0.52 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.73 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.09 (d, J = 9.8 Hz, 1H), 5.31 (ddd, J = 9.8, 7.3, 6.3 Hz, 1H), 3.83 (s, 3H), 2.65 (ddd, J = 12.7, 8.3, 6.0 Hz, 1H), 2.49 (ddd, J = 12.7, 8.4, 6.7 Hz, 1H), 1.87 Ð 1.69 (m, 2H), 1.64 Ð 1.48 (m, 2H), 1.34 (ddq, J = 13.9, 8.8, 7.2 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 166.19, 162.35, 128.69, 128.69, 126.22, 113.82, 56.04, 55.44, 31.83, 30.49, 29.59, 21.99, 13.63, 10.86. HRMS analysis (ESI): calculated for (M+Na): C 15H23NO2SNa 304.1347; found: 304.1362 ONHONHS 20 mol% XtalFluoro-E ¨n-BuSH:DCM (1:1) (0.1 M) rt, 2 h OOIV-39 IV-60 ONHONHO 20 mol% XtalFluoro-E ¨MeOH:DCM (1:1) (0.1 M) rt, 5 h OOIV-41 IV-62 280 General procedure A was used with 18 mg (0.102 mmol) of IV-41 yielding 21 mg (98 %) of IV-62 as a clear oil. Rf: 0.13 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.76 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.25 (d, J = 9.5 Hz, 1H), 5.49 (dd, J = 9.5, 5.8 Hz, 1H), 3.85 (s, 4H), 3.39 (s, 3H), 1.43 (d, J = 5.9 Hz, 4H). 13C NMR (125 MHz, CDCl 3) % 166.67, 162.45, 128.83, 126.09, 113.81, 78.17, 55.78, 55.43, 21.82. HRMS analysis (ESI): calculated for (M+Na): C 11H15NO3Na 232 .0950; found: 232.0954 General procedure A was used with 17.5 mg (0.1 mmol) of IV-42 yielding 18.9 mg (9% ) of IV-63; 17.5 mg (0.1 mmol) of IV-43 yielding 14.9 mg (72%) of IV-63. Yellowish solid, M.P.: 56 - 63 ¼C Rf: 0.35 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.71 Ð 7.67 (m, 2H), 7.28 Ð 7.18 (m, 2H), 6.22 (d, J = 9.7 Hz, 1H), 5.26 (dtd, J = 9.8, 6.1, 1.8 Hz, 1H), 3.38 (d, J = 1.4 Hz, 3H), 2.38 (s, 2H), 1.77 (dddd, J = 13.7, 7.6, 6.1, 1.5 Hz, 1H), 1.67 Ð 1.57 (m, 1H), 0.97 (td, J = 7.5, 1.4 Hz , 3H). 13C NMR (125 MHz, CDCl 3) % 167.44, 142.35, 131.10, 129.30, 126.96, 82.73, 56.01, 28.83, 21.47, 9.22. HRMS analysis (ESI): calculated for (M+Na): C 12H17NO2Na 230.1157; found: 230.1154 ONHONHO 20 mol% XtalFluoro-E ¨MeOH:DCM (1:1) (0.1 M) rt, 5 h ONHorIV-42 IV-43 IV-63 281 General procedure A was used with 16.1 mg (0.1 mmol) of IV-36 yielding 18.4 mg (95 %) of IV-54; 16.1 mg (0.1 mmol) of IV-37 yielding 18.9 mg (9 8%) of IV-54; Rf: 0.71 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.81 Ð 7.71 (m, 2H), 7.55 Ð 7.47 (m, 1H), 7.43 (dd, J = 8.2, 6.9 Hz, 2H), 6.26 (d, J = 9.6 Hz, 1H), 5.26 (dt, J = 9.6, 6.2 Hz, 1H), 3.39 (s, 3H), 1.78 (ddd, J = 14.0, 7.7, 6.5 Hz, 1H), 1.65 (ddd, J = 14.0, 7.7, 6.5 Hz, 1H), 0.98 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 167.56, 134.01, 131.85, 128.67, 126.97, 82.83, 56.06, 28.82, 9. 21. HRMS analysis (ESI): calculated for (M+Na): C 11H15NO2Na 216.1000; found: 216.1004 General procedure A was used with 17.9 mg (0.1 mmol) of IV-44 yielding 14.2 mg (67 %) of IV-64 as a clear oil. Rf: 0.53 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 8.06 (td, J = 7.9, 1.9 Hz, 1H), 7.47 (dddd, J = 8.3, 7.2, 5.2, 1.9 Hz, 1H), 7.27 Ð 7.21 (m, 1H), 7.11 (ddd, J = 12.1, 8.2, 1.1 Hz, 1H), 6.77 (d, J = 12.4 Hz, 1H), 5.29 (dddd, J = 9.0, 6.1, 6.1, 2.7 Hz, 1H), 3.39 (s, 3H), 1.76 (dddd, J = 14.9, 13.5, 7.5 , 7.5, 6.0 Hz, 1H), 1.73 Ð 1.62 (m, 1H), 0.97 (t, J = 7.5 Hz, 3H). ONHONHO 20 mol% XtalFluoro-E ¨MeOH:DCM (1:1) (0.1 M) rt, 48 h IV-36 IV-54 ONHIV-37 orONHONHO 20 mol% XtalFluoro-E ¨MeOH:DCM (1:1) (0.1 M) rt, 48 h FFIV-44 IV-64 282 13C NMR (125 MHz, CDCl 3) % 163.56 (d, J = 2.9 Hz), 161.59, 159.62, 133.60 (d, J = 9.3 Hz), 132.17 (d, J = 2.2 Hz), 124.88 (d, J = 3.2 Hz), 116.11 (d, J = 24.8 Hz), 82.77, 56.05, 28.68, 9.01. HRMS analysis (ESI): calculated for (M+Na): C 11H14NO2FNa 234.0906; found: 234.0904 General procedure A was used with 20 mg (0.202 mmol) of IV-48 yielding 18.8mg (71 %) of IV-68 as a clear oil. Rf: 0.08 (30% EtOAc in Hexane, dye with PMA) 1H NMR (500 MHz, CDCl 3) % 5.70 (s, 1H), 5.32 Ð 5.12 (m, 1H), 3.29 (d, J = 1.3 Hz, 2H), 2.21 (q, J = 7.6, 2H), 1.29 (dd, J = 5.9, 1.3 Hz, 3H), 1.14 (td, J = 7.6, 1.2 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 173.79, 77.47, 55.60, 29.77, 21.57, 9.68. HRMS analysis (ESI): calculated for (M+Na): C 6H13NO2Na 154.0844; found: 154.0843 General procedure A was used with 25 mg (0.2 mmol) of IV-49 yielding 31 mg (98 %) of IV-69 as a clear oil. Rf: 0.09 (30% EtOAc in Hexane, dye with PMA) 1H NMR (500 MHz, CDCl 3) % 5.05 (t, J = 6.9 Hz, 1H), 3.34 (dt, J = 9.9, 6.9 Hz, 1H), 3.27 (dt, J = 9.9, 7.2 Hz, 1H), 3.24 (s, 3H), 2.51 Ð 2.37 (m, 2H), 2.09 Ð 1.94 (m, 2H), 1.82 Ð 1.65 (m, 2H), 1.60 Ð 1.42 (m, 2H), 0.88 (t, J = 7.5, 3H). 20 mol % XtalFluoro-E ¨10 equiv. MeOH DCM (0.2 M) rt, 3.5 h HNOHNOOIV-48 IV-68 NO 20 mol% XtalFluoro-E ¨HFIP-MeOH (v/v, 9:1, 0.2 M) rt, 4 h NOOIV-49 IV-69 283 13C NMR (125 MHz, CDCl 3) % 176.27, 83.80, 55.62, 40.83, 31.68, 25.55, 18.26, 9.25. HRMS analysis (ESI): calculated for (M+Na): C 8H15NO2Na 180.1000; found: 180.1000 General procedure A was used with 22.2 mg (0.2 mmol) of IV-50 yielding 26.8 mg (100 %) of IV-70 as a clear oil. Rf: 0.14 (30% EtOAc in Hexane, dye with PMA) 1H NMR (500 MHz, CDCl 3) % 5.28 (q, J = 6.1 Hz, 1H), 3.37 Ð 3.24 (m, 2H), 3.18 (d, J = 1.1 Hz, 3H), 2.47 Ð 2.34 (m, 2H), 2.08 Ð 1.89 (m, 2H), 1.27 (dd, J = 6.1, 1.1 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 175.74, 78.77, 55.41, 40.73, 31.68, 18.67, 18.09. HRMS analysis (ESI): calculated for (M+Na): C 7H13NO2Na 166.0844; found: 166.0844 General procedure A was used with 22.2 mg (0.2 mmol) of IV-50 yielding 31 mg (100 %) of IV-71as a clear oil. Rf: 0.14 (30% EtOAc in Hexane, dye with PMA) 1H NMR (500 MHz, CDCl 3) % 5.40 (q, J = 6.1 Hz, 1H), 3.42 Ð 3.27 (m, 4H), 2.41 (td, J = 8.2, 1.7 Hz, 2H), 2.00 (p, J = 7.7 Hz, 2H), 1.27 (s, 2H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 175.55, 77.18, 63.14, 40.83, 31.71, 18.88, 18.07, 14.98. HRMS analysis (ESI): calculated for (M+Na): C 8H15NO2Na 180.1000; found: 180.0996 NO20 mol% XtalFluor-E ¨DCM:MeOH(v/v, 1:1, 0.2 M) rt, 5 h NOOIV-50 IV-70 NO20 mol% XtalFluor-E ¨DCM:EtOH(v/v, 1:1, 0.2 M) rt, 5 h NOOIV-50 IV-71 284 General procedure A was used with 31 mg (0.22 mmol) of IV-46 yielding 37 mg (98 %) of IV-66 as a clear oil. Rf: 0.15 (30% EtOAc in Hexane, dye with PMA) 1H NMR (500 MHz, CDCl 3) % 5.71 (q, J = 6.1 Hz, 1H), 3.30 (ddd, J = 15.4, 7.7, 1.7 Hz, 1H), 3.23 Ð 3.07 (m, 4H), 2.56 (ddd, J = 13.8, 10.3, 1.8 Hz, 1H), 2.47 (ddd, J = 13.8, 9.3, 1.6 Hz, 1H), 1.78 Ð 1.43 (m, 6H), 1.20 (d, J = 6.1 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 176.66, 80.78, 55.47, 40.83, 37.73, 30.09, 29.32, 23.59, 19.13. HRMS analysis (ESI): calculated for (M+Na): C 9H17NO2Na 194.1157; found: 194.1160 General procedure A was used with 22.6 mg (0.2 mmol) of IV-47 yielding 24 mg (83 %) of IV-67 as a colorless oil. Rf: 0.30 (30% EtOAc in Hexane, dye with PMA) 1H NMR (500 MHz, CDCl 3) % 5.86 Ð 5.68 (m, 1H), 5.26 (dq, J = 9.6, 5.4 Hz, 1H), 3.29 (d, J = 1.1 Hz, 3H), 2.43 Ð 2.24 (m, 1H), 1.30 (dd, J = 5.9, 1.0 Hz, 3H), 1.15 (ddd, J = 12.8, 7.0, 1.0 Hz, 6H). 13C NMR (125 MHz, CDCl 3) % 177.12, 77.40, 55.49, 35.78, 21.55, 19.73, 19.35. HRMS analysis (ESI): calculated for (M+Na): C 7H15NO2Na 168.1000 found: 168.1002 NOONO20 mol% XtalFluor-E ¨DCM:MeOH(v/v, 1:1, 0.2 M) rt, 5 h IV-46 IV-66 ONH20 mol% XtalFluor-E ¨DCM:MeOH(v/v, 1:1, 0.2 M) rt, 5 h ONHOIV-47 IV-67 285 General procedure A was used with 25.4 mg (0.2 mmol) of IV-45 yielding 27.4 mg (86 %) of IV-65 as a clear oil. Rf: 0.26 (30% EtOAc in Hexane, dye with PMA) 1H NMR (500 MHz, CDCl 3) % 5.76 (d, J = 9.6 Hz, 1H), 5.27 (dq, J = 9.5, 5.9 Hz, 1H), 3.30 (d, J = 0.9 Hz, 3H), 2.19 (t, J = 7.6 Hz, 2H), 1.67 Ð 1.46 (m, 2H), 1.32 (dd, J = 19.5, 6.7 Hz, 5H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 173.18, 77.44, 55.59, 36.59, 27.64, 22.37, 21.60, 13.77. HRMS analysis (ESI): calculated for (M+Na): C 8H17NO2Na 182.1157; found: 182.1156 General procedure A was used with 23.3 mg (0.1 mmol) of IV-40 yielding 26.5 mg (100 %) of IV-61 as a clear oil. Rf: 0.39 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.80 Ð 7.70 (m, 2H), 6.96 Ð 6.84 (m, 2H), 6.17 (d, J = 9.7 Hz, 1H), 5.31 (dt, J = 9.7, 6.2 Hz, 1H), 3.83 (s, 4H), 3.37 (s, 3H), 1.82 Ð 1.64 (m, 1H), 1.50 Ð 1.31 (m, 1H), 1.32 Ð 1.23 (m, 6H), 0.86 (q, J = 6.9, 5.5 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 166.90, 162.45, 128.82, 126.18, 113.83, 81.61, 55.96, 55.45, 35.81, 31.53, 24.60, 22.5 4, 14.00. HRMS analysis (ESI): calculated for (M+Na): C 15H23NO3Na 288.1576; found: 288.1574 ONH20 mol% XtalFluor-E ¨DCM:MeOH(v/v, 1:1, 0.2 M) rt, 5 h ONHOIV-45 IV-65 ONH20 mol% XtalFluor-E ¨DCM:MeOH(v/v, 1:1, 0.1 M) rt, 24 h MeO ONHMeO OIV-40 IV-61 286 Rf: 0.86 (30% EtOAc in Hexane, dye with PMA) 1H NMR (500 MHz, CDCl 3) % 7.32 Ð 7.28 (m, 2H), 6.86 Ð 6.82 (m, 2H), 4.00 Ð 3.94 (m, 1H), 3.91 Ð 3.84 (m, 1H), 3.78 (d, J = 0.7 Hz, 3H), 2.19 Ð 2.11 (m, 1H), 2.02 Ð 1.90 (m, 2H), 1.79 (dt, J = 7.2, 0.8 Hz, 1H), 1.49 (d, J = 0.7 Hz, 3H). 13C NMR (125 MHz, CDCl 3) % 158.05, 140.24, 1 25.81, 113.38, 83.98, 67.44, 55.23, 39.43, 29.76, 25.76. HRMS analysis (ESI): calculated for (M+ H): C 12H17O2 193.1229; found: 193.1227 Rf: 0.26 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.33 Ð 7.19 (m, 4H), 7.16 (t, J = 7.4 Hz, 1H), 7.04 (dd, J = 7.4, 1.6 Hz, 2H), 6.95 Ð 6.87 (m, 2H), 3.82 (s, 3H), 2.76 Ð 2.63 (m, 1H), 2.63 Ð 2.53 (m, 1H), 2.26 (dd, J = 9.5, 6.3 Hz, 2H), 1.68 (s, 3H). 13C NMR (125 MHz, CDCl 3) % 175.06, 158.75, 136.94, 136.85, 128.61, 126.76, 126.36, 126.33, 113.94, 67.20, 55.29, 38.19, 30.27, 26.11. HRMS analysis (ESI): calculated for (M+Na): C 18H19NO2Na 304.1313; found: 304.1315 OOMe MeO OH10 mol% XtalFluor-E !DCM (0.1 M) R.TIV-74 IV-75 NOMe MeO HN1equiv. XtalFluor-E !DCM (0.1 M) R.TOPhOPhIV-72 IV-73 287 4.3.4 General procedure for synthesis of unsaturated amides and analytical data General procedure B: The appropriate aryl chloride (1 equiv) was dissolved in freshly distilled dichloromethane (15 mL) at room temperature. K 2CO3 (1 equiv) was added in one portion to the solution at 0 ¡C. After stirring for 5 min, allylamine (3 equiv) was added in one portion. The reaction mixture was stirred for 2 h and gradually warmed to room temperature. The reaction was quenched with addition of H 2O, the organic layer was separated and washed with dichloromethane. The combined organic fraction was dried over Na 2SO4, and concentrated in vacuo. The residue was purif ied by silica gel chromatography (25% EtOAc in Hexane). The purified allyl amide product was used in the next step. Freshly distilled i-Pr2NH (2.2 equiv) was dissolved in anhydrous THF (0.3 M) and the solution was cooled down to Ð78 ¡C. n-BuLi (2.5 M in he xane, 2.2 equiv) was added dropwise to the solution. After stirring for 15 min, allyl amide (1 equiv) in anhydrous THF was added dropwise to the LDA solution at Ð78 ¡C. The reaction mixture was warmed to room temperature gradually. After 1 h, saturated NH 4Cl solution was added to work up the reaction. The organics were separated and dried over Na 2SO4. The organic fraction was concentrated under vacuo and the residue was purified by silica gel column chromatography (15% EtOAc in Hex). ClO3 equiv allylamine 1 equiv. K 2CO3DCM, rt, 2 h NHO2.2 equiv LDA THFÐ78¡ C, 1hNHO+NHORRRRIV-36 -IV-39 , IV-42 -IV-44 288 General procedure B was used with 2 .0 g (12.5 mmol) of benzoyl chloride yielding 1.1 g (55%) of IV-36 and 600 mg (30%) of IV-37 as a white solid. For IV-36: White solid, M.P.: 68 - 73 ¼C Rf: 0.72 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.81 Ð 7.74 (m, 2H), 7.59 (d , J = 9.6 Hz, 1H), 7.55 Ð 7.48 (m, 1H), 7.47 Ð 7.39 (m, 2H), 6.92 (ddq, J = 10.8, 8.9, 1.8 Hz, 1H), 4.97 Ð 4.87 (m, 1H), 1.69 (dd, J = 7.1, 1.8 Hz, 3H). 13C NMR (126 MHz, CDCl 3) % 164.30, 133.98, 131.92, 128.75, 126.99, 122.24, 106.08, 10.99. HRMS analysis (ESI): calculated for (M+H): C 10H12NO 162.0919; found: 162.0920 For IV-37: White solid, M.P.: 92 - 97 ¼C Rf: 0.51 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.86 Ð 7.72 (m, 2H), 7.63 (s, 1H), 7.54 Ð 7.39 (m, 3H), 6.94 (ddq, J = 14.0, 10.4, 1.7 Hz, 1H), 5.29 (dq, J = 13.6, 6.7 Hz, 1H), 1.72 (dd, J = 6.7, 1.7 Hz, 3H). 13C NMR (126 MHz, CDCl 3) % 164.16, 133.84, 131.78, 128.67, 126.95, 123.55, 108.79, 14.97. HRMS analysis (ESI): calculated for (M+H): C 10H12NO 162.0919; found: 162.0920 ONHIV-36 ONHIV-37 289 General procedure B was used with 2 .0 g (11.72 mmol) of p-MeObenzoyl chloride yielding 560 mg (26%) of IV-38 and 630 mg (28%) of IV-39 after 2 steps as a white solid. For IV-38: white solids; M.P.: 70 - 75 ¼C Rf: 0.38 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.78 Ð 7.72 (m, 2H), 7.54 (d, J = 10.4 Hz, 1H), 6.96 Ð 6.88 (m, 3H), 4.94 Ð 4.80 (m, 1H), 3.83 (s, 3H), 1.68 (dd, J = 7.1, 1.7 Hz, 3H). 13C NMR (126 MHz, CDCl 3) % 163.79, 162.49, 128.88, 126.13, 122.38, 113.91, 105.46, 55.44, 10.97. HRMS ana lysis (ESI): calculated for (M+H): C 11H14NO2 192.1025; found: 192.1025 For IV-39: white solids; M.P.: 122 -125 ¼C Rf: 0.33 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.76 Ð 7.70 (m, 2H), 7.66 (d, J = 10.4 Hz, 1H), 6.94 (dq, J = 12.5, 1.7 Hz, 1H), 6.91 Ð 6.86 (m, 2H), 5.26 (dq, J = 13.6, 6.7 Hz, 1H), 3.82 (s, 3H), 1.70 (dd, J = 6.7, 1.7 Hz, 3H). 13C NMR (126 MHz, CDCl 3) % 163.71, 162.37, 128.85, 126.02, 123.73, 113.82, 108.17, 55.42, 14.98. HRMS analysis (ESI): calculated for ( M+H): C 11H14NO2 192.1025; found: 192.1028 ONHOONHOIV-38 IV-39 290 General procedure B was used with 1.5 g (11.72 mmol) of p-Mebenzo yl chloride yielding 937 mg (56 %) of IV-42 and 468 mg (28 %) of IV-43 after 2 steps as a white solid. For IV-42: white solid, M.P.: 54 -58 ¼C Rf: 0.58 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.67 (d, J = 7.9 Hz, 3H), 7.20 (d, J = 7.8 Hz, 2H), 6.88 (ddd, J = 11.0, 8.9, 2.1 Hz, 1H), 4.92 Ð 4.83 (m, 1H), 2.36 (s, 3H), 1.67 (dd, J = 7.0, 1.9 Hz, 3H). 13C NMR (126 MHz, CDCl 3) % 164.33, 142.40 , 131.06, 129.33, 127.04, 122.31, 105.89, 21.47, 10.99. HRMS analysis (ESI): calculated for (M+H): C 11H14NO 176.1075; found: 176.1073 For IV-43: white solid, M.P.: 117 - 122 ¼C Rf: 0.47 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl 3) % 7.98 (d, J = 10.3 Hz, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 6.91 (t, J = 12.2 Hz, 1H), 5.29 (dq, J = 13.6, 6.7 Hz, 1H), 2.35 (s, 3H), 1.68 (d, J = 6.7 Hz, 3H). 13C NMR (126 MHz, CDCl 3) % 164.31, 142.18, 130.94, 129.23, 127.08, 123.71, 108.62, 21.4 6, 14.99. HRMS analysis (ESI): calculated for (M+H): C 11H14NO 176.1075; found: 176.1073 ONHONHIV-42 IV-43 291 General procedure B was used with 1 .0 g (6.3 mmol) of o-fluorobenzo yl chloride yielding 332 mg (29 %) of IV-44 after 2 steps as a colorless crystal. colorless crystal, M.P.: 30 - 35 ¼C Rf: 0.77 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 8.32 (s, 1H), 8.15 (tt, J = 8.0, 1.4 Hz, 1H), 7.53 Ð 7.45 (m, 1H), 7.28 (td, J = 7.6, 1.1 Hz, 1H), 7.14 (ddd, J = 12.6, 8.3, 1.2 Hz, 1H), 6.97 (m, 1H), 5.00 Ð 4.87 (m, 1H), 1.69 (dd, J = 7.1, 1.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) % 161.72, 160.09 (d, J = 3.7 Hz), 159.76, 133.77 (d, J = 9.7 Hz), 132.39 (d, J = 1.9 Hz), 125.06 (d, J = 3.2 Hz), 122.01, 116.06 (d, J = 25 Hz) , 106.82, 11.01. HRMS analysis (ESI): calculated for (M+H): C 10H11NOF 180.0825; found: 180.0826 General procedure C: Freshly distilled N-vinyl formamide (1 equiv), Et 3N (1.2 equiv), DMAP (5 mol%) and anhydrous THF (1M) were added to a round bott om flask. The resulting mixture was cooled to 0 ¡C. Acyl chloride (1.2 equiv) was then slowly added and the mixture was stirred at 0 -5 ¡C for 2 h, 5N NaOH solution was added at 0 ¡C and the solution was stirred for another 2 h. Organic layers were separated and dried over Na 2SO4 and concentrated under vacuo. The residue was isolated by silica gel column chromatography. NHOFIV-44 ROCl+HONH1. Et 3N, THF, 5 mol% DMAP 2. NaOHRONHIV-41 , R = 4-OMeC 6H4, 58%IV-48 , R = Et, 29% IV-47 , R = i-Pr, 59% IV-45 , R = n-Bu, 17% 292 General procedure C was used with 543 mg (7.64 mmol) of N-vin ylformamide yielding 788 mg (58 %) of IV-41 as a white solid. White so lid, M.P.: 76 - 83 ¼C Rf: 0.32 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 8.42 (d, J = 10.5 Hz, 1H), 7.83 Ð 7.70 (m, 2H), 7.21 Ð 7.06 (m, 1H), 6.88 Ð 6.78 (m, 2H), 4.76 (d, J = 15.8 Hz, 1H), 4.43 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H). 13C NMR (126 MHz, CDCl3) % 164.47, 162.54, 129.29, 129.19, 125.62, 113.80, 95.88, 55.40. HRMS analysis (ESI): calculated for (M+Na): C 10H11NO2Na 200.0687; found: 200.0679 General procedure C was used with 668 mg (9.4 0 mmol) of N-vinylformamide and propanoy l chloride 1 g (10.8 0 mmol) yielding 120 mg (29 %) of IV-48 as a purplish liquid. Rf: 0.30 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 9.23 (s, 1H), 6.50 (ddd, J = 15.9, 8.8, 0.6 Hz, 1H), 5.42 (dd, J = 15.9, 0.7 Hz, 1H), 5.35 Ð 5.24 (m, 1H), 2.66 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) % 171.90, 128.72, 95.17, 29.42, 9.50. NHOMeO IV-41 NHOIV-48 293 HRMS analysis (ESI): calculated for (M+H): C 5H10NO 100.0762; found: 100.0754 General procedure C was used with 600 mg (8.44 mmol) of N-vinylformamide and iso -butyryl chloride 1.03 g (9.70 mmol) yielding 563 mg (59 %) of IV-47 as a white solid. White solid, M.P.: 40 Ð 45 ¼C Rf: 0.47 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 7.19 (d, J = 47.1 Hz, 1H), 6.97 (ddd, J = 15.8, 10.8, 8.7 Hz, 1H), 4.58 (d, J = 15.8 Hz, 1H), 4.37 (d, J = 8.7 Hz, 1H), 2.37 (p, J = 6.9 Hz, 1H), 1.16 (d, J = 7.0 Hz, 6H). 13C NMR (126 MHz, CDCl3) % 174.39, 128.78, 94.90, 35.56, 19.35. HRMS analysis (ESI): calculated for (M+H): C 6H12NO 114.0919; found: 114.0918 Gen eral procedure C was used with 1.0 g (14.1 0 mmol) of N-vinylformamide and valeroyl chloride 1.95 g (1 6.20 mmol) yielding 310 mg (17 %) of IV-45 as a white solid. White solid, M.P.: 41 Ð 45 ¼C Rf: 0.44 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 7.07 Ð 6.89 (m, 3H), 4.56 (dd, J = 15.8, 0.8 Hz, 1H), 4.36 (dd, J = 8.2, 0.8 Hz, 1H), 2.25 Ð 2.14 (m, 2H), 1.68 Ð 1.55 (m, 2H), 1.34 (h, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H). NHOIV-47 ONHIV-45 294 13C NMR (126 MHz, CDCl3) % 170.98, 128.64, 94.66, 36.38, 27.42, 22.36, 13.77. HRMS analysis (ESI): calculated for (M+H): C 7H14NO 128.1075; found: 128.1063 (E)-1-(prop -1-en-1-yl)pyrrolidin -2-one IV-49 was synthesized according to the reported literature. 29 Rf: 0.20 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 6.85 (dq, J = 14.3, 1.9 Hz, 1H), 4.97 Ð 4.84 (m, 1H), 3.45 (dd, J = 8.6, 5.9 Hz, 2H), 2.44 (td, J = 8.1, 3.3 Hz, 2H), 2.11 Ð 1.98 (m, 2H), 1.69 (dt, J = 6.5, 1.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) % 172.61, 124.31, 106.83, 45.22, 31.23, 17.40, 15.19. HRMS analysis (ESI): calculated for (M+H): C 7H12NO 126.0919; found: 126.0921 1-iodoh exyne was synthesized accord to reported literature procedure in quantitative yield. 30 1-iodohexyne (1.15 g, 5.53 mmol) was dissolved in methanol (10 mL) and pyridine (1.65 mL), followed by adding potassium diazodiimide (2.7 g, 13.8 mmol) with vigorous stiring. Acetic acid (1.66 g) was added via syringe to the reaction mixture dropwise at room temperature. The reaction was followed by GC. A fter 8 h 15% of the hexyne was observed via GC. To the reaction 0.5 equiv of potassium diazodiimide and 1 equiv of NHOO+Dean-Stark reflux 0.5 mol% p-TsOH toluene (0.5 M), 130 ¡C NOIV-49 I2.5 equiv KCO 2NNCO2K5 equiv AcOH 7.5 equiv pyridine MeOH, rt IOONH220 mol% CuI 2 equiv CsCO 340 mol% DMEDA THF, 70 ¼C, 12 h NHOMeO IV-40 (Z)-1-iodohex-1-ene 295 AcOH were added. Aq. HCl (5%, 20 mL) was added and the mixture was extracted with Et2O. The organics were washed with brine, dried over Na 2SO4 and the solvents were removed in vacuo. The residue was purified through a flash column of SiO 2 (100% hexane). A pale yellow liquid 604 mg was isolated as (Z) -1-iodohex -1-ene (52% yield). The enamide substrate IV-40 was synthesized accord to reported li terature. 31 An oven -dried 25 mL screw -cap seal tube equipped with a Teflon -coated magnetic stir bar was charged with (Z) -1-iodohex -1-ene (540 mg, 2.57 mmol, 1 equiv), p-methoxybenzamide (466 mg, 3.08 mmol, 1.2 equiv), CuI ( 98 mg, 0.514 mmol, 20 mol%), and Cs2CO3 (1.67 g, 5.14 mmol, 2 equiv). The tube was then evacuated and backfilled with argon. DMEDA ( 91 mg, 1.03 mmol, 40 mol%) was added into the tube followed by anhydrous THF (10 mL) via a syringe. The sealed tube was placed in a preheated oil bath (70 ¡C). After stirring at the same temperature for 12 h, the reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through a thin layer of celite and washed by EtOAc. The filtrate was concentrated in vacuo. The crude residu e was purified by flash chromatography, 402 mg IV-40 was given as oil in 67% yield. Rf: 0.46 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 7.80 Ð 7.71 (m, 2H), 7.71 Ð 7.17 (m, 1H), 7.01 Ð 6.81 (m, 3H), 4.89 Ð 4.73 (m, 1H), 3.83 (s, 3H), 2.08 (qd, J = 7.2, 1.7 Hz, 2H), 1.53 Ð 1.28 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H). NHOnBuMeO IV-40 296 13C NMR (126 MHz, CDCl3) % 163.80, 162.46, 128.87, 126.14, 121.27, 113.89, 111.74, 55.42, 31.49, 25.55, 22.33, 13.94. HRMS analysis (ESI): calculated for (M+H): C 14H20NO2 234.1494; found: 234.1497 4-(4-methoxyphenyl)pent -4-enoic acid was synthesized via Wittig reaction according to reported procedure. 32 To 4-(4-methoxyphenyl)pen t-4-enoic acid (1 mmol, 206 mg) in freshly distilled dichloromethane (5 mL) was added DMAP (1 .4 mmol, 171 mg) and N,N' -dicyclohexylcarbodiimide (1.3 mmol, 268 mg) sequentially at 0 ¡C. After stirring for 5 min at 0 ¡C, aniline (1.2 mmol, 1.1 mL) was added in one portion. After 8 h, reaction was quenched with 1N HCl solution (2 mL) and H 2O ( 5 mL). The reaction was extracted with DCM three times and the organic portion was dried with Na 2SO4. The organic portion was concentrated under reduced pressure to afford crude residue. The product was purified via flash column (silica gel, 15% EtOAc in Hexane) to afford IV-72. Rf: 0.41 (30% EtOAc in Hexane, UV) 1H NMR (500 MHz, CDCl3) % 7.47 Ð 7.42 (m, 2H), 7.37 Ð 7.32 (m, 2H), 7.31 Ð 7.25 (m, 2H), 7.19 (s, 1H), 7.07 (tt, J = 7.3, 1.1 Hz, 1H), 6.89 Ð 6.83 (m, 2H), 5.24 (s, 1H), 5.02 (s, 1H), 3.79 (s, 3H), 2.94 Ð 2.87 (m, 2H), 2.47 (dd, J = 8.4, 6.8 Hz, 2H). 13C NMR (126 MHz, CDCl3) % 170.62, 159.27, 146.13, 137.83, 132.57, 128.96, 127.27, 124.21, 119.76, 113.85, 112.03, 55.31, 36.49, 31.14. MeO OHOMeO HNOPh1.2 equiv. aniline 1.4 equiv. DMAP 1.3 equiv. DCC DCM (0.2M) 0 ¼C to r.t. IV-72 297 HRMS analysis (ESI): calculated for (M+H): C 18H20NO2 282.1494; found: 28 2.1506 1H NMR (500 MHz, CDCl3) % 7.37 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.24 (d, J = 1.5 Hz, 1H), 5.02 (d, J = 1.4 Hz, 1H), 3.82 (s, 3H), 3.66 (t, J = 6.4 Hz, 2H), 2.64 Ð 2.52 (m, 2H), 1.80 Ð 1.67 (m, 2H), 1.61 (s, 1H). 13C NMR (126 MHz, CDCl3) % 159.04, 147.19, 133.33, 127.17, 113.66, 111.02, 62.42, 55.27, 31.58, 31.18. 4.4 Acknowledgement Thanks are due to Dr Gholami who worked as a wonderful originator and collaborator in this project. I had a lot of helpful discussions with him. He als o did a lot of work for preparing the paper for publication. Cheers Man! MeO OHIV-74 298 REFERENCES 299 REFERENCES 1. Grigoropoulou, G.; Clark, J. H.; Elings, J. A., Recent developments on the epoxidation of alkenes using hydrogen peroxide as an oxidant. Green Chemistry 2003, 5 (1), 1 -7. 2. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B., Catalytic Asymmetric Dihydroxylation. 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