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Methodology for natural product synthesis : sordarin, himandrine and lepadiformine Liang, Huan 2009

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METHODOLOGY FOR NATURAL PRODUCT SYNTHESIS: SORDARIN, HIMANDRINE AND LEPADIFORMINE  by HUAN LIANG B.Sc., Tianjin University, 2003  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  October 2009 © HUAN LIANG, 2009  Abstract  Fungal infection, of small concern in healthy individuals, can become problematic in immunosuppressed patients with illnesses such as AIDS, and the search for substances that exert antifungal action by new mechanisms continues. A noteworthy group of potent antimycotic natural products known as the sordarins meet this criterion. In order to investigate the effect of various functional and skeletal changes to sordarin on antipathogenic activity, we have devised practical, expeditious, and efficient routes to analogs of the natural product. The bioactivity of the new compounds against various pathogenic fungi was evaluated. This research constitutes the first half of my doctoral dissertation.  The second half of my work centers on the development of a practical method for the oxidative amidation of phenols. This reaction achieves the conversion of phenols into spirocyclic (sulfon)amido-dienones. The new methodology forms the centerpiece of envisioned syntheses of (±)-himandrine and (-)-lepadiformines. Himandrine, isolated from the bark of Galbulimima belgraveana, displays anticholinergic activity and is thus of potential interest for the treatment of a number of human ailments. Our himandrine skeleton synthesis centered on a tandem oxidative amidation and Diels-Alder reaction, using three different approaches. The alkaloid (-)-lepadiformines displays potency as a potassium channel blocker. Our synthetic study towards this substance utilizes the oxidative cyclization of a phenolic sulfonamide as the key step. The resulting dienone is then desymmetrized through a stereoselective Michael addition leading to an enantiopure tricyclic intermediate, to which hydrocarbon side chain was appended in high yield. Further elaboration will lead to the natural product.  ii  Table of Contents  Abstract .................................................................................................................................. ii Table of Contents .................................................................................................................. iii List of Tables ......................................................................................................................... xx List of Figures ......................................................................................................................xxi List of Schemes ...................................................................................................................xxxi List of Abbreviations ........................................................................................................ xxxv Acknowledgements ..........................................................................................................xxxix 1. INTRODUCTION .............................................................................................................. 1 1.1 Sordarin and its derivatives ............................................................................................ 1 1.1.1 Isolation, structure and bioactivity .......................................................................... 1 1.1.2 Semisynthetic analogs of sordarin........................................................................... 3 1.1.3 Previous total syntheses of sordarin and its congeners ........................................... 5 1.1.4 Previous synthesis of sordarin analogs in our laboratory ........................................ 8 1.2 Background information of himandrine ....................................................................... 11 1.2.1 Structure and biology activity ............................................................................... 11 1.2.2 Previous syntheses of himandrine and its analogs ................................................ 12 1.3 Background information of lepadiformines ................................................................. 16 1.3.1 Isolation and bioactivity ........................................................................................ 16 1.3.2 Previous total syntheses of lepadiformine A ......................................................... 17 2. SYNTHETIC STUDIES OF SORDARIN, HIMANDRINE, LEPADIFORMINE AND METHODOLOGY THEREOF ................................................................................. 23 2.1 Sordarin analogs via an intramolecular Diels-Alder reaction. ..................................... 23 iii  2.1.1 Retrosynthesis of sordarin analogs ........................................................................ 23 2.1.2 Model study of sordarin analog ............................................................................. 24 2.1.3 Synthesis of sordarin analogs ................................................................................ 26 2.2 Oxidative amidation of phenols ................................................................................... 38 2.2.1 Bimolecular oxidative amidation of phenols ........................................................ 39 2.2.2 Intramolecular oxidative amidation of phenols ..................................................... 48 2.3 Synthetic study of himandrine analogs ........................................................................ 63 2.3.1 Retrosynthesis of hiamdrine skeletons .................................................................. 63 2.3.2 Synthesis of himandrine skeletons ........................................................................ 64 2.4 Synthetic study of (-)-lepadiformines .......................................................................... 80 2.4.1 Retrosynthetic analysis of lepadiformines ............................................................ 80 2.4.2 Practical synthesis of L-homotyrosinol methanesulfonamide............................... 81 2.4.3 Synthetic study towards (-)-lepadiformines and its derivatives ............................ 86 REFERENCES ..................................................................................................................... 94 APPENDICES ..................................................................................................................... 106 A. EXPERIMENTAL PROTOCOLS ............................................................................... 106 B. SORDARIN EXPERIMENTAL SECTION ................................................................ 108 B.1 Synthesis and characterization of various sordarin intermediates ............................. 108 B.1.1 Preparation of 3-methoxycyclopent-2-enone (127) ............................................ 108 B.1.2 Preparation of methyl 4-methoxy-2-oxocyclopent-3-enecarboxylate (128) ...... 108 B.1.3 Preparation of methyl 4-methoxy-2-oxo-1-(3-oxopropyl)cyclopent-3enecarboxylate (129) ........................................................................................ 109 B.1.4 Preparation of methyl 1-(4-cyano-3-hydroxypent-4-enyl)-4-methoxy-2oxocyclopent-3-ene carboxylate (130) ............................................................. 110 iv  B.1.5 Preparation of cycloadduct 132 .......................................................................... 110 B.1.6 Preparation of 2-isopropyl-3-methoxycyclopent-2-enone (134) ........................ 111 B.1.7 Preparation of 4-carbomethoxy-2-isopropyl-3-methoxycyclopent-2-en-1-one (141) ................................................................................................................. 111 B.1.8 Preparation of methyl 3-isopropyl-2-methoxy-4-oxo-1-(3-oxopropyl)cyclopent-2enecarboxylate (142) ........................................................................................ 112 B.1.9 Preparation of methyl 1-(4-cyano-3-hydroxypent-4-enyl)-3-isopropyl-2-methoxy4-oxocyclopent-2-enecarboxylate (143) .......................................................... 113 B.1.10 Preparation of cycloadduct 145 ........................................................................ 113 B.1.11 Preparation of cycloadduct 146 ........................................................................ 114 B.1.12 Preparation of compound 147........................................................................... 115 B.1.13 Preparation of alcohol 148 ................................................................................ 115 B.1.14 Preparation of diketone 149 .............................................................................. 116 B.1.15 Preparation of methyl 1-(3-(tert-butyldimethylsilyloxy)-4-cyanopent-4-enyl)-3isopropyl-2-methoxy-4-oxocyclopent-2-enecarboxylate (153) ....................... 117 B.1.16 Preparation of methyl 1-(3-(tert-butyldimethylsilyloxy)-4-cyanopent-4-enyl)-2cyano-3-isopropyl-4-oxocyclopent-2-enecarboxylate (154) ............................ 118 B.1.17 Preparation of methyl 1-(3-(tert-butyldimethylsilyloxy)-4-cyanopent-4-enyl)-2cyano-4-hydroxy-3-isopropylcyclopent-2-enecarboxylate (162) .................... 119 B.1.18 Preparation of methyl 1-(3-(tert-butyldimethylsilyloxy)-4-cyanopent-4-enyl)-2cyano-3-isopropylcyclopenta-2,4-dienecarboxylate (158)............................... 119 B.1.19 Preparation of methyl 6-(tert-butyldimethylsilyloxy)-3,7-dicyano-2-isopropyl-1oxo-1,3a,4,5,6,7,8,8a-octahydroazulene-3a-carboxylate (165)........................ 120  v  B.1.20 Preparation of methyl 4-(tert-butyldimethylsilyloxy)-1-(3-(tert-butyl dimethyl silyloxy)-4-cyanopent-4-enyl)-2-cyano-3-isopropylcyclopenta-2,4dienecarboxylate (166) ..................................................................................... 121 B.1.21 Preparation of cycloadduct 167 ........................................................................ 122 B.1.22 Preparation of tricyclic ketone 169 ................................................................... 122 B.2 Proton and carbon-13 spectra for sordarin intermediates .......................................... 124 C. BIMOLECULAR OXIDATIVE AMIDATION EXPERIMENTAL SECTION ..... 145 C.1 Synthesis of various bimolecular oxidative amidation intermediates ....................... 145 C.1.1 Representative protocols for bimolecular oxidative amidation at dilute conditions .......................................................................................................................... 145 C.1.2 Representative procedures for preparative bimolecular oxidative amidation .... 145 C.2 Characterization of bimolecular oxidative amidation intermediates (Table 7) ......... 146 C.2.1 Characterization of N-(1-methyl-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = Me) ................................................................................................................... 146 C.2.2 Characterization of N-(1-ethyl-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = Et) ..................................................................................................................... 146 C.2.3 Characterization of N-(4-oxo-1-propylcyclohexa-2,5-dienyl)acetamide (186, R = n-Pr).................................................................................................................. 147 C.2.4 Characterization of N-(1-isopropyl-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = i-Pr) ............................................................................................................... 147 C.2.5 Characterization of N-(1,3-dimethyl-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = X = Me) ..................................................................................................... 147 C.2.6 Characterization of N-(3,5-dibromo-1-methyl-4-oxocyclohexa-2,5-dienyl) acetamide (186, R = Me, X = Y = Br) ............................................................. 148 vi  C.2.7 Characterization of N-(1-(cyanomethyl)-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = CH2CN) ............................................................................................ 148 C.2.8 Characterization of N-(1-(2-cyanoethyl)-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = CH2CH2CN) ..................................................................................... 148 C.2.9 Characterization of N-(1-(2-(4-methylphenylsulfonamido)ethyl)-4-oxocyclohexa2,5-dienyl)acetamide (186, R = CH2CH2NHTs) .............................................. 149 C.2.10 Characterization of N-(1-(2-bromoethyl)-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = CH2CH2Br) ...................................................................................... 149 C.2.11 Characterization of methyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (184) ................................................................................................................. 149 C.2.12 Characterization of benzyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (186, R = CH2CO2Bn) ...................................................................................... 150 C.3 Proton and carbon-13 spectra for bimolecular oxidative amidation intermediates ... 151 D. INTRAMOLECULAR OXIDATIVE AMIDATION EXPERIMENTAL SECTION .............................................................................................................................................. 163 D.1 Preparation and characterization of various intermediates towards amine 200 ........ 163 D.1.1 Preparation of 3-(4-hydroxyphenyl)-1-propanol (197) ...................................... 163 D.1.2 Preparation of compound 198 ............................................................................ 163 D.1.3 Preparation of 4-(3-azidopropyl)phenyl methanesulfonate (199) ...................... 164 D.1.4 Preparation of 4-(3-aminopropyl)phenyl methanesulfonate (200) ..................... 165 D.2 General procedure for coupling reactions between amine and sulfonyl chloride ..... 165 D.2.1 Characterization of compound 201, R = Me ...................................................... 166 D.2.2 Characterization of 4-(3-(trifluoromethylsulfonamido)propyl)phenyl methanesulfonate (201, R = CF3) ..................................................................... 166 vii  D.2.3 Characterization of 4-(3-(cyclopropanesulfonamido)propyl)phenyl methanesulfonate (201, R = cyclopropyl) ........................................................ 166 D.2.4 Characterization of 4-(3-(phenylmethylsulfonamido)propyl)phenyl methanesulfonate (201, R = Bn) ...................................................................... 167 D.2.5 Characterization of 4-(3-(methylsulfonylmethylsulfonamido)propyl)phenyl methanesulfonate (201, R = CH2SO2Me) ........................................................ 167 D.2.6 Characterization of compound 201, R = PhMe .................................................. 168 D.2.7 Characterization of 4-(3-(2-nitrophenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 2-NO2Ph) ............................................................ 168 D.2.8 Characterization of 4-(3-(3-nitrophenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 3-NO2Ph) ............................................................ 168 D.2.9 Characterization of 4-(3-(4-nitrophenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 4-NO2Ph) ............................................................ 169 D.2.10 Characterization of 4-(3-(4-bromophenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 4-BrPh) ............................................................... 169 D.2.11 Characterization of 4-(3-(4-methoxyphenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 4-MeOPh) ........................................................... 170 D.2.12 Characterization of 4-(3-(2,4,6-triisopropylphenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 2,4,6-triisopropylphenyl) .................................... 170 D.2.13 Characterization of 4-(3-(thiophene-2-sulfonamido)propyl)phenyl methanesulfonate (201, R = 2-thienyl)............................................................. 171 D.2.14 Characterization of (S)-4-(2-(4-methylphenylsulfonamido)-3-(methyl sulfonamido)propyl)phenyl methanesulfonate (223, R = Me) ......................... 171  viii  D.2.15 Characterization of (S)-4-(2,3-bis(4-methylphenylsulfonamido)propyl)phenyl methanesulfonate (223, R = PhMe) ................................................................. 171 D.3 General procedure of deprotection of mesyl-O-phenol derivatives .......................... 172 D.3.1 Characterization of compound 202, R = Me ...................................................... 172 D.3.2 Characterization of trifluoro-N-(3-(4-hydroxyphenyl)propyl)methane sulfonamide (202, R = CF3) ............................................................................. 173 D.3.3 Characterization of N-(3-(4-hydroxyphenyl)propyl)cyclopropanesulfonamide (202, R = cyclopropyl) ..................................................................................... 173 D.3.4 Characterization of N-(3-(4-hydroxyphenyl)propyl)(phenyl) methanesulfonamide (202, R = Bn).................................................................................................... 173 D.3.5 Characterization of N-(3-(4-hydroxyphenyl)propyl)(methylsulfonyl) methane sulfonamide (202, R = CH2SO2Me) ................................................................. 174 D.3.6 Characterization of compound 232, R = 4-Me ................................................... 174 D.3.7 Characterization of N-(3-(4-hydroxyphenyl)propyl)-2-nitrobenzenesulfonamide (232, R = 2-NO2) .............................................................................................. 175 D.3.8 Characterization of N-(3-(4-hydroxyphenyl)propyl)-3-nitrobenzenesulfonamide (232, R = 3-NO2) .............................................................................................. 175 D.3.9 Characterization of N-(3-(4-hydroxyphenyl)propyl)-4-nitrobenzenesulfonamide (232, R = 4-NO2) .............................................................................................. 176 D.3.10 Characterization of 4-bromo-N-(3-(4-hydroxyphenyl)propyl) benzene sulfonamide (232, R = 4-Br) ............................................................................ 176 D.3.11 Characterization of N-(3-(4-hydroxyphenyl)propyl)-4-methoxybenzene sulfonamide (232, R = 4-OMe) ........................................................................ 176  ix  D.3.12 Characterization of N-(3-(4-hydroxyphenyl)propyl)-2,4,6-triisopropyl benzenesulfonamide (232, R = 2,4,6-triisopropyl) .......................................... 177 D.3.13 Characterization of (S)-N-(1-(4-hydroxyphenyl)-3-(methylsulfonamido)propan2-yl)-4-methylbenzenesulfonamide (224, R = Me) ......................................... 177 D.3.14 Characterization of (S)-N,N'-(3-(4-hydroxyphenyl)propane-1,2-diyl)bis(4methylbenzenesulfonamide) (224, R = PhMe) ................................................ 178 D.3.15 Characterization of N-(3-(4-hydroxyphenyl)propyl)thiophene-2-sulfonamide (234, Z = H, R = SO2-2-thienyl) ...................................................................... 178 D.4 Other preparative methods for special substrates ...................................................... 179 D.4.1 Preparation of 4-acetyl-N-(3-(4-(tert-butyldimethylsilyloxy)phenyl)propyl) benzenesulfonamide (TBS analog of 201, R = 4-C(O)CH3)............................ 179 D.4.2 Preparation of 4-acetyl-N-(3-(4-hydroxyphenyl)propyl)benzenesulfonamide (232, R = 4-C(O)CH3) ............................................................................................... 180 D.4.3 Characterization of 4-(3-(1,1-dimethylethylsulfinamido)propyl)phenyl methanesulfonate (216) .................................................................................... 180 D.4.4 Preparation of 4-(3-(1,1-dimethylethylsulfonamido)propyl)phenyl methanesulfonate (217) .................................................................................... 181 D.4.5 Characterization of N-(3-(4-hydroxyphenyl)propyl)-2-methylpropane-2sulfinamide (sulfinamide analog of 218) ......................................................... 181 D.4.6 Characterization of N-(3-(4-hydroxyphenyl)propyl)-2-methylpropane-2sulfonamide (218) ............................................................................................ 182 D.4.7 Preparation of N-(3-(4-hydroxy-3,5-diiodophenyl)propyl)methanesulfonamide (220) ................................................................................................................. 182  x  D.4.8 Preparation of (S,E)-4-(4-methoxy-3-(methylsulfonamido)but-1-enyl)phenyl acetate (226) ..................................................................................................... 183 D.4.9 Preparation of (S)-N-(4-(4-hydroxyphenyl)-1-methoxybutan-2-yl) methane sulfonamide (227) ............................................................................................ 184 D.4.10 Preparation of (S)-N-(4-(4-hydroxyphenyl)-1-oxobutan-2-yl) methane sulfonamide (229) ............................................................................................ 184 D.4.11 Preparation of dimethyl 3-(4-hydroxyphenyl) propylphosphoramidate (240) . 185 D.5 General procedures of IMOA at para position ......................................................... 186 D.5.1 Characterization of compound 231, R = Me ...................................................... 186 D.5.2 Characterization of compound 231, R = CF3 ..................................................... 186 D.5.3 Characterization of compound 231, R = tBu ...................................................... 187 D.5.4 Characterization of compound 231, R = cyclopropyl ........................................ 187 D.5.5 Characterization of compound 231, R = Bn ....................................................... 187 D.5.6 Characterization of compound 231, R = CH2SO2Me ......................................... 188 D.5.7 Characterization of compound 233, R = 4-Me ................................................... 188 D.5.8 Characterization of compound 233, R = 2-NO2 ................................................. 188 D.5.9 Characterization of compound 233, R = 3-NO2 ................................................. 188 D.5.10 Characterization of compound 233, R = 4-NO2 ............................................... 189 D.5.11 Characterization of compound 233, R = 4-Br .................................................. 189 D.5.12 Characterization of compound 233, R = 4-CN................................................. 189 D.5.13 Characterization of compound 233, R = 4-C(O)CH3 ....................................... 190 D.5.14 Characterization of compound 233, R = 4-OMe .............................................. 190 D.5.15 Characterization of compound 233, R = 2,4,6-triisopropyl ............................. 191 D.5.16 Characterization of compound 235, Z = H, R = SO2-2-thienyl ........................ 191 xi  D.5.17 Characterization of compound 235, Z = I, R = Ms .......................................... 191 D.5.18 Characterization of compound 237, R = CH2OH ............................................. 192 D.5.19 Characterization of compound 237, R = CH2OMe .......................................... 192 D.5.20 Characterization of compound 237, R = CHO ................................................. 192 D.5.21 Characterization of compound 238, R = Me .................................................... 193 D.5.22 Characterization of compound 238, R = PhMe ................................................ 193 D.5.23 Characterization of compound 241 .................................................................. 194 D.6 Synthesis and characterization of intermediates for IMOA at ortho position........... 194 D.6.1 Preparation of 3-(2-methoxyphenyl)propan-1-ol (246)...................................... 194 D.6.2 Preparation of 3-(2-methoxyphenyl)propyl methanesulfonate (247) ................. 195 D.6.3 Preparation of 2-(3-bromopropyl)phenol (248) ................................................. 195 D.6.4 Preparation of 1-(3-azidopropyl)-2-methoxybenzene (249a)............................. 196 D.6.5 Preparation of 2-(3-azidopropyl)phenol (249b) ................................................. 197 D.6.6 Preparation of 3-(2-methoxyphenyl)propan-1-amine (250) ............................... 197 D.6.7 Preparation of N-(3-(2-methoxyphenyl)propyl)methanesulfonamide (251) ...... 198 D.6.8 Preparation of N-(3-(2-hydroxyphenyl)propyl)methanesulfonamide (252) ...... 199 D.6.9 Preparation of (2-(3-azidopropyl)phenoxy)(tert-butyl)dimethylsilane (253) ..... 200 D.6.10 Preparation of 3-(2-(tert-butyldimethylsilyloxy)phenyl)propan-1-amine (254) .......................................................................................................................... 200 D.6.11 Preparation of compound 255 .......................................................................... 201 D.6.12 Preparation of N-(3-(2-(tert-butyldimethylsilyloxy)phenyl)propyl)-2-nitro benzenesulfonamide (256) ............................................................................... 201 D.6.13 Preparation of N-(3-(2-hydroxyphenyl)propyl)-2-nitrobenzenesulfonamide (257) .......................................................................................................................... 202 xii  D.6.14 Preparation of 1-(allyloxy)-4-bromobenzene (259) ......................................... 203 D.6.15 Preparation of 2-allyl-4-bromophenol (260) .................................................... 203 D.6.16 Preparation of (2-allyl-4-bromophenoxy)(tert-butyl)dimethylsilane (261)...... 204 D.6.17 Preparation of 3-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)propan-1-ol (262) ................................................................................................................. 204 D.6.18 Preparation of 3-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)propyl methane sulfonate (263) ................................................................................................. 205 D.6.19 Preparation of (2-(3-azidopropyl)-4-bromophenoxy)(tert-butyl)dimethylsilane (264) ................................................................................................................. 206 D.6.20 Preparation of N-(3-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)propyl) methanesulfonamide (265) ............................................................................... 206 D.6.21 Preparation of N-(3-(5-bromo-2-hydroxyphenyl)propyl)methanesulfonamide (266) ................................................................................................................. 207 D.6.22 Preparation of 6-methylchroman-2-one (268) .................................................. 208 D.6.23 Preparation of 3-(2-hydroxy-5-methylphenyl)propanamide (269) .................. 208 D.6.24 Preparation of 3-(2-(tert-butyldimethylsilyloxy)-5-methylphenyl)propanamide (270) ................................................................................................................. 209 D.6.25 Preparation of N-(3-(2-(tert-butyldimethylsilyloxy)-5-methylphenyl)propyl) methanesulfonamide (271) ............................................................................... 210 D.6.26 Preparation of compound 272 .......................................................................... 211 D.7 General procedures for IMOA of ortho phenols (methods A and B, Table 15) ....... 211 D.7.1 Characterization of compound 275, X = H ........................................................ 212 D.7.2 Characterization of compound 275, X = Br ....................................................... 212 D.7.3 Characterization of compound 275, X = Me ...................................................... 213 xiii  D.8 Proton and carbon-13 spectra for IMOA intermediates ............................................ 214 E. HIMANDRINE EXPERIMENTAL SECTION .......................................................... 311 E.1 Synthesis and characterization of various intermediates for tandem reactions ......... 311 E.1.1 Preparation of N-(3-(2-methoxyphenyl)propyl)ethenesulfonamide (292) ......... 311 E.1.2 Preparation of N-(3-(2-hydroxyphenyl)propyl)ethenesulfonamide (293) .......... 311 E.1.3 Preparation of 2-(3-azidopropyl)phenyl acetate (294)........................................ 312 E.1.4 Preparation of 2-(3-aminopropyl)phenyl acetate (295) ...................................... 313 E.1.5 Preparation of N-(3-(2-(tert-butyldimethylsilyloxy)phenyl)propyl) ethane sulfonamide (296) ............................................................................................ 314 E.1.6 Preparation of 2-(3-(vinylsulfonamido)propyl)phenyl acetate (297) ................. 314 E.1.7 Preparation of bis(3-(2-(tert-butyldimethylsilyloxy)phenyl)propyl)amine (299) .......................................................................................................................... 315 E.1.8 Preparation of N,N-bis(3-(2-(tert-butyldimethylsilyloxy)phenyl)propyl) ethenesulfonamide (303) .................................................................................. 316 E.1.9 Preparation of 2-allyl-4-bromo-1-methoxybenzene (304) .................................. 316 E.1.10 Preparation of 3-(5-bromo-2-methoxyphenyl)propan-1-ol (305) ..................... 317 E.1.11 Preparation of 3-(5-bromo-2-methoxyphenyl)propyl methanesulfonate (306) 317 E.1.12 Preparation of 2-(3-(5-bromo-2-methoxyphenyl)propyl)isoindoline-1,3-dione (307) ................................................................................................................. 318 E.1.13 Preparation of 3-(5-bromo-2-methoxyphenyl)propan-1-amine (308) .............. 319 E.1.14 Preparation of N-(3-(5-bromo-2-methoxyphenyl)propyl)ethenesulfonamide (309) .......................................................................................................................... 319 E.1.15 Preparation of N-(3-(5-bromo-2-hydroxyphenyl)propyl)ethenesulfonamide (310) .......................................................................................................................... 320 xiv  E.1.16 Preparation of N-(3-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)propyl) ethenesulfonamide (311) .................................................................................. 321 E.1.17 Preparation of N-(3-(2-(tert-butyldimethylsilyloxy)-5-methylphenyl)propyl) ethenesulfonamide (312) .................................................................................. 322 E.1.18 Preparation of N-(3-(2-hydroxy-5-methylphenyl)propyl)ethenesulfonamide (313) .......................................................................................................................... 323 E.2 General procedures tandem reactions (conditions C and D, Table 17) ..................... 324 E.2.1 Characterization of compound 315, Y = H ......................................................... 324 E.2.2 Characterization of compound 315, Y = Br ........................................................ 325 E.2.3 Characterization of compound 315, Y = Me ...................................................... 325 E.3 Synthesis and characterization of various intermediates for routes A, B and C........ 326 E.3.1 Preparation of compound 317 ............................................................................. 326 E.3.2 Preparation of compound 318 ............................................................................. 326 E.3.3 Preparation of compound 316 ............................................................................. 327 E.3.4 Preparation of compound 316a ........................................................................... 328 E.3.5 Preparation of compound 319 ............................................................................. 329 E.3.6 Preparation of (E)-buta-1,3-diene-1-sulfonyl chloride (E-327) .......................... 329 E.3.7 Preparation of (Z)-buta-1,3-diene-1-sulfonyl chloride (Z-327) .......................... 330 E.3.8 Preparation of (E)-N-(3-(2-(tert-butyldimethylsilyloxy)phenyl)propyl)buta-1,3diene-1-sulfonamide (329) ............................................................................... 330 E.3.9 Preparation of (E)-N-(3-(2-hydroxyphenyl)propyl)buta-1,3-diene-1-sulfonamide (331) ................................................................................................................. 331 E.3.10 Preparation of compound 339 ........................................................................... 331 E.3.11 Preparation of compound 338 ........................................................................... 332 xv  E.3.12 Preparation of methyl 3-(4-(tert-butyldimethylsilyloxy)phenyl)propanoate (341) .......................................................................................................................... 332 E.3.13 Preparation of 3-(4-(tert-butyldimethylsilyloxy)phenyl)propan-1-ol (342) ..... 333 E.3.14 Preparation of 3-(4-(tert-butyldimethylsilyloxy)phenyl)propyl methanesulfonate (343) ................................................................................................................. 334 E.3.15 Preparation of (4-(3-azidopropyl)phenoxy)(tert-butyl)dimethylsilane (344) ... 334 E.3.16 Preparation of (E)-N-(3-(4-(tert-butyldimethylsilyloxy)phenyl)propyl)buta-1,3diene-1-sulfonamide (345) ............................................................................... 335 E.3.17 Preparation of (E)-N-(3-(4-hydroxyphenyl)propyl)buta-1,3-diene-1-sulfonamide (285) ................................................................................................................. 336 E.3.18 Preparation of compound 283 ........................................................................... 337 E.4 Proton and carbon-13 spectra for himandrine skeletons............................................ 338 F. LEPADIFORMINE EXPERIMENTAL SECTION ................................................... 384 F.1 Synthesis and characterization of various homotyrosinol derivatives ....................... 384 F.1.1 Preparation of (S)-methyl 2-(methylsulfonamido)-4-(methylthio)butanoate (358) .......................................................................................................................... 384 F.1.2 Preparation of (S)-N-(1-hydroxy-4-(methylthio)butan-2-yl)methanesulfonamide (359) ................................................................................................................. 384 F.1.3 Preparation of (S)-2-(methylsulfonamido)-4-(methylthio)butyl acetate (360) ... 385 F.1.4 Preparation of (S)-N-(1-(tert-butyldiphenylsilyloxy)-4-(methylthio)butan-2yl)methane sulfonamide (361) ......................................................................... 386 F.1.5 Preparation of (S)-N-(1-(tert-butyldimethylsilyloxy)-4-(methylthio)butan-2yl)methane sulfonamide (362) ......................................................................... 386 F.1.6 Preparation of (S)-2-(methylsulfonamido)but-3-enyl acetate (363) ................... 388 xvi  F.1.7 Preparation of (S)-N-(1-(tert-butyldiphenylsilyloxy)but-3-en-2-yl)methane sulfonamide (364) ............................................................................................ 388 F.1.8 Preparation of (S)-N-(1-(tert-butyldimethylsilyloxy)but-3-en-2-yl)methane sulfonamide (365) ............................................................................................ 388 F.1.9 Preparation of (S)-N-(1-hydroxybut-3-en-2-yl)methanesulfonamide (355, P’ = H) .......................................................................................................................... 389 F.1.10 Preparation of (S,E)-4-(4-(tert-butyldiphenylsilyloxy)-3-(methylsulfonamido) but-1-enyl)phenyl acetate (367) ....................................................................... 390 F.1.11 Preparation of (S,E)-N-(1-(tert-butyldiphenylsilyloxy)-4-(4-hydroxyphenyl)but3-en-2-yl) methanesulfonamide (370, P = H, P’ = TBDPS) ............................ 390 F.1.12 Preparation of (S,E)-N-(1-(tert-butyldimethylsilyloxy)-4-(4-hydroxyphenyl)but3-en-2-yl) methanesulfonamide (370, P = H, P’ = TBS) ................................. 391 F.1.13 Preparation of compound 370, P = P’ = Ac ...................................................... 391 F.1.14 Preparation of (S,E)-N-(1-hydroxy-4-(4-hydroxyphenyl)but-3-en-2-yl)methane sulfonamide (370, P = P’ = H) ......................................................................... 391 F.1.15 Preparation of (S,E)-4-(4-hydroxy-3-(methylsulfonamido)but-1-enyl)phenyl acetate (371) ..................................................................................................... 392 F.1.16 Preparation of (S)-N-(1-(tert-butyldiphenylsilyloxy)-4-(4-hydroxyphenyl)butan2-yl) methanesulfonamide (373) ...................................................................... 393 F.1.17 Preparation of (S)-N-(1-hydroxy-4-(4-hydroxyphenyl)butan-2-yl)methane sulfonamide (353) ............................................................................................ 393 F.1.18 Preparation of (S)-((S,E)-4-(4-acetoxyphenyl)-2-(methylsulfonamido)but-3-enyl) 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate, (S)-MTPA ester (372) .......... 394  xvii  F.1.19 Large-scale Heck coupling reaction, followed by deprotection of OAc group for easy purification ............................................................................................... 395 F.2 Synthesis and characterization of various lepadiformine derivatives ........................ 396 F.2.1 Preparation of compound 375 ............................................................................. 396 F.2.2 Preparation of compound 377 ............................................................................. 396 F.2.3 Preparation of compound 381 ............................................................................. 397 F.2.4 Preparation of compound 384 ............................................................................. 398 F.2.5 Preparation of compound 385 ............................................................................. 399 F.2.6 Preparation of compound 386 ............................................................................. 399 F.2.7 Preparation of compound 387 ............................................................................. 400 F.2.8 Preparation of compound 388 ............................................................................. 400 F.2.9 Preparation of compound 389 ............................................................................. 401 F.2.10 Preparation of compound 390 ........................................................................... 401 F.2.11 Preparation of compound 391 ........................................................................... 402 F.3 Proton and carbon-13 spectra for homotyrosinol and lepadiformine intermediates .. 404 G. X-RAY CRYSTALLOGRAPHY DATA ..................................................................... 434 G.1 X-ray data of compound 184 ..................................................................................... 434 G.2 X-ray data of compound 233 (R = 4-NO2)................................................................ 435 G.3 X-ray data of compound 233 (R = 3-NO2)................................................................ 436 G.4 X-ray data of compound 237, R = CH2OH or compound 374 .................................. 437 G.5 X-ray data of compound 238 ..................................................................................... 438 G.6 X-ray data of compound 315 (Y = H) ....................................................................... 439 G.7 X-ray data of compound 315 (Y = Br) ...................................................................... 440 G.8 X-ray data of compound 315 (Y = Me) .................................................................... 441 xviii  G.9 X-ray data of compound 316a ................................................................................... 442 G.10 X-ray data of compound 317 ................................................................................... 443 G.11 X-ray data of compound 318 ................................................................................... 444 G.12 X-ray data of compound 339 ................................................................................... 445 G.13 X-ray data of compound 283 ................................................................................... 446 G.14 X-ray data of compound 381 ................................................................................... 447 G.15 X-ray data of compound 386 ................................................................................... 448  xix  List of Tables  Table 1. Antifungal activity against Saccharomyces cerevisiae (strain YPH98) of sordarin and derivatives .......................................................................................................................... 2 Table 2. IC50 of sordarin against common fungi ...................................................................... 3 Table 3. Bioactivity of lepadiformine A ................................................................................. 17 Table 4. Methylation of compound 133 ................................................................................. 26 Table 5. Effect of TFA on the yield of desired product.......................................................... 43 Table 6. Effect of substrate concentration on the yield of desired product ............................ 44 Table 7. Comparison of the new vs. the old procedure .......................................................... 46 Table 8. Two generations of methods..................................................................................... 49 Table 9. Alkylsulfonamide-based intramolecular oxidative amidation .................................. 54 Table 10. Arylsulfonamide-based intramolecular oxidative amidation ................................. 54 Table 11. Other sulfonamides ................................................................................................. 55 Table 12. Cyclization of homotyrosine derivatives ................................................................ 56 Table 13. Cyclization of tyrosine derivatives ......................................................................... 57 Table 14. Solvent and temperature effects ............................................................................. 60 Table 15. A comparison of the two methods using different substituents.............................. 61 Table 16. A summary of oxidative amidation products ......................................................... 62 Table 17. Tandem reaction of ortho phenols .......................................................................... 70 Table 18. Alkene metathesis approach ................................................................................... 83 Table 19. Screened catalysts and ligands for Heck coupling ................................................. 83 Table 20. Screening on different substituents at the phenol and vinyl glycinol derivatives .. 84 Table 21. Effect of bases and temperature on Michael addition ............................................ 88 xx  List of Figures  Figure 1. Structure of sordarin (1) and sordaricin (2) ............................................................... 1 Figure 2. Modifications of glycosyl part .................................................................................. 4 Figure 3. Synthesis of six cyclopentane analogs ...................................................................... 5 Figure 4. Analogs synthesized by intermolecular Diels-Alder ............................................... 10 Figure 5. Structure of himbosine, himandrine and himandridine ........................................... 11 Figure 6. Structures of lepadiformines ................................................................................... 16 Figure 7. Sordarin analogs 132, 149 and 169 ......................................................................... 35 Figure 8. Poor substrates for oxidative amidation .................................................................. 47 Figure 9. X-ray structures of compound 233 (R= 3- and 4-NO2) ........................................... 55 Figure 10. X-ray structures of compound 237 (R = CH2OH)................................................. 56 Figure 11. X-ray structures of compound 238 (R = PhMe) .................................................... 57 Figure 12. X-ray structures of compounds 315 ...................................................................... 70 Figure 13. NMR spectra of compound 127 .......................................................................... 124 Figure 14. NMR spectra of compound 128 .......................................................................... 125 Figure 15. NMR spectra of compound 129 .......................................................................... 126 Figure 16. NMR spectra of compound 130 .......................................................................... 127 Figure 17. NMR spectra of compound 132 ......................................................................... 128 Figure 18. NMR spectra of compound 134 .......................................................................... 129 Figure 19. NMR spectra of compound 141 ......................................................................... 130 Figure 20. NMR spectra of compound 142 ......................................................................... 131 Figure 21. NMR spectra of compound 143 .......................................................................... 132 Figure 22. NMR spectra of compound 145 .......................................................................... 133 xxi  Figure 23. NMR spectra of compound 146 .......................................................................... 134 Figure 24. NMR spectra of compound 147 .......................................................................... 135 Figure 25. NMR spectra of compound 148 .......................................................................... 136 Figure 26. NMR spectra of compound 149 .......................................................................... 137 Figure 27. NMR spectra of compound 153 .......................................................................... 138 Figure 28. NMR spectra of compound 154 .......................................................................... 139 Figure 29. NMR spectra of compound 162 .......................................................................... 140 Figure 30. NMR spectra of compound 158 .......................................................................... 140 Figure 31. NMR spectra of compound 165 .......................................................................... 141 Figure 32. NMR spectra of compound 166 .......................................................................... 142 Figure 33. NMR spectra of compound 167 .......................................................................... 143 Figure 34. NMR spectra of compound 169 .......................................................................... 144 Figure 35. NMR spectra of compound 186, R = Me ............................................................ 151 Figure 36. NMR spectra of compound 186, R = Et .............................................................. 152 Figure 37. NMR spectra of compound 186, R = n-Pr .......................................................... 153 Figure 38. NMR spectra of compound 186, R = i-Pr ........................................................... 154 Figure 39. NMR spectra of compound 186, R = X = Me ..................................................... 155 Figure 40. NMR spectra of compound 186, R = Me, X = Y = Br ........................................ 156 Figure 41. NMR spectra of compound 186, R = CH2CN ..................................................... 157 Figure 42. NMR spectra of compound 186, R = CH2CH2CN .............................................. 158 Figure 43. NMR spectra of compound 186, R = CH2CH2NHTs .......................................... 159 Figure 44. NMR spectra of compound 186, R = CH2CH2Br................................................ 160 Figure 45. NMR spectra of compound 184 .......................................................................... 161 Figure 46. NMR spectra of compound 186, R = CH2CO2Bn ............................................... 162 xxii  Figure 47. NMR spectra of compound 197 .......................................................................... 214 Figure 48. NMR spectra of compound 198 .......................................................................... 215 Figure 49. NMR spectra of compound 199 .......................................................................... 216 Figure 50. NMR spectra of compound 200 .......................................................................... 217 Figure 51. NMR spectra of compound 201, R = Me ............................................................ 218 Figure 52. NMR spectra of compound 201, R = CF3 ........................................................... 219 Figure 53. NMR spectra of compound 201, R = cyclopropyl .............................................. 220 Figure 54. NMR spectra of compound 201, R = Bn ............................................................. 221 Figure 55. NMR spectra of compound 201, R = CH2SO2Me ............................................... 222 Figure 56. NMR spectra of compound 201, R = PhMe ........................................................ 223 Figure 57. NMR spectra of compound 201, R = 2-NO2Ph ................................................... 224 Figure 58. NMR spectra of compound 201, R = 3-NO2Ph ................................................... 225 Figure 59. NMR spectra of compound 201, R = 4-NO2Ph ................................................... 226 Figure 60. NMR spectra of compound 201, R = 4-BrPh ...................................................... 227 Figure 61. NMR spectra of compound 201, R = 4-OMePh.................................................. 228 Figure 62. NMR spectra of compound 201, R = 2,4,6-triisopropylphenyl .......................... 229 Figure 63. NMR spectra of compound 201, R = 2-thienyl ................................................... 230 Figure 64. NMR spectra of compound 223, R = Me ............................................................ 231 Figure 65. NMR spectra of compound 223, R = PhMe ........................................................ 232 Figure 66. NMR spectra of compound 202, R = Me ............................................................ 233 Figure 67. NMR spectra of compound 202, R = CF3 ........................................................... 234 Figure 68. NMR spectra of compound 202, R = cyclopropyl .............................................. 235 Figure 69. NMR spectra of compound 202, R = Bn ............................................................. 236 Figure 70. NMR spectra of compound 202, R = CH2SO2Me ............................................... 237 xxiii  Figure 71. NMR spectra of compound 232, R = 4-Me ......................................................... 238 Figure 72. NMR spectra of compound 232, R = 2-NO2 ....................................................... 239 Figure 73. NMR spectra of compound 232, R = 3-NO2 ....................................................... 240 Figure 74. NMR spectra of compound 232, R = 4-NO2 ....................................................... 241 Figure 75. NMR spectra of compound 232, R = 4-Br .......................................................... 242 Figure 76. NMR spectra of compound 232, R = 4-OMe ...................................................... 243 Figure 77. NMR spectra of compound 232, R = 2,4,6-triisopropyl ..................................... 244 Figure 78. NMR spectra of compound 224, R = Me ............................................................ 245 Figure 79. NMR spectra of compound 224, R = PhMe ........................................................ 246 Figure 80. NMR spectra of compound 234, Z = H, R = SO2-2-thienyl ............................... 247 Figure 81. NMR spectra of TBS analog of 121 .................................................................... 248 Figure 82. NMR spectra of compound 232, R = 4-C(O)CH3 ............................................... 249 Figure 83. NMR spectra of compound 216 .......................................................................... 250 Figure 84. NMR spectra of compound 217 .......................................................................... 251 Figure 85. NMR spectra of sulfinamide analog of compound 218 ...................................... 252 Figure 86. NMR spectra of compound 218 .......................................................................... 253 Figure 87. NMR spectra of compound 220 .......................................................................... 254 Figure 88. NMR spectra of compound 226 .......................................................................... 255 Figure 89. NMR spectra of compound 227 .......................................................................... 256 Figure 90. NMR spectra of compound 229 .......................................................................... 257 Figure 91. NMR spectra of compound 240 .......................................................................... 258 Figure 92. NMR spectra of compound 231, R = Me ............................................................ 259 Figure 93. NMR spectra of compound 231, R = CF3 ........................................................... 260 Figure 94. NMR spectra of compound 231, R = tBu............................................................ 261 xxiv  Figure 95. NMR spectra of compound 231, R = cyclopropyl .............................................. 262 Figure 96. NMR spectra of compound 231, R = Bn ............................................................. 263 Figure 97. NMR spectra of compound 231, R = CH2SO2Me ............................................... 264 Figure 98. NMR spectra of compound 233, R = 4-Me ......................................................... 265 Figure 99. NMR spectra of compound 233, R = 2-NO2 ....................................................... 266 Figure 100. NMR spectra of compound 233, R = 3-NO2 ..................................................... 267 Figure 101. NMR spectra of compound 233, R = 4-NO2 ..................................................... 268 Figure 102. NMR spectra of compound 233, R = 4-Br ........................................................ 269 Figure 103. NMR spectra of compound 233, R = 4-CN ...................................................... 270 Figure 104. NMR spectra of compound 233, R = 4- C(O)CH3 ............................................ 271 Figure 105. NMR spectra of compound 233, R = 4-OMe .................................................... 272 Figure 106. NMR spectra of compound 233, R = 2,4,6-triisopropyl ................................... 273 Figure 107. NMR spectra of compound 235, Z = H, R = SO2-2-thienyl ............................. 274 Figure 108. NMR spectra of compound 235, Z = I, R = Ms ................................................ 275 Figure 109. NMR spectra of compound 237, R = CH2OH ................................................... 276 Figure 110. NMR spectra of compound 237, R = CH2OMe ................................................ 277 Figure 111. NMR spectra of compound 237, R = CHO ....................................................... 278 Figure 112. NMR spectra of compound 238, R = Me .......................................................... 279 Figure 113. NMR spectra of compound 238, R = PhMe ...................................................... 280 Figure 114. NMR spectra of compound 241 ........................................................................ 281 Figure 115. NMR spectra of compound 246 ........................................................................ 282 Figure 116. NMR spectra of compound 247 ........................................................................ 283 Figure 117. NMR spectra of compound 248 ........................................................................ 284 Figure 118. NMR spectra of compound 249a ...................................................................... 285 xxv  Figure 119. NMR spectra of compound 249b ...................................................................... 286 Figure 120. NMR spectra of compound 250 ........................................................................ 287 Figure 121. NMR spectra of compound 251 ........................................................................ 288 Figure 122. NMR spectra of compound 252 ........................................................................ 289 Figure 123. NMR spectra of compound 253 ........................................................................ 290 Figure 124. NMR spectra of compound 254 ........................................................................ 291 Figure 125. NMR spectra of compound 255 ........................................................................ 292 Figure 126. NMR spectra of compound 256 ........................................................................ 293 Figure 127. NMR spectra of compound 257 ........................................................................ 294 Figure 128. NMR spectra of compound 259 ........................................................................ 295 Figure 129. NMR spectra of compound 260 ........................................................................ 296 Figure 130. NMR spectra of compound 261 ........................................................................ 297 Figure 131. NMR spectra of compound 262 ........................................................................ 298 Figure 132. NMR spectra of compound 263 ........................................................................ 299 Figure 133. NMR spectra of compound 264 ........................................................................ 300 Figure 134. NMR spectra of compound 265 ........................................................................ 301 Figure 135. NMR spectra of compound 266 ........................................................................ 302 Figure 136. NMR spectra of compound 268 ........................................................................ 303 Figure 137. NMR spectra of compound 269 ........................................................................ 304 Figure 138. NMR spectra of compound 270 ........................................................................ 305 Figure 139. NMR spectra of compound 271 ........................................................................ 306 Figure 140. NMR spectra of compound 272 ........................................................................ 307 Figure 141. NMR spectra of compound 275, X = H ............................................................ 308 Figure 142. NMR spectra of compound 275, X = Br ........................................................... 309 xxvi  Figure 143. NMR spectra of compound 275, X = Me .......................................................... 310 Figure 144. NMR spectra of compound 292 ........................................................................ 338 Figure 145. NMR spectra of compound 293 ........................................................................ 339 Figure 146. NMR spectra of compound 294 ........................................................................ 340 Figure 147. NMR spectra of compound 295 ........................................................................ 341 Figure 148. NMR spectra of compound 296 ........................................................................ 342 Figure 149. NMR spectra of compound 297 ........................................................................ 343 Figure 150. NMR spectra of compound 299 ........................................................................ 344 Figure 151. NMR spectra of compound 303 ........................................................................ 345 Figure 152. NMR spectra of compound 304 ........................................................................ 346 Figure 153. NMR spectra of compound 305 ........................................................................ 347 Figure 154. NMR spectra of compound 306 ........................................................................ 348 Figure 155. NMR spectra of compound 307 ........................................................................ 349 Figure 156. NMR spectra of compound 308 ........................................................................ 350 Figure 157. NMR spectra of compound 309 ........................................................................ 351 Figure 158. NMR spectra of compound 310 ........................................................................ 352 Figure 159. NMR spectra of compound 311 ........................................................................ 353 Figure 160. NMR spectra of compound 312 ........................................................................ 354 Figure 161. NMR spectra of compound 313 ........................................................................ 355 Figure 162. NMR spectra of compound 315, Y = H ............................................................ 356 Figure 163. HMQC spectrum of compound 315, Y = H ...................................................... 357 Figure 164. HMBC spectrum of compound 315, Y = H ..................................................... 357 Figure 165. NMR spectra of compound 315, Y = Br ........................................................... 358 Figure 166. HMQC spectrum of compound 315, Y = Br ..................................................... 359 xxvii  Figure 167. HMBC spectrum of compound 315, Y = Br ..................................................... 359 Figure 168. NMR spectra of compound 315, Y = Me .......................................................... 360 Figure 169. HMQC spectrum of compound 315, Y = Me.................................................... 361 Figure 170. HMBC spectrum of compound 315, Y = Me .................................................... 361 Figure 171. NMR spectra of compound 317 ........................................................................ 362 Figure 172. NMR spectra of compound 318 ........................................................................ 363 Figure 173. NMR spectra of compound 316 ........................................................................ 364 Figure 174. HMQC spectrum of compound 316 .................................................................. 365 Figure 175. HMBC spectrum of compound 316 .................................................................. 365 Figure 176. NMR spectra of compound 316a ...................................................................... 366 Figure 177. NMR spectra of compound 319 ........................................................................ 367 Figure 178. NMR spectra of compound E-327 .................................................................... 368 Figure 179. NMR spectra of compound Z-327 ..................................................................... 369 Figure 180. NMR spectra of compound 329 ........................................................................ 370 Figure 181. NMR spectra of compound 331 ........................................................................ 371 Figure 182. NMR spectra of compound 338 ........................................................................ 372 Figure 183. HMQC spectrum of compound 338 .................................................................. 373 Figure 184. HMBC spectrum of compound 338 .................................................................. 373 Figure 185. NMR spectra of compound 339 ........................................................................ 374 Figure 186. HMQC spectrum of compound 339 .................................................................. 375 Figure 187. HMBC spectrum of compound 339 ................................................................. 375 Figure 188. NMR spectra of compound 341 ........................................................................ 376 Figure 189. NMR spectra of compound 342 ........................................................................ 377 Figure 190. NMR spectra of compound 343 ........................................................................ 378 xxviii  Figure 191. NMR spectra of compound 344 ........................................................................ 379 Figure 192. NMR spectra of compound 345 ........................................................................ 380 Figure 193. NMR spectra of compound 285 ........................................................................ 381 Figure 194. NMR spectra of compound 283 ........................................................................ 382 Figure 195. HMQC spectrum of compound 283 .................................................................. 383 Figure 196. HMBC spectrum of compound 283 .................................................................. 383 Figure 197. NMR spectra of compound 358 ........................................................................ 404 Figure 198. NMR spectra of compound 359 ........................................................................ 405 Figure 199. NMR spectra of compound 360 ........................................................................ 406 Figure 200. NMR spectra of compound 361 ........................................................................ 407 Figure 201. NMR spectra of compound 362 ........................................................................ 408 Figure 202. NMR spectra of compound 363 ........................................................................ 409 Figure 203. NMR spectra of compound 364 ........................................................................ 410 Figure 204. NMR spectra of compound 365 ........................................................................ 411 Figure 205. NMR spectra of compound 355, P’ = H............................................................ 412 Figure 206. NMR spectra of compound 367 ........................................................................ 413 Figure 207. NMR spectra of compound 370, P = H, P’ = TBDPS....................................... 414 Figure 208. NMR spectra of compound 370, P = H, P’ = TBS ............................................ 415 Figure 209. NMR spectra of compound 370, P = P’ = Ac ................................................... 416 Figure 210. NMR spectra of compound 370, P = P’ = H ..................................................... 417 Figure 211. NMR spectra of compound 371 ........................................................................ 418 Figure 212. NMR spectra of compound 373 ........................................................................ 419 Figure 213. NMR spectra of compound 353 ........................................................................ 420 Figure 214. NMR spectra of compound 372 ........................................................................ 421 xxix  Figure 215. 19F-NMR spectra of compound 372 .................................................................. 422 Figure 216. NMR spectra of compound 375 ........................................................................ 423 Figure 217. NMR spectra of compound 377 ........................................................................ 424 Figure 218. NMR spectra of compound 381 ........................................................................ 425 Figure 219. NMR spectra of compound 384 ........................................................................ 426 Figure 220. NMR spectra of compound 385 ........................................................................ 427 Figure 221. NMR spectra of compound 386 ........................................................................ 428 Figure 222. NMR spectra of compound 387 ........................................................................ 429 Figure 223. NMR spectra of compound 388 ........................................................................ 430 Figure 224. NMR spectra of compound 389 ........................................................................ 431 Figure 225. NMR spectra of compound 390 ........................................................................ 432 Figure 226. NMR spectra of compound 391 ........................................................................ 433  xxx  List of Schemes  Scheme 1. Prevention of hemi-acetalization ............................................................................ 2 Scheme 2. Simplified model of sordarin .................................................................................. 4 Scheme 3. Key steps in Kato’s synthesis.................................................................................. 6 Scheme 4. Key steps in Mander’s synthesis ............................................................................. 7 Scheme 5. Key steps in Narasaka’s synthesis .......................................................................... 7 Scheme 6. Avenue to sordarin analogs by intermolecular Diels-Alder reaction ...................... 8 Scheme 7. Synthesis of analog 42 ............................................................................................ 9 Scheme 8. Limitations of the Schüle strategy ........................................................................ 10 Scheme 9. Mander’s retrosynthesis of analog 56 ................................................................... 12 Scheme 10. Opening moves of the Mander synthesis of a himandrine analog ...................... 13 Scheme 11. Mander’s himandrine analog synthesis ............................................................... 14 Scheme 12. Movassaghi’s retrosynthesis of (-)-himandrine .................................................. 15 Scheme 13. Movassaghi’s synthesis of (-)-himandrine .......................................................... 15 Scheme 14. Weinreb’s synthesis ............................................................................................ 18 Scheme 15. Kibayashi’s synthesis .......................................................................................... 19 Scheme 16. Craig’s synthesis of (±)-lepadiformine A (Part I) ............................................... 19 Scheme 17. Craig’s synthesis of (±)-lepadiformine A (Part II).............................................. 20 Scheme 18. Lygo’s synthesis .................................................................................................. 21 Scheme 19. Retrosynthetic plan of sordarin analogs by intramolecular Diels-Alder............. 23 Scheme 20. Preparation of aldehyde 129 ............................................................................... 24 Scheme 21. Model intramolecular Diels-Alder reaction ........................................................ 25 Scheme 22. Presumed course of the deprotonation of 135 with LDA and LHMDS.............. 27 xxxi  Scheme 23. Thermodynamic and kinetic products ................................................................. 28 Scheme 24. Acylation with phenyl methyl carbonate ............................................................ 29 Scheme 25. Preparation of compound 143 ............................................................................. 29 Scheme 26. Preparation of analog 149 ................................................................................... 30 Scheme 27. Retrosynthesis of compound 150 ........................................................................ 31 Scheme 28. Failure of enol silylation of compound 154 ........................................................ 32 Scheme 29. Reported formation of Danishefsky-type diene .................................................. 33 Scheme 30. Possible intramolecular Diels-Alder reaction of 158 .......................................... 33 Scheme 31. Unsuccessful intramolecular Diels-Alder route .................................................. 34 Scheme 32. Synthesis of Michael adduct 165 ........................................................................ 34 Scheme 33. Preparation of analog 169 ................................................................................... 35 Scheme 34. A summary of synthetic routes to sordarin analogs ............................................ 36 Scheme 35. Oxidative amidation of phenols .......................................................................... 38 Scheme 36. Previous bimolecular oxidative amidation .......................................................... 39 Scheme 37. Possible oxidative amidation mechanism and pathway ...................................... 40 Scheme 38. Effect of concentration ........................................................................................ 42 Scheme 39. Intramolecular oxidative amidation at para- or ortho-position .......................... 48 Scheme 40. Preparation of precursors for intramolecular oxidative amidation ..................... 49 Scheme 41. Formation of the unusual product 204 ................................................................ 50 Scheme 42. Possible mechanism of the formation of 211 ...................................................... 51 Scheme 43. Preparation of special sulfonamides ................................................................... 52 Scheme 44. Preparation of L-tyrosine derivatives .................................................................. 52 Scheme 45. Preparation of homotyrosine derivatives ............................................................ 53 Scheme 46. Preparation of phenolic phosphoramide ............................................................. 57 xxxii  Scheme 47. Preparation of ortho-substituted phenols ............................................................ 58 Scheme 48. Bromo-substituted ortho phenols ........................................................................ 59 Scheme 49. Methyl-substituted ortho phenols ....................................................................... 59 Scheme 50. Retrosynthetic analysis of himandrine skeleton.................................................. 63 Scheme 51. A design for oxidative amidation / Diels-Alder tandem reaction ....................... 64 Scheme 52. Wood’s intermolecular Diels-Alder reaction with different Y groups ............... 64 Scheme 53. First generation synthesis of compound 293....................................................... 65 Scheme 54. Second generation large scale synthesis of compound 293 ................................ 66 Scheme 55. Unexpected homo-coupling reaction .................................................................. 67 Scheme 56. Oxidative amidation of compound 303 ............................................................... 67 Scheme 57. Preparation of compound 310 from 304 ............................................................. 68 Scheme 58. Preparation of compound 310 from azide 264 .................................................... 68 Scheme 59. Preparation of precursor 313 ............................................................................... 69 Scheme 60. Vinyl metal reagent approach ............................................................................. 71 Scheme 61. Preparation of compound 316 ............................................................................. 72 Scheme 62. Liao’s system ...................................................................................................... 73 Scheme 63. Unsuccessful route of oxy-Cope rearrangement ................................................. 74 Scheme 64. Possible modes of reactivity of 280 .................................................................... 74 Scheme 65. Preparation of compound 330 and 331 ............................................................... 75 Scheme 66. Unsuccessful improvement ................................................................................. 76 Scheme 67. Preparation of compounds 338 and 339 .............................................................. 76 Scheme 68. Preparation of final compound 283 ..................................................................... 77 Scheme 69. A summary of himandrine skeleton synthesis .................................................... 78 Scheme 70. Retrosynthetic analysis of lepadiformines .......................................................... 80 xxxiii  Scheme 71. Retrosynthesis of L-homotyrosinol methanesulfonamide .................................. 81 Scheme 72. Preparation of different vinyl moieties ............................................................... 82 Scheme 73. Preparation of (S)-MPTA ester ........................................................................... 85 Scheme 74. Synthesis of L-homotyrosinol methanesulfonamide........................................... 85 Scheme 75. A summary of L-homotyrosinol methanesulfonamide synthesis ....................... 86 Scheme 76. Diastereoselective Michael addition ................................................................... 87 Scheme 77. Comparison of different reduction conditions .................................................... 89 Scheme 78. Synthesis of intermediate 389 ............................................................................. 90 Scheme 79. Formation of enone 391 ...................................................................................... 91 Scheme 80. Attempts of 1,4- enone reduction ........................................................................ 92 Scheme 81. Future work ......................................................................................................... 92 Scheme 82. A summary of synthesis towards (-)-lepadiformines .......................................... 93  xxxiv  List of Abbreviations  Ac  acetyl  AIBN  azobisisobutyronitrile  aq  aqueous  Ar  aryl  Bn  benzyl  Boc  tert-butyloxycarbonyl  Bu  butyl  ca.  circa (Latin)  calc.  calculated  Cbz  benzyloxycarbonyl  Chromat.  flash chromatography column  cf.  confer (Latin)  conc.  concentrated  18-cr-6  18-crown-6 or 1,4,7,10,13,16-hexaoxacyclooctadecane  DABCO  1,4-diazabicyclo[2.2.2]octane  dba  dibenzylideneacetone  DBU  1,8-diazabicyclo[5.4.0]undec-7-ene  DCM  dichloromethane  DDQ  2,3-dichloro-5,6-dicyano-1,4-benzoquinone  DMF  N,N-dimethylformamide  DIB  (diacetoxyiodo)benzene  DMS  dimethyl sulfide  DMSO  dimethyl sulfoxide  xxxv  Et  ethyl  ESI  electrospray ionization  h  hour(s)  HFIP  hexafluoroisopropanol  HMBC  heteronuclear multiple bond correlation  HMPA  hexamethyl phosphoramide  HMQC  heteronuclear multiple quantum coherence  HOMO  highest occupied molecular orbital  HRMS  high resolution mass spectrum  Hz  Hertz (s-1)  i  iso  IMDA  intramolecular Diels-Alder  IMOA  intramolecular oxidative amidation  IR  infrared  LAH  lithium aluminum hydride  LG  leaving group  LUMO  lowest unoccupied molecular orbital  m  multiplet  mCPBA  meta-chloroperoxybenzoic acid  Me  methyl  min  minute(s)  MOM  methoxymethyl  m.p.  melting point  MPTA  methoxytrifluorophenylaceticacid  Ms  methanesulfonyl  xxxvi  MS  mass spectrometry  n  normal (as an alkyl group)  n-BuLi  n-butyllithium  NBS  N-bromosuccinmide  NCS  N-chlorosuccinmide  NIS  N-iodosuccinmide  NMR  nuclear magnetic resonance  Ns  nitrobenzenesulfonyl  Nu  nucleophile  [O]  oxidation  o  ortho  p  para  Ph  phenyl  Pht  1,2-phenylenedicarbonyl  PIFA  phenyliodine(III) bis(trifluoroacetate)  ppm  parts per million  Pr  propyl  Pyr.  pyridine  Quan.  quantitative  r.t.  room temperature  s  singlet  SAR  structure-activity relationship  sat.  saturated  t  tertiary (as an alkyl group)  TBAF  tetra-n-butylammonium fluoride  xxxvii  TBDMS  tert-butyldimethylsilyl  TBDPS  tert-butyldiphenylsilyl  TES  triethylsilyl  Tf  triflate  TFA  trifluoroacetic acid  THF  tetrahydrofuran  TIPS  triisopropylsilyl  TLC  thin layer chromatography  TMEDA  tetramethylethylenediamine  TMS  trimethylsilyl  Ts  4-toluenesulfonyl  xxxviii  Acknowledgements  I wish to express my gratitude to my advisor and mentor, Professor Marco Ciufolini. I have admired his dedication to science, commitment to his students’ success and his willingness to share his wisdom. I truly consider myself fortunate to have worked under his direction. I would also like to thank the members of the Ciufolini research group, past and present, for their friendship, insightful discussions, and kind advice. Special thanks must go to Charles Dylan Turner for his help in proof-reading my thesis and Yuan Zhou for her assistance in the lepadiformine project. I want to acknowledge the staff of the NMR, Mass spectrometry and X-ray services at UBC, especially Dr. Yun Ling, Dr. Brian Patrick and David Wong for their help running experiments and discussing the resultant data. A special thanks is given to my wife, Lin, and my parents, Chunli Zhang and Fengtong Liang for their love and support. Financial support in the form of a Graduate Fellowship from the University of British Columbia and a Gladys Estella Laird Research Fellowship from the Department of Chemistry are gratefully acknowledged.  xxxix  1. INTRODUCTION  Throughout human history, valuable chemotherapeutic substances have been derived from natural sources. The historical record is replete with examples. Suffice it to recount the use of quinine present in “quinquina” for the treatment of malaria, 1 of camptothecin contained in “xi shu” for the treatment of cancer,2 and, in the early part of the 20th Century, of life-saving antibiotics such as penicillin.3  1.1 Sordarin and its derivatives 1.1.1 Isolation, structure and bioactivity Despite the advent of powerful new methods for the identification of bioactive substances, such as computer-assisted drug design and screening, compounds obtained from nature continue to reveal uniquely potent activity. An example is the noteworthy antifungal agent, sordarin, 1. Sordarin was isolated in 1969 from the mushroom Sordaria araneosa by scientists of Sandoz Company in Switzerland and patented the same year under the name of SL 2266 (Figure 1).4 Fermentation is currently the preferred method of sordarin production.5  OH HO  OMe  H O H  CO2H CHO 1  H OH  O H  CO2H CHO 2  Figure 1. Structure of sordarin (1) and sordaricin (2)  1  The degradation of sordarin in acidic medium (conc. HCl in acetone) affords a diterpenoid aglycone, 2, which is called sordaricin.6 This material is essentially devoid of biological activity (Table 1). Its exact structure, together with that of sordarin, was disclosed in 1973.7  OH  H OR  OMe  3, R = O  H  Compound sordarin (1) sordaricin (2)  HO  CO2H CN  IC50 10 µg/mL >250 µg/mL  4, R = H  Compound 3 4  IC50 2 µg/mL 20 µg/mL  Table 1. Antifungal activity against Saccharomyces cerevisiae (strain YPH98) of sordarin and derivatives  Sordarin presents an aldehyde and a carboxylic acid in a vicinal arrangement. The tetracyclic framework of the molecule imposes a dihedral angle of 67° between these two groups,8 preventing cyclization to the corresponding pseudo-acid 5 (Scheme 1).  H  H OH  H  CO2H CHO 2  OH  X  H HO  O  O  5  Scheme 1. Prevention of hemi-acetalization  2  Unlike common antimycotic agents, which undermine the integrity of the fungal cell membrane by binding ergosterol or inhibiting its biosynthesis, 9 the target of 1 is the elongation factor 2 (EF2). 10 The compound thus stabilizes the EF2/ribosome complex, thereby blocking translocation and inhibiting protein synthesis. Such a novel mode of action has engendered considerable interest in sordarin as a new antimycotic resource. However, the natural product displays species-dependent activity. For instance, it is quite potent against pathogens such as Candida11 (Table 2), or against Saccharomyces cerevisiae,12 but it appears to be inactive toward other fungal organisms. As a result, pharmaceutical laboratories have sought analogs with a broadened spectrum of activity.  Sordarin  C. albicans 2005E  C. glabrata 2375E  C. neoformans 2867E  IC50  0.01µg/mL  0.2µg/mL  0.06µg/mL  Table 2. IC50 of sordarin against common fungi  1.1.2 Semisynthetic analogs of sordarin Several pharmaceutical laboratories, notably Merck,  13  GSK,  14  Bristol-Myers-  Squibb,15 and Sankyo,16 have explored modifications of the glycosyl segment in order to improve bioactivity. For example, a series of analogs developed by GSK (Figure 2) showed increased potency against a variety of human pathogens including Candida, Aspergillus, and Pneumocystis species.  3  H  R  R=  H  O O  HO  H  O H  H H  O  COOH CHO  O  O GM193663  O  O  O  GW471552  O  O H  O  O GM237354  N  O  H  O H  GM191519  N O  H  O  GM222712  N  N O  O  O GW515716  GW471558  O  O  GW570009  Figure 2. Modifications of glycosyl part  Considerably less research activity has been reported in regard to possible modification of the terpenoid nucleus. It is known that conversion of the aldehyde function into a nitrile provides analogs with comparable or improved potency (cf. Table 1).13 More extensive alterations of the terpenoid nucleus are significantly more challenging and arguably require a great deal of synthetic work. Pioneering efforts in this area were reported in 1998 by Cuevas et al.17 These workers described substituted cyclopentanes of the type 6 as simplified analogs of the tetracyclic framework of sordarin (Scheme 2). The new compounds retain aldehyde, carboxylic acid and hydroxymethyl groups as pharmacophores. Interestingly, the dihedral angle between formyl and carboxy groups in 6 and 2 is very close to that of sordaricin.  H OH  OR  Br Br  H  CO2H CHO 2  CO2H CHO 6  O 7  Scheme 2. Simplified model of sordarin 4  The synthesis of these materials started with commercially available (+)-3,9dibromocamphor (7). Six different analogs were synthesized (Figure 3), all of which showed unsatisfactory activity towards C. albicans. However, analogs 8b, 10, 12 were between 3.6 and 6.7 times more potent than essentially inactive sordaricin in the C. albicans 2005E assay. These results indicate that simplification of the sordarin skeleton may be feasible.  OR  O O  CO2H CHO 8a R = H 8b R = Bz 9 R = MeOCH2CO 10 R = THP  CO2H CHO 11  O O  O  CO2H CHO 12  Figure 3. Synthesis of six cyclopentane analogs  However, a more thorough structure-activity correlation for the terpenoid core of these molecules has yet to emerge. The role and importance of the isopropyl group, carboxylic acid and tetracyclic structure are all unknown. As detailed in the following paragraph, previous total syntheses of the natural product did not address these issues.  1.1.3 Previous total syntheses of sordarin and its congeners To date, three total syntheses of sordarins have been published, by Kato, Mander and Narasaka. In the following, we provide only a brief outline of the key steps in these routes, since a comprehensive review on the subject appeared in 2008.18  5  H  OBn  Cl  13  H  H "addition" H  H  H  H MOMO  modification  H H OMOM 16  15  Diels-Alder O H  H  Cope  OBn OMOM  14 O OMe  functional group  BnO OMe  OMe  O  H  H  H OMOM 17  OH CO2Me CHO 18  Scheme 3. Key steps in Kato’s synthesis  The first total synthesis of optically pure sordaricin methyl ester (18) was achieved by the Kato group in 1993 (Scheme 3). 19 It relied on two key transformations for the construction of the tetracyclic diterpene core: a Cope rearrangement (15 to 16) and an intramolecular Diels-Alder reaction (17 to 18). The substrate for the Cope rearrangement was prepared by the merger of two cyclopentene units, chloride 1320 and aldehyde 14.21 Sordaricin methyl ester (18) was synthesized in 16 steps with an overall yield of 2 %. The Mander group reported initial model studies in 1991,22 and a full synthesis of sordaricin in 2003 (Scheme 4). 23 Again, a key step was an intramolecular [4+2] cycloaddition for the assembly of the bicyclo[2.2.1] subunit. Thus, the combination of iodide 19 and nitrile 20 led to 21. This compound underwent a retro-Diels-Alder reaction to give enone 22. After several functional group modifications, a Diels-Alder cycloaddition furnished sordaricin methyl ester, which was converted to sordaricin (2). The approach involved 27 steps with an overall yield of 3 %.  6  OMOM I  CN OMOM  addition  Retro-  H  O  OMOM  20 O Diene formation  H  Diels-Alder  O 19  OMOM  O  21 H  H  H  OMOM 22  OH  OH  Diels-Alder H  CO2Me CHO 23  CO2H CHO 2  Scheme 4. Key steps in Mander’s synthesis  Narasaka and coworkers avoided the use of Diels-Alder chemistry, relying instead on a novel Pd catalyzed Tsuji-Trost reaction to furnish the diterpene core. Their approach successfully yielded (±)- sordaricin in 200424 and (-)-sordarin in 2006.25 Key steps of their enantioselective synthesis of (-)-1 are outlined in Scheme 5.  H  O  O  H TBSO  O 25  Br  CO2Et  H  O  O H TBSO  24  OH H  H  Tsuji-Trost  H OCO2Et  26  H "  O CO2Et 28  CO2Et  H  Mt"  27  H  H  "  Mt  Me  OH  "  MeO H OHC  OPMB O F β-selective  O CO2Et 29  (-)-1 O  glycosidation  MeOPh 30  Scheme 5. Key steps in Narasaka’s synthesis  The natural product was synthesized through a β-selective glycosidation reaction of sordaricin ester 29 with glycosyl fluoride 30. A remarkable intramolecular Tsuji-Trost 7  reaction26 of allylic carbonate 27, followed by installation of the isopropyl group, delivered the core of sordaricin 28. The substrate for this reaction was obtained by sequential vinyl addition to 26, the product of condensation between ketones 24 and 25. In all, (-)-sordarin was reached in an overall yield of 5 % over 27 steps.  1.1.4 Previous synthesis of sordarin analogs in our laboratory A collaboration between our group and the Bayer CropScience Company was launched in the early 2000’s in order to explore the structure-activity relationship (SAR) of the terpenoid nucleus in greater detail. The objective of this effort was to devise a general route to sordaricin analogs. More accurately, we wished to create a building block that could be readily elaborated into a variety of structurally simplified analogs. Our design aimed for low cost and ease of execution. Issues of absolute stereocontrol were a secondary goal, at least at this stage. Certainly, this research could have led to an ultimate total synthesis of 1; however, this was not the principal objective of the work. A former member of our group, Dr. Arnaud Schüle, devised a synthesis of structures of the general type 32 through an intramolecular radical cyclization of compounds 33  R1 ?  1  ?  R  OR2 CN 31  n  n  O  Cl OR2 CN 33  R1 Z R1, R2 = alkyl chain R = "O"  Diels-Alder  R  ?  R2O  n  intramolecular radical cyclization  OR2 CN 32  n  Cl + CN  n = 0,1  OCH3 34  35  Scheme 6. Avenue to sordarin analogs by intermolecular Diels-Alder reaction  8  (Scheme 6).27 The size of the new ring formed during this step is determined by the length of the apical chain of 33, which may be obtained by an intermolecular Diels-Alder reaction of dienes 34 with 2-chloroacrylonitrile (35). Dienes 34 are available via a double alkylation of 3-alkoxycyclopent-2-en-1-one, which in turn is easily prepared from commercial 1, 3cyclopentanedione. The following example demonstrates the overall route (Scheme 7). Compound 36 was bis-allylated in 49 % yield. Enol silylation of enone 37 using TIPSOTf and Hünig’s base afforded cyclopentadiene 38, which reacted with 35 the presence of K2CO3 to furnish 39 in 53 % yield. Ketone 40 was obtained via hydrolysis of the vinyl ether, followed by an intramolecular AIBN-initiated radical cyclization. A straightforward sequence advanced 40 to alcohol 41, which was O-alkylated to produce a diverse family of ether derivatives. Scheme 7 illustrates the ethylation of 41 and the elaboration of the resultant to the final product 42, which was obtained in 5 % yield from compound 36 over 13 steps.28  LDA, allyl-Br  O  repeat 49%  OMe 36  TIPSOTf  O  Hünig base 37  OMe  CN  OTIPS  2. AIBN, TMS3SiH, 65%  39  OEt  OMe  K2CO3 53%  38 OH  1. NaBH4, 84% O 2. BnBr, NaH, 99%  OMe 1. 4N HCl, 96% Cl  35  TIPSO  CN  OTIPS  OBn  3. O3, 99% 4. NaBH4, 93%  40  CN  H OTIPS 41  1. NaH, Et-I O  2. Pd(OH)2, 44% 3. Swern ox., 85% CN  OTIPS 42  Scheme 7. Synthesis of analog 42  9  Six other analogs (Figure 4) were assembled in a like fashion and tested against a broad range of phytopathogenic fungi. Substances 43 and 44 showed marginal efficacy at 50 ppm; however, none of the new entities were particularly potent.  OC5H11  O OBn  CN  O  OBn  H OTIPS  CN  H OTIPS  CN OH  44  43  45 OEt  O  O  CN OH  O  OH CN 47  46  CN OH 48  Figure 4. Analogs synthesized by intermolecular Diels-Alder  Possible reasons for this may be the lack of an isopropyl, or other small alkyl group, at the position adjacent to the carbonyl functionality, and/or the absence of the bridgehead COOH group. Unfortunately, the Schüle strategy was not amenable to the preparation of more highly substituted variants of 32.  R  R bases,  O  NC  OTIPS  O  R'-X or R'-CO-R"  NC  49  OTIPS 50  G  G = Me, allyl, Me2C-OH, PhCH-OH 35  TIPSO  heat OMe 51  OMe  Cl NC OTIPS 52  Scheme 8. Limitations of the Schüle strategy  10  To wit, the alkylation of the enolate of 49 failed, arguably because of severe steric congestion around the nucleophilic site (Scheme 8). Moreover, the reaction of 51 with 35 failed to yield any of the desired 52. Evidently, the steric effect engendered by a mere methyl group suffices to extinguish the Diels-Alder reactivity of the diene. For this reason, analogous reactions of dienes carrying bulkier substituents, e.g., an isopropyl group, were not explored. It is apparent from the foregoing that the development of new medicinal agents from structurally unique natural products requires considerable synthetic work. Indeed, the challenge posed by the chemical synthesis of a complex molecular architecture is one of the engines driving progress and innovation in organic chemistry. Recent synthetic efforts towards the natural product, himandrine, provide an illustration of this principle.  1.2 Background information of himandrine 1.2.1 Structure and biology activity Himandrine (53), along with himbosine (54) and himandridine (55), were isolated from the bark of Galbulimima belgraveana, a plant that grows in Papua New Guinea and Northern Australia (Figure 5).29  MeOOC PhOCO  MeOOC AcO  OH  OAc  PhOCO  MeO N  himandrine (53)  MeOOC PhOCO  OH  MeO  OAc himbosine (54)  N  OH  N  himandridine (55)  Figure 5. Structure of himbosine, himandrine and himandridine  11  These  structurally  interesting  alkaloids,  which  incorporate  an  unusual  spiropyrrolidine annulated to a trans-decalin backbone, belong to the family of galbulimima. This family consists of 28 different alkaloids so far; absolute configurations of 18 alkaloids were established in 2006.30 These natural products, along with other isolated species, like himbacine, display anticholinergic activity and are thus of potential interest for the treatment of a number of human ailments.31  1.2.2 Previous syntheses of himandrine and its analogs The intricate structure of 53 and the promise of valuable bioactivity have attracted substantial attention in the synthetic arena. Pioneering work in this field was disclosed by Mander and coworkers, who in 2004 published the synthesis of compound 56, an analog of himandrine.32 In a retrosynthetic sense, compound 56 would issue from 57 through the C-N bond forming steps detailed in Scheme 9.  R  R'  R  R' N  NH2  SN2 ring closure 56 R' H  H  R' H  N-P 59  H R  Birch reduction O  H R  ring opening & functional group transformations Curtius rearrang.  H  OMe  N-P 60 Diels-Alder  LG  N-P 58  Wacker oxidation R' H  H R H  LG  57  reductive amination  R  R'  O  OTBS  R R''O2C  H MeOOC  OMe 61  OMe  62 63  Scheme 9. Mander’s retrosynthesis of analog 56  12  Intermediate 58 is reachable from compound 59, which was envisioned to result through a stereoselective Diels-Alder cycloaddition of 62 with 63, followed by Curtius rearrangement33 and Birch reduction. The Diels-Alder union of fragments 64 and 62 resulted in the stereoselective formation of adduct 65 (Scheme 10). Cleavage of the silyl enol ether provided the cis-fused isomer of decalone 66, which epimerized to the more thermodynamically favorable transisomer during release of the methyl ester with i-PrSNa in hot HMPA. The emerging acid was subjected to Curtius rearrangement and the intermediate isocyanate was trapped with MeOH to furnish carbamate 67.  TBSO  OMOM  OMe 64  1. nPrSNa HMPA, 97% 2. (COCl)2, then NaN3, 77%  H OMOM  H MeOOC  OMe 66  H MeOOC  OMe 65  O H  100 oC  HOAc, aq. THF  H OMOM  62  MeO2C  3. toluene, heat, then MeOH 100%  87% over 2 steps  O H  H OMOM  H MeOOCHN  OMe 67  Scheme 10. Opening moves of the Mander synthesis of a himandrine analog  Birch reduction of 67 took place with concomitant reduction of the ketone (Scheme 11). Alcohol 68 was MOM protected before acid-promoted isomerization to the conjugated enone. A series of redox operations served to cleave the newly formed cyclohexenone unit to provide a transient aldehyde, which was advanced to alkyne 70 using the Bestmann reagent.34  13  O H  HO H  H OMOM  H MeOOCHN  OMe  2. HOAc aq. THF  67 MOMO H  1. 9-BBN, 87% 2. OsO4, 75%  H OMOM  H MeOOCHN  H MeOOCHN  69  OMOM  MOMO  1. MsCl, 93% OH  MeO2CHN  73  O  MeO2CHN 70  OMOM  MOMO  72  N H  O  Li, NH3, 95%  71  OMOM  2. HCl/CHCl3 32% overall  OMOM  2. NaH, 97%  MOMO  1. MOMCl  68  MOMO  3. Pb(OAc)4, 70% 4. Bestmann O reagent, 91%  H  H OMOM  1. Li, NH3  1. PdCl2, CuCl, O2, 85% 2. Rh, H2, 95% 3. Dowex 50W 60%  nPrSH, HMPA 90%  N MeOOC OH  HO  N 74  Scheme 11. Mander’s himandrine analog synthesis  A second dissolving metal reduction reaction simultaneously converted the ketone to an alcohol and the alkyne to an alkene. This set up the stage for a nucleophilic closure of the pyrrolidine ring. After Wacker oxidation, in situ enamine formation, catalytic hydrogenation and global deprotection, the himandrine analog 74 was obtained in 3.2 % overall yield from compound 64 in 20 steps. In mid 2009, the first total synthesis of (-)-himandrine was achieved by the Movassaghi group at MIT. As shown in Scheme 12, compound 76 could be synthesized through a stereoselective intermolecular formal [3+3] cycloaddition between cyclic enamine 78 and enone 77. 35 Compound 76 could be advanced to intermediate 75, which might undergo spirocyclization to give himandrine (53).  14  MeOOC PhOCO  H OH  H OH  OH  H H  spirocyclization  H  MeO  N  N  MeO2C  53  H OH carboxylation H [O]  NH P 76  N P MeO2C  53  "Michael"  H O  OMe 75  N-HCl  H  OMe  H 77 R  OMe  H O  H  O  H H H  H  OMe  H OBz  H H  78  Scheme 12. Movassaghi’s retrosynthesis of (-)-himandrine  To begin the synthesis, a copper-promoted formal [3+3] cycloaddition occurred between iminium chloride 78 and enone 79 to afford imine 80 (Scheme 13). When this labile compound was then subjected to NaBH4 reduction, Cbz protection and hydrolysis, ketone 81 was obtained in a highly diastereoselective manner.  H OH  H  O  78  H  OMe  H N  79  O H OH H NCbz MeO2C  BuLi, CuBr  NH 80  H N  H O 82  1. TMSI, 66% H OMe 2. HF, 90%  2. Cbz-Cl, 50% 3. TsOH, 81% OMe  H  H O  OMe 4. CH2N2, 61%  81 H H H  NH MeO2C  1. POCl3, DMF, 71% 2. DDQ 3. Pinnick ox.  H H H  NH Cbz  O  H OH H H H  H OH  1. NaBH4  H H H  H O 83  H OH NCS OMe 89%  H H  H N MeO2C  H O 84  1. NaBH4, 90% OMe  2. BzCl, 87%  (-)-53  Scheme 13. Movassaghi’s synthesis of (-)-himandrine  Ketone 81 was advanced to compound 82 with the aid of Vilsmeier’s reagent,36 DDQ oxidation, 37 Pinnick oxidation 38 and diazomethane esterification. The Cbz group was removed by sequential treatment with TMSI39 and HF. The cyclization of compound 83 was  15  triggered by NCS via an intramolecular allylic displacement to yield intermediate 84. After 1,2 reduction and benzylation, the synthesis of the natural product (-)-himandrine (53) was completed in 7.3 % overall yield over 13 steps from compound 79.  1.3 Background information of lepadiformines 1.3.1 Isolation and bioactivity An equally telling instance of structural novelty driving chemical innovation is apparent from the synthetic work that has targeted lepadiformine and related alkaloids. Lepadiformine A (85) was isolated in 1994 from the marine tunicate Clavelina lepadiformis, collected in the Mediterranean off the coast of Tunisia, and later from Clavelina moluccensis, found off the coast of Djibouti. In 2006, Lepadiformine B (86) and C (87) were also isolated from C. moluccensis (Figure 6).40  HO  N R H H H  R= C6H13 Lepadiformine A (85) R= C4H9  H  N C4H9 H H H  Lepadiformine C (87)  Lepadiformine B (86)  Figure 6. Structures of lepadiformines  The compounds exhibited in vitro cytotoxicity against human nasopharynx carcinoma KB, murine leukemia cell line P388, Human colonic adenocarcinoma cell HT29 and non-small-cell lung carcinoma NSCLC-N6 (Table 3). They also displayed in vitro and in vivo cardiovascular effects attributable to the blocking of potassium channels in the cardiac muscle.41  16  Substrates KB HT29 P388 P388 doxorubicin-resistant NSCLC-N6  IC50 (µg/mL) 9.20 0.75 3.10 6.30 6.10  Table 3. Bioactivity of lepadiformine A  The biological potency and interesting structures of the lepadiformines have elicited a great deal of interest from the organic chemical community. A number of total syntheses, both of the racemate and of enantioenriched material, have been achieved.  1.3.2 Previous total syntheses of lepadiformine A An excellent review of the voluminous literature on this subject was published by Weinreb.42 The reader is referred to this landmark publication for details of synthetic work that appeared in print through early 2006. Two representative syntheses of enantioenriched lepadiformines are summarized to show the key steps employed in the approaches. In 2002 the Weinreb group published an enantioselective synthesis of 85 (Scheme 14).43 Alkene 91 was prepared through a condensation between (S)-Cbz-lactam 88 and lithio (Z)-allylsilane 89, followed by a selective Lewis acid induced attack of the tethered allylsilane. After elongation of the terminal alkene, redox,44 protective manipulations, and cyanide addition, alpha-amino nitrile 93 was obtained. A Grignard addition (dr 3:1 desired/undesired) to iminium ion 94, prepared in situ by the expulsion of cyanide, and removal of the Bn group, afforded (-)-85 in 8.3 % overall yield from compound 88.  17  Li Ph Si  N O Cbz 88  TMS Ph  89  Ph  N H H Cbz  Si 90  N H Cbz  OMe  hydroformylation Si  TMS  addition  HO H  NH H  BnO  OMe  93  92  91  N CN H H H  C6H13 BnO H  BnO  N H H  94  N  H H H 95 dr 3:1  C6H13  (-)-85  Scheme 14. Weinreb’s synthesis  In the same year Kibayashi et al developed a more convergent synthesis of (-)lepadiformine A (Scheme 15).45 Boc-protected lactam 96 was attacked by Grignard reagent 97 and the resultant was treated with formic acid to yield intermediate 99. After hydrolysis, MnO2 oxidation and (S)-BINALH induced 1,2-reduction of the corresponding enone, allyic alcohol 100 was obtained in a highly diastereoselective manner. This enantiopure compound was then hydrogenated and Boc-deprotected to give precursor 101. A SN2 replacement, followed by debenzylation, occurred to afford (-)-85 in 9 steps with a 32 % overall yield from compound 96.  18  MgBr OBn  N O Boc  C6H13 97  96  OCOH BnO  addition BnO then HCOOH  OH  redox  C6H13  N H H Boc  98  BnO  N H H Boc  99 OH BnO H  C6H13 97% de  100  SN2 BnO  C6H13  NH H  C6H13  N H Boc  101  (-)-85  N C6H13 H H H 95  Scheme 15. Kibayashi’s synthesis  Several total syntheses of 85 have been disclosed since the publication of Weinreb’s review.46 Two representative racemic syntheses will be discussed. In 2007, Craig and his group46c obtained (±)-lepadiformine A through a sequence that involved the cyclization of 105 and the introduction of the side chain via a stereoselective alkylative cleavage of an  O  O O  1. Me3S(O)I NaH, 96%  SES-HN N HO  2. SES-NH2 85%  102  103  BuLi, 97%  SES-HN 105  O O  O  SES-N  PMe3, 95%  O  2 eq. nBuLi BnOCH2CHO  PhO2S  PhSO2Me  O  N= )2 O 104  O  PhSO2  then PhCOCl 60%  BnO  O  N SES  O 106  PhSO2  PhSO2 N BnO SES 107  1. TBAF, 97%  O O  N  2. BBr3, 85% O  108  Scheme 16. Craig’s synthesis of (±)-lepadiformine A (Part I)  19  oxazolidine with an alkynylmagnesium reagent. Thus, ketone 102 was subjected to CoreyChaykovsky reaction, and the emerging epoxide underwent regioselective opening upon treatment with 2-(trimethylsilyl)ethylsulfonamide to afford 103. This substance underwent Mitsunobu cyclization to aziridine 104, which was nucleophilically cleaved with the anion of phenyl methyl sulfone to furnish 105. The elaboration of the latter to 107 involved an unusual 5-endo-trig nucleophilic addition of the anionic form of the sulfonamide to vinyl sulfone 106. Ensuing TBAF and BBr3 deprotection gave the tricyclic aminal 108 (Scheme 16). Oxazolidine 108 reacted diastereoselectively (dr 86:13, Scheme 17) with the chloromagnesium derivative of 1-hexyne to afford 109, which was elaborated to 110. This substance is an epimer of the natural product, from which it differs for the configuration at C-1. Epimerization of this stereocenter was therefore achieved through Jones oxidation to an acid and esterification thereof, followed by treatment with NaOMe and final LAH reduction. The final 85 resulted in 23 % yield over 16 steps from compound 102.  PhSO2  PhSO2 N  C4H9C CMgCl  108  C4H9  1  MeOOC  2. MeOH H2SO4  N  NaOMe  109  1  MeOOC  N  111  LAH, 88%  85  over 4 steps  C6H13  C6H13  1  HO  N 3. Na/ NH3 C6H13 4. TsOH 70% over 4 steps 110  N  99% dr 86:13  O  1. Jones oxidn.  HO  1. DHP, TsOH 2. Pd(Al2O3), H2  112  Scheme 17. Craig’s synthesis of (±)-lepadiformine A (Part II)  20  In 2008, Lygo reported another synthesis of racemic 85 that involved a concise 9 step sequence (the authors claim 7 steps).46d The key transformation was an intramolecular hetero-Diels-Alder reaction of a diene with an imine (Scheme 18). Commercial trans-2nonenal (113) was transformed into ketone 114 in a straightforward manner. The anion of glycine derivative reacted with 114 in a Michael mode, and the resultant was converted into imine 115 under aqueous acidic conditions. Heating of 115 in HFIP triggered the diastereoselective (dr 5 : 1) formation of 116, which formally arises through an endoselective Diels-Alder reaction. The minor product of the reaction is believed to be the exodiastereomer. While no secondary orbital interactions 47 subsist in the present case, the authors suggest that conformational effects may be responsible for the observed endoselectivity. In any event, this (apparent) cycloaddition step occurred exclusively from the imine face opposite the carboxy substituent, and proceeded with concomitant release of the tert-butyl ester (recall, HFIP is an acidic solvent). The synthesis was rapidly completed by hydrogenation of the double bond and reduction of the acid. The overall yield of 85 was 14 % from 113 over 9 steps.  O CHO  C6H13  1. BrPh3P  5 COOH  2. I2 113  (CF3)2CHOH 53% dr 5:1  3. MeNHOMe, 94% 4. H2C CHMgBr 79%  HOOC C6H13  COOtBu  Cs2CO3, 114  2. aq. citric acid, 77%  C6H13  1. Pd/C, H2 N  1. Ph2C N  89%  BuOOC 115  N  C6H13  85  2. LAH, 52% 116  Scheme 18. Lygo’s synthesis  21  Not immune to the challenges posed by the unusual structures of the foregoing natural products, we have carried out studies aiming to develop new methodology to facilitate their assembly and to illustrate the opportunities offered by such advances in the context of total synthesis. Such endeavors have, of course, generated structurally novel intermediates for biological evaluation. In the next chapter, we shall detail research directed toward the synthesis of analogs of sordarin, with the aim to identify new classes of potential antifungal agents. We shall also illustrate the development of new methodology for the creation of spirocyclic heterocycles and its application to the natural product synthetic study.  22  2. SYNTHETIC STUDIES OF SORDARIN, HIMANDRINE, LEPADIFORMINE AND METHODOLOGY THEREOF  In this chapter, we shall discuss the synthesis of sordarin analogs, the development and optimization of oxidative amidation reactions, and the application of such a methodology to the synthesis of the himandrine skeleton and to synthetic study of (-)lepadiformines.  2.1 Sordarin analogs via an intramolecular Diels-Alder reaction. 2.1.1 Retrosynthesis of sordarin analogs In the introduction, we outlined several difficulties that were encountered during efforts aiming to reach an advanced intermediate suitable for the generation of sordarin  CO2Me  CO2Me  X'  O  CN Z  CN Z R  R  O  X  X  O CN Z  CO2Me  X'  119  118  117  R  R = H or alkyl Z= COOH, CN, OMe P= protective group  CO2Me  CO2Me  O O O  OP  O CN Z  R 125  PO  R  CN Z  R  120 acylation  redox  intramolecular Diels-Alder  CO2Me  CO2Me  O CO2Me  OHC  Michael  124  R  OP  P'O CN Z  O R'O  121  BaylisHillman  R  1,4-addition 123  P'O CN Z 122  R enol silylation  Scheme 19. Retrosynthetic plan of sordarin analogs by intramolecular Diels-Alder  23  analogs (Scheme 19). One of the objectives of this dissertation is to resolve the foregoing problems through the implementation of an intramolecular Diels-Alder reaction as an avenue to sordaricin building blocks. The chosen approach relies on Diels-Alder cyclization of 122 to tricyclic intermediate 121, which could be elaborated to sordaricin congeners 117 – 119. A key step in the assembly of monocyclic precursor 123 would be a Baylis-Hillman reaction of aldehyde 124 with acrylonitrile. Substrate 124 can be readily prepared from 2alkylcyclopentanedione.  2.1.2 Model study of sordarin analog A model study to validate the planned approach was carried out starting with commercial 1,3-cyclopentanedione (126, Scheme 20). In accord with Porta, compound 126 was converted into 127 in 80 % yield upon exposure to TiCl4/MeOH.48 However, we found that 127 was obtained in quantitative yield by O-methylation of 126 using dimethyl sulfate and K2CO3 in refluxing acetone. Deprotonation of enone 127 with LDA produced a kinetic enolate, which was trapped with the Mander reagent 49 to give 128. 50 Michael reaction between 128 and acrolein, catalyzed by DBU (2 mol % in MeCN), afforded highly pure aldehyde 129 in 99 % yield after an aqueous workup.  O  O  O K2CO3  LDA  Me2SO4 O 126  99%  DBU  MeO2CCN OMe 127  52%  CO2Me  acrolein  MeO2C OMe  99%  128  CHO  OMe  O 129  Scheme 20. Preparation of aldehyde 129  24  The use of THF as the solvent for this reaction produced inferior results. The desired compound was formed together with several contaminants that had to be removed chromatographically. However, 129 proved to be intolerant of silica gel, contact with which promoted its decomposition. This was accompanied by the development of a pink color in the column, suggesting that the compound was undergoing self-condensation to a conjugated system. An NMR assay of a batch of crude product 129 obtained from a reaction run in THF indicated a yield of 85 %. However, purification of a small aliquot (ca. 200 mg) of this mixture returned only about a 10-15 % yield of 129; while attempted chromatography of a larger batch of material (grams) resulted in complete loss of product. Reactions run on a gram scale in MeCN required approximately 12 hours (overnight) to complete. Attempts to accelerate their rate by increasing the amount of base elicited the opposite effect. Thus, stalling at an intermediate extent of conversion occurred. This is probably attributable to a competing retro-Michael reaction of 129, which is accelerated by larger amounts of DBU.  CO2Me CHO  CO2Me  CH2=CH-CN  OMe  DABCO dr 1.5:1 57%  O 129  HO  OMe NC  72% CO2Me  CO2Me OMe NC  OTIPS  Hünig base  O 130  TIPSO  TIPSOTf  OMe  TIPSO NC  OTIPS 132  131  Scheme 21. Model intramolecular Diels-Alder reaction  25  Baylis-Hillman reaction51 of 129 in neat acrylonitrile produced allylic alcohol 130 as a ca. 1.5 : 1 mixture of two unassigned alcohol diastereoisomers (Scheme 21). Since these two isomers would ultimately be oxidized to a ketone, no effort was made to separate them at this stage. The kinetics of the Baylis-Hillman reaction are notoriously slow; indeed, two days were necessary to achieve complete conversion of 129 to 130. Exposure of the latter to TIPSOTf and Hünig’s base produced Danishefsky-type52 diene 131, which spontaneously underwent intramolecular Diels-Alder reaction at room temperature. Tricyclic compound 132 thus emerged in 18 % overall yield from 126 over 5 steps. The use of TESOTf instead of TIPSOTf in this reaction resulted in significantly diminished yield.  2.1.3 Synthesis of sordarin analogs Encouraged by the success of the model study, we proceeded to extend the strategy to a series of compounds emanating from 2-isopropyl-1,3-cyclopentanedione (133). This material was prepared as described by Majetich,53 and it was converted into the vinylogous  O  methylation O 133  No. 1 2 3 4 5 6 7  O OMe 134  Reagent (MeO)3CH TiCl4 / MeOH TsOH/ MeOH DMF + (COCl)2 then KOH / MeOH Me2CO3 Me3OBF4 Me2SO4  Yield 39 % 80 % 65 % 70 % 77 % 82 % 99 %  Table 4. Methylation of compound 133  26  ester 134 using the Me2SO4 / K2CO3 method (vide supra). This procedure performed significantly better than other methods (Table 4). The subsequent acylation of ketone 134 requires the regioselective formation of anion 139, which corresponds to the thermodynamic isomer of the enolate (Scheme 22).54 The regioselectivity of deprotonation of 2-alkyl-3-alkoxy-cyclopentenones has been thoroughly studied by Koreeda, who determined that the action of LDA produces the kinetic enolate 136, while LHMDS yields the thermodynamic isomer, 138. 55 Such an effect is attributable to differences in the rate of deprotonation of the substrate. Thus, LDA is more basic (pKa ca. 37) than LHMDS (pKa ca. 28)56 and it is also kinetically more reactive. This ensures a rapid, irreversible, sterically controlled deprotonation of the substrate via a tightly bound (Zimmerman-Traxler-type) transition state, 57 leading to a kinetic enolate. The slower rate of deprotonation with LHMDS is believed to permit concomitant equilibration of the  G N G  H Li MeO  O  G = i-Pr  H  fast, irrev.  135  R  MeO R  OLi  136 kinetic enolate  G = TMS slow H  MeO  MeO  MeO R  OLi  136 kinetic enolate  O  R 137  R  OLi  138 thermodynamic enolate  Scheme 22. Presumed course of the deprotonation of 135 with LDA and LHMDS  enolate isomers, presumably through proton transfer between a molecule of enolate and a molecule of intact ketone, resulting in formation of the thermodynamic enolate. In accord  27  with these important observations, we found that treatment of 134 with LDA followed by addition of the Mander reagent gave compound 140 in 85 % yield, while the conduct of the  LDA / THF, or LHMDS / THF /  O MeO2C  140 product from kinetic enolate  HMPA, then MeO2C-CN 85% with LDA 80% with LHMDS  O  OMe  OMe 134  O LHMDS / THF then MeO2C-CN 81 %  MeO2C  OMe  141 product from thermodynamic enolate  Scheme 23. Thermodynamic and kinetic products  same reaction with LHMDS in THF furnished required isomer 141 in 81 % yield (Scheme 23). However, we also discovered that deprotonation of 134 with LHMDS in the presence of HMPA, followed by Mander reagent, again yielded product 140 arising from the kinetic enolate. This observation is consistent with the documented ability of HMPA to accelerate the rates of many organometallic reactions.58 Evidently, this cosolvent accelerates the rate of deprotonation of 134 to such an extent that equilibration by the above mechanism is no longer possible. A drawback of the Mander reagent is the release of toxic cyanide upon reaction with nucleophiles. In the interest of eliminating this hazard, we examined the acylation of 134 with phenyl methyl carbonate. Disappointingly, the desired 141 was obtained in a modest 40 % yield (Scheme 24).  28  O  O  LHMDS / THF OMe  PhO-CO2Me  MeO2C  40%  134  OMe 141  Scheme 24. Acylation with phenyl methyl carbonate  The next two steps involve the transformation of ester 141 into alcohol 143 (Scheme 25). Michael addition of 141 to acrolein in the presence of 2 mol % DBU in MeCN led to aldehyde 142 in quantitative yield. Again, this sensitive compound was immediately committed to a subsequent Baylis-Hillman reaction, which, however, proceeded at an abnormally slow rate. Four days were required for complete conversion into 143 upon dissolution of the substrate in neat acrylonitrile containing 20 mol % of DABCO. Other solvents like MeOH, or catalysts, like tributylphosphine, did not facilitate the reaction to any appreciable extent. Fortunately the yield of 143 was a satisfactory 68 % isolated yield. The reasons behind the poor reactivity of 142 remain unclear. Regardless, a 9-fold rate acceleration was achieved under Aggarwal conditions,59 which involve the use of a catalytic amount of the 1:10 complex of La(OTf)3 (5 mol %) and triethanolamine (50 mol %) as a Lewis acid promoter. However, the yield of 143 dropped to 50 % (after chromatography). We thus favored the longer, but higher-yielding, traditional protocol.  CO2Me O  CO2Me acrolein DBU 99%  MeO 141  OHC  O  MeO  CO2Me CH2=CH-CN DABCO dr 1.5:1  142  68%  HO NC  O MeO 143  Scheme 25. Preparation of compound 143  29  The formation of Danishefsky-type diene 144 upon treatment of 143 with 2.5 equivalents of Hünig’s base and 2.2 equivalents of a trialkylsilyl triflate in DCM at 0 oC again triggered intramolecular Diels-Alder reaction (Scheme 26). Either TIPSOTf, TBSOTf, or  CO2Me HO NC  ROTf O MeO  CO2Me  CO2Me  OR  OR  Hünig Base  RO  RO  OMe CN 144  143  145 R = TES, 52% dr 52:48 146 R = TBS, 45% dr 51:49 147 R = TIPS, 61% dr 63:37  CO2Me O  HF·Pyr 100%  HO  OMe CN 148  OMe CN  CO2Me Swern ox. 67%  O  O NC  OMe  149  Scheme 26. Preparation of analog 149  TESOTf functioned effectively in the present case, providing 145, 146, and 147 in 61, 45 and 52 % yield, respectively. The products were formed as mixtures of diastereoisomers at the level of protected hydroxy substituents. The release of the TIPS groups in 147 using either TBAF or HF·Pyridine complex was very slow. Prolonged exposure to these fluoride reagents induced extensive degradation of the substrate. Fortunately, the more labile TES group in 145 was smoothly cleaved with HF.Pyridine complex in MeCN to provide a mixture of the two diastereoisomeric alcohols 148 in quantitative yield. Swern oxidation of these produced the tricyclic sordaricin analog 149 in 67 % yield. In all, intermediate 149 was synthesized in 19 % overall yield from 133 over 7 steps.  30  Compounds of the type 149 possess a bridgehead alkoxy group, whereas a COOH unit is present in the natural products. Access to a series of tricyclic compounds more closely resembling 1 requires an advanced intermediate 150 (Scheme 27), wherein Z is a carboxy functionality or an equivalent thereof.  CO2Me O  O NC Z 150  CO2Me RO NC  OR Z  151  OR NC  CO2Me O  MeO  i-Pr 152  Z additionelimination [?]  Scheme 27. Retrosynthesis of compound 150  Among several possibilities for the assembly of the requisite educt, an especially attractive one involves a selective 1,4-addition-elimination of a nucleophilic form of Z onto the enone segment of compound 152. But this material contains two electrophilic sites, the second and undesired site of reactivity being the conjugate position of the side chain nitrile. We presumed that selective addition of Z to the enone might be possible through the use of a Lewis acidic catalyst that would preferentially coordinate the C=O group over the CN functionality. It seemed likely that if the nucleophile were cyanide ion, then the desired transformation was achievable through the use of the Nagata reagent (diethylaluminum cyanide).60 This would be a consequence of the strongly oxophilic nature of Al3+.61 A nitrile version of 150 (Z = CN) could display interesting biological properties of its own. Alternatively, the bridgehead cyano could be later hydrolyzed to a carboxylic acid. To test these hypotheses, the OH group in 143 was protected as a TBS ether and the resultant 153 was treated with Nagata reagent (Scheme 28). Indeed, a selective reaction  31  occurred, which produced nitrile 154 in 56 % yield over the 2 steps. Alcohol silylation was best effected by the use of TBSCl, imidazole and a catalytic amount of DMAP in DMF. Other conditions, like TBSOTf and 2,6-lutidine or TBSCl / NaI, were less satisfactory. Also, the Nagata reagent proved to be superior to TMSCN in combination with AlEt3 62 or to acetone cyanohydrin in methanol.63  CO2Me  CO2Me HO NC  O  TBSCl  O Et AlCN 2  TBSO  75%  MeO  CO2Me  75%  CN OMe 153  143  O TBSO CN CN 154  CO2Me  ROTf RO Hünig base  OR  CN NC 155  R = TES, TBS, TIPS  Scheme 28. Failure of enol silylation of compound 154  Unexpectedly, cyanoenone 154 failed to yield a silyl enol ether 155 upon reaction with a diversity of silylating agents. The compound was immune to the action of silyl triflates in the presence of Hünig’s base, and it was recovered unchanged after many such attempts. Silyl enol ether formation also failed to occur under Corey-Gross (LDA, R3SiCl),64 Miller (TMS2NH, TMSI),65 and Lewis acid-induced (ZnCl2, TiCl4)66 conditions. The ketone also resisted the action of specialized reagents such as N,O-bis(trimethylsilyl)acetamide and N,O-bis(trimethylsilyl) trifluoroacetamide. 67  It should be noted that cyanoenone 156  reportedly forms a silyl enol ether 157 without difficulty (Scheme 29).68 The failure of 154 to undergo the same reaction was baffling, and the reasons for such a behavior remain unknown.  32  ZnCl2/ Et3N NC  O 156  TMSCl  NC  57%  OTMS 157  Scheme 29. Reported formation of Danishefsky-type diene  In an effort to circumvent the problems affecting enol silylation of 154, we targeted diene 158 (Scheme 30) with the intent of inducing Diels-Alder cyclization to 159. This  CO2Me  CO2Me  [?] TBSO  TBSO CN CN  NC  H  H  CO2Me  CO2Me CHO 160  CN 159  158  H  CO2Me  Toluene, 40 °C 100%  H  CO2Me CHO 161  Scheme 30. Possible intramolecular Diels-Alder reaction of 158  closely parallels Mander’s approach,23 which relied on the IMDA of compound 160. The diene was readily made by Luche reduction69 of 154 and Burgess70 dehydration (Scheme 31). However, no IMDA whatsoever occurred upon prolonged heating of 158 at temperatures below 160 ºC. Above this temperature, the material polymerized.  33  CO2Me  CO2Me TBSO  51%  CN CN  Burgess  OH  Luche  O TBSO  54%  CN CN 162  154  CO2Me  CO2Me TBSO  TBSO  NC  CN CN  CN 159  158  Scheme 31. Unsuccessful intramolecular Diels-Alder route  The foregoing difficulties induced us to question whether 154 could form an enolate at all. To address this issue, 154 was treated with NaH in THF, whereupon Michael cyclization occurred to afford compound 165, as a mixture of diastereomers, in 29 % yield (Scheme 32). Of course, we cannot exclude an alternative reaction pathway leading to 165 via an anionic Diels-Alder reaction, followed by retro-Michael fragmentation. In any event, this experiment confirmed that the enolate of 154 is accessible, and induced us to research a method for the formation of the corresponding silyl ether.  CO2Me O  CO2Me NaH  TBSO  O TBSO  CN CN  CN CN Michael  163  154  O  CO2Me  D-A  OMe CN  retro TBSO  O NC CN 164  Michael  TBSO O 29% yield  NC 165  Scheme 32. Synthesis of Michael adduct 165  34  Success came about in the form of an unusual enol silylation protocol. Exposure of the ketone to an excess of LHMDS and LiCl71 in THF/HMPA, and trapping with TBSCl, delivered the desired diene 166 in 82 % yield (Scheme 33). The corresponding TMS enol ether was too labile, while the TES or TIPS enol ether afforded poor yields in the subsequent intramolecular Diels-Alder reaction.  TBSO  O  CN NC  CO2Me  CO2Me  CO2Me  LHMDS, LiCl TBSCl, HMPA  Toluene  TBSO  OTBS  CN NC  82%  OTBS NC  77%  CO2Me  CO2Me Dess-Martin  HO  OTBS NC  CN  167  166  154 HF·Pyr  TBSO  140 oC  CN  50% over 2 steps  O  OTBS NC  CN  169  168  Scheme 33. Preparation of analog 169  The latter step was also problematic. Compound 166 displayed no tendency to undergo IMDA reaction at or near room temperature. Indeed, it required thermal activation to 140 ºC for 12 h in a sealed tube to afford cycloadduct 167, a ca. 1:1 mixture of diastereoisomers, in 77 % chromatographed yield. After selective deprotection of the vicinal  CO2Me  CO2Me OMe  TIPSO NC  OTIPS 132  O  O NC  OMe 149  CO2Me O  OTBS NC  CN 169  Figure 7. Sordarin analogs 132, 149 and 169  35  cyanohydrin with HF and Dess-Martin oxidation, analog 169 was obtained in 6 % overall yield from 133 over 10 steps.  Model study O  O  O K2CO3  LDA  Me2SO4 O  99%  HO  DABCO  NC  57%  OMe  52%  OMe  O  99% CO2Me  CO2Me  CH2=CH-CN  CHO  DBU  MeO2CCN OMe  CO2Me  acrolein  MeO2C  TIPSOTf  OMe O  OMe  TIPSO  Hünig base  NC  61%  OTIPS  IMDA pathway with iPr substituent  O  O  K2CO3  CH2=CH-CN DABCO  OMe MeO2CCN 81% MeO C 2  Me2SO4 99%  O  O  LHMDS  68%  O  CO2Me OHC  O  MeO  CO2Me TESOTf  MeO  DBU 99%  OMe  CO2Me HO NC  acrolein  OTES  Hünig base TESO 52%  OMe CN  CO2Me HF·Pyr  Swern ox. 67%  O  O NC  CO2Me  CO2Me TBSCl 75%  O Et2AlCN TBSO  75%  CN OMe  O TBSO CN CN  82% CO2Me  CO2Me O  OTBS NC  CN  HF·Pyr Dess-Martin 50%  OTBS NC  CN  LHMDS, LiCl TBSCl, HMPA CO2Me  Toluene  TBSO  OMe  140 oC 77%  TBSO CN NC  OTBS  Scheme 34. A summary of synthetic routes to sordarin analogs  36  In conclusion, we have described syntheses of building blocks 132, 149 and 169, which are useful for the preparation of analogs of the potent antifungal agent sordarin (Figure 7). Congeners of 1 constructed from these analogs should permit detailed SAR investigations of the terpenoid core of the natural product. Further studies will be performed to investigate the biological activity of these analogs. Coupled with the observations recorded during efforts centering on modification of the glycosyl sector, this knowledge may well lead to new antifungal agents with a broad spectrum and potent activity. A summary of synthetic routes to analogs 132, 149 and 169 is listed in Scheme 34. A second, equally important goal of this thesis is the refinement of a reaction developed in these laboratories, the oxidative amidation of phenols. This technology is a key to ongoing work toward himandrine and lepadiformine. We shall discuss these in the following chapters.  37  2.2 Oxidative amidation of phenols In the oxidative amidation of phenols, a 4-substituted phenolic substrate 170 is converted into a 4-amidodienone 171 (Scheme 35). The reaction may also be carried out with 2-substituted phenols, and can occur either in the intramolecular or bimolecular mode. The overall process offers interesting opportunities in the synthesis of nitrogenous substances,72 as demonstrated in the total synthesis of the natural products, (-)-cylindricine C,73 FR901483 and TAN1251C.74  N  (CF3)2CHOH  HO 170  N  PhI(OAc)2  N = amide nitrogen  O 171  Scheme 35. Oxidative amidation of phenols  However, as with any methodology, this method has limitations. Reactions are usually performed in polyfluorinated alcohol solvents such as hexafluoroisopropanol (HFIP), which are expensive. Yields range from fair to good, and purification is sometimes problematic due to the formation of polymeric by-products. In order to overcome these difficulties, improve the efficiency of the reaction, and further explore the scope of this methodology, we have researched a more efficient and practical procedure. In this section we detail improved protocols for the conduct of both bimolecular and intramolecular variants of this reaction, using either para- or ortho-substituted phenols.  38  2.2.1 Bimolecular oxidative amidation of phenols This transformation converts a 4-substituted phenol 172 into a 4-acetamidodienone 173 by treatment with a hypervalent iodine reagent such as diacetoxy iodobenzene (DIB) and acetonitrile (Scheme 36). The original procedure75 entailed the conduct of the reaction in a 1:1 mixture of MeCN and HFIP. Products 173 were isolated in 40-60 % yield from reactions run on small scale (200-300 mg). However, ongoing synthetic research unveiled several problems during scale-up. Yields dropped substantially on scales greater than 500 mg, and the product was accompanied by a multitude of polymeric contaminants, necessitating costly and time-consuming flash chromatographic purifications. Also, the cost of HFIP, even when recycled from previous runs of the same reaction, became a serious issue on large scales. 76 The objective of this investigation was threefold. First, it was necessary to find conditions suitable for the conduct of the reaction on scale and in synthetically useful yields. Furthermore, it was essential to suppress the need for expensive HFIP. Finally, the formation of polymeric byproducts had to be contained or suppressed. These side reactions consume substrate in a non-productive manner and complicate isolation and purification schemes.  R HO  MeCN 172  NHAc  PhI(OAc)2 HFIP  R O 173  Scheme 36. Previous bimolecular oxidative amidation  A mechanistic understanding of the reaction is necessary in order to address the aforementioned problems. The reaction is believed to commence with the ionization of DIB  39  S  HO  H O Ph  I  Ph I  O HOAc  OAc  R  R  R  H-S  O  O  OAc  Ph  I  175  Ph I  OAc 176  O  S H O 177  Me  174  Nu :  HOAc  R  O  :  Ph-I Ph  N  R  O  I 178  O  179 Nu  Nu = OAc or HFIP O  NHAc  H2O  R  R 180  Me  N  Me  N  R  HS: H-donating solvent  O 173  181 When Nu: = MeOH  R  O  OMe  MeOH  R O  179  182  Scheme 37. Possible oxidative amidation mechanism and pathway  promoted by hydrogen bonding with a molecule of relatively acidic (pKa  = 9.3) HFIP.77  This would yield iodonium ion 175, which combines with the phenol to form presumed complex 176. Solvent-assisted ionization of the latter results in formation of a new iodonium species 178, which undergoes fragmentation to a molecule of iodobenzene plus one of the presumed reactive intermediate 179. This cationic agent is intercepted by MeCN in a Rittertype mode.78 Presumed nitrilium ion intermediate 180 then reacts with acetate ion or with HFIP to form 181, which is hydrolyzed to the final product 173 upon aqueous workup (Scheme 37). Previous study has shown that in aprotic solvents such as MeCN, MeNO2 and CH2Cl2, the reaction between 4-substituted phenols and PhI(OAc)2 proceeds poorly and  40  furnishes unidentified polymeric products. If protic solvents like alcohols or water are employed, alleged reactive intermediate 179 undergoes solvolysis to give products 182.79 As suggested by Kita,80 protic but non-nucleophilic solvents like polyfluoroalcohols react less readily with species such as 179 and enable their capture with various other nucleophiles, in both an intra- and an intermolecular manner. Fluoroalcohol solvents, especially HFIP, have since become a standard feature of many such reactions. Noteworthy examples of this chemistry involving carbon nucleophiles have recently been disclosed by Canesi.81 One modification 82 of the oxidative amidation of phenols leads to products 173 through the reaction of the substrate with the more reactive, but also more expensive, 83 phenyliodine bis(trifluoroacetate), PhI(OCOCF3)2 (PIFA) in neat MeCN. Arguably, the use of PIFA was mandated by the very poor solubility of DIB in pure MeCN. Attempts to adapt this procedure to our own objectives resulted in formation of the desired 173 (30 % yield after chromatography) as a component of a complex mixture of products. Thus, while the use of PIFA eliminated the need for HFIP, it did not overcome the formation of polymeric materials. An attempt to carry out the reaction by the use of the milder DIB (again, poorly soluble in MeCN) resulted in the exclusive formation of polymeric byproducts. The source of polymeric byproducts must be a competitive reaction, wherein the presumed electrophilic species 179 combines with a molecule of intact phenol via an electrophilic aromatic substitution process (Scheme 38). If so, the probability of interaction between two species (reactive species 179 and starting phenol) could be diminished by the use of higher dilutions. A practical way to do so would be to add the substrate slowly, maybe with a syringe pump, to a solution of oxidant in MeCN. Increasing the solubility of DIB in the medium should also have a beneficial effect. The reagent rapidly oxidizes the phenol to (presumed) reactive intermediate 179. By increasing the DIB concentration, one would 41  drastically diminish the quantity of intact phenol remaining in solution after the addition of each aliquot of substrate. Low temperatures may also favor solvolysis of 179 over electrophilic aromatic substitution, because of a slower rate of diffusion of solvated intermediates. Thus, solvated 179 may more easily react with a molecule of MeCN located in its solvation sphere.  R  CH3CN  H CH3CN  CH3CN  HO H  CH3CN  CH3CN  CH3CN  H  R  R O  O CH3CN  H  H  179  CH3CN  Situation A concentrated  H  179  CH3CN  CH3CN  Situation B diluted  Scheme 38. Effect of concentration  On the other hand, the postulated reaction mechanism holds that protic solvents favor the dissociation of hypervalent iodine complexes by hydrogen bonding or reversible protonation. Some facts84 also demonstrate that other acidic reagents, like heteropolyacids or TMSBr, promote DIB activation in aprotic media. This suggests that HFIP could be replaced with a suitable non-nucleophilic Lewis or Bronsted acid. In conclusion, three major factors are anticipated to influence the product distribution of the reaction: (1) the choice of Lewis or Bronsted acid activator of the hypervalent iodine agent; (2) the concentrations of oxidant and of substrate, and (3) the temperature. Compound 183, methyl 4-hydroxyphenyl acetate, was employed to study the effect of different Lewis and Bronsted acids on oxidative amidation in dilute MeCN solution (8mM). The results showed that Lewis acids, specifically, BF3•OEt2 and TiCl4, and Bronsted  42  acids such as TsOH•H2O, AcOH, 4M HCl in 1,4-dioxane, 98 % H2SO4, 85 % H3PO4, and 70 % HNO3, did not give any of the desired dienone product. Instead, intractable mixtures formed under these conditions. Fortunately, we found that a slight molar excess of trifluoroacetic acid (TFA) greatly increases the solubility85 of DIB in MeCN and efficiently promotes the oxidative amidation reaction. The effect of TFA on the DIB-mediated oxidation of compound 183 to product 184 is summarized in Table 5. In each case, a MeCN solution of substrate was added over 10 min (syringe pump) to a MeCN solution of DIB and TFA. The final concentration was equivalent to 8 mmol/L of substrate. From the data, it is apparent that at least 1 equivalent of TFA relative to DIB is required for efficient conversion. Excess TFA decreased the yields and made purification more difficult. Large quantities of TFA also trigger dienone-phenol rearrangement of certain products, such as those arising from phenols carrying a 4-iso-propyl substituent. The best results were obtained when a  OMe O  HO  NHAc  DIB, TFA MeCN  OMe  O  O  184  183  184  TFA : DIB mol ratio Yield  50  25  10  5  2.5  1.3  1.0  75 %  75 %  79 %  85 %  86 %  86 %  80 %  0.5  0  36 % 0 %  Table 5. Effect of TFA on the yield of desired product  MeCN solution of phenol 183 (1 eq.) was slowly added to a MeCN solution of DIB (1.2 eq.) and TFA (1.3 eq. vs. DIB for small scale, 1.5 eq. vs. DIB for large scale). Workup was significantly simplified since little to no polymeric byproducts were formed. Aqueous 43  workup was not necessary but was sometimes problematic as some dienone products were found to be water-soluble. On small scales, solid NaHCO3 was added at the end of the reaction. After concentration, the reaction mixture could be purified by chromatography. For large scale operations, it was more convenient to concentrate the reaction mixture and isolate the product by filtration through a pad of silica gel, which could be followed by crystallization in the case of solid materials. This is the method of choice for product 184, an X-ray crystal structure of which is included in Table 5.86 The dilute conditions described above do reduce the extent of polymer formation, but problematic for preparative work, because of the large volumes of solvent required. Although the MeCN utilized in such reactions may be recycled without further purification and with no adverse effect on yields,87 it was desirable to identify conditions that permitted to operate in more concentrated solutions. The effect of concentration was examined with phenol 183 and para-cresol as representative substrates (Table 6). Substrate (4 mmol) in 200 mL MeCN was slowly added  R HO  NHAc  DIB, TFA MeCN  R O  NMR yield Isolated Yield Concentration mmol / L R = Me R = CH2CO2Me R = Me R = CH2CO2Me 8 94 91 89 86 16 87 84 80 80 32 82 80 71 73 64 73 74 59 69 125 63 70 48 62 250 51 54 38 49 500 42 40 25 35 Table 6. Effect of substrate concentration on the yield of desired product  44  to 1.2 eq. DIB and 1.3 eq. TFA (vs. DIB) in 300 mL MeCN at room temperature. Yields88 diminished with increasing concentration; however, good results were obtained by operating in the 0.1 M range. It is noteworthy that the DIB-TFA system was more efficient than PIFA for the oxidation of 183 at a final concentration of 110 mM (66 % vs. 53 %). Preparative runs of this reaction carried out with 10-30 g batches of phenol 183 consistently gave yields in the 65-70 % range. The effect of temperature on the transformation of phenol 183 to product 184 was also examined. The above procedure was tested on a 400-500 mg scale in the range of –30 to +70 °C at intervals of 15-20°C. The rate of the reaction is slow at –30 °C: more than 2 hours are required for complete conversion. Not unexpectedly, the rate increases greatly as the temperature rises from –30 to +20 °C, at which point the reaction becomes virtually instantaneous (immediate disappearance of substrate by TLC). Interestingly, chemical yields remained constant over the entire temperature range. The reaction is thus most conveniently carried out at room temperature. The optimal procedure was as follows: substrate (9.1 g, 1 eq.) in MeCN (20 mL) was added over 3 h (syringe pump) to a MeCN (480 mL) solution of 1.2 eq. DIB and 1.5 eq. TFA (vs. DIB), at room temperature (final formal concentration of substrate = 0.1 M). A detailed procedure is given in the experimental section. A series of 4-substituted phenols was tested using these optimal conditions (Table 7). Relative to the original procedure, the new method afforded significantly purer products in generally higher yields–sometimes by a factor of 2 or more. As determined earlier,75 the reaction tolerates various functional groups, such as primary alkyl (entry 1-3), nitrile (entry 7, 8), sulfonamide (entry 9), halide (entry 10) and ester (entry 11, 12). Substituents at the ortho position (entry 5, 6) were also tolerated. One limitation of the new procedure is that phenols possessing a secondary alkyl substituent at the para- position generate dienones that are 45  susceptible to dienone-phenol rearrangement in the presence of TFA. For example, oxidation of 4-isopropyl phenol provided a mixture of 186 (X = Y = H, R = iPr) in a reduced 40 % yield, plus 30 % of 3-isopropyl-4-acetamido-phenol (entry 4).  X  R  TFA  PO  NHAc  X  DIB  R  O  Y 185  Y 186  No. R  X  Y  P  Old %b  New %a  1 2  Me Et  H H  H H  H H  56 --  89 87  3  n-Pr  H  H  H  54  82  4  i-Pr  H  H  H  62  40  5 6 7  Me Me CH2CN  Me H Br Br H H  H H H  -24 31  41 41 71  8  (CH2)2CN  H  H  H  67  81  9  (CH2)2NHTs  H  H  H  53  59  10 11  (CH2)2Br CH2CO2Me  H H  H H  H H  <10 35  57 86  12  CH2CO2Bn  H  H  H  --  65  13 14  CH2CO2Me CH2CO2Me  H H  H H  TMS TES  ---  81 33  a: Slow addition of 4 mmol of substrate to 1.2 eq. DIB and 1.3 eq. TFA (vs. DIB) at room temperature, in a total of 500 mL MeCN. b: Old% refers to the old procedure using HFIP. Table 7. Comparison of the new vs. the old procedure  Efforts to further reduce the amount of polymeric byproducts centered on the oxidation of silyl ether derivatives of phenols 185. This modification proved to be inferior to the oxidation of unprotected substrates (entry 13, 14). The TBS ether of 185 resisted the  46  action of DIB, and underwent oxidation in poor yield when TBAF was added to the reaction medium. The DIB/TFA system did convert TES and TMS ethers of 185 to 186 in the absence of fluoride ion, but in only 33 % and 81 % yield, respectively. Use of a silylated phenol thus offers no advantage. The phenols shown in Figure 8 are poor substrates for the reaction. Substrates 187 and 188 were converted into mixtures of undesired products, some of which may have formed through a mechanism involving capture of an intermediate of the type 179 by a side chain carbonyl group.89 Steric effects may complicate the reaction of BHT (190). Phenol 192 is unstable and decomposes upon standing at room temperature: the poor results obtained with this substrate are attributable to its rapid degradation in the reaction medium. Finally, attempted oxidative amidation of 189 and 191 yielded none of the desired product. It is not clear whether the expected dienones were formed and underwent undesired side reactions in situ, or whether alternative reaction pathways became operative.  O  I  I  NPht  OMe  OH  OH  OH  187  188  189  OH  OH  OH  190  191  192  Figure 8. Poor substrates for oxidative amidation  In general, trifluoroacetic acid (TFA) is an effective promoter of the bimolecular Ritter-like oxidative amidation of 4-substituted phenols promoted by PhI(OAc)2 in MeCN. Its use, under dilute conditions, eliminates the need for fluoroalcohol co-solvents, increases yields, and facilitates isolation / purification procedures.  47  2.2.2 Intramolecular oxidative amidation of phenols The success of the above effort encouraged us to explore the use of similar conditions in other types of oxidative amidations. The new procedures performed exceptionally well in an intramolecular variant of the reaction, wherein an ortho- or paraphenolic sulfonamide oxidatively cyclizes to the corresponding spiropyrrolidine (Scheme 39). These findings offer much opportunity in the synthesis of azaspirocycles. In the following section, we shall detail these developments.  O  O O S N R H  DIB N O S O 193 R  ortho  HO  194  DIB para  O  N O S O 195 R  Scheme 39. Intramolecular oxidative amidation at para- or ortho-position  In its original form, the intramolecular oxidative amidation (IMOA) reaction, like the bimolecular variant, required HFIP as the solvent.90 Inspired by the success of the modified bimolecular oxidative amidation, we tested the intramolecular variant under similar conditions. Specifically, a MeCN, CH2Cl2 or toluene solution of substrate was added to a dilute MeCN, CH2Cl2 or toluene solution of DIB and TFA (concentration of substrate = 10 mM). As outlined earlier, the technique was tested in a range of temperatures between -78 oC and room temperature (Method A).91 The IMOA proceeded very well, and again it was best run at room temperature (Table 8). Furthermore, it was discovered that the reaction proceeded best in neat TFA, which allow one to greatly increase the concentration of substrate without adverse effect on efficiency. Thus, reactions run at a formal final  48  concentration of 0.3 M of substrate (Method B) were as high-yielding as those carried out under dilute conditions. This completely eliminated the need for HFIP and other co-solvents.  NMs  O  N Ms  HO  1.1 eq. DIB, 1.5 eq. TFA, [C] = 10 mM in toluene / MeCN (10 : 1) 1.1 eq. DIB, [C] = 0.3 M in TFA  Method A Method B  Yield: 95 % 95 %  Table 8. Two generations of methods  In order to explore the scope and limitations of the reaction, various substrates were synthesized and tested. Most were easily prepared from 3-(4-hydroxyphenyl)-1-propanol (197), which is commercially available, but expensive.92 We favored a less costly alternative  O  HO  91%  HO 197  196  98% MsO  O O R S Cl  NH2 200  199 O N H  S  O R  O K2CO3/MeOH  N H HO  201  198  93% MsO  MsO  MsO  OMs  MsCl  PPh3 N3 aq. THF  NaN3 95%  OH  LAH  OH  S  O R  R = alkylarylheterocyclo-  202  Scheme 40. Preparation of precursors for intramolecular oxidative amidation  involving LAH reduction of inexpensive 3-(4-hydroxyphenyl) propionic acid (196) (Scheme 40). Alcohol 197 was elaborated to 200 in a conventional fashion. One aspect of the  49  synthetic sequence is the use of a Staudinger reaction 93 to reduce azide 199 to the corresponding amine, which was easily purified by aqueous acid/base workup. Target substrates 202 were obtained by treatment with various sulfonyl chlorides and selective deprotection of the phenol with K2CO3 in refluxing MeOH. In most circumstances, this particular demesylation method proved superior to the customary treatment with aq. NaOH in 1,4-dioxane at 90 ºC. However, 4-cyanophenyl- and 4-acetylphenylsulfonamides were intolerant of the basic conditions necessary to release the phenolic mesylate. In such cases, the phenol was more conveniently protected as a TBS ether, which was ultimately cleaved with TBAF. An unusual reaction occurred when the mesylation of compound 200 was attempted using an excess MsCl and Et3N (3 and 4 equivalents, respectively) in CH2Cl2 at room temperature overnight (Scheme 41). Thus, the noteworthy product 203 was obtained in 85 % yield. Essentially no 201 (R = Me) was formed.  NH2 MsO 200  Et3N (4 eq.) CH2Cl2, r.t.  N H  O  SO2Me  203 O N H  HO  S  MsO  85%  K2CO3/MeOH 89%  O  MsCl (3 eq.)  S  O  SO2Me  204  Scheme 41. Formation of the unusual product 204  The pathway leading to 203 is likely to involve reaction of the amine with sulfene 207, arising through elimination of HCl from MsCl promoted by Et3N (Scheme 42).94 Ndeprotonation of the zwitterion 209 yields 210, which undergoes C-mesylation by reaction  50  with more MsCl, or possibly with a second molecule of 207. The presumed intervention of reactive species 210 finds support in an observation recorded earlier.95 Thus, treatment of a 2-aminobenzaldehyde 212 with MsCl and Et3N produced variable amounts of cyclic sulfonamide 214 in addition to the desired 215. Exposure of the latter to bases (Et3N, tBuOK, NaH, NaHMDS) failed to promote cyclization to 214, which therefore must ensue from an intermediate such as 213.  CH3-SO2Cl  Et3N  205  CH2-SO2Cl  CH2=SO2  206  207  Et3N 210 CHO NH2 212  R-NH2-SO2-CH2 209  CH3-SO2Cl R-NH-SO2-CH2  R  R-NH2 (208)  CH3-SO2Cl  R  or 207  R-NH-SO2-CH2-SO2Me 211 R  CHO  R  CH2  Et3N, CH2Cl2 213  N S H O2 [?]  214  N H  SO2  CHO  + NHMs 215  bases  Scheme 42. Possible mechanism of the formation of 211  The tert-butylsulfonamide 217 was obtained through mCPBA oxidation of the corresponding sulfinamide 216 in 90 % yield (Scheme 43). This synthetic method was dictated by the instability of tert-butylsulfonyl chloride.96 Finally, bis-iodo substrate 220 was prepared in 92 % yield by iodination of 219 using bis(pyridine)iodonium tetrafluoroborate.97 This reagent gave the best yield, compared to NIS or I2.  51  tert-BuSOCl  NH2  93%  MsO  200  MsO  O S N O H  MsO  216  K2CO3 MeOH 90%  217 NHMs  HO  N H  HO  (Pyr)2IBF4 CH2Cl2/MeCN 5:1  219  O S  mCPBA 90%  O S N O H  218 I  NHMs  HO I  220  92%  Scheme 43. Preparation of special sulfonamides  A number of chiral substrates were derived from appropriate amino acids (Scheme 44). For example, L-tyrosine methyl ester was transformed to its N-tosyl derivative 221 by reaction with TsCl, followed by LAH reduction and MsCl protection. Exchange of OMs with azide, followed by Staudinger reaction, yielded primary amine 222. After installation of an appropriate sulfonamide group and hydrolysis, compound 224 was obtained in high yield. In a like vein, homotyrosinol served as the starting point for the preparation of compounds 227 and 229 (Scheme 45). Key steps in this sequence were a TMS-diazomethane (230) methylation of an alcohol98 and a Parikh-Doering oxidation.99  L-tyrosine methyl ester  OMs NHTs  MsO  NH2 NHTs  MsO  221 O O R S Cl  O  MsO  N H NHTs 223  S  222  O  O  R  N H NHTs  HO  S  O R  224  Scheme 44. Preparation of L-tyrosine derivatives  52  It should be noted that homotyrosinol is not commercially available, but the hydrobromide salt of the parent homotyrosine is. However, the high cost of this intermediate 100 induced us to devise a synthesis of homotyrosinol from inexpensive intermediates. Details will be discussed in the latter part of this chapter.  OMe  TMSCHN2 (230)  NHMs  75% AcO  OH NHMs AcO  225  227  H  OH  Pd/C, H2 K2CO3 MeOH 95% HO  NHMs  MeOH 91% HO  226  OMe  Pd/C, H2, K2CO3  NHMs 228  SO3⋅Pyr 85% HO  O NHMs  229  Scheme 45. Preparation of homotyrosine derivatives  Sulfonamides 202 were oxidatively cyclized in uniformly good to excellent yields using Method B (cf. Table 8). The resulting products 231 were easily purified. Benzyl- and tert-butyl sulfonamides (Table 9, entry 3, 5) afforded slightly lower yields compared to methyl, trifluoromethyl, cyclopropyl, and CH2Ms sulfonamides (entry 1, 2, 4, 6). This is probably due to steric effects. The reaction failed with tert-butylsulfinamide, which generated a complex mixture of products.  53  O O S N R H  HO  DIB  O  TFA  202  No. 1 2 3  Substrate (R) R = Me R = CF3 R = t-Bu  Yield 95 % 94 % 85 %  No. 4 5 6  N O S O 231 R  Substrate (R) R = cyclopropane R = CH2Ph R = CH2Ms  Yield 90 % 89 % 92 %  Table 9. Alkylsulfonamide-based intramolecular oxidative amidation  Arylsulfonamides also reacted efficiently. As shown in Table 10, yields were largely insensitive to the nature of substituents on the aromatic nucleus. Sterically hindered sulfonamides (cf. triisopropylsulfonamide, entry 15) or sulfonamides incorporating electrondonating groups on the aromatic ring (cf. 4-methoxysulfonamide, entry 14) reacted less efficiently, but still in more than 80 % yield. All positional isomers of nitrophenyl (“nosyl”) sulfonamides101 cyclized efficiently (entry 8-10). The x-ray crystal structures of entry 9 and 10 are shown in Figure 9.  O N H  HO  S  232  No. 7 8 9 10 11  Substrate (R) R = 4-Me R = 2-NO2 R = 3-NO2 R = 4-NO2 R = 4-Br  Yield 94 % 95 % 95 % 96 % 93 %  O  2  DIB  O  3  R  TFA  4  No. 12 13 14 15 --  N O S 233 O  R  Substrate (R) R = 4-CN R = 4-C(O)CH3 R = 4-OMe R = 2,4,6-triisopropyl  Yield 93 % 93 % 85 % 83 %  Table 10. Arylsulfonamide-based intramolecular oxidative amidation  54  R = 4-NO2  R= 3-NO2  Figure 9. X-ray structures of compound 233 (R= 3- and 4-NO2)  Thienyl sulfonamide (entry 16), and bis-iodo substrate (entry 17) reacted normally and in high yield (Table 11).  Z Z  NHR  HO Z  No. 16 17  DIB TFA  234  O Z  235  Substrate Z = H, R = SO2-2-thienyl Z = I, R = Ms  N R  Yield 91 % 92 %  Table 11. Other sulfonamides  Excellent results were also obtained with amino-acid-derived substrates (Table 12). Homotyrosinol derivatives in which the primary OH was either free or protected with a group of modest steric demand (e.g, Me) cyclized in nearly quantitative yield. On the other hand, sterically demanding protecting groups, such as TBDPS, suppressed the spirocyclization pathway and promoted the formation of polymeric side products (entry 21). No spiropyran product was observed when compound 236 (entry 18, R = CH2OH) cyclized  55  to spiropyrolidine. This result can be attributed to the kinetically favorable formation of a five membered ring. The x-ray crystal structure of the resulting 237 (R = CH2OH) appears in Figure 10.  R β  α NHMs  DIB TFA  HO  237  236  No. 18 19  Substrate R = CH2OH R = CH2OMe  β O  Yield 95 % 95 %  No. 20 21  N α R Ms  Substrate R = CHO R = CH2OTBDPS  Yield 94 % --  Table 12. Cyclization of homotyrosine derivatives  Figure 10. X-ray structures of compound 237 (R = CH2OH)  Tyrosine derivatives (Table 13, entry 22, 23) underwent the reaction in a decreased yield of about 80 %. At this time, we cannot account for such diminished yields in this series. The x-ray structure of 238 (R = PhMe) appears in Figure 11.  56  α O O S N R H NHTs β  HO  β NHTs  DIB O  TFA  224  No. 22 23  N α O S O R 238  Substrate R = Me R = PhMe  Yield 83 % 80 %  Table 13. Cyclization of tyrosine derivatives  Figure 11. X-ray structures of compound 238 (R = PhMe)  The new technique was also extended to phosphoramide substrate 240, which was obtained via deprotection and Michaelis-Arbuzov reaction102 of 199. On the other hand,  K2CO3  N3  MeOH  MsO  P(OMe)3  N3  70% over 2 steps  HO  199  239 O P OMe N OMe H  HO  DIB  O (MeO)2P  TFA 88%  240  N  O O P R N R H  HO 242 R = Et  241 O R2P  DIB  N  TFA O  244  243 R = Ph  Scheme 46. Preparation of phenolic phosphoramide  57  phosphinic amide 242, 243 produced an intractable mixture of compounds containing none of the desired 244 (Scheme 46). Parallel research into the oxidative amidation of ortho-substituted phenols has also produced interesting results. Substrates suitable for an exploration of this mode of reactivity were prepared starting with the LAH reduction of commercially available 3-(2methoxyphenyl)propionic acid (245) (Scheme 47). Alcohol 246 was then elaborated to amines 250 and 254, which were advanced to sulfonamides 252 and 257.  OMe  CO2H  LAH  245  91%  OMe 246  NaN3  247 or 248  BBr3  OMs  OH MsCl  95%  Br  93%  OMe 247  248  OH  N3 OR  249a (R = Me, 93% from 247) 249b (R = H, 97% from 248)  PPh3 249a  H2O 92%  NH2  NHMs  MsCl 96%  OMe 250  OMe  BBr3  NHMs OH  89%  251  TBAF TBSCl 249b 94%  N3 OTBS 253  NH2  MsCl  OTBS 254  96%  Pd/C, H2 87%  252  95% NHMs OTBS 255  NsCl 95% NHNs OTBS 256  NHNs  TBAF 94%  OH  257  Scheme 47. Preparation of ortho-substituted phenols  The 4-bromo congener of 252 was prepared via Claisen rearrangement,  103  hydroboration/oxidation, protection and deprotection (Scheme 48). It is worthy of note that,  58  (a) an iodo anolog could not be synthesized because deiodination occurred at the high temperature necessary for the Claisen rearrangement; (b) a weak base, NaHCO3, was necessary to preserve the TBS group during the hydroboration step (NaOH resulted in hydrolysis) (261 to 262); (c) use of volatile trimethyl phosphine, 104 instead of PPh3, simplified the purification of the Staudinger reaction (264 to 265); additionally, a TBS phenol would not survive the traditional acid / base method of amine purification.  allyl bromide  OTBS  OH  O-allyl  OH  TBSCl  220 °C 84% Br 259  95% Br 258  MsCl  3OMs  Br  260  NaN3  263  Br  OTBS 3OH  Br  262  OP 3N3  NHMs Br  264  Br  261  PMe3 then MsCl 86% over 2 steps  95%  96%  NaHCO3 83%  97% Br  OTBS  OTBS  BH3 H2O2  TBAF 94%  265 P = TBS 266 P = H  Scheme 48. Bromo-substituted ortho phenols  6-Methylcoumarin (267) served as the starting point to prepare 4-methyl-substituted phenol 272 (Scheme 49). Hydrogenation of the double bond and ammonolysis of the  O  Pd/C O  NH3  O 96%  O  267  O  NH2  97%  OH  268 O NH2  OTBS 270  93% 269  NHMs  LAH then MsCl 90% over 2 steps  TBSCl  TBAF 92% OTBS  NHMs OH  272  271  Scheme 49. Methyl-substituted ortho phenols  59  emerging 268 yielded amide 269. 105 Operations similar to those shown previously led to substrate 272. Initial experiments revealed that the ortho-oxidative amidation of phenols is less efficient than the para-case. Accordingly, we investigated the effect of solvent, temperature and concentration on the reaction using compound 273.  NHMs  NMs  OH 273  O 274  Conditions: 1.1 eq. DIB + 1.5 eq. TFA, -78 to r.t., [C] = 10 mM Solvent DCM THF Toluene Toluene + MeCN (10 : 1)  Yield 50 % 45 % 51 % 59 %  Conditions: 1.1 eq. DIB + 1.5 eq. TFA, Toluene / MeCN = 10 : 1 Temperature -78 °C to r.t. -30 °C to r.t. 0 °C to r.t. r.t. 60 °C reflux  Yield 59 % 52 % 50 % 50 % 45 % 45 %  Table 14. Solvent and temperature effects  Results obtained during attempts to adapt Method A (cf. Table 8) to the present reaction appear in Table 14. The reaction appeared to favor nonpolar solvent such as toluene (51 % yield of 274), or moderately polar ones such as CH2Cl2 (yield = 50 %), always  60  containing the customary 1.5 equivalents of TFA. However, the substrate is poorly soluble in these media. Switching to a solvent system comprising toluene and MeCN in a 10 : 1 ratio improved the solubility of 273 and increased the yield to 59 %. Contrary to the paraoxidative amidation process, the present reaction was best carried out at -78 oC to r.t.. Thus, increasing the temperature to 60 oC reduced the yield from 59 % to 45 %.  X  NHMs  X  NMs  OH  O 275  Substrate (X) 252 X= H 266 X= Br 272 X= Me  Yield (Method A) 59 % 30 % 51 %  Yield (Method B) 60 % 29 % 47 %  Table 15. A comparison of the two methods using different substituents  Reactions run in neat TFA at room temperature at concentrations of 0.3 M (Method B, cf. Table 8) were equally effective to those run in conventional solvents (Table 15). It was found that methyl or bromo substitution at the 4-position hampered the reaction. The reaction failed altogether with nosyl substrate 257, which delivered an intractable mixture of products. Steric problems may have played a role in this case. In conclusion, the oxidative amidation chemistry of suitably functionalized para- and ortho-substituted phenols was studied. A procedure was developed to improve yields, eliminate the need for costly solvents and simplify the purification process. A full list of products prepared by this method is shown in Table 16. Two of many possible synthetic applications of this methodology will be discussed in the next two chapters.  61  Bimolecular oxidative amidation products NHAc  NHAc  O  NHAc  NHAc  O  OMe  O  CN  NHAc  O  CN  O  NHTs  O  NHAc  O  OBn  O  NHAc  NHAc  NHAc Br  O  O  O  O NHAc  NHAc  NHAc  Br O  O  Br  Intramolecular oxidative amidation products O O  O  O  O  O  O  Br  N Ms  O  N SO2Bn  O  N Ns(3-)  O  N O S O  O  O  N Ms  OMe  O  N  O  O  N Ms  O  N O S O  N Ns(4-)  N O S O Pri  OMe  O  N Ns(2-)  N Ts  Ms  N O S O  N O S O  O  O  S O2  O  N O S O  N O S O CF3  Br  O  N Ms  iPr  OH  NHTs  O  N Ts  H  CN  iPr  NHTs  O  N O S O  N Ms  I  N P O MeO OMe  NMs O  O  Me  N O S O  S  NMs  NMs  O I  N Ms  --  O  --  O  Table 16. A summary of oxidative amidation products  62  2.3 Synthetic study of himandrine analogs 2.3.1 Retrosynthesis of hiamdrine skeletons As an application of the above findings, we first envisioned routes to the himandrine skeleton that employ a key sequence involving tandem intramolecular oxidative amidation – intramolecular Diels-Alder reaction. Three possible frameworks were targeted for this model study (Scheme 50). First, ortho-IMOA of vinylsulfonamide 282, followed by Diels-Alder cyclization, would prepare the molecule for the installment of a vinyl group and ultimate oxy-Cope rearrangement of 277 to subtarget 276 (route A). A similar sequence involving  MeOOC PhOCO  OH  MeO N  53  A  C  B O  O S N H  O 276  H  283  279  O  S  H  O  Diels-Alder  Diels-Alder O  O S N  O S N H  O  H  Oxy-Cope O  O  O O S N H  O  N  O S N  addtion OP 277  O  CH2=CH-Mt & Diels-Alder O S  ortho-IMOA  OH ortho-IMOA 278  O  281 R = 1-(1,3-butadien)yl  284  para-IMOA  NHSO2R  O N  O  280  NHSO2R HO 285 R = 1-(1,3-butadien)yl  282 R = vinyl  Scheme 50. Retrosynthetic analysis of himandrine skeleton  63  butadienyl sulfonamide 281 would produce 279 in a more direct fashion as apparent from route B. Finally, in route C, para-IMOA of butadienylsulfonamide 285 and Diels-Alder cyclization of the resultant 284 would produce 285. All three avenues were explored through experiment as detailed in the following section.  2.3.2 Synthesis of himandrine skeletons Route A was investigated using substrates 286, in which group Y was either H, Br, or Me (Scheme 51). Our interest in the bromo substrate emanated from Wood’s observation82  O Y  N  Y  OH 286 R = vinyl or equivalent synthon  O  O  S  NHSO2R  Y  287 O  288  O S N  O  Scheme 51. A design for oxidative amidation / Diels-Alder tandem reaction  that Diels- Alder reactions of such halogenated ortho-dienones tend to be more efficient than those of unsubstituted or alkyl-substituted analogs (Scheme 52).  O Y  O  OEt  O  O Y = CH3  24%  Y=I  90%  O  O 289  D-A  EtO Y  290  291  Scheme 52. Wood’s intermolecular Diels-Alder reaction with different Y groups  The synthesis of the unsubstituted substrate (Y = H) is illustrated in Scheme 53. The reaction of amine 250 with vinylsulfonyl chloride106 afforded 292 in only 32 % yield. Better 64  results were obtained by the use of 2-chloro-1-ethanesulfonyl chloride, which provided the same end product 292 in 57 % yield. Evidently, beta-elimination of chloride occurred in  O S Cl 32% O  NH2 OMe  250  or Cl  O S Cl 57% O  O  OP  63% BBr3  N S H O  292 P = Me 293 P = H  Scheme 53. First generation synthesis of compound 293  parallel with the condensation with the amine. Subsequent BBr3 deprotection (63 % yield) led to precursor 293. This sequence did provide sufficient material to explore subsequent chemistry; however, the yield of sulfonamide 293 was low regardless of which sulfonyl chloride was employed. Interestingly, O-TBS and O-acetyl variants of 250 underwent sulfonamide formation considerably more efficiently. The reasons for this remain unclear. Thus, the phenol 249b was re-protected as a TBS ether or an acetate ester. Azide hydrogenation was superior to Zn / HOAc reduction for the formation of amines 254 and 295, and allowed easy purification. The action of 2-chloro-1-ethanesulfonyl chloride and Et3N converted 254 and 295 into vinylsulfonamides 296 and 297 in 84 % and 79 % yield, respectively. Cleavage of the silyl group in 296 proceeded in only 49 % yield when the compound was treated with basic TBAF. However, the acidic reagent, HF-pyridine complex, afforded the product in 86 % yield. Evidently, the sulfonamide is sensitive to the action of basic reagents. As a further illustration, attempted release of the acetate from 297 using K2CO3 / MeOH produced none of the desired 293, but provided compound 298 in 84 % yield. Techniques for acetyl group cleavage under acidic conditions, such as treatment with  65  BF3 etherate in MeCN / H2O or 1N aqueous HCl, also failed to produce 293. In any event, the route to 293 through TBS ether 253 was significantly more efficient (53 % yield over 6 steps vs. 30 % yield over 4 steps from the same intermediate), and it was found to be compatible with large scale synthetic operations (20-30 g). A more efficient synthesis was devised as delineated in Scheme 54.  N3 OH 249b  TBSCl  N3  or Ac2O  OX  253 294 Cl O  S  Cl  NH2  H2  OX  254 X= TBS 87% 295 X= OAc 83% O  O  O OX  HF⋅Pyr 86% K2CO3, MeOH  X= TBS 94% X= OAc 98%  Pd/C  N S H O  296 X = TBS 84% 293 X = H 297 X = OAc 79%  OAc  K2CO3, MeOH 84%  N S H O  OMe  298  Scheme 54. Second generation large scale synthesis of compound 293  An interesting side reaction occurred during the preparation of compound 254 on large scale. Hydrogenation (MeOH, Pd/C) of azide 253 that had been roughly purified by filtration through a pad of silica gel resulted in clean formation of the homo-coupled product 299 in 80 % yield (Scheme 55). Remarkably, if azide 253 was submitted to the hydrogenation step without prior passage though silica gel, then the expected amine 254 was obtained in 87 % yield. Therefore azide 253 was best carried on to the next step after only an aqueous workup. The formation of 299 is believed to involve in situ dehydrogenation of initially formed 300 to imine 301. Transimination of 301 with a molecule of 300 leads to 302, which is then reduced to the observed 299. We postulate that traces of silica gel inadvertently  66  carried into the hydrogenation reaction could act as an acidic catalyst to promote the transimination step, facilitating formation of the undesired product.  OTBS  OTBS  1. silica pad filtration N3  2 NH  2. H2, Pd/C, MeOH  253  299  75% [H]  [H]  R-CH2-NH2 300  R-CH=NH Pd(0) PdH2  R-CH2-NH2  301  R-CH=N-CH2-R 302  NH3  Scheme 55. Unexpected homo-coupling reaction  Curiosity led us to explore the behavior of a sulfonamide derivative of 299 under the conditions of the oxidative amidation reaction (Scheme 56). Unfortunately, the desilylated adduct of 303 delivered a complex mixture of materials upon addition to a toluene / MeCN (10:1) solution of DIB and TFA (cf. Method A, Table 8).  Cl  OTBS 2 NH  O  S  Cl  OTBS  OTBS  O  N O S O  Et3N 299  65%  303  HF⋅Pyr then DIB/TFA  complex mixture  Tol : MeCN 10 : 1  Scheme 56. Oxidative amidation of compound 303  The 4-bromo analog was synthesized by two different routes. Mesylate 306 was obtained in overall 83 % yield from phenol 260 through O-methylation, hydroboration and mesylation (Scheme 57). The robust methyl ether 306 was advanced to primary amine 308 under classic Gabriel conditions.107 As before, the vinyl sulfonamide 310 was reached by  67  condensation of 308 with 2-chloro-1-ethanesulfonyl chloride followed by BBr3 demethylation. Substrate 310 emerged in 24 % yield over 7 steps from phenol 260.  OH  OMe  OMe Me2SO4 304  Br  260  PhtNK  NPht  OMe  307 O S N H O  Br  306  O  S  Cl O  Et3N 65%  308  OH  O S N H O  BBr3 60%  309  Br Cl  NH2  85% Br  Br  305  NH2NH2  87%  MsO  94% Br OMe  OMe  OMe MsCl  NaOH 90%  98% Br  HO  BH3 H2O2  310  Br  Scheme 57. Preparation of compound 310 from 304  Switching the phenolic protecting group to a TBS ether again afforded improved overall yields. As shown in Scheme 58, azide 264 was subjected to Staudinger reduction with PMe3 in aqueous THF and the resulting amine was sulfonylated with 2-chloro-1ethanesulfonyl chloride to give 311 in 81 % yield over 2 steps. Release of the silyl group with HF-pyridine provided the desired 310 in 91 % yield.  OTBS N3 Br  OP  PMe3, aq. THF  264  then Cl Et3N  O  S  O S N H O  Cl O  81% over 2 steps  Br  HF⋅Pyr 91%  311 P = TBS 310 P = H  Scheme 58. Preparation of compound 310 from azide 264  68  A methyl substituent at the para position of the phenol allowed us to explore the effect of alkyl substitution on the planned transformations. Thus, precursor 313 was assembled from amide 270 in 78 % yield over three steps (Scheme 59). We were now ready to research the tandem ortho-oxidative amidation / Diels-Alder reaction sequence.  LAH then Cl  O NH2 OTBS  270  Et3N O  S  O S N H O  Cl O  87% over 2 steps  OTBS  O S N H O  HF⋅Pyr 90%  312  OH  313  Scheme 59. Preparation of precursor 313  Substrates 293, 310 and 313 underwent oxidative cyclization equally well either by Method A or Method B (cf. Table 8). The IMOA product 314 was detectable by NMR spectral analysis as the major component of the crude reaction mixture. However, serious loss of material was incurred during attempts to purify the product by silica gel column chromatography. This was probably due to its strong tendency to act as a Michael acceptor. We found it more expedient to heat the crude IMOA reaction mixture in an oil bath set at 120 oC, whereupon Diels-Alder cyclization afforded tetracyclic products 315 directly. Results are summarized in Table 17. Overall yields of products 315 were in 30-40 % range. The x-ray crystal structures of all the products are shown in Figure 12.  69  O S N H O  Y OH  O  oxidative amidation  Y  O O S N  Diels-Alder  Y  O  315  314  Substituent 293, Y = H 310, Y = Br 313, Y = Me  Yield of 315 (C) Y = H, 35 % Y = Br, 30 % Y = Me, 43 %  O S N  O  Yield of 315 (D) 40 % 31 % 43 %  Conditions C: 1eq. substrate, 1.1 eq. DIB, 1.5 eq.TFA, Toluene / MeCN = 10 : 1, final concentration = 10 mM, -78 oC to r.t., then to reflux. Conditions D: 1eq. substrate, 1.1 eq. DIB, neat TFA as solvent, r.t., initial concentration = 0.3 M, then toluene added to final concentration = 0.1 M, r.t. to reflux. (See experimental section for details) Table 17. Tandem reaction of ortho phenols  Y=H  Y = Br  Y = Me  Figure 12. X-ray structures of compounds 315  When Y = H, condition D gave a slightly better yield, whereas the other two substrates behaved the same under the two sets of conditions tested. Contrary to the Wood substrates, a halogen substituent had an adverse effect on the present reaction. Thus, the bromophenol 310 produced 315 (Y = Br) in only ca. 30 % yield regardless of which method  70  was used. Also, a methyl group was beneficial in the present case, as apparent from the outcome of experiments involving substrate 313. The discrepancy between the Wood observations and ours may be rationalized as follows. Wood induced the Diels-Alder reaction of the dienone with an electron-rich dienophile. Such an inverse-demand process108 is anticipated to proceed faster in the presence of LUMO-lowering electron-withdrawing groups on the dienone. But in our case, the dienone must combine with an electron-deficient dienophile. Therefore, a HOMO-raising electron-donating substituent, such as a Me group, is anticipated to favor the reaction, while an electron-withdrawing one, e.g., Br should impede it. The study of the assembly of the himandrine skeleton utilized the unsubstituted product 315 (Y = H). As shown in Scheme 60, a vinyl group or equivalent should be installed at the carbonyl position to induce a subsequent anionic oxy-Cope rearrangement. The most logical course of action involves the addition of a vinylmetallic (Grignard or organo-Li) reagent to the carbonyl group. Unfortunately, this transformation proceeded in disappointing yield (only 10-15 % after a troublesome purification) regardless of the nature  O  Y  O S N  O  vinyl metal reagent see text 10-15%  O 315, Y= H  O S N OH  316  MgBr  O  O S N  70% H  OH  316a  316a  Scheme 60. Vinyl metal reagent approach  71  of the organometallic. Thus, vinylmagnesium bromide in THF, with or without added HMPA or other promoters like TMEDA 109 or CeCl3, 110 as well as vinyllithium prepared from either vinyltributyltin/BuLi 111 or tetravinyltin/BuLi 112 at various temperatures, fared uniformly poorly. There are two possible reasons for the failure of this addition. One is that the ketone is sterically shielded from attack by external nucheophiles by the shape of the molecule. This possibility is strengthened by the observed reduction, in lieu of addition, upon exposure of 315 (Y = H) to 3-butenylmagnesium bromide, because Grignard reagents are generally sensitive to sterics.113 The other could be attributed to the relatively weak nucleophilicity of vinylmetal reagents.114 This problem was soon circumvented by a three step sequence that entailed addition of the bromomagnesio derivative of TMS-acetylene (prepared in situ by reaction of the acetylene with EtMgBr in THF), TBAF deprotection and lithium aluminum hydride reduction of the triple bond,115 leading to the oxy-Cope precursor 316 (Scheme 61).  O  O  Y  O  S N  MgBr 93%  TMS or TMS  Li 86%  OH  O  TBAF 95% or K2CO3 / MeOH 83%  LAH  Lindlar catalyst 85% O  66% O  O S N  OH 317  O S N  OH 318  317  TMS  315, Y = H  O  O S N  318  319  O S N OH  NOESY confirmed 316  Scheme 61. Preparation of compound 316  72  Several comments are in order at this juncture. First, the acetylenic Grignard reagent was superior to the lithium variant in the addition reaction. Second, desilylation proceeded more smoothly with TBAF than with K2CO3 / MeOH. Third, we initially anticipated employing a Lindlar hydrogenation 116 of the alkyne to reach 316. However, the ethynyl substituent in 317 resides on the underside of the molecule, and it is sterically shielded from attack by external agents. Indeed, attempted Lindlar hydrogenation of 317 resulted in exclusive reduction of the olefin. Schwartz hydrozirconation117 of the acetylene also failed. Only LAH and Red-Al proved to be competent in this transformation, affording the desired 316 in about 60 % overall yield over 3 steps. The configuration of 316 is further supported by a NOESY experiment, the results of which match the x-ray structures of intermediates 317 and 318. Solid literature precedent exists for the oxy-Cope rearrangement of structures of the general type 316. For instance, Liao and collaborators described the oxy-Cope chemistry of compound 320, 118 which is structurally similar to our substrate. This provided some optimism for the feasibility of the same reaction with 316.  Me  O OMe OH  320  H  KH 18-cr-6 THF 87%  Me  H  O OMe O  321  Scheme 62. Liao’s system  Distressingly, thermal activation of 316 afforded none of the rearranged product. Either the substrate was recovered intact, or decomposition occurred at temperatures around  73  200 °C. Identical behavior was observed upon attempts to induce rearrangement in the anionic mode119 (deprotonation of the OH group with KH, NaH, or KHMDS; 18-crown-6; different solvents at various temperatures from 25 oC to ca. 200 °C). Decomposition also occurred when amine 322, which was obtained in situ by dissolving metal reduction of 316, was subjected to the above Cope conditions. This route A (cf. Scheme 50) was thus abandoned. On a positive note, a wealth of valuable information about the reactivity of systems 316 emerged from these experiments.  HN  R N  Na/NH3  OH 322  OH 316  R = -SO2base or heat  R N H  H  O  323  decomposition, R = H-, -H  Scheme 63. Unsuccessful route of oxy-Cope rearrangement  Our attention now refocused on route B. This approach comports a selectivity problem. Certainly, thermal activation of 280 could trigger formation of the desired 279  O  O  S  S  O N  O  O N  280  O  heat  324  [?]  O  O2S N H  H 279  O S N  O  O  O 326  325  O  O S N  Scheme 64. Possible modes of reactivity of 280  74  However, an equally likely outcome would be the formation of the isomeric cycloadduct 326 through an alternative Diels-Alder cyclization, in which the dienone functions as a diene (Scheme 64). Only experiment could determine the favorable mode of reactivity. The 1,3-butadiene-1-sulfonyl chloride (327) required for the implementation of this strategy was prepared as a mixture of Z and E isomers by with base-promoted eliminative ring opening of 3-sulfolene, and trapping of the intermediate sulfinate with NCS.  120  Remarkably, the two isomers are separable by column chromatography.  Condensation of amine 254 with either isomer of the sulfonyl chloride afforded the two sulfonamides 328 121 and 329, which underwent uneventful desilylation with HF-pyridine (Scheme 65).  O  S  O  nBuLi NCS  O Cl S O  chromat. 327  3-sulfolene  O O S N H  NH2 327 OTBS  Et3N  254  OTBS  328 Z-isomer 62% 329 E-isomer 60%  O Cl S O  O Cl S O  and E-327  Z-327  HF⋅Pyr  O O S N H OH  330 Z-isomer 93% 331 E-isomer 92%  Scheme 65. Preparation of compound 330 and 331  Alternative approaches to the preparation of butadienyl sulfonamides were briefly researched, but without success. For instance, attempted desulfurization (Raney Ni) of the thiophene segment in compound 332 gave only fully reduced butanesulfonamide 333 (Scheme 66). Furthermore, compound 335 failed to undergo intramolecular Diels-Alder reaction upon refluxing in toluene.  75  HO  O O S N nBu H  O O S S N H  "Ni" HO  333  O O S N H  "Ni" HO 334  332 DIB TFA  O O S N  O2S  heat  N  S  S  O  O 335  336  Scheme 66. Unsuccessful improvement  Oxidative cyclization of 330 under the conditions D (cf. Table 17) resulted in exclusive formation of product 338 in 27 % yield (Scheme 67). Under the same conditions, substrate 331 was converted into compound 339 in 34 % yield. The x-ray crystal structure of product 339 is reproduced in the scheme below. Thus, the undesired mode of Diels-Alder cyclization is dominant with these substrates. This induced us to abandon research on pathway B and re-center our efforts on approach C.  O O S N H  O  DIB neat TFA then toluene reflux  OH  O S N  O  O  R1  O S R2 N O  337 330 Z-isomer  338 R1 = H, R2= vinyl, 27%  331 E-isomer  339 R1 = vinyl, R2 = H, 34%  339  Scheme 67. Preparation of compounds 338 and 339  76  Strategy C should resolve the above problem, because the Diels Alder cyclization of 285 would proceed with unambiguous selectivity. To wit (Scheme 68), phenol 340 was protected with a TBS group, and the resulting ether was subjected to LAH reduction and mesylation. The standard operations of sodium azide substitution (91 %), hydrogenation and coupling with the E-isomer of sulfonyl chloride 327 gave product 345 in 53 % yield over the latter 2 steps. Substrate 285 was obtained after HF pyridine desilylation. Oxidative cyclization of this material (condition D) afforded the desired product 283 in 39 % yield. The x-ray structure of 283 is included in Scheme 68. The overall yield of 283 was 14 % over 8 steps from phenol 340. It is worth mentioning that the rate of intramolecular Diels-Alder reaction of intermediate 284 is six times slower than that of its congener 337.  TBSCl  OMe HO  94%  340  TBSO O  S  TBSO  341  92%  342  TBSO  O2S N  O N H  92%  HO  then (E)-327 53% over 2 steps  S  O (E)  285  O2S N H  then toluene, reflux, 39% 284 O  Pd/C H2  344  HF⋅Pyr (E)  TBSO  N3  345  DIB, neat TFA  LAH  O  N H TBSO  OMe  OMs NaN 3 343 91%  MsCl 95%  OH  O  O  283  H  O  283  Scheme 68. Preparation of final compound 283  77  Preparation of important intermediates O LAH  OH  OH MsCl  91%  OMe N3  95%  OMe  94%  OH  93%  OMe  87%  OTBS  97%  OH  NH2  N3 Pd/C, H2  TBSCl  Br NaN3  OMs BBr3  OTBS  254  Oxy-Cope Route A Cl 254  Et3N O  S  OTBS O  O  S N  MgBr  86% O  TBAF  O S N  95%  93%  OH O  LAH  O S N  then toluene reflux, 40% Oxy-Cope  O  O2S N H  O  66%  OH  OH  O S N  O  DIB neat TFA  N S H O  HF⋅Pyr  N S H O  O  84% TMS  O  O  Cl  OH  H  TMS  Butadiene Route B ortho variant O O S Cl  254  O O S N H  327  HF⋅Pyr OH  OTBS  Et3N  R1  330 Z-isomer 93% 331 E-isomer 92%  328 Z-isomer 62% 329 E-isomer 60%  O  DIB neat TFA  O O S N H  O S R2 N  338 R1 = H, R2= vinyl, 27% 339 R1 = vinyl, R2 = H, 34%  then toluene reflux O  Butadiene Route C para variant O  O OMe  TBSCl 94%  N3  OMs NaN3 91% TBSO O  HF 92%  92%  TBSO  HO  TBSO  N H HO  S  LAH  OMe  Pd/C H2 then E-327 53% over 2 steps  O DIB, neat TFA (E)  TBSO  OH MsCl 95% O N H  S  O (E)  TBSO  O2S N H  then toluene, reflux, 39% H  O  Scheme 69. A summary of himandrine skeleton synthesis  78  In conclusion, a tandem sequence involving ortho- or para- IMOA of phenolic sulfonamides, followed by Diels-Alder cyclization of the primary products was extensively investigated. A successful approach to the himandrine skeleton started with the para-IMOA reaction of a butadienyl sulfonamide. A complete list of the products prepared in the course of this study is provided in Scheme 69.  79  2.4 Synthetic study of (-)-lepadiformines 2.4.1 Retrosynthetic analysis of lepadiformines The culmination of this study is an effort leading to the enantioselective synthesis towards lepadiformines. The chosen approach retraces a synthesis of (-)-cylindricine C disclosed earlier by us.73 Accordingly, lepadiformines would be obtained by a diastereoselective reductive amination of 347. This material would arise through a baseinduced SO2 elimination from sulfonamide 349 and a 1,4-reduction. The latter emerges upon alkylation of 350, which is the product of reduction of 351. This enone is available by a diastereoselective intramolecular 1,4-addition of anion 352, which may be generated by deprotonation of the corresponding mesylamide with LHMDS. The mesylamide is the product of IMOA of phenolic substrates 353 (Scheme 70). Compound 353 is recognized as a methanesulfonamide derivative of Lhomotyrosinol. As alluded to earlier, this substance may be prepared from commercial but  OH N  Lepadiformines and its derivatives  NH R H 348  fragmentation  H 349  H 351  H 350  O  N  SO2  SO2  R  OP 1,4-addition  OP N  alkylation  SO2  OP  O  347 O  OP N  eliminative  O  N  R H  346  [H]  NH  amination  H  OP  OP  reductive  R  IMOA  HO  OH  SO2 O  NHMs 352  353  Scheme 70. Retrosynthetic analysis of lepadiformines  80  expensive L-homotyrosine hydrobromide. Cost issues induced us to seek an alternative route to enantiopure 353. These efforts will be discussed in the following section.  2.4.2 Practical synthesis of L-homotyrosinol methanesulfonamide We considered three possible avenues to the requisite L-homotyrosinol derivatives (Scheme 71). A direct Suzuki coupling122 of an appropriate haloaryl fragment with segment 356 would be possible if Y were a boryl group. An unsaturated variant 354 could be made starting with educt 355 by Heck123 reaction with a haloarene or by cross-metathesis with a suitable styrene. In any case, vinyl compound 355 is required.  HO  OH  [H]  PO  NHMs  Suzuki [ Ar-X ]  354  Heck [ Ar-X ] OP'  Y 356  OP'  NHMs  hydroboration  NHMs  or metathesis [ Ar-CH=CH2 ] OP' NHMs 355  Scheme 71. Retrosynthesis of L-homotyrosinol methanesulfonamide  This material was prepared from L-methionine by an adaptation of a method described by Rapoport,124 leading to products 363-365 in good overall yield (Scheme 72). A key difference between the literature procedure and the present one is that sulfoxide elimination from the oxidation intermediate of 360-362, was best carried out in the presence of base. Not all bases were satisfactory. Excellent results were obtained with Na2CO3, which  81  induced formation of 364 in 83 % yield. By contrast, the yield of 364 dropped to a mere 40 % when K2CO3 was used instead.  O S  MsCl, Et3N OMe  357  NH2 S  R3SiCl or Ac2O  O S  DCM quan.  OP NHMs  360 P = Ac, 95% 361 P = TBDPS, quan. 362 P = TBS, 90%  OMe NHMs 358  LAH  S  THF 91%  359  NaIO4 then  OP NHMs  dichlorobenzene Na2CO3 200 oC  OH NHMs  363 364 365  P = Ac, 72% P = TBDPS, 83% P = TBS, 85%  Scheme 72. Preparation of different vinyl moieties  Initial attempts focused on Suzuki coupling. Unfortunately, the hydroboration of 364 with different reagents, such as 9-BBN, catecholborane, pinacolborane and BH3·THF, failed to give the desired product. No reaction took place at low temperature, while decomposition occurred upon heating. This was surprising in light of recorded cases of successful hydroboration of an N-Boc protected vinylglycine derivative.125 The crossed alkene metathesis was extensively studied using styrene 366. As seen in Table 18, this approach gave disappointing results. Most reactions stalled at about 30-40 % conversion to afford low yields of the desired 367, irrespective of catalyst, solvent, and temperature used. Fortunately, a Heck coupling between 364 and para-iodophenyl acetate resolved the foregoing problem.126 Nonetheless, extensive screening of ligands, protecting groups both on the phenol and vinyl glycinol segments, solvent, and reaction conditions was necessary in order to scale up the reaction to preparatively useful levels. As shown in Table 19, the use of Pd(OAc)2 as the source of metal gave 367 in 91 % yield on 0.5 mmol scale, while other 82  catalyst  OTBDPS NHMs  AcO  364  366  Catalyst Grubbs I Grubbs II Hoveyda I Hoveyda II  OTBDPS NHMs  AcO 367  Conversion 15 % 40 % 25 % 35 %  Yield 8% 20 % 11 % 21 %  Conditions: catalyst (5 mol %), vinyl moiety (0.5 mmol), styrene moiety (0.6 mmol), DCM or benzene, from r.t. to reflux, concentration = 0.2 M. Table 18. Alkene metathesis approach  AcO  I 368  OTBDPS NHMs  catalyst  367  364  Pd catalyst Pd(OAc)2 Pd2(dba)3 Pd(PPh3)4 Pd(PPh3)2Cl2  OTBDPS NHMs  AcO  conversion 100 % 80 % 30 % 65 %  yield 91 % 50 % brsm 30 % brsm 75 % brsm  Conditions: catalyst (10 mol %), SPhos (20 mol %), 1.2 eq. K2CO3, DMF ([C] = 0.35 / vinyl moiety), 100-105 oC, 0.5 mmol scale (vinyl moiety), 4 h. brsm= based on recovered starting materials OMe  OMe  P  SPhos Table 19. Screened catalysts and ligands for Heck coupling  83  common Pd sources provided inferior results. The phosphine, SPhos, 127 proved to be a particularly competent ligand; however, its use on large scale incurred serious issues of cost. Pleasingly, inexpensive phenyl urea 128 emerged as an outstanding substitute. With either ligand, a catalyst load between 3 and 5 % was adequate for large scale work. The Heck reaction requires a base, such as K2CO3, to absorb the liberated H-X. In the present case, K2CO3 promoted a variable extent of cleavage of the phenolic acetyl group. While this is inconsequential as far as 353 is concerned, deacetylation of the reactant iodophenol has an adverse effect on the reaction. The use of NaHCO3 as the base minimized the release of the phenolic acetate, to the advantage of overall efficiency.  PO  X 369  No. 1 2 3 4a 5b 6  OP' NHMs  370  355  X I Br I I I I  P Ac Ac H Ac Ac H  OP' NHMs  PO  P’ TBDPS TBDPS TBDPS TBS Ac H  Yield 91 % 15 % 10 % 21 % 41 % 36 %  Conditions: Pd(OAc)2 (10 mol %), SPhos (20 mol %), K2CO3, DMF ([C] = 0.35 / vinyl moiety), 100-105 oC, 0.5 mmol scale (vinyl moiety) a: product is 370 (P = H, P’ = TBS). b: if reaction time prolonged, deprotected product 370 (P = P’ = H) was also detected. Table 20. Screening on different substituents at the phenol and vinyl glycinol derivatives  84  As far at the aryl fragment is concerned, 4-iodophenyl acetate was the reagent of choice. A screen of protective groups on the vinylglycinol unit revealed that O-acetyl and OTBS protections were labile under the conditions of the reaction, while a more robust OTBDPS performed well (Table 20). The reaction did not proceed well if unprotected phenol and glycinol were used. Also, temperatures higher than 100~105 oC were required to force the reaction to completion. No racemization occurred during the reaction. Indeed, compound 371 emerged in enantiomerically pure form, as determined by scrutiny of its Mosher derivative129 by 1H, 13C, and 19F NMR spectroscopy (Scheme 73). O OMe  Cl  CF3  O OMe  OH NHMs  AcO 371  O NHMs  AcO (R)-MPTA chloride  CF3  372  Scheme 73. Preparation of (S)-MPTA ester  OTBDPS Pd/C, H2 HO NHMs K2CO3 MeOH, 95%  AcO 367 HF  OTBDPS NHMs  HF, 80% yield TBAF, 71% yield  373  95%  OH NHMs  AcO 371  Pd/C, H2 K2CO3 MeOH, 95%  HO  OH NHMs  L-homotyrosinol 353 methanesulfonamide  Scheme 74. Synthesis of L-homotyrosinol methanesulfonamide  85  Heck product 367 was uneventfully advanced to the desired L-homotyrosinol methanesulfonamide by desilylation with HF-pyridine and one-pot hydrogenation / methanolysis (Scheme 74). Inverting the order of these two steps resulted in diminished yield. The desired product was thus prepared in 60 % yield over 8 steps from L-methionine methyl ester.  O S  MsCl, Et3N OMe  NH2  O S  DCM quan.  LAH  OMe NHMs  NaIO4 then S  Na2CO3 200 oC  OH NHMs  AcO  dichlorobenzene  OTBDPS NHMs  S  THF 91%  83%  TBDPSCl quan.  I  OTBDPS NHMs Pd(OAc)2  DMF  Phenyl Urea NaHCO3 91%  OR NHMs  AcO HF 95%  Pd/C, H2, K2CO3 MeOH 95%  HO  OH NHMs  R = TBDPS R=H  Scheme 75. A summary of L-homotyrosinol methanesulfonamide synthesis  In  conclusion,  a  robust  preparative  synthesis  of  L-homotyrosinol  methanesulfonamide from L-methionine is now available. A procedure for its large-scale synthesis is detailed in the appendices.130 A complete synthesis scheme is outlined above (Scheme 75).  2.4.3 Synthetic study towards (-)-lepadiformines and its derivatives The synthesis began with IMOA of 353 to afford spiropyrrolidine 374131 in 95 % yield using method B (cf. Table 8). In the ensuing Michael addition, there are two possible  86  ways to achieve diastereoselectivity (Scheme 76). First, a bulky protecting group on the alcohol might induce facial differentiation (cf. 376) on account of steric effects. Second, one could generate a dianion 378 in which the two negative charges repel each other. To wit, alcohol 374 was protected as a TBDPS ether 375 to maximize its steric corpulence. This substrate, along with unprotected alcohol 374, were exposed to various bases at low temperature to test the aforementioned assumptions.  OP DIB/TFA  OH NHMs  HO  N  Ms  O  353  TBDPS-Cl, 91%  374 P = H  374  375 P = TBDPS  Route A, when P = TBDPS  O  TBDPS-O  N  bases  S  O  OTBDPS N SO2  375  O O  Route B, when P = H  376 TBDPS-Cl  O Li O  bases  H major isomer 377  N  S  O  OH N SO2  374  O O  378  H major isomer  379  not isolated  Scheme 76. Diastereoselective Michael addition  As shown in Table 21, lower temperatures provided better selectivity in both route A and B. The reaction was best performed at -100 oC using an EtOH / liq. N2 cold bath. Bases containing three different counterions were examined. In route A, there was no significant  87  difference in yield or selectivity observed between K, Na and Li cations (entry 2-4), and the addition of copper salts did not provide any benefit (entry 5). Reverse addition—adding substrate to base—impeded selectivity (entry 6). Better results were obtained when route B was employed. LHMDS (entry 8) offered superior selectivity to Na and K variants (entry 10 and 11). This observation can be attributed to the coordination by Li cation. Again, copper salts did not aid the reaction (entry 9). In accordance with these results, route B was utilized to synthesize Michael adduct 379 via deprotonation of 374 by 2.2 equivalents of LHMDS. This material was then protected as a TBDPS ether 377 in 78 % yield over two steps.  Steric effect repulsion  Ratioa  KHMDS KHMDS NaHMDS LHMDS LHMDS + CuCN LHMDS  Overall Yield 72 % 81 % 77 % 80 % 79 % 58 %  LHMDS LHMDS LHMDS + CuCN NaHMDS KHMDS  67 % 78 % 78 % 77 % 79 %  6:1 14 : 1 14 : 1 8:1 7:1  Entry  P  Temperature Base  1 2 3 4 5 6b 7 8 9 10 11  TBDPS TBDPS TBDPS TBDPS TBDPS TBDPS  -78 oC -100 oC -100 oC -100 oC -100 oC -100 oC  H H H H H  -78 oC -100 oC -100 oC -100 oC -100 oC  3:1 7:1 7:1 7:1 7:1 1.5 : 1  Overall yield: calculated from 374 to 377 over 2 steps, route A or B a: ratio = desired product : undesired product, based on isolated yields of two isomers of compound 377 (round up to integer) b: reverse addition, substrate to base Table 21. Effect of bases and temperature on Michael addition  88  An enantiopure tricyclic intermediate 350 (cf. Scheme 70) was the next target to further elaborate the lepadiformine framework. A screening and selection of optimal reducing conditions was made on the racemic compound 381, a congener of enone 377 lacking the hydroxymethylene group. Preparation of 381 arose through a Michael addition of IMOA product 380131, which was triggered by adding LHMDS to a THF solution of 380 at -78 oC to afford 381 in 90 % yield (Scheme 77). This material was then reduced to afford tricyclic intermediate 386 by three different avenues. In routes C and E, hydrogenation of the enone was expected to afford compound 384; however, when using PtO2 as the catalyst (route C) an over-reduction occurred to give alcohol 382 in 92 % yield. A classic Barton-McCombie reaction132 was  DIB  NHMs  N  neat TFA  HO  S  O  LHMDS  O  -78 oC  O  90%  N SO2 O  H 381  380 route C NaH, CS2, MeI AIBN, Bu3SnH 40%  PtO2, H2  N SO2 HO  H  382  381 SO2 H NiCl2  386  70%  PhSH  N  Raney Ni PhS PhS  SO2 H  BF3⋅OEt2 75%  383  70%  NaBH4  route E  386  N PhS PhS  route D  PhS  N  92%  SO2 H  385  BF3⋅OEt2 86%  Pd/C, H2  N  PhSH  SO2 O  H  85%  384  Scheme 77. Comparison of different reduction conditions  89  used to deoxygenate this material, providing 386. Unfortunately, the yield of the deoxygenation (40 %) was not satisfactory. Route D was then developed with the aim of improving efficiency. To this end, a one-pot thiophenol Michael addition/ thioacetalization was carried out to furnish compound 383 in 75 % yield. A global desulfurization (70 % yield) was then followed by treatment with Raney Ni133 in MeOH / THF. This sequence provided a 53 % overall yield for the transformation of 381 to 386; however, the purification was complicated by an inseparable impurity when the desulfurization reaction was performed on more than 1 g scale. A remedy was found by the utilization of a three-step route involving hydrogenation with Pd/C of enone 381 to ketone 384, followed by thioacetalization to provide dithiophenol derivative 385 (route E). By decreasing the sulfur content from three atoms to two and using Ni2B desulfurization (generated in situ from NiCl2 and NaBH4 in MeOH / EtOH),134 a slightly improved yield (60 % overall), and much simpler purification resulted. It is worthy of note that anhydrous NiCl2 gave a better yield than hydrated NiCl2. MeOH / EtOH were found to be an optimal solvent system in the desulfurization compared to THF. X-ray structures of 381 and 386 are included in Scheme 77.  OTBDPS SO2 O  OTBDPS Pd/C, H2  N  EtOH, 87%  H  N SO2 O  377  H  DCM 84%  387  OTBDPS N PhS PhS  H  OTBDPS NiCl2, NaBH4  SO2  MeOH / EtOH 71%  388  PhSH, BF3 OEt2  N SO2 H 389  Scheme 78. Synthesis of intermediate 389  90  Based on the above studies, enone 377 was carried through route E to afford 389 in 52 % yield over 3 steps (Scheme 78). Compound 389 was then elaborated to secondary amine 391 via epoxide opening, oxidation and base-induced SO2 elimination (Scheme 79). The sequence began with attack on 1,2-epoxyhexane by the anion of 389. To our surprise, compound 389 was immune to deprotonation by strong bases, such as LDA, LHMDS, and n- / s-BuLi. Finally, this problem was circumvented by using tBuLi. A dark yellow solution of the anion in THF at -78 oC was quenched with 1,2-epoxyhexane and BF3·OEt2. Dess-Martin oxidation of the resultant alcohol gave ketone 390 in an 89 % overall yield from 389. Normally, a sulfonamide group is difficult to cleave under basic conditions. However, in ketone 390 the formation of the conjugated system in 391 facilitates the elimination of gaseous SO2. In the event, enone 391 was afforded in 93 % yield in only 10 min upon exposure of the starting material in DMF solvent to 1.5 eq. DBU. Other bases, like triethylamine and Hünig’s base, gave inferior yields.  OTBDPS N SO2 H 389  1. tBuLi then O  OTBDPS  C6H13  and BF3⋅OEt2 2. Dess-Martin  OTBDPS  N SO2 H  89% over 2 steps 390  C6H13  NH  DBU 93%  O  C6H13 H  O 391  Scheme 79. Formation of enone 391  At this point in the synthesis, we encountered unexpected difficulties during the selective 1,4-reduction of enone 391 (Scheme 80). Conventional conditions, like Pd / C hydrogenation, Wilkinson’s catalyst with Et3SiH, 135 CuH with or without TMSCl, 136  91  NaTeH,137 and other variants,138 gave a mixture of inseparable compounds 393 and 394 (a mixture of two isomers) in low yield. Furthermore, the use of excess reagents and prolonged reaction times did not advance 393 to 394.  OP  OP  1,4-reduction  NH  1  C6H13  C6H13  C6H13 H  OP N  NH H  O 392  H  O 393  P = TBDPS or H  394  Scheme 80. Attempts of 1,4- enone reduction  In the future, we envision an OH-directed hydrogenation of 395 using Crabtree’s catalyst139 to furnish lepadiformines in a diastereoselective mode (Scheme 81). Alternatively, protection of secondary amine 391 followed by Pd hydrogenation should be expected to give 397. After global deprotection, a traditional reductive amination using NaBH(OAc)3 and HOAc,73 benefitting from coordination between a boron-hydride species and the free alcohol, would yield the lepadiformines in a straightforward manner.  OH  OTBDPS TBAF  NH  C6H13  C6H13 H 391  OH-directed "Ir" H2  NH H  O  Lepadiformines and its derivatives  O 395  OH-directed reductive amination  P'-LG OTBDPS  396  O  NH  N-P'  C6H13 H  OH  OTBDPS  [H]  N-P'  C6H13  C6H13 H  397 O  H  398 O  Scheme 81. Future work 92  OH OH NHMs  HO  O  N  DIB / TFA 95%  OH TBDPSCl N dr 14 : 1 SO2 78% over 2 steps O H  OTBDPS N  1. tBuLi then O  PhS PhS  H  OTBDPS N  NiCl2, NaBH4  SO2 H  60% yield over 2 steps  OTBDPS N SO2 H  SO2 O  MeOH / EtOH  H  and BF3⋅OEt2  89% over 2 steps  87%  H  SO2  C6H13  2. Dess-Martin  OTBDPS N  Pd/C, H2  SO2  N  BF3 OEt2  -100 oC  O  OTBDPS PhSH,  excess LHMDS  Ms  C6H13  OTBDPS NH  DBU 93%  C6H13 H  O  O  Scheme 82. A summary of synthesis towards (-)-lepadiformines  In conclusion, our synthesis, utilizing the oxidative cyclization of a phenolic sulfonamide as the key step, provides a concise route to (-)-lepadiformines. By following this step with desymmetrizing Michael addition, epoxide opening, oxidation and DBUinduced elimination, enone 391 was achieved in consistently high yield and with excellent stereoselectivity. Further elaboration will lead to the natural product. 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(b) Peuchmaur, M.; Wong, Y-S. J. Org. Chem. 2007, 72, 5374. (c) Chang, J.; Chan, B.; Ciufolini, M. A. Tetrahedron Lett. 2006, 47, 3599.  90  Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M. A. Tetrahedron Lett. 2002, 43, 5193.  91  No bimolecular oxidative amidation product was detected when MeCN as a co-solvent.  92  For 3-(4-hydroxyphenyl)-1-propanol: about $ 200 for 5 g; For 3-(4-hydroxyphenyl) propionic acid: about $ 140 for 50 g, Sigma-Aldrich, Inc.  93  (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta. 1919, 2, 635. (b) Gololobov, Y. G. Tetrahedron 1981, 37, 437.  101  94  (a) Opitz, G. Angew. Chem. Int. Ed. 1967, 6, 107. (b) Truce, W. E.; Liu, K. Mech. React. Sulfur Comp. 1969, 4, 145. (c) King, J. F. Acc. Chem. Res. 1975, 8, 10.  95  Unpublished results from this laboratory.  96  (a) Sun, P.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62, 8604. (b) King, J. F.; Lam, J. Y. L.; Dave, V. J. Org. Chem. 1995, 60, 2831.  97  (a) Barluenga, J.; González, J. M.; Campos, P. J.; Asensio, G. Angew.Chem. Int. Ed. 1985, 24, 319. (b) Barluenga, J.; González, J. M.; Campos, P. J.; Asensio, G. Tetrahedron Lett. 1986, 27, 1715. (c) Muniz, K. Synlett, 1999, 1679.  98  (a) Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1990, 31, 5507. (b) Lin, Y.; Jones, G. B. Org. Lett. 2005, 7, 71.  99  (a) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505. (b) Nakamura, M.; Miyashita, H.; Yamaguchi, M.; Shirasaki, Y.; Nakamura, Y.; Inoue, J. Bioorg. Med. Chem. 2003, 11, 5449.  100  It is about $400 per 5g, Chem-Impex International, Inc.  101  Kan, T.; Fukuyama, T. Chem. Comm. 2004, 353.  102  (a) Michaelis, A.; Kaehne, R. Ber. 1898, 31, 1048. (b) Arbuzov, A. E. J. Russ. Phys. Chem. Soc. 1906, 38, 687. (c) Arbuzov, A. E. Chem. Zentr. 1906, 2, 1639. (d) Arbuzov, B. A. Pure Appl. Chem. 1964, 9, 307. (e) Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415.  103  (a) Claisen, L. Ber. 1912, 45, 3157. (b) Claisen, L.; Tietze, E. Ber. 1925, 58, 275. (c) Claisen, L.; Tietze, E. Ber. 1926, 59, 2344. (d) Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (e) Kurosawa, W.; Kobayashi, H.; Kan, T.; Fukuyama, T. Tetrahedron 2004, 60, 9615.  102  104  The boiling point of trimethyl phosphine is 38-39 ºC. The by-product, trimethyl phosphine oxide, is water-soluble.  105  Kaupp, G.; Schmeyers, J.; Boy, J. Tetrahedron 2000, 56, 6899.  106  For the preparation of vinyl sulfonyl chloride, see: (a) King, J. F.; Loosmore, S. M.; Aslam, M.; Lock, J. D.; McGarrity, M. J. J. Am. Chem. Soc. 1982, 104, 7108. (b) King, J. F.; Hillhouse, J. H.; Skonieczny, S. Can. J. Chem. 1984, 62, 1977.  107  (a) Gabriel, S. Ber. 1887, 20, 2224. (b) Sheehan, J. C.; Bolhofer, V. A. J. Am. Chem. Soc. 1950, 72, 2786. (c) Gibson, M.S.; Bradshaw, R.W. Angew. Chem. Int. Ed. 1968, 7, 919.  108  Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure-5th ed.; John Willy & Sons, Inc.: Toronto, 2001; p.1067.  109  Collum, D. B. Acc. Chem. Res. 1992, 25, 448.  110  Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392.  111  Seyferth, D.; Weiner, M. A.; Vaughan, L. G.; Raab, G.; Welch, D. E.; Cohen, H. M.; Alleston, D. L. Bull. Soc. Chim. Fr. 1963, 7, 1364.  112  Dunne, K. S.; Lee, S. E.; Gouverneur, V. J. Organomet. Chem. 2006, 691, 5246.  113  (a) Cowan, D. O.; Mosher, H. S. J. Org. Chem. 1962, 27, 1. (b) Landa, S.; Vais, J.; Burkhard, J. Coll. Czech. Chem. Comm. 1967, 32, 570.  114  Lefranc,D. Dissertation, University of British Columbia, 2008.  115  Chanley, J. D.; Sobotka, H. J. Am. Chem. Soc. 1949, 71, 4140.  116  (a) Lindlar, H.; Dubuis, R. Org. Synth. 1973, Coll. Vol. 5, 880. (b) Lindlar, H. Helv. Chim. Acta. 1952, 35, 446.  117  Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115.  103  118  (a) Juo, W-J.; Lee, T-H.; Liu, W-C.; Ko, S.; Chittimalla, S. K.; Rao, C. P.; Liao, C-C. J. Org. Chem. 2007, 72, 7992. (b) Lee, T-H.; Liao, C-C.; Liu, W-C. Tetrahedron Lett. 1996, 37, 5897.  119  Lutz, R. Chem. Rev. 1984, 84, 205.  120  Lee, Y. S.; Ryu, E. K.; Yun, K-Y.; Kim, Y. H. Synlett 1996, 247.  121  For some unknown reason, compound 328 and 330 are contaminated with some impurities after flash chromatography column. The purification is effective after the transformation from 330 to 338. NMR spectra of these compounds 328 and 330 are not included in the appendices.  122  Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.  123  Heck, R. F.; Nolley, Jr., J. P. J. Org. Chem. 1972, 37, 2320.  124  Afzali-Ardakani, A.; Rapoport, H. J. Org. Chem. 1980, 45, 4817.  125  Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.; Taylor, R. J. K. J. Org. Chem. 2002, 67, 1802.  126  For a similar Heck example, see: Suhartono, M.; Weidlich, M; Stein, T.; Karas, M.; Dürner, G.; Göbel, M. W. Eur. J. Org. Chem. 2008, 1608. However, the conditions, particularly catalyst and ligand, in this reference are not compatible with our system.  127  Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.  128  Cui, X.; Zhou, Y.; Wang, N.; Liu, L.; Guo, Q-X. Tetrahedron Lett. 2007, 48, 163.  129  Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.  130  A slightly different operation is included in the appendices when reaction scale of Heck coupling is more than 5 g.  104  131  Alcohol 374 and compound 273, R = CH2OH are identical. For the ease of discussion, we prefer to use number 374 in this lepadiformine chapter. This is also true for compound 380, which is identical to compound 231, R = Me.  132  Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 16, 1574.  133  Raney, M. 1927, US 1628190.  134  (a) Back, T. G.; Baron, D. L.; Yang, K. J. Org. Chem. 1993, 58, 2407. (b) Khurana, J. M.; Kukreja, G. Synth. Comm. 2002, 32, 1265.  135  Iwao Ojima, I.; Kogure, T. Tetrahedron Lett. 1972, 49, 5085.  136  (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1988, 110, 291. (b) Lee, D. W.; Yun, J. Tetrahedron Lett. 2005, 46, 2037.  137  (a) Yamashita, M.; Kato, Y.; Suemitsu, R. Chem. Lett. 1980, 847. (b) Yamashita, M.; Tanaka, Y.; Arita, A.; Nishida, M. J. Org. Chem. 1994, 59, 3500. (c) Bargues, V.; Blay, G.; Cardona, L.; Garcia, B.; Pedro, J. R. Tetrahedron 1998, 54, 1845.  138  Ito, H.; Ishizuka, T.; Arimoto, K.; Miura, K.; Hosomi, A. Tetrahedron Lett. 1997, 38, 8887.  139  Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.  105  APPENDICES A. EXPERIMENTAL PROTOCOLS  Unless otherwise indicated, 1H (300 MHz) and  13  C (75 MHz) NMR spectra were  recorded at room temperature from CDCl3 solutions. Chemical shifts are reported as ppm on the δ scale and coupling constants, J, are in Hz. Multiplicities are described as s (singlet), d / dd / ddd (doublet / doublet of doublets / doublet of doublet of doublets), t (triplet), q (quartet), p (pentet), sept (septuplet), m (multiplet), and further qualified as app (apparent), b (broad), c (complex). All 2D NMR spectra were recorded at 300 MHz (1H) / 75 MHz (13C). Infrared (IR) spectra (cm–1) were recorded on a Perkin–Elmer model 1710 Fourier transform spectrophotometer from films deposited on NaCl plates while optical rotations were measured on a Jasco P–1010 polarimeter at the sodium D line (589 nm). Unless otherwise stated, low resolution mass spectra (m/z) were obtained, in the electrospray (ESI) mode, atmospheric pressure chemical ionization (APCI) mode on a Waters Micromass ZQ mass spectrometer. High–resolution mass spectra (m/z) were recorded in the ESI or APCI mode on a Micromass LCT mass spectrometer by the UBC Mass Spectrometry laboratory. Low and high resolution mass spectra obtained in electron impact (EI) mode were recorded on MASPEC II System mass spectrometer by the UBC Mass Spectrometry laboratory. Melting points (uncorrected) were measured on a Mel–Temp apparatus. All x-ray single crystal measurements were made by Dr. Brian Pratick (UBC x-ray service) on a Bruker X8 APEX II diffractometer and the refinements were performed using the SHELXTL crystallographic software package of Bruker-AXS.  106  All reagents and solvents were commercial products and used without further purification except THF (freshly distilled from Na/benzophenone under Ar) and CH2Cl2 (freshly distilled from CaH2 under Ar). Commercial anhydrous DMF and LHMDS solution were used as received. Commercial n-BuLi was titrated against N-benzylbenzamide in THF at –78 oC until persistence of a light blue color. Flash chromatography was performed on Silicycle 230 – 400 mesh silica gel. All reactions were performed under dry Ar in flame or oven dried flasks equipped with TeflonTM stirbars. All flasks were fitted with rubber septa for the introduction of substrates, reagents, and solvents via syringe.  107  B. SORDARIN EXPERIMENTAL SECTION B.1 Synthesis and characterization of various sordarin intermediates B.1.1 Preparation of 3-methoxycyclopent-2-enone (127) Neat Me2SO4 (0.125 g, 1 mmol; CAUTION: toxic, corrosive, cancer O  OMe  suspect agent) was added at room temperature to a vigorously stirred  suspension of 1,3-cyclopentanedione (126) (98.0 mg, 1 mmol) and K2CO3 (138 mg, 1 mmol) in acetone (10.0 mL). The mixture was then heated to 60 °C for 8 h with continued stirring. After that it was cooled and concentrated. The residue was partitioned between EtOAc (10.0 mL) and aq. 1 M NaOH (10.0 mL), the layers were separated, and the aqueous phase was further extracted with EtOAc (3 x 10.0 mL). The combined extracts were washed with brine (15.0 mL) and dried (MgSO4) and concentrated. Chromatography of the residue (EtOAc / MeOH = 100 / 1) gave 111 mg (0.990 mmol, 99.0 %) product as a light yellow oil. (known compound) [cf. Tetrahedron, 2001, 57, 217.] 1H: 5.25 (t, J = 1.2, 1H); 3.78 (s, 3H); 2.54 (m, 2H); 2.38 (m, 2H). 13C: 204.7; 190.1; 103.4; 57.7; 33.1; 27.2. HRMS: calc. for C6H8O2 [M + Na]+ 135.0422; found 135.0419.  B.1.2 Preparation of methyl 4-methoxy-2-oxocyclopent-3-enecarboxylate (128) To a THF solution (6.00 mL) of diisopropylamine (0.900 mL, 6.38  O MeOOC  mmol) was added n-butyllithium in hexane solution (1.60 M, 3.60 mL, OMe  5.80 mmol) at -78 oC under N2. The clear solution was stirred for 30  min at -50 oC. A solution of 127 (500 mg, 4.50 mmol) in THF (1.50 mL) was added dropwise to above solution at the same temperature and the resulting mixture was stirred for 30 min at –50 °C. Neat MeOOCCN (0.400 mL, 4.90 mmol; CAUTION: source of highly toxic HCN) was injected. The solution was stirred for 2.5 h, during which time it was 108  allowed to warm to room temperature, then it was cooled to 0 °C, neutralized with aq. 1.00 N HCl (10.0 mL; CAUTION: formation of highly toxic HCN), and extracted with EtOAc (3 x 15.0 mL). The combined extracts were washed with brine (10.0 mL) and dried (Na2SO4) and evaporated. Chromatography of the residue (EtOAc / hexanes = 1 : 1) gave 394 mg (2.32 mmol, 52.0 %) product as a light yellow oil. 1H: 5.28 (s, 1H); 3,87 (s, 3H); 3.76 (s, 3H); 3.53 (dd, J = 7.5, 3.0, 1H); 3.04 (dd, J = 17.7, 3.0, 1H); 2.77 (dd, J = 17.7, 7.5, 1H). 13C: 198.3; 191.1; 169.9; 103.2; 59.6; 53.1; 51.7; 32.5. HRMS: calc. for C8H11O4 [M + H]+ 171.0657; found 171.0654.  B.1.3 Preparation of methyl 4-methoxy-2-oxo-1-(3-oxopropyl)cyclopent-3enecarboxylate (129) Neat DBU (4.00 μL, 24.0 μmol) was added to a cold (0 °C) MeCN (2.40 COOMe CHO O  OMe  mL) solution of 128 (204 mg, 1.20 mmol) and acrolein (90.0 μL, 1.30 mmol; CAUTION: toxic, cancer suspect agent). The solution was then  warmed to room temperature, stirred for 3 h, and finally diluted with EtOAc (10.0 mL). The mixture was sequentially washed with aq. sat. NH4Cl (5.00 mL) and brine (5.00 mL) and dried (Na2SO4) and evaporated to afford 271 mg (1.19 mmol, 99.0 %) product as a light yellow oil. 1H: 9.74 (s, 1H); 5.27 (s, 1H); 3.88 (s, 3H); 3.71 (s, 3H); 3.16 (d, J = 18.0, 1H); 2.55 (m, 2H); 2.44 (d, J = 18.0, 1H); 2.28 (m, 1H); 2.15 (m, 1H). 13C: 201.3; 200.9; 190.2; 171.4; 102.6; 59.6; 58.3; 53.3; 39.8; 38.9; 26.8. IR: 1731, 1698. HRMS: calc. for C11H15O5 [M + H]+ 227.0919; found 227.0920.  109  B.1.4 Preparation of methyl 1-(4-cyano-3-hydroxypent-4-enyl)-4-methoxy-2oxocyclopent-3-ene carboxylate (130)  HO  COOMe  A mixture of 129 (70.0 mg, 301 μmol), acrylonitrile (0.600 mL;  OMe  CAUTION: toxic, cancer suspect agent) and DABCO (7.00 mg,  NC O  62.0 μmol) was stirred at room temperature for 2 days, then it was concentrated. Chromatography of the residue (EtOAc / hexanes = 1 : 1) provided 49 mg (176 μmol, 57.0 %) product in ca. 1.5 : 1 diastereoisomeric ratio. 1H: 6.02 (dd, J = 17.0, J = 2.0, 2H); 5.28 (s, 1H); 4.27 (m, 1H); 3.90 (s, 3H); 3.72 (s, 3H); 3.19 (d, J = 18.0, 1H); 2.53 (d, J = 18.0, 1H); 2.30-2.10 (m, 2H); 1.95-1.60 (m, 3H).  13  C: 201.5; 190.9; 171.6; 130.8; 126.6;  117.4; 102.6; 71.9; 59.6; 59.0; 53.3; 38.3; 30.9; 29.6. HRMS: calc. for C14H18NO5 [M + H]+ 280.1185; found 280.1183.  B.1.5 Preparation of cycloadduct 132 COOMe OMe  TIPSO NC  OTIPS  Neat TIPS-OTf (2.70 mL, 11.2 mmol) was added to a cold (0 °C) solution of 130 (1.30 g, 4.50 mmol) and diisopropylethylamine (2.00 mL, 11.2 mmol) in CH2Cl2 (18.0 mL), then the mixture was  allowed to warm to room temperature and stirred for 12 h. The solution was diluted with a 3 : 1 mixture of pentane-CH2Cl2 (100 mL), resulting in the appearance of a colorless precipitate that was filtered off. The organic filtrate was washed with aq. sat. NaHCO3, dried (Na2SO4) and evaporated. Chromatography of the residue (EtOAc / hexanes = 5 : 95) provided 1.90 g (3.20 mmol, 72.0 %) product as a nearly 1:1 mixture of diastereomers. 1H: 4.85-4.80 (m, 2H); 4.13 (t, J = 4.1, 2H); 3.32 (s, 3H); 3.25 (s, 3H); 3.16 (s, 3H); 3.13 (s, 3H); 2.71 (d, J = 4.1, 2H); 2.38 (d, J = 4.5, 2H); 2.27 (dd, J = 13.6, J = 4.1, 2H); 2.17 (m, 2H);  110  2.00-1.80 (m, 6H); 1.50-0.90 (m, 21H). 13C: 174.0; 173.4; 170.9; 169.5; 128.7; 123.6; 123.0; 96.6; 97.3; 91.6; 91.2; 76.0; 70.2; 66.5; 65.9; 56.9; 54.7; 53.2; 51.8; 51.7; 47.2; 42.6; 33.3; 28.1; 27.9; 25.1; 19.5; 19.3; 18.8; 18.3; 14.6; 13.5; 13.1. HRMS: calc. for C32H58NO5Si2 [M + H]+ 592.3854; found 592.3859.  B.1.6 Preparation of 2-isopropyl-3-methoxycyclopent-2-enone (134) Neat Me2SO4 (4.50 g, 36.0 mmol; CAUTION: toxic, corrosive, cancer suspect  O  agent) was added at room temperature to a vigorously stirred suspension of 133 OMe  (5.00 g, 36.0 mmol) and K2CO3 (4.50 g, 36.0 mmol) in acetone (60.0 mL). The  mixture was then heated to 60 °C for 8 h with continued stirring, then it was cooled and concentrated. The residue was partitioned between EtOAc (10.0 mL) and aq. 1 M NaOH (15.0 mL), the layers were separated, and the aqueous phase was further extracted with EtOAc (3 x 30.0 mL). The combined extracts were washed with brine (30.0 mL) and dried (MgSO4) and concentrated. Chromatography of the residue (25 % EtOAc / hexanes) gave 5.50 g (35.6 mmol, 99.0 %) of 74 as an oil. 1H: 3.91 (s, 3H); 2.73 (sept, J = 7,0, 1H); 2.62 (m, 2H); 2.39 (m, 2H); 1.11 (d, J = 7.0, 6H). 13C: 204.8; 184.6; 125.8; 56.5; 33.8; 24.4; 23.1; 20.4. IR: 1682, 1621. HRMS: calc. for C9H15O2 [M + H]+ 155.1072; found: 155.1078.  B.1.7 Preparation of 4-carbomethoxy-2-isopropyl-3-methoxycyclopent-2-en-1-one (141) A solution of 134 (306 mg, 2.00 mmol) in THF (2.00 mL) was added  O  dropwise to a cold (–78 °C) solution of LHMDS (2.10 mL of MeO2C  OMe  commercial 1.00 M THF solution, 2.10 mmol, diluted an additional 2.00  mL of THF), and the mixture was stirred at –78 °C for 2 h. Neat MeOOCCN (160 μL, 2.00 mmol; CAUTION: source of toxic HCN) was injected and the solution was stirred –78 °C 111  for 30 min. The reaction was quenched at –78 °C by addition of aq. 1.00 N HCl (4.00 mL; CAUTION: formation of HCN), allowed to warm to room temperature, and extracted with EtOAc (3 x 15.0 mL). The combined extracts were washed with brine (10.0 mL) and dried (Na2SO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 1 : 1) gave 340 mg (1.62 mmol, 81.0 %) product as an light yellow oil. 1H: 3.90 (s, 3H); 3.83 (dd, J = 7.6, 2.3, 1H); 3.78 (s, 3H); 2.79 (dt, J = 6.7, 1H); 2.72 (d, J = 7.4, 1H); 2.47 (dd, J = 17.8, 2.3, 1H); 1.14 (d, J = 6.8, 6H). 13C: 202.2; 179.5; 172.1; 128.1; 57.4; 53.2; 42.7; 39.3; 23.4; 20.2. HRMS: calc. for C9H17O4 [M + H]+ 213.1127; found 213.1131. IR: 1736; 1702; 1620.  B.1.8 Preparation of methyl 3-isopropyl-2-methoxy-4-oxo-1-(3-oxopropyl)cyclopent-2enecarboxylate (142) Neat DBU (13.0 μL, 87.0 μmol) was added to a cold (0 oC) solution of CO2Me OHC MeO  O  141 (920 mg, 4.30 mmol) and acrolein (308 μL, 4.60 mmol; CAUTION: toxic, cancer suspect agent) in MeCN (9.00 mL). The mixture was stirred at 0 °C for 30 min, then at room temperature for 4 h,  and finally it was concentrated. The residue was treated with aq. sat. NH4Cl (20.0 mL) and extracted with EtOAc (4 x 10.0 mL). The combined extracts were washed with brine (15.0 mL) and dried (MgSO4) and concentrated to afford crude product 1.1 g (4.25 mmol, 99.0 %) product, which was used without further purification. 1H: 9.76 (s, 1H); 3.99 (s, 3H); 3.74 (s, 3H); 2.99 (sept, J = 6.8, 1H); 2.69 (d, J = 17.8, 1H); 2.48 (m, 1H); 2.32-2.28 (m, 3H); 2.23 (d, J = 17.7, 1H); 1.23 (dd, J = 7.1, 4.3, 6H). 13C: 202.8; 200.9; 180.2; 173.6; 126.6; 59.7; 53.1; 52.2; 45.3; 39.0; 26.1; 24.5; 20.7; 20.4. HRMS: calc. for C14H21O5 [M + H]+ 269.1389; found 269.1390. IR: 1730; 1692; 1611.  112  B.1.9 Preparation of methyl 1-(4-cyano-3-hydroxypent-4-enyl)-3-isopropyl-2-methoxy4-oxocyclopent-2-enecarboxylate (143) A solution of 142 (65.0 mg, 242 μmol), DABCO (5.50 mg, 48.0  O OMe  HO NC  O  μmol), in acrylonitrile (1.00 mL; CAUTION: cancer suspect agent) was stirred at room temperature for four days, then it was  MeO  concentrated. The residue was taken up with aq. sat. NaHCO3 (20.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were washed with brine (15.0 mL) and dried (MgSO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 1 : 1) gave 53.0 mg (165 μmol, 68.0 %) product as a light yellow oil in a ca. 1.5 : 1 mixture of diastereoisomers. 1H: 6.04 (d, J = 10.2, 2H); 4.29 (m, 1H); 4.01 (d, J = 3.0, 3H); 3.71 (s, 3H); 3.01 (m, 1H); 2.69 (dd, J = 17.8, 3.5, 1H); 2.30 (d, J = 17.7, 1H); 2.05-1.98 (m, 2H); 1.75-1.50 (m, 2H); 1.24 (m, 6H). 13C: 203.7; 181.1; 180.8; 174.1; 174.0; 130.7; 126.9; 126.8; 126.7; 117.4; 117.3; 72.0; 71.5; 59.9; 59.8; 52.7; 45.4; 45.3; 30.3; 30.1; 29.3; 28.8; 24.6; 20.9; 20.8. HRMS: calc. for C17H24NO5 [M + H]+ 322.1654; found: 322.1654. IR: 3367; 2223; 1732; 1688; 1606.  B.1.10 Preparation of cycloadduct 145 CO2Me OTES TESO  OMe CN  Neat TES-OTf (190 μL, 830 μmol) was added to a cold (0° C) CH2Cl2 (1.50 mL) solution of 143 (121 mg, 380 μmol, 65 : 35 mixture of diastereomers) and diisopropylethylamine (160 μL,  940 μmol). The solution was warmed to room temperature and stirred for 12 h, then it was diluted with a 3 : 1 mixture of pentane / CH2Cl2 (10.0 mL), resulting in precipitation of a  113  colorless solid which was filtered off. The filtrate was washed with aq. sat. NaHCO3 (3.00 mL) and dried (Na2SO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 5 : 95) gave 108 mg (198 μmol, 52.0 %) product as a light yellow oil in a ca. 52 : 48 mixture of diastereoisomers. 1H (major diastereomer): 4.39 (m, 1H); 4.25 (t, J = 7.6, 1H); 3.88 (s, 3H); 3.75 (s, 3H); 3.65 (s, 3H); 3.61 (s, 3H); 2.71-2.67 (m, 2H); 2.51 (m, 2H); 2.41 (m, 2H); 2.17-1.87 (m, 8H); 1.70-1.40 (m, 2H); 1.30 (dd, J = 6.7, 1.5, 6H); 1.14 (dd, J = 6.9, 5.7, 6H); 1.02-0.90 (m, 36H); 0.75-0.62 (m, 24H).  13  C: 173.7; 173.6; 157.3; 154.9; 123.8;  123.5; 123.4; 122.0; 94.5; 93.4; 74.8; 68.9; 66.5; 65.9; 58.6; 56.4; 56.1; 51.9; 48.8; 48.4; 47.9; 41.4; 32.8; 27.3; 27.2; 25.6; 25.4; 22.4; 22.3; 20.6; 20.2; 6.8; 6.7; 6.6; 6.4; 5.5; 5.0; 4.8. HRMS: calc. for C29H52NO5Si2 [M + H]+ 550.3384; found 550.3383.  B.1.11 Preparation of cycloadduct 146 CO2Me OTBS TBSO  OMe CN  Neat TBS-OTf (147 μL, 550 μmol) was added to a cold (0 °C) THF (1.30 mL) solution of 143 (30.0 mg, 93.0 μmol) and DIPEA (140 μL, 810 μmol). The solution was warmed to room  temperature and then heated to 60 °C for 12 h. It was diluted with EtOAc (15.0 mL) and neutralized with aq. sat. NaHCO3 (5.00 mL). The organic phase was separated and washed with brine (5.00 mL) and dried (Na2SO4) and concentrated. Chromatography of the residue (CH2Cl2 / hexanes = 3 : 7) gave 23.0 mg (42.0 μmol, 45.0 %) product as a colorless oil in a ca. 51 : 49 mixture of diastereoisomers. 1H (major diastereoisomer): 4.39 (m, 1H); 3.74 (s, 3H); 3.62 (s, 3H); 2.71 (d, J = 4.3, 1H); 2.51 (sept, J = 6.9, 1H); 2.46 (dd, J = 13.1, 4.4, 1H); 2.04-1.87 (m, 2H); 1.73-1.54 (m, 2H); 1.48 (d, J =13.1, 1H); 1.32 (d, J = 6.8, 3H); 1.15 (d, J = 6.8, 3H); 0.96 (s, 9H); 0.91 (s, 9H); 0.22 (s, 3H); 0.21 (s, 3H); 0.19 (s, 3H); 0.11 (s, 3H). 13  C (single diastereoisomer): 174.7; 158.7; 124.6; 122.9; 95.6; 70.1; 67.4; 57.4; 52.8; 52.6; 114  49.1; 33.7; 28.1; 26.7; 26.5; 25.7; 25.5; 23.5; 21.4; 19.0; 18.9; -2.2; -2.7; -3.2; -3.6. HRMS: calc. for C29H51NO5Si2 [M + Na]+ 572.3306; found 572.3305. IR: 2315; 1730.  B.1.12 Preparation of compound 147 CO2Me OTIPS TIPSO  Neat TIPSOTf (190 µL, 0.710 mmol) was added to a cold (0 °C) CH2Cl2 (1.30 mL) solution of 143 (104 mg, 320 μmol) and Hünig’s base (140 μL, 810 μmol). The solution was warmed to  OMe CN  room temperature and stirred for 12 h, then it was diluted with a 3 : 1 mixture of pentane / CH2Cl2 (10.0 mL), resulting in precipitation of a colorless solid which was filtered off. The filtrate was washed with aq. sat. NaHCO3 (3.00 mL) and dried (Na2SO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 5 : 95) gave 123 mg (195 μmol, 61.0 %) product as a colorless oil in a ca. 63 : 37 mixture of diastereoisomers. 1H: 4.57 (ddapp., J = 8.6, 6.1, 1H); 4.41 (t, J = 8.3, 1H); 3.91 (s, 3H); 3.77 (s, 3H); 3.64 (s, 3H); 3.59 (s, 3H); 2.75-2.65 (m, 2H); 2.58 (m, 2H); 2.49-2.42 (m, 2H); 2.16 (d, J = 12.9, 2H); 2.05-1.80 (m, 6H); 1.75-1.40 (m, 2H); 1.34 (d, J = 6.7, 12H); 1.23-1.00 (m, 21H). 13C: 173.8; 156.6; 154.4; 124.2; 123.9; 123.8; 122.9; 94.8; 94.2; 75.9; 69.8; 66.6; 66.1; 56.8; 56.5; 52.1; 51.9; 49.9; 49.2; 48.8; 42.5; 33.4; 27.8; 27.7; 26.5; 25.5; 25.1; 22.7; 21.3; 20.6; 18.3; 13.5; 12.9. HRMS: calc. for C35H64NO5Si2 [M + H]+ 634.4323; found 634.4322. IR: 2324; 1745; 1645.  B.1.13 Preparation of alcohol 148 COOMe O  HO NC MeO  Pyridine-HF complex (70 % HF, 2 mL) was added to a cold (0 °C) solution of 145 (206 mg, 380 μmol) in MeCN (2.00 mL). The mixture was stirred for 1 h, during which it was allowed to warm to room  temperature, then it was diluted with EtOAc (20.0 mL) and neutralized with aq. sat. 115  NaHCO3 (5.00 mL). The organic phase was separated and washed with brine (5.00 mL) and dried (Na2SO4) and concentrated to afford 120 mg (380 μmol, 100.0 %) product as a light yellow oil in a mixture of diastereoisomers. 1H: 4.48 (dd, J = 10.5, 6.2, 1H); 4.00 (m, 1H); 3.71 (s, 3H); 3.68 (s, 3H); 3.58 (s, 3H); 3.47 (s, 3H); 2.82 (d, J = 6.0, 1H); 2.76 (d, J = 6.2, 1H) ; 2.70 (d, J = 10.0, 1.5H); 2.68-2.38 (m, 4.5H); 2.18-1.80 (m, 8H); 1.60 (d, J = 15.0, 2H); 1.31 (d, J = 6.4, 6H); 1.24 (dd, J = 6.8, 4.5, 6H). 13C: 206.9, 205.7; 173.6, 173.2; 121.1; 91.4; 90.5; 75.0; 67.7; 57.3; 57.0; 54.3; 54.1; 53.6; 53.3; 53.0; 52.8; 49.2; 44.7; 29.8; 27.4; 27.3; 25,9; 25,6; 24.4; 24.4; 23.5; 22.5; 22.4; 21.6. HRMS: calc. for C17H24NO5 [M + H]+ 322.1654; found 322.1652. IR: 3455; 2246; 1728.  B.1.14 Preparation of diketone 149 Neat DMSO (70.0 μL, 900 μmol) was added to a cold (–78 °C) solution CO2Me  of (COCl)2 (40.0 μL, 430 μmol) in CH2Cl2 (500 μL; CAUTION:  O  O NC  OMe  formation of toxic CO). The mixture was stirred at –78 °C for 15 min, then a solution of 148 (60.0 mg, 190 μmol) in CH2Cl2 (0.600 mL) was  added dropwise and the mixture was stirred at –78 °C for 30 min. Neat Et3N (210 μL, 1.50 mmol) was then slowly injected and the mixture was stirred at –78 °C for another 30 min, then it was allowed to warm to room temperature. The mixture was diluted with aq. sat. NH4Cl (2.00 mL) and CH2Cl2 (10.0 mL). The organic phase was separated, dried (Na2SO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 3 : 7) gave 40 mg (127 μmol, 67.0 %) product as a light yellow oil in a ca. 1 : 1 mixture of diastereoisomers. 1  H: 3.76 (s, 3H); 3.50 (s, 3H); 2.92 (d, J = 6.0, 1H); 2.83-2.73 (m, 4H); 2.65-2.53 (m, 1H);  2.50 (dd, J = 15.2, 5.8, 1H); 2.25-2.10 (m, 2H); 1.31 (d, J = 6.6, 3H); 1.21 (d, J = 6.7, 3H). 13  C: 206.8; 199.1; 172.8; 117.0; 94.4; 56.9; 56.0; 55.8; 55.3; 54.3; 53.3; 31.9; 30.3; 27.0; 116  23.5; 23.1; 22.8. HRMS: calc. for C17H22NO5 [M + H]+ 320.1498; found 320.1499. IR: 2954; 2872; 2238; 1750; 1716; 1621; 1435.  B.1.15 Preparation of methyl 1-(3-(tert-butyldimethylsilyloxy)-4-cyanopent-4-enyl)-3isopropyl-2-methoxy-4-oxocyclopent-2-enecarboxylate (153) CO2Me O TBSO CN OMe  A solution of 143 (800 mg, 2.50 mmol), imidazole (253 mg, 3.70 mmol), DMAP (30.0 mg, 245 μmol) and TBSCl (747 mg, 5.00 mmol) in dry DMF (2.00 mL) was stirred at 60 °C for 11 h, then it  was cooled to room temperature, diluted with aq. sat. NH4Cl (20.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were washed with brine (15.0 mL) and dried (MgSO4) and concentrated. Chromatography of the residue (gradient 0 % to 25 % EtOAc in hexanes) gave 812 mg (1.88 mmol, 75.0 %) product as a light yellow oil in a ca. 6 : 4 mixture of diastereoisomers. 1H: 5.98-5.89 (m, 2H); 4.30-4.20 (m, 1H); 3.98-3.93 (m, 3H); 3.72 (s, 3H); 3.01-2.91 (m, 1H); 2.66 (dd, J = 17.5, 4.2, 1H); 2.26 (dd, J = 17.5, 6.6, 1H); 1.95-1.82 (m, 2H); 1.56-1.43 (m, 2H); 1.22 (dd, J = 6.9, 4.3, 6H); 0.90 (s, 9H); 0.06-0.04 (m, 6H).  13  C: 202.5; 179.8, 179.7; 173.5; 129.6; 126.6; 126.5; 126.4; 116.8; 99.5; 72.0; 71.8;  59.2; 59.1; 52.6; 52.0; 45.0; 44.9; 30.5; 30.3; 28.0; 27.6; 25.5; 24.1; 24.0; 20.3; 19.97; 19.95; 17.95; -4.96; -4.98; -5.16; -5.18. HRMS: calc. for C23H38NO5Si [M + H]+ 436.2516; found 436.2519. IR: 2223; 1736; 1619.  117  B.1.16 Preparation of methyl 1-(3-(tert-butyldimethylsilyloxy)-4-cyanopent-4-enyl)-2cyano-3-isopropyl-4-oxocyclopent-2-enecarboxylate (154) CO2Me O  Commercial Et2AlCN solution (1.0 M in toluene, 3.30 mL, 3.30 mmol; CAUTION: source of toxic HCN) was added at room  TBSO CN CN  temperature to a stirred solution of 153 (729 mg, 1.70 mmol) in  dry benzene (15 mL). The mixture was stirred at room temperature for 1.5 h, then it was quenched with 1 M NaOH (4 mL; CAUTION: exothermic reaction, formation of cyanide) and concentrated. The residue was taken up with aq. sat. NaHCO3 (20.0 mL) and with EtOAc (20.0 mL). The organic phase was recovered and the aqueous phase was further extracted with EtOAc (3 x 10.0 mL). The combined extracts were washed with brine (15.0 mL) and dried (MgSO4), and concentrated.  Chromatography of the residue (EtOAc /  hexanes = 1 / 3) gave 544 mg (1.28 mmol, 75.0 %) product as a light yellow oil in a ca. 3 : 2 mixture of diastereoisomers. 1H: 6.05-5.95 (m, 2H); 4.35-4.25 (m, 1H); 3.85-3.77 (m, 3H); 3.07 (dd, J = 19.0, 3.0, 1H); 3.01-2.95 (m, 1H); 2.37 (dd, J = 19.0, 3.0, 1H); 2.25-2.15 (m, 1H); 1.85-1.45 (m, 3H); 1.30-1.23 (m, 6H); 0.95-0.85 (m, 9H); 0.12-0.05 (m, 6H).  13  C:  203.1; 171.6; 171.5; 161.8; 161.7; 136.0; 135.9; 130.5; 126.3; 126.1; 117.0; 116.9; 113.8; 113.7; 71.9; 71.7; 53.7; 53.6; 43.8; 43.6; 31.5; 31.3; 31.0; 30.6; 26.7; 25.9; 25.8; 20.2; 20.1; 4.60; -4.8. HRMS: calc. for C23H34N2O4Si [M + Na]+ 453.2183; found. 453.2186. IR: 2225; 1726.  118  B.1.17 Preparation of methyl 1-(3-(tert-butyldimethylsilyloxy)-4-cyanopent-4-enyl)-2cyano-4-hydroxy-3-isopropylcyclopent-2-enecarboxylate (162) CO2Me OH TBSO CN CN  Solid NaBH4 (4.00 mg) was added to a cold (0 °C) solution of 154 (40.0 mg, 90.0 μmol) and CeCl3·7H2O (22.0 mg, 59.0 μmol) in MeOH (1.00 mL), and the mixture was stirred for 15 min. The  reaction was quenched with aq. sat. NH4Cl (5.00 mL) and the mixture was concentrated. The residue was partitioned between EtOAc (10.0 mL) and aq. sat. NH4Cl (10.0 mL). The organic phase was recovered and the aqueous phase was further extracted with EtOAc (3 x 10.0 mL). The combined extracts were washed with brine (15.0 mL) and dried (MgSO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 1 : 3) gave 20.0 mg (46.0 μmol, 51.0 %) product as a light yellow oil. 1H: 6.02-5.91 (m, 2H); 5.08-4.95 (m, 1H); 4.334.20 (m, 1H); 3.84-3.68 (m, 3H); 3.01-2.84 (m, 2.2H); 2.59-2.48 (m, 0.4H); 2.29-1.76 (m, 3H); 1.76-1.47 (m, 1.4H); 1.40-1.13 (m, 6H); 0.97-0.77 (m, 9H); 0.23-0.01 (m, 6H). HRMS: calc. for C23H36N2O4Si [M + Na]+ 455.2343; found 455.2342. IR: 3473; 2221; 1734.  B.1.18 Preparation of methyl 1-(3-(tert-butyldimethylsilyloxy)-4-cyanopent-4-enyl)-2cyano-3-isopropylcyclopenta-2,4-dienecarboxylate (158) CO2Me  A solution of 162 (19.0 mg, 44.0 μmol) and Burgess reagent (21.0 mg, 88.0 μmol) in dry benzene (0.500 mL) was stirred at 60 °C for  TBSO CN CN  15 h, then it was cooled and concentrated. The residue was  partitioned between EtOAc (10.0 mL) and aq. sat. NaHCO3 (10.0 mL), the organic phase was recovered and the aqueous phase was further extracted with EtOAc (3 x 10.0 mL). The combined extracts were washed with brine (15.0 mL) and dried (MgSO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 1 : 3) gave 10.0 mg (24.0 μmol, 54.0 %) 119  product as a light yellow oil in a ca. 7 : 3 mixture of diastereoisomers. 1H: 6.60-6.44 (m, 1H); 6.03-5.91 (m, 3H); 4.33-4.16 (m,1H); 3.83-3.62 (m, 3H); 3.13-3.00 (m, 1H); 3.00-2.85 (m, 1H); 2.37-1.87 (m, 3H); 1.37-1.10 (m, 6H); 0.97-0.77 (m, 9H); 0.14-0.01 (m, 6H). HRMS: calc. for C23H34N2O4Si [M + Na]+ 437.2233; found 437.2236. IR: 2222; 1739.  B.1.19 Preparation of methyl 6-(tert-butyldimethylsilyloxy)-3,7-dicyano-2-isopropyl-1oxo-1,3a,4,5,6,7,8,8a-octahydroazulene-3a-carboxylate (165)  O  OMe CN  TBSO  A cold (–78 °C) solution of 154 (1.00 g, 2.32 mmol) in dry THF (15.0 mL), containing 95 % NaH (84.0 mg, 3.50 mmol; CAUTION: evolution of flammable H2 gas) was stirred for 1.3 h,  O  NC  then it was carefully quenched with aq. sat. NH4Cl (5.00 mL) and  concentrated. The residue was partitioned between EtOAc (30.0 mL) and aq. sat. NH4Cl (30.0 mL). The organic phase was recovered and the aqueous phase was further extracted with EtOAc (3 x 20.0 mL). The combined extracts were washed with brine (15.0 mL) and dried (MgSO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 1 : 9) gave 298 mg (0.670 mmol, 29.0 %) product as a light yellow oil in a mixture of diastereoisomers. 1H: 4.47-4.42 (m, 0.3H); 4.42-4.34 (m, 0.2H); 4.32-4.21 (m, 0.5H); 3.883.81 (s, 1.3H); 3.81-3.74(m, 1.7H); 3.37-3.29 (m, 0.45H); 3.05-2.90 (m, 1H); 2.85-2.65 (m, 1H); 2.64-2.29 (m, 1.85H); 2.29-1.90 (m, 2.95H); 1.85-1.44 (m, 1.75H); 1.42-1.34 (d, J = 6.3, 0.6H); 1.34-1.22 (m, 4.2H); 1.13-1.03 (d, J = 6.8, 1.2H); 0.99-0.82 (m, 9H); 0.25-0.08 (m, 6H).  13  C: 205.3 205.2; 204.4; 172.0; 171.2; 171.0; 160.4; 136.3; 121.0; 119.1; 116.2;  115.0; 114.1; 70.3; 69.5; 62.0; 59.8; 59.0; 58.2; 57.9; 53.9; 53.7; 53.5; 52.6; 51.9; 50.8; 47.9; 37.3; 32.2; 29.8; 29.3; 27.9; 27.8; 27.6; 27.4; 26.9; 26.4; 26.1; 26.0; 25.9; 25.8; 25.0; 24.3;  120  24.1; 22.5; 20.4; 20.3; 20.0; 18.3; 18.2; -3.93; -3.99; -4.29; -4.52; -4.63. HRMS: calc. for C23H34N2O4Si [M + Na]+ 453.2185; found 453.2186. IR: 2260; 1767; 1735.  B.1.20 Preparation of methyl 4-(tert-butyldimethylsilyloxy)-1-(3-(tert-butyl dimethyl silyloxy)-4-cyanopent-4-enyl)-2-cyano-3-isopropylcyclopenta-2,4-dienecarboxylate (166) Commercial LHMDS solution (1.0 M in THF, 0.300 mL, 0.300 CO2Me  mmol) was slowly added to a cold (–78 °C), stirred solution of  TBSO NC  OTBS  154 (133 mg, 0.300 mmol), LiCl (347 mg, 8.70 mmol) and  NC  TBSCl (924 mg, 6.20 mmol) in dry THF (2.00 mL) and HMPA (0.700 mL; CAUTION: cancer suspect agent). The mixture was stirred at –78 °C for 30 min, then it was heated to 50 °C. An additional 5 portions of LHMDS (1.0 M in THF, each portion 0.300 mL, 0.300 mmol) were added at regular intervals over 8 h. Finally, the mixture was cooled, carefully quenched with aq. sat. NH4Cl (2.00 mL), and concentrated. The residue was partitioned between EtOAc (20.0 mL) and aq. sat. CuSO4 (20.0 mL), the organic phase was recovered and the aqueous phase was extracted with EtOAc (3 x 10.0 mL). The combined extracts were washed with brine (15.0 mL) and dried (MgSO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 1 / 9) gave 138 mg (0.250 mmol, 82.0 %) product as a light yellow oil in a ca. 1 : 1 mixture of diastereoisomers. 1H: 6.00-5.95 (m, 2H); 5.36-5.30 (m, 1H); 4.30-4.20 (m, 1H); 3.74-3.70 (m, 3H); 3.09-2.85 (m, 1H); 2.26-2.08 (m, 1H); 2.02-1.80 (m, 2H); 1.72-1.47 (m, 1H); 1.34-1.25 (m, 6H); 1.03-0.84 (m, 18H); 0.370.02 (m, 12H).  13  C: 172.3; 172.2; 171.0; 170.8; 157.4; 156.5; 131.3; 128.0; 127.9; 118.3;  116.7; 116.6; 114.6; 114.5; 113.4; 73.8; 73.5; 54.6; 54.3; 32.2; 31.1; 29.6; 29.3; 27.1; 27.0; 21.9; 21.8; 21.6; 21.5; 21.4; 21.3; 19.5; -3.3; -3.4; -3.5; -3.7. HRMS: calc. for C29H48N2O4Si2 [M + Na]+ 567.3054; found 567.3050. IR: 2209; 1736. 121  B.1.21 Preparation of cycloadduct 167 A solution of 166 (80.0 mg, 147 μmol) in dry toluene (1.00 mL) CO2Me TBSO  was stirred at 140 °C in a 20 mL glass pressure vessel for 12 h,  OTBS NC  CN  then it was cooled to room temperature and applied to a silica silica gel column (10.0 g). Elution (gradient 0 % to 15 % EtOAc  / hexanes) gave 62.0 mg (113 μmol, 77.0 %) product as a light yellow oil in a ca. 1 : 1 mixture of diastereoisomers. 1H: 4.43-4.32 (m, 1H); 3.76-3.66 (m, 3H); 2.85-2.78 (m, 1H); 2.65-2.49 (m, 2H); 2.26-1.89 (m, 3H); 1.81 (dd, J = 12.0, 4.0, 1H); 1.62 (d, J = 12.0, 1H); 1.24 (d, J = 8.0, 3H) 1.15 (d, J = 8.0, 3H); 0.98-0.86 (m, 18 H); 0.21-0.09 (m, 12H).13C: 172.1; 171.7; 158.1; 157.9;120.7; 120.9; 119.8; 120.5; 116.4; 116.7; 72.9; 70.1; 67.1; 66.8; 52.1; 52.0; 51.3; 50.4; 50.0; 38.2; 32.9; 29.5; 26.7; 26.4; 25.6; 25.3; 22.0; 22.5; 20.4; 20.3; 17.7; 17.8; -3.7; -3.6; -4.2; -4.5; -4.96; -4.94. HRMS: calc. for C29H48N2O4Si2 [M + Na]+ 567.3053; found 567.3050. IR: 2210; 1739.  B.1.22 Preparation of tricyclic ketone 169 Commercial HF - pyridine complex (70 % HF, 0.90 mL) was added CO2Me O  OTBS NC  CN  to a cold (0 °C), stirred solution of 167 (91.0 mg, 167 μmol) in MeCN (3.00 mL). The mixture was stirred for 6 h, during which time it was allowed to warm to room teperature, and then quenched with  aq. sat. NaHCO3 (2 mL) and concentrated. The residue was partitioned between EtOAc (15.0 mL) and aq. sat. NaHCO3 (20.0 mL). The organic phase was recovered and the aqueous phase was extracted with more EtOAc (3 x 10.0 mL). The combined extracts were washed with brine (15.0 mL) and dried (MgSO4), and concentrated. The crude product was oxidized without further purification. Thus, a solution of above alcohol and Dess-Martin periodinane 122  (73.0 mg, 172 μmol) in CH2Cl2 was stirred at room temperature for 3 h, then it was concentrated. Chromatography of the residue (gradient 5 % to 10 % EtOAc / hexanes) gave 36.0 mg (84.0 μmol, 50 % over two steps) product as a colorless oil. 1H: 3.78 (s, 3H); 3.05 (d, J = 3.9, 1H); 2.90-2.68 (m, 2H); 2.62 (sept, J = 7.0, 1H), 2.47 (dd, J = 13.5, 3.9, 1H), 2.292.18 (m, 1H), 2.10 (d, J = 3.5, 1H); 2.04-1.90 (m, 1H); 1.30 (d, J = 6.8, 3H); 1.17 (d, J = 6.8, 3H); 0.96 (s, 9H); 0.26 (s, 3H); 0.23 (s, 3H). 13C: 198.8; 170.9; 156.7; 120.7; 116.3; 115.8; 66.5; 59.6; 57.1; 52.9; 52.7; 36.6; 31.2; 27.2; 25.6; 23.6; 22.1; 20.8; -3.3; -3.9. HRMS: calc. for C23H33N2O4Si [M + H]+ 429.2206; found 429.2210. IR: 2359; 1734; 1646.  123  B.2 Proton and carbon-13 spectra for sordarin intermediates  Figure 13. NMR spectra of compound 127  124  Figure 14. NMR spectra of compound 128  125  Figure 15. NMR spectra of compound 129  126  Figure 16. NMR spectra of compound 130  127  Figure 17. NMR spectra of compound 132  128  Figure 18. NMR spectra of compound 134  129  Figure 19. NMR spectra of compound 141  130  Figure 20. NMR spectra of compound 142  131  Figure 21. NMR spectra of compound 143  132  Figure 22. NMR spectra of compound 145  133  Figure 23. NMR spectra of compound 146  134  Figure 24. NMR spectra of compound 147  135  Figure 25. NMR spectra of compound 148  136  Figure 26. NMR spectra of compound 149  137  Figure 27. NMR spectra of compound 153  138  Figure 28. NMR spectra of compound 154  139  Figure 29. NMR spectra of compound 162  Figure 30. NMR spectra of compound 158  140  Figure 31. NMR spectra of compound 165  141  O OMe  TBSO NC  200  OTBS NC  150  100  50  0  ppm (f1)  Figure 32. NMR spectra of compound 166  142  Figure 33. NMR spectra of compound 167  143  Figure 34. NMR spectra of compound 169  144  C. BIMOLECULAR OXIDATIVE AMIDATION EXPERIMENTAL SECTION C.1 Synthesis of various bimolecular oxidative amidation intermediates C.1.1 Representative protocols for bimolecular oxidative amidation at dilute conditions  OMe O  HO  NHAc  DIB, TFA MeCN  O  183  OMe  O 184  A MeCN (20.0 mL) solution of 183 (53.0 mg, 0.320 mmol, 1 eq.) was added over 10 min (syringe pump) to a solution of DIB (123 mg, 0.380 mmol, 1.2 eq.) and TFA (47.0 mg, 0.400 mmol, 1.3 eq. vs. DIB) in MeCN (20.0 mL), at room temperature with good stirring. The final concentration was equal to 8 mmol of substrate / L. At the end of the addition, the solution was light yellow. Solid NaHCO3 (107 mg, 1.30 mmol, 4 eq.) was added and the mixture was stirred for 15 min, then it was filtered through Celite and concentrated. Chromatographic purification (1 % MeOH in EtOAc) gave 61.0 mg (0.280 mmol, 86.0 %) product, off-white solid, m.p. 100-102 °C.  C.1.2 Representative procedures for preparative bimolecular oxidative amidation A MeCN (20.0 mL) solution of 183 (9.10 g, 55.0 mmol, 1eq.) was added over 3 h (syringe pump) to a solution of DIB (23.9 g, 74.0 mmol, 1.3 eq.) and TFA (6.40 mL, 82.5 mmol, 1.5 eq. vs. DIB) in MeCN (480 mL), at room temperature with good stirring. The final concentration was equal to 110 mmol of substrate / L. The progress of the reaction was monitored by 1H NMR. At the end of the addition, the solution had become light brown. The mixture was concentrated and the residue was taken up with toluene (10.0 mL). The  145  suspension was concentrated and the procedure was repeated to azeotropically remove all residual TFA. The brown residue was filtered through a silica pad (45.0 g) using first 300 mL of Et2O (removal of brown tar and iodobenzene) and then 300 mL Et2O / CH3CN (2.5 : 1, elution of the product). Concentration afforded a brown solid, which was re-filtered through fresh silica gel using the same procedure (complete removal of polymeric material). The solid residue was taken up with 20.0 mL of EtOAc and kept at –20 °C for 5 h. The resulting precipitate was essentially pure product. Concentration of the mother liquor afforded an additional crop of crystalline material. A total of 8.13 g (36.3 mmol, 66.0 %) product was obtained. A recrystallized sample (EtOAc / hexanes = 2 : 1) had m.p. 100102 °C.  C.2 Characterization of bimolecular oxidative amidation intermediates (Table 7) C.2.1 Characterization of N-(1-methyl-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = Me) NHAc  foam, 1H (acetone-d6): 7.66 (br, 1H); 6.96 (d, J = 10.2, 2H); 6.08 (d, J = 10.2, 2H) ; 1.89 (s, 3H); 1.48 (s, 3H). 13C (acetone-d6): 184.6; 169.5; 152.6;  O  127.0; 52.3; 25.5; 22.2. HRMS: calc. for C9H12NO2 [M + H]+ 166.0868,  found 166.0867. IR: 1662.  C.2.2 Characterization of N-(1-ethyl-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = Et) NHAc  foam, 1H (acetone-d6): 7.43 (br, 1H); 6.88 (d, J = 10.2, 2H); 6.16 (d, J = 10.2, 2H); 1.91 (q, J = 7.4, 2H); 1.88 (s, 3H); 0.82 (t, J = 7.4, 3H). 13C  O  (acetone-d6): 184.9; 168.9; 151.0; 128.5; 56.1; 30.7; 22.3; 6.9. HRMS: calc.  for C10H13NO2Na [M + Na]+ 202.0844, found 202.0839. IR: 1664. 146  C.2.3 Characterization of N-(4-oxo-1-propylcyclohexa-2,5-dienyl)acetamide (186, R = n-Pr) foam, 1H (acetone-d6): 7.41 (br, 1H); 6.91 (d, J = 10.2, 2H); 6.14 (d, J = NHAc  10.2, 2H) ; 1.87 (s, 3H); 1.86-1.79 (m, 2H); 1.35-1.21 (m, 2H); 0.88 (t, J O  = 7.4, 3H). 13C (acetone-d6): 184.9; 168.8; 151.4; 128.1; 55.7; 40.2; 22.3;  16.4; 13.4. HRMS: calc. for C11H15NO2Na [M + Na]+ 216.1000, found 216.1006. IR: 3250, 1672.  C.2.4 Characterization of N-(1-isopropyl-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = i-Pr) NHAc  foam, 1H (acetone-d6): 7.38 (br, 1H); 6.95 (d, J = 10.4, 2H); 6.20 (d, J = 10.4, 2H) ; 2.43 (sept, J = 6.8, 1H); 1.90 (s, 3H); 0.94 (d, J = 6.8, 6H). 13C  O  (acetone-d6): 184.9; 169.1; 149.4; 129.0; 58.9; 33.9; 22.4; 16.3. HRMS:  calc. for C11H15NO2Na [M + Na]+ 216.1000, found 216.1006. IR: 1660.  C.2.5 Characterization of N-(1,3-dimethyl-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = X = Me) NHAc  yellow oil, 1H (acetone-d6): 7.41 (br, 1H); 6.96 (dd, J = 9.9, 3.0, 1H); 6.756.71 (m, 1H); 6.07 (d, J = 9.9, 1H); 1.85 (s, 3H); 1.80-1.78 (m, 3H); 1.46 (s,  O  3H). 13C (acetone-d6): 185.1; 168.7; 152.3; 147.6; 133.1; 126.6; 52.4; 25.6;  22.3; 14.9. HRMS: calc. for C10H14NO2 [M + H]+ 180.1025, found 180.1022. IR: 1668.  147  C.2.6 Characterization of N-(3,5-dibromo-1-methyl-4-oxocyclohexa-2,5-dienyl) acetamide (186, R = Me, X = Y = Br) foam, 1H (acetone-d6): 7.82 (br, 1H); 7.49 (s, 2H); 1.89 (s, 3H); 1.59 (s,  NHAc  Br  3H).  13  C (acetone-d6): 171.9; 169.3; 154.3; 119.7; 56.8; 24.1; 21.8.  O  HRMS: calc. for C9H10NO279Br81Br [M + H]+ 323.9058, found 323.9049.  Br  IR: 1673.  C.2.7 Characterization of N-(1-(cyanomethyl)-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = CH2CN) yellow oil, 1H (acetone-d6): 7.84 (br, 1H); 7.18 (d, J = 10.2, 2H); 6.30 (d, J  NHAc O  CN  = 10.2, 2H); 3.41 (s, 2H); 1.95 (s, 3H).  13  C (acetone-d6): 183.7; 170.1;  146.4; 129.4; 115.6; 53.1; 26.1; 22.4. HRMS: calc. for C10H10N2O2Na [M + Na]+ 213.0640, found 213.0639. IR: 2255; 1673.  C.2.8 Characterization of N-(1-(2-cyanoethyl)-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = CH2CH2CN) foam, 1H (acetone-d6): 7.58 (br, 1H); 7.02 (d, J = 10.2, 2H); 6.22 (d, J =  NHAc O  CN  10.2, 2H); 2.51-2.44 (m, 2H); 2.39-2.32 (m, 2H); 1.90 (s, 3H).  13  C  (acetone-d6): 184.3; 169.4; 148.9; 129.2; 119.2; 54.9; 32.9; 22.4; 11.4.  HRMS: calc. for C11H12N2O2Na [M + Na]+ 227.0796, found 227.0790. IR: 2249; 1667.  148  C.2.9 Characterization of N-(1-(2-(4-methylphenylsulfonamido)ethyl)-4-oxocyclohexa2,5-dienyl)acetamide (186, R = CH2CH2NHTs) colorless oil, 1H (acetone-d6): 7.70 (d, J = 7.9, 2H); 7.49 (br, 1H);  NHAc NHTs  O  7.39 (dd, J = 7.9, 0.66, 2H); 6.95 (d, J = 10.2, 2H); 6.47 (t, J = 6, 1H); 6.12 (d, J = 10.2, 2H); 2.93-2.87 (m, 2H); 2.42 (s, 3H); 2.16-2.12 (m,  2H); 1.86 (s, 3H). 13C (acetone-d6): 184.4; 169.0; 150.1; 143.1; 137.7; 129.5; 128.3; 126.8; 54.5; 38.1; 37.4; 22.3; 20.5. HRMS: calc. for C17H20N2O432SNa [M + Na]+ 371.1041, found 371.1044. IR: 1665.  C.2.10 Characterization of N-(1-(2-bromoethyl)-4-oxocyclohexa-2,5-dienyl)acetamide (186, R = CH2CH2Br) yellow oil, 1H (acetone-d6): 7.62 (br, 1H); 7.04 (d, J = 10.2, 2H); 6.20 (d,  NHAc Br  O  J = 10.2, 2H); 3.44-3.35 (m, 2H); 2.58-2.48 (m, 2H); 1.90 (s, 3H). 13C (acetone-d6): 184.4; 169.2; 149.5; 128.7; 55.8; 40.8; 26.0; 22.3. HRMS:  calc. for C10H12NO279BrNa [M + Na]+ 279.9949, found 279.9944. IR: 1667.  C.2.11 Characterization of methyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (184) off-white solid, m.p. 100-102 °C. 1H (acetone-d6): 7.54 (br, 1H); 7.17 (d, NHAc O O  MeO  J = 10.3, 2H); 6.15 (d, J = 10.3, 2H); 3.62 (s, 3H); 3.02 (s, 2H); 1.88 (s, 3H). 13C (acetone-d6): 184.3; 169.4; 169.0; 148.8; 128.1; 53.3; 51.1; 41.7;  22.5. HRMS: calc. for C11H13NO4Na [M + Na]+ 246.0737, found 246.0742. IR: 3200; 1738; 1666.  149  C.2.12 Characterization of benzyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (186, R = CH2CO2Bn) light yellow oil, 1H (acetone-d6): 7.57 (br, 1H); 7.42-7.32 (m, 5H); 7.20  NHAc O O  OBn  (d, J = 10.3 , 2H); 6.14 (d, J = 10.3, 2H); 5.12 (s, 2H); 3.10 (s, 2H); 1.86 (s, 3H).  13  C (acetone-d6): 184.3; 169.4; 168.4; 148.6; 136.1; 128.4;  128.19; 128.16; 128.11; 66.2; 53.4; 41.8; 22.5. HRMS: calc. for C17H17NO4Na [M + Na]+ 322.1055, found 322.1056. IR: 1738; 1668.  150  C.3 Proton and carbon-13 spectra for bimolecular oxidative amidation intermediates  NHAc O  NHAc O  Figure 35. NMR spectra of compound 186, R = Me  151  NHAc O  NHAc O  Figure 36. NMR spectra of compound 186, R = Et  152  NHAc O  NHAc O  Figure 37. NMR spectra of compound 186, R = n-Pr  153  NHAc O  NHAc O  Figure 38. NMR spectra of compound 186, R = i-Pr  154  NHAc O  NHAc O  Figure 39. NMR spectra of compound 186, R = X = Me  155  NHAc  Br O Br  NHAc  Br O Br  Figure 40. NMR spectra of compound 186, R = Me, X = Y = Br  156  NHAc CN O  NHAc CN O  Figure 41. NMR spectra of compound 186, R = CH2CN  157  NHAc CN O  NHAc CN O  Figure 42. NMR spectra of compound 186, R = CH2CH2CN  158  NHAc NHTs O  NHAc NHTs O  Figure 43. NMR spectra of compound 186, R = CH2CH2NHTs  159  NHAc Br  O  NHAc O  Br  Figure 44. NMR spectra of compound 186, R = CH2CH2Br  160  NHAc O O  MeO  NHAc O O  MeO  Figure 45. NMR spectra of compound 184  161  NHAc O O  OBn  NHAc O O  OBn  Figure 46. NMR spectra of compound 186, R = CH2CO2Bn  162  D. INTRAMOLECULAR OXIDATIVE AMIDATION EXPERIMENTAL SECTION D.1 Preparation and characterization of various intermediates towards amine 200 D.1.1 Preparation of 3-(4-hydroxyphenyl)-1-propanol (197) OH  [known compound, see ref: Tetrahedron Letters, 49, 3260.] Lithium aluminum hydride powder (3.80 g, 100 mmol) was slowly  HO  added over a period of 45 min to a solution of 3-(4-hydroxyphenyl) propionic acid (8.30 g, 50.0 mmol) in THF (300 mL) at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. The progress of the reaction was monitored by 1H NMR. Upon the completion of the reaction, the mixture was cooled to 0 °C. H2O (3.80 mL), 15.0 % NaOH (3.80 mL) solution, H2O (11.4 mL) and appropriate amount of drying reagent (MgSO4) was sequentially added in the interval of 20 min with vigorous stirring. The resulting suspension solution was warmed to room temperature and filtered through Celite using EtOAc (3 x 200 mL). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 6.92 g (45.5 mmol, 91.0 %) product as a light yellow oil. 1H: 7.07 (d, J = 8.7, 2H); 6.76 (d, J = 8.6, 2H); 4.93 (br, 1H); 3.73-3.63 (m, 2H); 2.65 (t, J = 7.8, 2H); 1.87 (papp, J = 7.6, 2H); 1.35 (br, 1H).  13  C: 153.7; 133.8; 129.4; 115.2; 62.3; 34.4; 31.1. HRMS: calc. for C9H12O2Na [M +  Na]+ 175.0735; found 175.0739. IR: 3410; 3223; 2916; 1517; 1241.  D.1.2 Preparation of compound 198 OMs MsO  [known compound, see ref: Indian Pat. Appl., 2003CH01004] Methanesulfonyl  chloride  (1.13  mL,  14.5  mmol)  and  triethylamine (2.74 mL, 19.7 mmol) was slowly added over a period of 10 min to a solution of 197 (1.00 g, 6.58 mmol) in DCM (30.0 mL) at 0 °C and with good stirring. At the end of 163  the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 15.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (15.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 1.98 g (6.45 mmol, 98.0 %) product as a light yellow solid, m.p. 54-54.5 oC. 1H: 7.23 (d, J = 2.4, 4H); 4.24 (t, J = 5.3, 2H); 3.14 (s, 3H); 3.00 (s, 3H); 2.77 (t, J = 7.4, 2H); 2.07 (p, J = 6.35, 2H).  13  C: 147.6; 139.8; 129.9; 122.1; 68.8; 37.4; 37.3; 30.9; 30.5. HRMS: calc. for  C11H16O6S2Na [M + Na]+ 331.0286; found 331.0290. IR: 3031; 2940; 1350; 1129.  D.1.3 Preparation of 4-(3-azidopropyl)phenyl methanesulfonate (199) N3 MsO  Sodium azide (0.840 g, 12.9 mmol) was slowly added to a solution of 198 (1.98 g, 6.45 mmol) in DMF (15.0 mL) and H2O (15.0 mL)  at room temperature and with good stirring. Then reaction mixture was warmed to 70 °C and stirred over night. Upon the completion of the reaction, the mixture was cooled to room temperature, extracted with EtOAc (3 x 20.0 mL), brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (DCM / hexanes = 1 / 1) gave 1.56 g (6.13 mmol, 95.0 %) product as a yellow oil. 1H: 7.23 (s, 4H); 3.31 (t, J = 6.4, 2H); 3.14 (s, 3H); 2.73 (t, J = 8.0, 2H); 1.91 (p, J = 8.0, 2H). 13C: 147.5; 140.3; 129.9; 122.0; 50.4; 37.2; 32.0; 30.3. LRMS: [M - N2 + H]+ 228.3. IR: 3055; 2940; 2100; 1307.  164  D.1.4 Preparation of 4-(3-aminopropyl)phenyl methanesulfonate (200) NH2  [known compound, ref: Tetrahedron Letters, 43, 5193.] Triphenylphosphine (3.20 g, 12.3 mmol) was slowly added to a  MsO  solution of 199 (1.56 g, 6.13 mmol) in THF (15.0 mL) and H2O (2.00 mL) at room temperature and stirred over night. Upon the completion of the reaction, the mixture was concentrated to about 5 mL under vacuum and diluted with 20 mL of ethyl ether. A 1.00 N HCl solution was added (15.0 mL). The organic phase was separated from aqueous phase, and washed again with 1 N HCl solution (15.0 mL). Aqueous phases were collected and adjusted to pH = 10 using 3.00 M NaOH solution. The mixture was extracted with EtOAc (3 x 10.0 mL), brine (15.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum to afford 1.3 g (5.70 mmol, 93.0 %) product as a light yellow oil without request for further purification. 1H: 7.23-7.13 (m, 4H); 3.10 (s, 3H); 2.72 (t, J = 6.9, 2H); 2.65 (t, J = 8.7, 2H); 1.84-1.70 (m, 4H). 13C: 147.3; 141.5; 129.8; 121.8; 41.4; 37.1; 34.8; 32.6. HRMS: calc. for C10H16NO3S [M + H]+ 230.0851; found 230.0846. IR: 3403; 3054; 1367; 1265.  D.2 General procedure for coupling reactions between amine and sulfonyl chloride Appropriate sulfonyl chloride (1.1 eq.) and triethylamine (1.3 eq.) was slowly added over a period of 10 min to a solution of primary amine 200 in DCM ([C] = 0.300 M) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl and extracted with EtOAc. The combined extracts were sequentially washed with aq. sat.  165  NH4Cl, brine, dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue would give the corresponding product.  D.2.1 Characterization of compound 201, R = Me NMs  95.0 % yield, light yellow solid, m.p. 105 oC, eluting solvent (EtOAc / hexanes = 1 / 1), 1H: 7.36 (d, J = 8.5, 2H); 7.27 (d, J =  MsO  8.5, 2H); 6.03 (br, 1H); 3.27 (s, 3H); 3.16 (q, J = 5.8, 2H); 2.91 (s, 3H); 2.77 (t, J = 7.8, 2H); 1.92 (p, J = 7.4, 2H). 13C: 147.9; 141.1; 129.8; 122.1; 42.4; 38.8; 36.5; 31.8; 31.7. HRMS: calc. for C11H17NO5S2Na [M + Na]+ 330.0446; found 330.0441. IR: 3240; 1359; 1129.  D.2.2 Characterization of 4-(3-(trifluoromethylsulfonamido)propyl)phenyl methanesulfonate (201, R = CF3)  MsO  O O S N CF3 H  91.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 2), 1H (acetone-d6): 7.38 (d, J = 8.6, 2H); 7.29 (d, J = 8.6, 2H); 3.38 (t, J = 6.5, 2H); 3.27 (s, 3H); 2.80 (t, J  = 7.4, 2H); 2.00 (p, J = 7.4, 2H).  13  C (acetone-d6): 153.2; 145.7; 135.0; 127.3; 125.3 (q);  48.6; 41.8; 36.9; 36.7. HRMS: calc. for C11H14NO5F3S2Na [M + Na]+ 384.0163; found 384.0156. IR: 1361; 1173; 1143; 869.  D.2.3 Characterization of 4-(3-(cyclopropanesulfonamido)propyl)phenyl methanesulfonate (201, R = cyclopropyl)  MsO  O O S N H  85.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 2 / 1), 1H: 7.25-7.16 (m, 4H); 4.55 (t, J = 6.3, 1H);  3.17 (q, J = 6.5, 2H); 3.13 (s, 3H); 2.71 (t, J = 7.5, 2H); 2.45-2.34 (m, 1H); 1.88 (p, J = 7.3, 166  2H); 1.19-1.09 (m, 2H); 1.03-0.93 (m, 2H). 13C: 147.5; 140.4; 129.8; 122.0; 42.6; 37.3; 32.0; 31.7; 29.9; 5.3. HRMS: calc. for C13H19NO5S2Na [M + Na]+ 356.0602; found 356.0596. IR: 1362; 1145; 870.  D.2.4 Characterization of 4-(3-(phenylmethylsulfonamido)propyl)phenyl methanesulfonate (201, R = Bn)  MsO  87.0 % yield, light yellow oil, eluting solvent (EtOAc /  O O S N H  hexanes = 1 / 1), 1H (acetone-d6): 7.52-7.22 (m, 9H); 6.11 (br, 1H); 4.33 (s, 2H); 3.26 (s, 3H); 3.09 (q, J =  6.5, 2H); 2.72 (t, J = 7.6, 2H); 1.86 (p, J = 7.6, 2H). 13C (acetone-d6): 147.9; 141.1; 130.8; 130.7; 129.8; 128.3; 128.0; 122.0; 57.6; 42.6; 36.5; 31.9; 31.7. HRMS: calc. for C17H21NO5S2Na [M + Na]+ 406.0759; found 406.0752. IR: 3213; 1361; 1151; 546.  D.2.5 Characterization of 4-(3-(methylsulfonylmethylsulfonamido)propyl)phenyl methanesulfonate (201, R = CH2SO2Me)  MsO  O O S N H  Note: 3 eq. MsCl and 4 eq. Et3N was employed to this SO2Me  reaction. 82.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H (acetone-d6): 7.37 (d, J  = 8.5, 2H); 7.27 (d, J = 8.5, 2H); 6.59 (br, 1H); 4.91 (s, 2H); 3.27 (s, 3H); 3.22 (s, 3H); 3.313.19 (m, 2H); 2.78 (t, J = 7.7, 2H); 1.96 (p, J = 7.7, 2H). 13C (acetone-d6): 147.9; 141.0; 129.9; 122.0; 67.8; 42.7; 41.2; 36.5; 31.7; 31.5. HRMS: calc. for C12H19NO7S3Na [M + Na]+ 408.0221; found 408.0217. IR: 3220; 1359; 1298; 1130.  167  D.2.6 Characterization of compound 201, R = PhMe NTs MsO  93.0 % yield, light yellow solid, m.p. 84 oC, eluting solvent (EtOAc / hexanes = 1 / 1), 1H: 7.74 (d, J = 8.5, 2H); 7.30 (d, J =  8.5, 2H); 7.18-7.09 (m, 4H); 5.00 (t, J = 6.3, 1H); 3.12 (s, 3H); 2.94 (q, J = 6.2, 2H); 2.61 (t, J = 7.8, 2H); 2.42 (s, 3H); 1.83-1.71 (m, 2H). 13C: 147.4; 143.5; 140.4; 136.7; 136.7; 129.9; 129.7; 127.0; 121.9; 42.4; 37.2; 31.9; 31.0; 21.5. HRMS: calc. for C17H21NO5S2Na [M + Na]+ 406.0759; found 406.0754. IR: 3220; 1359; 1146.  D.2.7 Characterization of 4-(3-(2-nitrophenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 2-NO2Ph) 95.0 % yield, light yellow oil, eluting solvent (EtOAc / NHNs(2-)  hexanes = 1 / 1), 1H: (acetone-d6): 8.14-8.07 (m, 1H); 7.99-  MsO  7.86 (m, 3H); 7.32-7.20 (m, 4H); 6.73 (br, 1H); 3.26 (s, 3H); 3.21-3.13 (m, 2H); 2.71 (t, J = 7.9, 2H); 1.90 (p, J = 7.3, 2H). 13C: 148.2; 147.9; 140.8; 133.9; 133.4; 132.6; 130.4; 129.8; 124.8; 122.1; 42.7; 36.6; 31.7; 31.2. HRMS: calc. for C16H18N2O7S2Na [M + Na]+ 437.0453; found 437.0450 IR: 3225; 2937; 1539; 1515; 1362; 1163.  D.2.8 Characterization of 4-(3-(3-nitrophenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 3-NO2Ph) NHNs(3-) MsO  95.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H: (acetone-d6): 8.62 (t, J = 2.0, 1H);  8.51 (dd, J = 8.3, 1.0, 1H); 8.27 (d, J = 7.8, 1H); 7.95 (t, J = 8.0, 1H); 7.32-7.21 (m, 4H); 6.94 (br, 1H); 3.63 (t, J = 6.5, 1H); 3.26 (s, 3H); 3.05 (q, J = 5.7, 2H); 2.70 (t, J = 7.7, 2H); 1.91-1.78 (m, 2H). 13C: 148.5; 147.9; 142.8; 140.7; 132.6; 131.0; 129.8; 126.8; 122.0; 121.7; 168  42.5; 36.5; 31.6; 31.1. HRMS: calc. for C16H18N2O7S2Na [M + Na]+ 437.0453; found 437.0462. IR: 1705; 1532; 1350; 1147.  D.2.9 Characterization of 4-(3-(4-nitrophenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 4-NO2Ph) NHNs(4-)  95.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H (acetone-d6): 8.45 (d, J = 8.8, 2H); 8.13  MsO  (d, J = 8.8, 2H); 7.32-7.21 (m, 4H); 6.93 (br, 1H); 3.26 (s, 3H); 3.09-3.01 (m, 2H); 2.70 (t, J = 7.5, 2H); 1.85 (p, J = 7.5, 2H). 13C (acetone-d6): 150.0; 147.9; 146.7; 140.7; 129.8; 128.3; 124.3; 122.0; 42.4; 36.5; 31.6; 31.1. HRMS: calc. for C16H18N2O7S2Na [M + Na]+ 437.0453; found 437.0447. IR: 3286; 1531; 1346; 1168.  D.2.10 Characterization of 4-(3-(4-bromophenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 4-BrPh)  MsO  O O S N H  90.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H: 7.75-7.61 (m, 4H); 7.20-7.08 Br  (m, 4H); 5.03 (t, J = 6.4, 1H); 3.14 (s, 3H); 2.95 (q, J  = 6.6, 2H); 2.61 (t, J = 7.5, 2H); 1.77 (p, J = 7.5, 2H). 13C: 147.4; 140.2; 138.8; 132.4; 129.8; 128.5; 127.6; 122.0; 42.4; 37.3; 31.9; 31.0. HRMS: calc. for C16H18NO5S2BrNa [M + Na]+ 469.9707; found 469.9699. IR: 3245; 1366; 1150; 562.  169  D.2.11 Characterization of 4-(3-(4-methoxyphenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 4-MeOPh)  MsO  O O S N H  85.0 % yield, light yellow oil, eluting solvent OMe  (EtOAc / hexanes = 2 / 1), 1H (acetone-d6): 7.78 (d,  J = 8.5, 2H); 7.32-7.21 (m, 4H); 7.10 (d, J = 8.5, 2H); 6.38 (br, 1H); 3.90 (s, 3H); 3.26 (s, 3H); 2.92 (q, J = 6.4, 2H); 2.68 (t, J = 7.8, 2H); 1.80 (p, J = 7.8, 2H). 13C (acetone-d6): 162.7; 147.9; 141.0; 132.6; 129.8; 128.9; 122.0; 114.1; 55.1; 42.3; 36.6; 31.7; 31.1. HRMS: calc. for C17H21NO6S2Na [M + Na]+ 422.0708; found 422.0717. IR: 3247; 1362; 1142; 832.  D.2.12 Characterization of 4-(3-(2,4,6-triisopropylphenylsulfonamido)propyl)phenyl methanesulfonate (201, R = 2,4,6-triisopropylphenyl) 89.0 % yield, light yellow oil, eluting solvent  MsO  O O S N H  (EtOAc / hexanes = 1 / 3), 1H: 7.21-7.06 (m, 6H); 4.46 (t, J = 6.3, 1H); 4.15 (p, J = 6.6, 2H); 3.12 (s, 3H); 3.06-2.85 (m, 3H); 2.63 (t, J = 7.3, 2H); 1.81  (p, J = 7.5, 2H); 1.26 (d, J = 6.7, 18H). 13C: 152.7; 150.2; 147.5; 140.3; 132.2; 129.8; 123.8; 121.9; 42.1; 37.2; 34.1; 32.1; 31.2; 29.6; 24.8; 23.6. HRMS: calc. for C25H37NO5S2Na [M + Na]+ 518.2011; found 518.2003. IR: 1361; 1146; 867.  170  D.2.13 Characterization of 4-(3-(thiophene-2-sulfonamido)propyl)phenyl methanesulfonate (201, R = 2-thienyl)  MsO  O O S S N H  89.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H: 7.63-7.56 (m, 2H); 7.23-7.13 (m, 4H); 7.09 (t, J = 4.3, 1H); 4.62 (t, J = 6.0, 1H); 3.14 (s, 3H);  3.06 (q, J = 6.6, 2H); 2.67 (t, J = 7.6, 2H); 1.84 (p, J = 7.3, 2H). 13C: 147.5; 140.7; 140.2; 132.1; 131.9; 129.8; 127.4; 122.1; 42.7; 37.3; 32.0; 30.9. HRMS: calc. for C14H17NO5S3Na [M + Na]+ 398.0167; found 398.0168. IR: 1328; 1144; 866.  D.2.14 Characterization of (S)-4-(2-(4-methylphenylsulfonamido)-3-(methyl sulfonamido)propyl)phenyl methanesulfonate (223, R = Me)  MsO  NHMs NHTs  85.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 3 / 1), 1H (acetone-d6): 7.55 (d, J = 8.1, 2H); 7.27 (d, J = 8.1,  2H); 7.18 (d, J = 8.7, 2H); 7.10 (d, J = 8.7, 2H); 6.55 (d, J = 7.8, 1H); 6.15 (t, J = 6.3, 1H); 3.66-3.52 (m, 1H); 3.26 (s, 3H); 3.28-3.19 (m, 2H); 3.00 (dd, J = 13.9, 5.5, 1H); 2.94 (s, 3H); 2.69 (dd, J = 13.9, 5.5, 1H); 2.41 (s, 3H). 13C (acetone-d6): 148.3; 142.9; 138.1; 136.9; 130.7; 129.4; 126.7; 121.8; 55.4; 46.9; 38.9; 37.3; 36.6; 20.5. HRMS: calc. for C18H24N2O7S3 [M + H]+ 477.0824; found 477.0826. IR: 3280; 1308; 1137. [α]D23 = -10° (MeOH, c = 0.5)  D.2.15 Characterization of (S)-4-(2,3-bis(4-methylphenylsulfonamido)propyl)phenyl methanesulfonate (223, R = PhMe)  MsO  NHTs NHTs  82.0 % yield, light yellow solid, m.p. 100oC. eluting solvent (EtOAc / hexanes = 1 / 2), 1H: (acetone-d6): 8.09 (s, 1H); 7.06  (d, J = 8.1, 2H); 6.76 (d, J = 8.1, 2H); 5.98 (br, 1H); 3.12 (q, J = 6.7, 2H); 2.90 (s, 3H); 2.62 171  (t, J = 7.9, 2H); 1.85 (p, J = 7.2, 2H). 13C (acetone-d6): 155.5; 132.2; 129.2; 115.1; 42.5; 38.7; 32.0; 31.7. HRMS: calc. for C10H15NO3S [M + H]+ 230.0851; found 230.0856. IR: 3410; 3300; 1309; 1138. [α]D21 = -54.12° (acetone, c = 1.08).  D.3 General procedure of deprotection of mesyl-O-phenol derivatives Potassium carbonate (3.00 eq.) was added to a MeOH ([C] = 0.100 M) solution of mesylated compound (1.00 eq.) at room temperature and with good stirring. Then reaction mixture was heated to 60 °C and stirred overnight. Upon the completion of the reaction, the mixture was evaporated to dryness, filtered over Celite using EtOAc. The filtrate was sequentially washed with aq. sat. NH4Cl, brine, dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue afforded product.  D.3.1 Characterization of compound 202, R = Me 93.0 % yield, light yellow solid, m.p. 100 oC, eluting solvent NMs HO  (EtOAc / hexanes = 1 / 2), 1H (acetone-d6): 8.09 (s, 1H); 7.06 (d, J  = 8.1, 2H); 6.76 (d, J = 8.1, 2H); 5.98 (br, 1H); 3.12 (q, J = 6.7, 2H); 2.90 (s, 3H); 2.62 (t, J = 7.9, 2H); 1.85 (p, J = 7.2, 2H). 13C (acetone-d6): 155.5; 132.2; 129.2; 115.1; 42.5; 38.7; 32.0; 31.7. HRMS: calc. for C10H15NO3S [M + H]+ 230.0851; found 230.0856. IR: 3410; 3300; 1309; 1138.  172  D.3.2 Characterization of trifluoro-N-(3-(4-hydroxyphenyl)propyl)methane sulfonamide (202, R = CF3)  HO  O O S N CF3 H  89.0 % yield, light yellow solid, eluting solvent (EtOAc / hexanes = 1 / 3), 1H (acetone-d6): 8.06 (br, 1H); 7.07 (d, J =  8.4, 2H); 6.77 (d, J = 8.4, 2H); 3.34 (t, J = 7.1, 2H); 2.64 (t, J = 7.6, 2H); 1.92 (p, J = 7.6, 2H). 13C (acetone-d6): 160.8; 136.9; 134.4; 125.1 (q); 120.3; 48.7; 37.3; 36.5. HRMS: calc. for C11H12NO3F3SNa [M + Na]+ 306.0388; found 306.0387. IR: 3311; 1366; 1188; 1144.  D.3.3 Characterization of N-(3-(4-hydroxyphenyl)propyl)cyclopropanesulfonamide (202, R = cyclopropyl)  HO  O O S N H  87.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 2), 1H (acetone-d6): 8.08 (br, 1H); 7.06 (d, J = 8.5, 2H); 6.76 (d, J = 8.5, 2H); 5.99 (br, 1H); 3.16 (q, J = 6.8,  2H); 2.62 (t, J = 7.6, 2H); 2.56-2.46 (m, 1H); 1.86 (p, J = 7.4, 2H); 1.00-0.91 (m, 4H). 13C (acetone-d6): 155.5; 132.3; 129.2; 115.1; 42.4; 32.2; 31.7; 29.2; 4.3. HRMS: calc. for C12H17NO3SNa [M + Na]+ 278.0827; found 278.0823. IR: 3277; 1514; 1137.  D.3.4 Characterization of N-(3-(4-hydroxyphenyl)propyl)(phenyl) methanesulfonamide (202, R = Bn)  HO  O O S N H  91.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H (acetone-d6): 8.10 (br, 1H); 7.497.31 (m, 5H); 7.03 (d, J = 8.3, 2H); 6.76 (d, J = 8.3, 2H);  6.04 (br, 1H); 4.31 (s, 2H); 3.06 (q, J = 6.7, 2H); 2.57 (t, J = 7.6, 2H); 1.80 (p, J = 7.6, 2H). 13  C (acetone-d6): 155.5; 132.3; 130.8; 130.7; 129.2; 128.3; 127.9; 115.0; 57.5; 42.7; 32.3; 173  31.6. HRMS: calc. for C16H19NO3SNa [M + Na]+ 328.0983; found 328.0989. IR: 3396; 3222; 1328; 1165; 735.  D.3.5 Characterization of N-(3-(4-hydroxyphenyl)propyl)(methylsulfonyl) methane sulfonamide (202, R = CH2SO2Me)  HO  O O S N H  90.0 % yield, light yellow oil, eluting solvent (EtOAc / SO2Me  hexanes = 4 / 6), 1H (acetone-d6): 8.07 (br, 1H); 7.07 (d, J = 8.6, 2H); 6.76 (d, J = 8.6, 2H); 6.54 (br, 1H); 4.88 (s,  2H); 3.27-3.16 (m, 2H); 3.21 (s, 3H); 2.63 (t, J = 7.6, 2H); 1.89 (p, J = 7.6, 2H). 13C (acetone-d6): 155.5; 132.1; 129.3; 115.1; 67.8; 42.8; 41.2; 31.9; 31.6. HRMS: calc. for C11H17NO5S2Na [M + Na]+ 330.0446; found 330.0442. IR: 3430; 3280; 1305; 1134.  D.3.6 Characterization of compound 232, R = 4-Me NHTs HO  84.0 % yield, light yellow solid, m.p. 103 oC, eluting solvent (EtOAc / hexanes = 1 / 1), 1H: 7.73 (d, J = 8.5, 2H); 7.29 (d, J =  8.5, 2H); 6.91 (d, J = 8.1, 2H); 6.73 (d, J = 8.1, 2H); 5.40 (br, 1H); 4.73 (t, J = 5.9, 1H); 2.93 (q, J = 6.4, 2H); 2.50 (t, J = 7.6, 2H); 2.42 (s, 3H); 1.71 (p, J = 7.6, 2H). 13C: 153.9; 143.5; 136.6; 132.8; 129.7; 129.4; 127.0; 115.3; 42.5; 31.7; 31.2; 21.5. HRMS: calc. for C16H19NO3S [M + H]+ 306.1164; found 306.1168. IR: 3495; 3270; 1318; 1149.  174  D.3.7 Characterization of N-(3-(4-hydroxyphenyl)propyl)-2-nitrobenzenesulfonamide (232, R = 2-NO2) NHNs(2-)  95.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 4 / 6), 1H: 8.12-8.06 (m, 1H); 7.90-7.83 (m, 1H);  HO  7.78-7.70 (m, 2H); 6.95 (d, J = 8.4, 2H); 6.72 (d, J = 8.4, 2H); 5.30 (t, J = 5.6, 1H); 4.89 (br, 1H); 3.10 (q, J = 6.5, 2H); 2.57 (t, J = 7.5, 2H); 1.82 (p, J = 7.3, 2H). 13C: 153.9; 147.9; 133.7; 133.3; 132.9; 132.5; 131.0; 129.4; 125.4; 115.3; 43.0; 31.6; 31.2. HRMS: calc. for C15H16N2O5SNa [M + Na]+ 359.0678; found 359.0670. IR: 3289; 2942; 1535; 1515; 1363; 1163.  D.3.8 Characterization of N-(3-(4-hydroxyphenyl)propyl)-3-nitrobenzenesulfonamide (232, R = 3-NO2) NHNs(3-) HO  94.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 2), 1H (acetone-d6): 8.62 (t, J = 1.9, 1H); 8.49 (d,  J = 8.3, 1H); 8.26 (d, J = 7.9, 1H); 8.09 (br, 1H); 7.93 (t, J = 8.0, 1H); 6.96 (d, J = 8.4, 2H); 6.86 (br, 1H); 6.71 (d, J = 8.4, 2H); 3.00 (q, J = 6.2, 2H); 2.54 (t, J = 7.4, 2H); 1.77 (p, J = 7.4, 2H). 13C (acetone-d6): 155.5; 148.4; 142.8; 132.6; 131.9; 130.9; 129.2; 126.8; 121.7; 115.1; 42.5; 31.5. HRMS: calc. for C15H16N2O5SNa [M + Na]+ 359.0678; found 359.0683. IR: 3450; 3313; 1353; 1085.  175  D.3.9 Characterization of N-(3-(4-hydroxyphenyl)propyl)-4-nitrobenzenesulfonamide (232, R = 4-NO2) NHNs(4-)  95.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 2), 1H (acetone-d6): 8.44 (d, J = 8.9, 2H); 8.12  HO  (d, J = 8.9, 2H); 6.96 (d, J = 8.6, 2H); 6.72 (d, J = 8.6, 2H); 3.01 (t, J = 6.9, 2H); 2.54 (t, J = 7.5, 2H); 1.76 (p, J = 7.5, 2H). 13C (acetone-d6): 155.5; 149.9; 146.6; 131.9; 129.2; 128.3; 124.3; 115.0; 42.4; 31.5; 31.4. HRMS: calc. for C15H16N2O5SNa [M + Na]+ 359.0678; found 359.0672. IR: 3460; 3290; 1527; 1348; 1158.  D.3.10 Characterization of 4-bromo-N-(3-(4-hydroxyphenyl)propyl) benzene sulfonamide (232, R = 4-Br)  HO  O O S N H  87.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 2), 1H (acetone-d6): 8.09 (s, 1H); 7.79 (s, Br  4H); 6.96 (d, J = 8.1, 2H); 6.73 (d, J = 8.1, 2H); 6.59  (br, 1H); 2.95 (q, J = 6.5, 2H); 2.53 (t, J = 7.5, 2H); 1.75 (p, J = 7.5, 2H). 13C: 155.5; 140.4; 132.2; 132.0; 129.2; 128.8; 126.3; 115.1; 42.4; 31.54; 31.52. HRMS: calc. for C15H16NO3SBrNa [M + Na]+ 391.9932; found 391.9925. IR: 3360; 3260; 1144; 559.  D.3.11 Characterization of N-(3-(4-hydroxyphenyl)propyl)-4-methoxybenzene sulfonamide (232, R = 4-OMe)  HO  O O S N H  83.0 % yield, light yellow oil, eluting solvent OMe  (EtOAc / hexanes = 1 / 1), 1H: 7.77 (d, J = 8.9, 2H); 7.00-6.87 (m, 4H); 6.73 (d, J = 8.9, 2H); 5.47 (s,  1H); 4.72 (t, J = 6.2, 1H); 3.86 (s, 3H); 2.92 (q, J = 6.6, 2H); 2.50 (t, J = 7.5, 2H); 1.71 (p, J 176  = 7.5, 2H). 13C: 162.8; 153.9; 132.8; 131.2; 129.4; 129.2; 115.3; 114.2; 55.6; 42.5; 31.7; 31.2. HRMS: calc. for C16H20NO4S [M + H]+ 322.1113; found 322.1120. IR: 3277; 1145; 830.  D.3.12 Characterization of N-(3-(4-hydroxyphenyl)propyl)-2,4,6-triisopropyl benzenesulfonamide (232, R = 2,4,6-triisopropyl) 85.0 % yield, light yellow oil, eluting solvent  HO  O O S N H  (EtOAc / hexanes = 1 / 4), 1H (acetone-d6): 8.07 (br, 1H); 7.31 (s, 2H); 6.91 (d, J = 8.4, 2H); 6.70 (d, J = 8.4, 2H); 6.36 (t, J = 5.8, 1H); 4.26 (p, J = 6.8, 2H);  2.99 (p, J = 6.7, 2H); 2.53 (t, J = 7.6, 2H); 1.78 (p, J = 7.4, 2H); 1.34-1.18 (m, 18H). 13C: 155.5; 152.2; 150.0; 133.9; 132.1; 129.1; 123.6; 115.0; 41.8; 33.9; 31.69; 31.63; 24.3; 23.0. HRMS: calc. for C24H35NO3SNa [M + Na]+ 440.2235; found 440.2226. IR: 3343; 3231; 2954; 1143.  D.3.13 Characterization of (S)-N-(1-(4-hydroxyphenyl)-3-(methylsulfonamido)propan2-yl)-4-methylbenzenesulfonamide (224, R = Me)  HO  NHMs NHTs  82.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 2 / 1), 1H (acetone-d6): 8.15 (br, 1H); 7.58 (d, J = 8.2, 2H);  7.27 (d, J = 8.2, 2H); 6.88 (d, J = 8.4, 2H); 6.62 (d, J = 8.4, 2H); 6.40 (d, J = 7.6, 1H); 6.04 (t, J = 6.1, 1H); 3.55-3.41 (m, 1H); 3.19 (t, J = 6.0, 2H); 2.92 (s, 3H); 2.85-2.74 (m, 1H); 2.61-2.50 (m, 1H); 2.41 (s, 3H). 13C: 156.0; 142.8; 138.2; 130.1; 129.4; 128.0; 126.7; 115.0; 55.7; 46.6; 39.0; 37.2; 20.5. HRMS: calc. for C17H23N2O5S2 [M + H]+ 399.1048; found 399.1047. IR: 3420; 3281; 1131. [α]D23 = -88 ° (MeOH, c = 0.5)  177  D.3.14 Characterization of (S)-N,N'-(3-(4-hydroxyphenyl)propane-1,2-diyl)bis(4methylbenzenesulfonamide) (224, R = PhMe)  HO  NHTs NHTs  81.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H: 7.68 (d, J = 8.1, 2H); 7.47 (d, J = 8.1, 2H); 7.27 (d, J  =8.1, 2H); 7.17 (d, J =8.1, 2H); 6.67 (d, J =8.4, 2H); 6.58 (d, J = 8.4, 2H); 5.65 (br, 1H); 5.32 (t, J = 6.4, 1H); 4.97 (d, J = 6.8, 1H); 3.34-3.20 (m, 1H); 3.09-2.88 (m, 2H); 2.71-2.59 (m, 1H); 2.49 (dd, J = 14.0, 7.8, 1H); 2.41 (s, 3H); 2.39 (s, 3H). 13C: 154.8; 143.68; 143.67; 136.3; 136.0; 130.1; 129.9; 129.8; 129.7; 127.7; 127.0; 126.9; 126.8; 115.5; 54.8; 46.4; 37.6; 21.5. HRMS: calc. for C23H27N2O5S2 [M + H]+ 475.1361; found 475.1373. IR: 3287; 1701; 1323; 1152. [α]D21 = -51.10o (acetone, c = 0.82)  D.3.15 Characterization of N-(3-(4-hydroxyphenyl)propyl)thiophene-2-sulfonamide (234, Z = H, R = SO2-2-thienyl)  HO  O O S S N H  90.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 2), 1H: 7.58 (d, J = 4.2, 2H); 7.08 (t, J = 4.4, 1H); 6.96 (d, J = 8.2, 2H); 6.74 (d, J = 8.2, 2H); 4.98 (br,  1H); 4.63 (t, J = 6.1, 1H); 3.04 (q, J = 6.6, 2H); 2.56 (t, J = 7.5, 2H); 1.78 (p, J = 7.5, 2H). 13  C: 153.8; 140.7; 132.8; 132.1; 131.8; 129.4; 127.4; 115.3; 42.8; 31.7; 31.1. HRMS: calc.  for C13H15NO3S2Na [M + Na]+ 320.0391; found 320.0388. IR: 3278; 1513; 1146.  178  D.4 Other preparative methods for special substrates D.4.1 Preparation of 4-acetyl-N-(3-(4-(tert-butyldimethylsilyloxy)phenyl)propyl) benzenesulfonamide (TBS analog of 201, R = 4-C(O)CH3)  TBSO  O O S N H  4-Acetylbenzene-1-sulfonyl chloride (842 mg, O  3.85 mmol) and triethylamine (460 mg, 4.55 mmol) was slowly added over a solution of 3-(4-(tert-  butyldimethylsilyloxy)phenyl)propan-1-amine (930 mg, 3.50 mmol) in DCM (12.0 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (10.0 mL) and extracted with EtOAc (25.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (10.0 mL), brine (15.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave the corresponding product (1.33 g, 2.97 mmol, 85.0 %). 1H: 8.06 (d, J = 8.5, 2H); 7.92 (d, J = 8.5, 2H); 6.92 (d, J = 8.4, 2H); 6.72 (d, J = 8.4, 2H); 4.54 (t, J = 5.8, 1H); 2.99 (q, J = 6.6, 2H); 2.65 (s, 3H); 2.53 (t, J = 7.5, 2H); 1.76 (p, J = 7.5, 2H); 0.97 (s, 9H); 0.18 (s, 6H). 13C: 196.7; 153.9; 143.9; 139.9; 133.1; 129.1; 128.9; 127.3; 120.0; 42.6; 31.8; 31.2; 26.8; 25.6; 18.1; -4.5. HRMS: calc. for C23H33NO4SiSNa [M + Na]+ 470.1797; found 470.1791. IR: 3290; 2960; 1687; 1509; 1250; 1154.  179  D.4.2 Preparation of 4-acetyl-N-(3-(4-hydroxyphenyl)propyl)benzenesulfonamide (232, R = 4-C(O)CH3)  HO  O O S N H  1 M TBAF in THF solution (3.27 mL, 3.27 mmol) O  was added to a solution of above compound (1.33 g, 2.97 mmol) in THF (5.00 mL) at 0 °C and with good  stirring. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 941 mg (2.82 mmol, 95.0 %) product as a light yellow oil. 1H (acetone-d6): 8.17 (d, J = 8.6, 2H); 8.09 (br, 1H); 7.96 (d, J = 8.6, 2H); 6.95 (d, J = 8.5, 2H); 6.72 (d, J = 8.5, 2H); 6.68 (br, 1H); 2.96 (q, J = 6.2, 2H); 2.67 (s, 3H); 2.53 (t, J = 7.3, 2H); 1.75 (p, J = 7.4, 2H). 13C (acetone-d6): 196.4; 155.5; 144.8; 139.8; 132.0; 129.2; 128.8; 127.0; 115.0; 42.4; 31.5; 26.1. HRMS: calc. for C17H19NO4SNa [M + Na]+ 356.0932; found 356.0940. IR: 3278; 1687; 1514; 1159.  D.4.3 Characterization of 4-(3-(1,1-dimethylethylsulfinamido)propyl)phenyl methanesulfonate (216)  MsO  N H  O S  See general procedure for coupling of amine and sulfonyl chloride, 93 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 3 / 1), 1H: 7.24-7.15 (m, 4H); 3.25-3.14  (m, 2H); 3.12 (s, 3H); 2.68 (t, J = 7.5, 2H); 1.88 (p, J = 7.2, 2H); 1.20 (s, 9H). 13C: 147.4; 140.8; 129.8; 121.9; 55.6; 44.9; 37.2; 32.4; 32.2; 22.6. HRMS: calc. for C14H23NO4S2Na [M + Na]+ 356.0966; found 356.0972. IR: 1360; 1147; 866. 180  D.4.4 Preparation of 4-(3-(1,1-dimethylethylsulfonamido)propyl)phenyl methanesulfonate (217)  MsO  O S N H O  mCPBA (303 mg, 1.75 mmol) was added to a DCM (5.00 mL) solution of compound 216 (450 mg, 1.35 mmol) at room temperature. The reaction mixture was stirred over  night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. Na2S2O3 (10.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 4 / 1) gave 424 mg (1.22 mmol, 90.0 %) product as a light yellow oil. 1H (acetone-d6): 7.37 (d, J = 8.6, 2H); 7.27 (d, J = 8.6, 2H); 5.83 (br, 1H); 3.26 (s, 3H); 3.24 (q, J = 6.7, 2H); 2.76 (t, J = 7.7, 2H); 1.90 (p, J = 7.6, 2H); 1.34 (s, 9H). 13C (acetone-d6): 147.9; 141.2; 129.8; 122.0; 58.8; 43.7; 36.5; 32.9; 31.8; 23.7. HRMS: calc. for C14H23NO5S2Na [M + Na]+ 372.0915; found 372.0910. IR: 1355; 1117; 858.  D.4.5 Characterization of N-(3-(4-hydroxyphenyl)propyl)-2-methylpropane-2sulfinamide (sulfinamide analog of 218)  HO  N H  O S  See general procedure for deprotection of mesyl-O-phenol derivatives for 216, 90 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 3 / 1), 1H: 7.47 (br, 1H); 6.96 (d,  J = 8.3, 2H); 6.77 (d, J = 8.3, 2H); 3.34-3.25 (m, 1H); 3.24-3.03 (m, 2H); 2.57 (td, J = 7.4, 2.7, 2H); 1.85 (p, J = 7.2, 2H); 1.22 (s, 9H). 13C: 154.8; 132.3; 129.2; 115.4; 55.8; 45.5; 32.8;  181  32.1; 22.6. HRMS: calc. for C13H21NO2SNa [M + Na]+ 278.1191; found 278.1185. IR: 3243; 1515; 1020. D.4.6 Characterization of N-(3-(4-hydroxyphenyl)propyl)-2-methylpropane-2sulfonamide (218) O S N O H  HO  See general procedure for deprotection of mesyl-O-phenol derivatives for 217, 90 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 3 / 1), 1H (acetone-d6): 8.07 (br,  1H); 7.06 (d, J = 8.5, 2H); 6.76 (d, J = 8.5, 2H); 5.76 (br, 1H); 3.20 (q, J = 6.7, 2H); 2.61 (t, J = 7.8, 2H); 1.84 (p, J = 7.5, 2H); 1.34 (s, 9H). 13C (acetone-d6): 155.4; 132.4; 129.2; 115.1; 58.8; 44.0; 33.3; 31.6; 23.8. HRMS: calc. for C13H21NO3SNa [M + Na]+ 294.1140; found 294.1146. IR: 3314; 1518; 1291; 1110.  D.4.7 Preparation of N-(3-(4-hydroxy-3,5-diiodophenyl)propyl)methanesulfonamide (220) Bis(pyridine)iodonium tetrafluoroborate (450 mg, 1.20 mmol)  I  NHMs  was added to a DCM / MeCN ( 2.00 mL, 5 : 1 v / v) solution of  HO I  compound 202, R = Me (252 mg, 1.10 mmol) at -78 °C and with  good stirring. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. Na2S2O3 (3.00 mL) and extracted with EtOAc (3 x 7.00 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 481 mg (1.00 mmol, 92.0 %) product as a light yellow oil. 1H: 7.50 (s, 2H); 5.65 (s, 1H); 4.28 (br, 1H); 3.14 (q, J = 6.7, 2H); 2.97 (s, 3H); 2.57 (t, J = 7.8, 2H); 1.85 (p, J = 7.3, 2H). 13C: 152.0; 138.9; 136.8; 82.2; 182  42.4; 40.4; 31.7; 30.7. HRMS: calc. for C10H13NO3SI2Na [M + Na]+ 503.8603; found 503.8617. IR: 3420; 3248; 1461; 1326; 1117.  D.4.8 Preparation of (S,E)-4-(4-methoxy-3-(methylsulfonamido)but-1-enyl)phenyl acetate (226) OMe  TMSCHN2 (0.64 mL, 1.27 mmol, 2 M hexane solution) was  NHMs  added to a solution of compound 225 (380 mg, 1.27 mmol)  AcO  and tetrafluoroboric acid (17.0 mL, 1.27 mmol, 48 wt % in  water) in DCM (5.00 mL) at 0 °C with good stirring. Another two batches of TMSCHN2 (0.64 mL x 2) was added at intervals of 30 min. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NaHCO3 (10.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NaHCO3 (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 298 mg (0.95 mmol, 75.0 %) product as a light yellow oil. 1H: 7.39 (d, J = 8.5, 2H); 7.06 (d, J = 8.5, 2H); 6.67 (d, J = 16.0, 1H); 6.11 (dd, J = 16, 7.6, 1H); 4.94 (d, J = 6.3, 1H); 4.28 (p, J = 5.5, 1H); 3.63-3.43 (m, 2H); 3.40 (s, 3H); 2.96 (s, 3H); 2.30 (s, 3H). 13C: 169.4; 150.4; 133.6; 132.3; 127.5; 126.2; 121.8; 74.7; 59.0; 55.7; 42.2; 21.1. HRMS: calc. for C14H19NO5SNa [M + Na]+ 336.0882; found 336.0879. IR: 1755; 1320; 1194. [α]D21 = +34.45o (acetone, c = 1.055)  183  D.4.9 Preparation of (S)-N-(4-(4-hydroxyphenyl)-1-methoxybutan-2-yl) methane sulfonamide (227) OMe NHMs  Commercial 10 wt % palladium on carbon (53.0 mg, 5.00 mol %) and potassium carbonate (138 mg, 1.00 mmol) was added to a solution of substrate 226 (298 mg, 0.950 mmol) in  HO  MeOH (5.00 mL) under inert atmosphere, at room temperature and with good stirring. Hydrogen gas was bubbled into the solution for 20 min. Upon the completion of the reaction, the mixture was filtered through 2-inch Celite using EtOAc. Chromatography of the residue (EtOAc / hexanes = 2 / 1) gave 236 mg (0.860 mmol, 91.0 %) product as a light yellow oil. 1  H: 6.99 (d, J = 8.2, 2H); 6.74 (d, J = 8.2, 2H); 5.85 (br, 1H); 4.82 (d, J = 8.6, 1H); 3.60-3.50  (m, 1H); 3.48-3.33 (m, 2H); 3.36 (s, 3H); 3.00 (s, 3H); 2.75-2.50 (m, 2H); 1.88-1.67 (m, 2H). 13  C: 154.0; 132.9; 129.4; 115.3; 74.9; 59.0; 53.8; 41.8; 34.5; 31.0. HRMS: calc. for  C12H19NO4SNa [M + Na]+ 296.0932; found 296.0925. IR: 3317; 1522. [α]D22 = -3.52° (acetone, c = 1.305)  D.4.10 Preparation of (S)-N-(4-(4-hydroxyphenyl)-1-oxobutan-2-yl) methane sulfonamide (229) H  HO  O  SO3-pyridine complex (722 mg, 4.50 mmol) and Hünig’s base  NHMs  (0.780 mL, 4.50 mmol) in a DMSO (5.00 mL) and DCM (5.00 mL) solution were added to a DMSO (5.00 mL) and DCM  (5.00 mL) solution of L-homotyrosinol methanesulfonamide (389 mg, 1.50 mmol) at room temperature. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NaHCO3 (10.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NaHCO3 (3 x 5.00 mL), brine 184  (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 2 / 1) gave 328 mg (1.28 mmol, 85.0 %) product as a light yellow oil. 1H (acetone-d6): 9.62 (s, 1H); 8.14 (br, 1H); 7.10 (d, J = 8.2, 2H); 6.77 (d, J = 8.2, 2H); 6.58 (d, J = 7.0, 1H); 4.13-4.00 (m, 1H); 2.98 (s, 3H); 2.822.64 (m, 2H); 2.25-2.10 (m, 1H); 1.97-1.80 (m, 1H). 13C (acetone-d6): 200.1; 155.7; 131.6; 129.4; 115.2; 61.6; 40.6; 31.4; 30.3. HRMS: calc. for C11H14NO4S [M-H]+ 256.0644; found 256.0641. IR: 3278; 1514; 1310. [α]D22 = -7.41° (acetone, c = 1.06)  D.4.11 Preparation of dimethyl 3-(4-hydroxyphenyl) propylphosphoramidate (240)  HO  O OMe P N H OMe  Potassium carbonate (704 mg, 5.10 mmol) was added to a MeOH (7.00 mL) solution of compound 199 (301 mg, 1.70 mmol) at room temperature. The reaction mixture was heated  at reflux for 8 h. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (10.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Then, trimethyl phosphite (422 mg, 3.40 mmol) and water (2.00 mL) were added to a THF (8.00 mL) solution of above crude product at room temperature. The reaction mixture was heated at 50 oC for 10 h. Upon the completion of the reaction, the mixture was cooled to 0 °C and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with brine (10.0 mL x 2) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / MeOH = 25 / 1) gave 308 mg (1.20 mmol, 70.0 % over 2 steps) product as a light yellow oil. 1H: 7.54 (s, 1H); 6.97 (d, J = 8.4, 2H); 6.80 (d, J = 8.4, 2H); 3.72 (s, 3H); 3.68 (s, 3H); 2.97-2.83 (m, 2H); 2.81185  2.67 (m, 1H); 2.53 (t, J = 7.7, 2H); 1.76 (p, J = 7.5, 2H).  13  C: 154.8; 132.3; 129.2; 115.4;  53.2; 53.1; 40.8; 33.5; 33.4; 31.9. HRMS: calc. for C11H19NO4P [M + H]+ 260.1052; found 260.1057. IR: 3223; 2951; 1706; 1220; 1027.  D.5 General procedures of IMOA at para position (Diacetoxy)iodobenzene (1.10 eq) was added slowly in a TFA ([C] = 0.300 M) solution of phenolic compound (1.00 eq.) at room temperature. Upon the completion of the reaction, the crude product was evaporated to dryness under reduced pressure. Chromatography of the residue would afford the corresponding spirocyclization product.  D.5.1 Characterization of compound 231, R = Me O  95.0 % yield, light yellow solid, m.p. 106 oC, eluting solvent (EtOAc / N Ms  hexanes = 3 / 1), 1H: 6.92 (d, J = 9.8, 2H); 6.26 (d, J = 9.8, 2H); 3.75-3.66  (m, 2H); 2.91 (s, 3H); 2.20-2.14 (m, 4H). 13C: 184.7; 149.1; 128.4; 63.3; 49.1; 40.3; 39.2; 23.5. HRMS: calc. for C10H13NO3S [M+H]+ 228.0694; found 228.0692. IR: 1664; 1322; 1149.  D.5.2 Characterization of compound 231, R = CF3 O  94.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 2 / 1), N O S O CF3  1  H: 6.86 (d, J = 10, 2H); 6.27 (d, J = 10, 2H); 3.90-3.81 (m, 2H); 2.31-  2.15 (m, 4H).  13  C: 184.3; 147.3; 128.7; 119.8 (q); 65.2; 51.0; 40.6; 24.0.  HRMS: calc. for C10H10NO3F3SNa [M + Na]+ 304.0231; found 304.0229. IR: 1668; 1389; 1186.  186  D.5.3 Characterization of compound 231, R = tBu 85.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1),  O  N O S O  1  H: 6.97 (d, J = 10.1, 2H); 6.18 (d, J = 10.1, 2H); 3.73 (t, J = 6.7, 2H);  2.15-2.07 (m, 4H); 1.39 (s, 9H). 13C: 185.0; 150.9; 127.4; 65.4; 61.5; 51.3; 40.6; 25.0; 24.5. HRMS: calc. for C13H19NO3SNa [M + Na]+ 292.0983; found 292.0989. IR: 1660; 1303; 1116.  D.5.4 Characterization of compound 231, R = cyclopropyl 90.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1),  O  N O S O  1  H: 6.98 (d, J = 10.0, 2H); 6.22 (d, J = 10.0, 2H); 3.73 (t, J = 6.6, 2H);  2.42-2.31 (m, 1H); 2.18-2.11 (m, 4H); 1.18-1.11 (m, 2H); 1.01-0.92 (m, 2H).  13  C: 184.9; 150.2; 127.9; 63.3; 49.3; 40.3; 29.7; 23.7; 5.7. HRMS: calc. for  C12H15NO3SNa [M + Na]+ 276.0670; found 276.0664. IR: 1666; 1327; 1140; 1057.  D.5.5 Characterization of compound 231, R = Bn 89.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 2 / 1), O  N SO2Bn  1  H: 7.40 (s, 5H); 6.53 (d, J = 9.9, 2H); 6.09 (d, J = 9.9, 2H); 4.24 (s, 2H);  3.47 (t, J = 6.5, 2H); 2.08-1.94 (m, 4H). 13C: 184.8; 149.6; 130.7; 129.1;  128.9; 128.8; 127.8; 63.6; 58.8; 49.6; 40.2; 23.9. HRMS: calc. for C16H17NO3SNa [M + Na]+ 326.0827; found 326.0834. IR: 1667; 1326; 1127; 536.  187  D.5.6 Characterization of compound 231, R = CH2SO2Me 92.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 2 / O  N  S Ms O O  1), 1H: 7.00 (d, J = 10.2, 2H); 6.30 (d, J = 10.2, 2H); 4.44 (s, 2H); 3.94 (t, J = 6.5, 2H); 3.22 (s, 3H); 2.29-2.10 (m, 4H). 13C: 184.4;  148.5; 128.8; 69.9; 63.4; 51.7; 42.1; 40.7; 23.7. HRMS: calc. for C11H15NO5S2Na [M + Na]+ 328.0289; found 328.0287. IR: 1665; 1345; 1308. D.5.7 Characterization of compound 233, R = 4-Me 94.0 % yield, light yellow foam, eluting solvent (EtOAc / hexanes = 1 / 1), O  N Ts  1  H: 7.67 (d, J = 8.3, 2H); 7.28 (d, J = 8.3, 2H); 6.71 (d, J = 10, 2H); 6.17 (d,  J = 10, 2H); 3.74-3.65 (m, 2H); 2.43 (s, 3H); 2.13-2.02 (m, 4H). 13C: 185.1; 149.8; 143.8; 136.2; 129.6; 127.9; 127.7; 63.5; 49.0; 40.4; 23.4; 21.6. HRMS: calc. for C16H17NO3S [M + H]+ 304.1007; found 304.1003. IR: 1660; 1339; 1154.  D.5.8 Characterization of compound 233, R = 2-NO2 95.0 % yield, light yellow solid, eluting solvent (EtOAc / hexanes = 2 / O  N Ns(2-)  1), 1H: 7.94-7.85 (m, 1H); 7.75-7.55 (m, 3H); 6.83 (d, J = 10, 2H); 6.09  (d, J = 10, 2H); 3.95-3.88 (m, 2H); 2.24-2.10 (m, 4H). 13C: 184.6; 149.5; 148.0; 134.1; 133.1; 132.1; 131.5; 128.2; 123.9; 63.1; 50.7; 41.0; 23.5. HRMS: calc. for C15H14N2O5SNa [M + Na]+ 357.0521; found 357.0518. IR: 1667; 1542; 1365; 1163.  D.5.9 Characterization of compound 233, R = 3-NO2 O  95.0 % yield, light yellow solid, eluting solvent (EtOAc / hexanes = 1 / N Ns(3-)  1), 1H: 8.63 (t, J = 2.0, 1H); 8.45 (d, J = 8.2, 1H); 8.11 (d, J = 8.1, 1H);  7.74 (t, J = 8.1, 1H); 6.69 (d, J = 10, 2H); 6.23 (d, J = 10, 2H); 3.74 (t, J = 6.7, 2H); 2.18188  2.07 (m, 4H). 13C: 184.6; 148.7; 148.2; 141.5; 133.1; 130.4; 128.4; 127.3; 122.6; 64.0; 49.5; 40.3; 23.6. HRMS: calc. for C15H14N2O5SNa [M + Na]+ 357.0521; found 357.0514. IR: 1667; 1531; 1353; 1165.  D.5.10 Characterization of compound 233, R = 4-NO2 O  96.0 % yield, light yellow solid, eluting solvent (EtOAc / hexanes = 1 / N Ns(4-)  1), 1H: 8.35 (d, J = 8.8, 2H); 7.98 (d, J = 8.8, 2H); 6.67 (d, J = 10, 2H);  6.21 (d, J = 10, 2H); 3.73 (t, J = 6.7, 2H); 2.18-2.06 (m, 4H). 13C: 184.5; 150.1; 148.7; 145.0; 128.7; 128.4; 124.3; 64.0; 49.5; 40.3; 23.6. HRMS: calc. for C15H14N2O5SNa [M + Na]+ 357.0521; found 357.0526. IR: 1666; 1525; 1348; 1090.  D.5.11 Characterization of compound 233, R = 4-Br 93.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 2 / 1), O  N O S O  1  H: 7.64 (s, 4H); 6.69 (d, J = 10, 2H); 6.19 (d, J = 10, 2H); 3.68 (t, J = 6.5,  2H); 2.19-2.01 (m, 4H). 13C: 184.8; 149.3; 138.2; 132.3; 129.1; 128.1; 128.0; 63.7; 49.2; 40.3; 23.4. HRMS: calc. for C15H14NO3SBrNa [M +  Br  Na]+ 389.9775; found 389.9783. IR: 1661; 1340; 1089; 738; 568.  D.5.12 Characterization of compound 233, R = 4-CN O  ca. 93.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / N O S O  1), 1H: 7.91 (d, J = 8.3, 2H); 7.82 (d, J = 8.3, 2H); 6.67 (d, J = 10.1, 2H); 6.22 (d, J = 10.1, 2H); 3.72 (tapp, J = 6.6, 2H); 2.17-2.05 (m, 4H). 13  CN  C:184.6; 148.7; 143.5; 132.8; 128.4; 128.1; 117.1; 116.7; 63.9; 49.4;  189  40.3; 23.6. HRMS: calc. for C16H14N2O3SNa [M + Na]+ 337.0623; found 337.0621. IR: 2969; 1665; 1349; 1183.  D.5.13 Characterization of compound 233, R = 4-C(O)CH3 93.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), O  N O S O  1  H: 8.06 (d, J = 8.5, 2H); 7.88 (d, J = 8.5, 2H); 6.68 (d, J =10.2, 2H); 6.19  (d, J = 10.2, 2H); 3.72 (t, J = 6.5, 2H); 2.66 (s, 3H); 2.16-2.02 (m, 4H). 13  O  C: 196.7; 184.7; 149.1; 143.1; 140.1; 128.8; 128.2; 127.9; 63.7; 49.3;  40.3; 26.8; 23.5. HRMS: calc. for C17H17NO4SNa [M + Na]+ 354.0776;  found 354.0772. IR: 1688; 1666; 1345; 1154.  D.5.14 Characterization of compound 233, R = 4-OMe 85.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), O  N O S O  1  H: 7.68 (d, J = 8.9, 2H); 6.93 (d, J = 8.9, 2H); 6.71 (d, J = 10.1, 2H);  6.14 (d, J = 10.1, 2H); 3.85 (s, 3H); 3.65 (t, J = 6.9, 2H); 2.12-1.97 (m, 4H). 13C: 185.1; 163.1; 150.0; 130.6; 129.8; 127.8; 114.0; 63.4; 55.6; 48.9;  OMe  40.3; 23.4. HRMS: calc. for C16H17NO4SNa [M + Na]+ 342.0776; found  342.0774. IR: 1663; 1331; 1040; 672.  190  D.5.15 Characterization of compound 233, R = 2,4,6-triisopropyl 83.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / O  3), 1H: 7.15 (s, 2H); 6.91 (d, J = 9.8, 2H); 6.15 (d, J = 9.8, 2H); 4.16  N O S O  (hep, J = 6.7, 2H); 3.58 (t, J = 6.6, 2H); 2.89 (hep, J = 6.8, 1H); 2.172.04 (m, 4H); 1.34-1.14 (m, 18H).  13  C: 184.9; 153.7; 151.4; 149.7;  131.5; 127.7; 123.8; 63.5; 48.5; 40.7; 34.1; 29.2; 24.7; 23.5; 23.4. HRMS: calc. for C24H33NO3SNa [M + Na]+ 438.2079; found 438.2089. IR: 2959; 1668; 1147.  D.5.16 Characterization of compound 235, Z = H, R = SO2-2-thienyl 91.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), O  N O S O S  1  H: 7.59 (dd, J = 5.0, 1.3, 1H); 7.53 (dd, J = 3.7, 1.3, 1H); 7.10-7.06 (m,  1H); 6.75 (d, J = 10.1, 2H); 6.19 (d, J = 10.1, 2H); 3.76 (t, J = 6.6, 2H); 2.19-2.03 (m, 4H). 13C: 184.9; 149.0; 139.8; 133.0; 132.1; 128.2; 127.2;  63.7; 49.2; 40.3; 23.3. HRMS: calc. for C13H13NO3S2Na [M + Na]+ 318.0235; found 318.0242. IR: 1663; 1334; 1147; 1024  D.5.17 Characterization of compound 235, Z = I, R = Ms 92.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H:  I  7.68 (s, 2H); 3.68 (t, J = 6.6, 2H); 2.93 (s, 3H); 2.30-2.12 (m, 4H). 13C:  O I  N Ms  173.1; 157.6; 97.5; 69.3; 49.0; 39.3; 38.8; 23.5. HRMS: calc. for  C10H11NO3SI2Na [M + Na]+ 501.8447; found 501.8453. IR: 1650; 1340; 1148; 756; 658.  191  D.5.18 Characterization of compound 237, R = CH2OH 95.0 % yield, light yellow solid, eluting solvent (EtOAc / MeOH = OH O  N Ms  100 / 1), 1H (acetone-d6): 7.26 (dd, J = 9.8, 3.0, 1H); 7.04 (dd, J = 9.9, 3.0, 1H); 6.16 (dd, J = 9.9, 2.3, 1H); 6.10 (dd, J = 10.1, 2.1, 1H); 4.15  (br, 1H); 4.12-4.04 (m, 1H); 3.82-3.72 (m, 2H); 3.00 (s, 3H); 2.61-2.33 (m, 2H); 2.24-2.13 (m, 1H); 1.99-1.89 (m, 1H). 13C (acetone-d6): 184.4; 152.7; 148.7; 127.7; 127.3; 64.2; 63.9; 63.1; 39.3; 37.7; 26.5. HRMS: calc. for C11H15NO4SNa [M + Na]+ 280.0619; found 280.0619. IR: 3417; 2929; 1667; 1328. [α]D22 = -20.35° (acetone, c = 1.103)  D.5.19 Characterization of compound 237, R = CH2OMe 95.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 3 OMe O  N Ms  / 1), 1H: 7.03-6.91 (m, 2H); 6.24 (t, J = 11.3, 2H); 4.27-4.18 (m, 1H); 3.74-3.64 (m, 1H); 3.56-3.46 (m, 1H); 3.42 (s, 3H); 2.94 (s, 3H);  2.50-2.35 (m, 1H); 2.33-2.07 (m, 2H); 2.04-1.90 (m, 1H). 13C: 184.9; 150.9; 149.3; 128.6; 127.7; 74.1; 64.0; 61.3; 59.1; 41.1; 38.6; 27.4. HRMS: calc. for C12H17NO4SNa [M + Na]+ 294.0776; found 294.0780. IR: 1664; 1333; 1155. [α]D22 = -40.3° (acetone, c = 0.9)  D.5.20 Characterization of compound 237, R = CHO 94.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 3 / O  N Ms  O H  1), 1H: 9.67 (s, 1H); 6.98 (d, J = 9.9, 2H); 6.38-6.23 (m, 2H); 4.85 (dd, J = 9.2, 2.6, 1H); 3.05 (s, 3H); 2.52-2.03 (m, 4H). 13C: 198.3;  184.4; 149.1; 148.5; 129.7; 128.2; 68.8; 63.6; 41.9; 38.2; 24.3. HRMS: calc. for C11H12NO4S [M + H]+ 254.0487; found 254.0493. IR: 3435; 1664; 1624; 1327; 1146. [α]D22 = -22.77° (acetone, c = 1.12) 192  D.5.21 Characterization of compound 238, R = Me NHTs  83.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 3 / 1), 1H: 7.76 (d, J = 8.2, 2H); 7.36 (d, J = 8.2, 2H); 7.01 (dd, J = 9.9,  O N Ms  2.8, 1H); 6.82 (dd, J = 9.9, 2.8, 1H); 6.23 (td, J = 10.3, 2.2, 2H);  5.43 (d, J = 5.8, 1H); 4.03-3.91 (m, 1H); 3.82 (dd, J = 10.4, 6.4, 1H); 3.56 (dd, J = 10.4, 5.4, 1H); 2.91 (s, 3H); 2.46 (s, 3H); 2.33-2.12 (m, 2H). 13C: 184.5; 148.7; 148.0; 144.6; 136.1; 130.2; 128.54; 128.50; 127.0; 62.4; 53.7; 50.7; 45.3; 39.5; 21.6. HRMS: calc. for C17H21N2O5S2 [M + H]+ 397.0892; found 397.0897. IR: 3260; 1667; 1331; 1151. [α]D23 = +3 ° (MeOH, c = 0.5)  D.5.22 Characterization of compound 238, R = PhMe NHTs  O N Ts  80.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 2 / 1), 1H: 7.72 (d, J = 8.2, 2H); 7.58 (d, J = 8.2, 2H); 7.32 (d, J = 8.1,  2H); 7.27 (d, J = 8.1, 2H); 6.78 (dd, J = 9.6, 2.5, 1H); 6.53 (dd, J = 10.4, 3.3, 1H); 6.11 (d, J = 10.1, 2H); 5.54 (d, J = 6.8, 1H); 3.99-3.86 (m, 1H); 3.77 (dd, J = 10.2, 6.8, 1H); 3.45 (dd, J = 10.3, 5.9, 1H); 2.44 (s, 3H); 2.42 (s, 3H); 2.19-2.01 (m, 2H). 13C: 184.8; 149.6; 148.1; 144.4; 144.3; 136.5; 135.2; 130.0; 129.7; 128.1; 127.8; 127.7; 127.0; 62.6; 53.7; 50.4; 45.2; 21.6. HRMS: calc. for C23H24N2O5S2Na [M + Na]+ 495.1024; found 495.1021. IR: 1667; 1334; 1158. [α]D20 = -8.75° (acetone, c = 1.24)  193  D.5.23 Characterization of compound 241 88.0 % yield, light yellow oil, eluting solvent (EtOAc / MeOH = 100 / 6), O  N P O MeO OMe  1  H: HNMR: 6.84 (d, J = 10.1, 2H); 6.16 (d, J = 10.1, 2H); 3.66 (s, 3H);  3.62 (s, 3H); 3.54-3.47 (m, 2H); 2.09-2.01 (m, 4H). 13C: 185.3; 151.5;  127.1; 61.99 (61.93); 53.43 (53.36); 48.94 (48.87); 40.39 (40.25); 25.14 (25.01). HREI: calc. for EI: C11H16NO4P 257.0817; found 257.0821. IR: 3450; 1662; 1251; 1016.  D.6 Synthesis and characterization of intermediates for IMOA at ortho position D.6.1 Preparation of 3-(2-methoxyphenyl)propan-1-ol (246) OH OMe  [known compound, see ref: Chemical & Pharmaceutical Bulletin, 31(11), 4178-80; 1983] Lithium aluminum hydride powder (5.48 g, 144 mmol)  was slowly added over a period of 30 min to a solution of 3-(2-methoxyphenyl)-propionic acid (245) (13.0 g, 72.2 mmol) in THF (200 mL) at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. The progress of the reaction was monitored by 1H NMR. Upon the completion of the reaction, the mixture was cooled to 0 °C. H2O (5.48 mL), 15 % NaOH (5.48 mL) solution, H2O (16.4 mL) and appropriate amount of drying reagent (MgSO4) was sequentially added in the interval of 20 min with vigorous stirring. The resulting suspension solution was warmed to room temperature and filtered through Celite using EtOAc (3 x 200 mL). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 10.9 g (65.7 mmol, 91.0 %) product as a light yellow oil. 1H (acetone-d6): 7.15 (d, J = 6, 2H); 6.91 (d, J = 6, 1H); 6.85 (t, J = 6, 1H); 3.81 (s, 3H); 3.61-3.53 (m, 3H); 2.68 (t, J = 6, 2H); 1.84-1.75 (m, 2H).  13  C (acetone-d6): 158.6; 131.4; 130.7; 127.9; 121.3; 111.3;  194  62.3; 55.7; 34.1; 27.4. HRMS: calc. for C10H14O2 [M + Na]+ 189.0891; found 189.0892. IR: 3374.  D.6.2 Preparation of 3-(2-methoxyphenyl)propyl methanesulfonate (247) OMs  Methanesulfonyl chloride (3.04 mL, 39.1 mmol) and triethylamine (6.28 mL, 45.2 mmol) was slowly added over a period of 10 min to a  OMe  solution of 246 (5.00 g, 30.1 mmol) in DCM (150 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (50.0 mL) and extracted with EtOAc (3 x 75.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 20.0 mL), brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 6.98 g (28.6 mmol, 95.0 %) product as a light yellow oil. 1H (acetone-d6): 7.23-7.14 (m, 2H); 6.95 (d, J = 6, 1H); 6.88 (t, J = 6, 1H); 4.24 (t, J = 6, 2H); 3.83 (s, 3H); 3.07 (s, 3H); 2.73 (t, J = 6, 2H); 2.06-1.96 (m, 2H).  13  C (acetone-d6): 157.7; 130.0; 129.1; 127.7; 120.5; 110.6; 70.1;  54.9; 36.4; 29.3; 26.3. HRMS: calc. for C11H16O4S [M + Na]+ 267.0667; found 267.0669. IR: 1352; 1173.  D.6.3 Preparation of 2-(3-bromopropyl)phenol (248) Br OH  1 M BBr3 in DCM solution (37.0 mL, 37.0 mmol) was slowly added via syringe pump over a period of 30 min to a solution of 247 (6.03 g, 24.7  mmol) in DCM (30.0 mL) at -20 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the 195  mixture was cooled to 0 °C and transferred into 250 mL R.B. flask which filled with ice and aq. sat. NaHCO3 solution (50.0 mL). The reaction mixture was extracted with EtOAc (3 x 30.0 mL), washed with brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (Et2O / hexanes = 1 / 5) gave 4.91 g (22.9 mmol, 93.0 %) product as a colorless oil. 1H (acetone-d6): 8.29 (s, 1H); 7.12 (dd, J = 7.5, 1.3, 1H); 7.05 (td, J = 7.6, 1.4, 1H); 6.85 (d, J = 7.9, 1H); 6.78 (t, J = 7.5, 1H); 3.49 (t, J = 6.7, 2H); 2.77 (t, J = 7.5, 2H); 2.17 (p, J = 7.0, 2H). 13C (acetone-d6): 155.1; 130.2; 127.3; 126.9; 119.5; 115.0; 33.5; 32.8; 28.6. HREI: calc. for C9H11O79Br 213.99933; found 213.99943. IR: 3527.  D.6.4 Preparation of 1-(3-azidopropyl)-2-methoxybenzene (249a) Sodium azide (1.60 g, 24.6 mmol) was slowly added to a solution of 247 N3 OMe  (3.00 g, 12.3 mmol) in DMF (30.0 mL) and H2O (30.0 mL) at room  temperature and with good stirring. Then reaction mixture was warmed to 70 °C and stirred over night. Upon the completion of the reaction, the mixture was cooled to room temperature, extracted with EtOAc (3 x 30.0 mL), brine (30.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (DCM / hexanes = 1 / 1) gave 2.18 g (11.4 mmol, 93.0 %) product as a yellow oil. 1H (acetone-d6): 7.22-7.12 (m, 2H); 6.93 (d, J = 7.9, 1H); 6.86 (td, J = 7.3, 0.9, 1H); 3.83 (s, 3H); 3.32 (t, J = 7, 2H); 2.69 (t, J = 7.8, 2H); 1.85 (p, J = 7.4, 2H).  13  C (acetone-d6): 158.6; 130.8; 130.2;  128.4; 121.3; 111.4; 55.7; 51.7; 29.8; 28.2. LRESI: [M - N2 + H] + 164.2. IR: 2097.  196  D.6.5 Preparation of 2-(3-azidopropyl)phenol (249b) Sodium azide (2.98 g, 45.8 mmol) was slowly added to a solution of 248 N3  (4.91 g, 22.9 mmol) in DMF (70.0 mL) and H2O (48.0 mL) at room  OH  temperature and with good stirring. Then reaction mixture was warmed to 90 °C and stirred over night. Upon the completion of the reaction, the mixture was cooled to room temperature, extracted with EtOAc (3 x 30.0 mL), brine (30.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (Et2O / hexanes = 1 / 4) gave 3.93 g (22.2 mmol, 97.0 %) product as a light yellow oil. 1H (acetoned6): 8.29 (s, 1H); 7.11 (dd, J = 7.4, 1.6, 1H); 7.04 (td, J = 7.6, 1.7, 1H); 6.84 (dd, J = 8.0, 1.1, 1H); 6.77 (td, J = 7.4, 1.3, 1H); 3.36 (t, J = 6.8, 2H); 2.71 (t, J = 7.3, 2H); 1.90 (p, J = 7.33, 2H). 13C (acetone-d6): 155.0; 130.1; 127.4; 127.1; 119.5; 114.9; 50.7; 28.8; 27.1. ESI: [M N2 + H]+ 150.1. IR: 2099.  D.6.6 Preparation of 3-(2-methoxyphenyl)propan-1-amine (250) NH2 OMe  [known compound, see ref: Journal of Medicinal Chemistry, 31(1), 3754; 1988] Triphenylphsphine (2.97 g, 11.4 mmol) was slowly added to  a solution of 249a (1.08 g, 5.67 mmol) in THF (20.0 mL) and H2O (2.00 mL) at room temperature and stirred over night. Upon the completion of the reaction, the mixture was concentrated to about 5 mL under vacuum and diluted with 20 mL of ethyl ether. A 1.00 N HCl solution is added (15.0 mL). The organic phase was separated from aqueous phase, and washed again with 1 N HCl solution (15.0 mL). Aqueous phases were collected and adjusted to pH = 10 using 3.00 M NaOH solution. The mixture was extracted with EtOAc (3 x 20.0 mL), brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum to afford 911 mg (5.52 mmol, 92.0 %) product as a light yellow oil 197  without request for further purification. 1H (acetone-d6): 7.18-7.09 (m, 2H); 6.92 (d, J = 7.9, 1H); 6.84 (td, J = 7.3, 0.7, 1H); 3.81 (s, 3H); 3.18 (t, J = 7.1, 2H); 2.66 (t, J = 7.5, 2H); 1.931.71 (m, 4H).  13  C (acetone-d6): 157.7; 130.6; 129.7; 127.0; 120.3; 110.4; 54.8; 50.8; 31.1;  28.0. HRMS: calc. for C10H15NO [M + H]+ 166.1232; found 166.1234. IR: 2920.  D.6.7 Preparation of N-(3-(2-methoxyphenyl)propyl)methanesulfonamide (251) NHMs OMe  [known compound, see ref: Tetrahedron Letters, 36(6), 913-14; 1995] Methanesulfonyl chloride (0.557 mL, 7.20 mmol) and triethylamine  (1.15 mL, 8.28 mmol) was slowly added over a period of 10 min to a solution of 250 (911 mg, 5.52 mmol) in DCM (20.0 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 20.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 1.28 g (5.29 mmol, 96.0 %) product as a colorless oil. 1H (acetone-d6): 7.22-7.15 (m, 2H); 6.98-6.91 (m, 1H); 6.90-6.83 (m, 1H); 5.97 (br, 1H); 3.83 (s, 3H); 3.13 (q, J = 6.9, 2H); 2.91 (s, 3H); 2.10 (t, J = 7.7, 2H); 1.85 (p, J = 7.2, 2H). 13C (acetone-d6): 157.5; 129.7; 129.6; 127.3; 120.3; 110.4; 54.7; 42.7; 38.8; 30.2; 27.1. HRMS: calc. for C11H17NO3S [M + Na]+ 266.0827; found 266.0828. IR: 3287; 2936; 1318.  198  D.6.8 Preparation of N-(3-(2-hydroxyphenyl)propyl)methanesulfonamide (252) NHMs OH  Method A: 1 M BBr3 in DCM solution (15.8 mL, 15.8 mmol) was slowly added over a period of 30 min to a solution of 251 (1.28 g,  5.29 mmol) in DCM (30.0 mL) at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C and transferred into 250 mL R.B. flask which filled with ice and aq. sat. NaHCO3 solution (50.0 mL). The reaction mixture was extracted with EtOAc (3 x 30.0 mL), washed with brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 1.08 g (4.71 mmol, 89.0 %) product as a light yellow oil. Method B: 1 M TBAF in THF solution (3.14 mL, 3.14 mmol) was added to a solution of 255 (976 mg, 2.85 mmol) in THF (4.00 mL) at 0 °C and with good stirring. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 12.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 626 mg (2.74 mmol, 96.0 %) product as a light yellow oil. 1H (acetone-d6): 8.23 (s, 1H); 7.16-7.11 (m, 1H); 7.07-6.99 (m, 1H); 6.87-6.74 (m, 2H); 5.96 (br, 1H); 3.14 (q, J = 6.3, 2H); 2.91 (s, 3H); 2.71 (t, J = 7.5, 2H); 1.89 (p, J = 7.5, 2H). 13C (acetone-d6):154.9; 130.1; 127.7; 127.0; 119.6; 114.9; 42.7; 38.9; 30.1; 27.0. HRMS: calc. for C10H15NO3S [M + Na]+ 252.0670; found 252.0663. IR: 3299.  199  D.6.9 Preparation of (2-(3-azidopropyl)phenoxy)(tert-butyl)dimethylsilane (253) N3  t-Butyldimethylsilyl chloride (4.01 g, 26.6 mmol) and imidazole (2.26 g, 33.3 mmol) was added to a solution of 249b (3.93 g, 22.2 mmol) in DMF  OTBS  (25.0 mL) at room temperature and with good stirring. Upon the completion of the reaction, the mixture neutralized with aq. sat. NH4Cl (10.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 4) gave 6.07 g (20.9 mmol, 94.0 %) product as a light yellow oil. 1H (acetone-d6): 7.18 (dd, J = 7.4, 1.6, 1H); 7.11 (td, J = 7.6, 1.9, 1H); 6.94-6.85 (m, 2H); 3.37 (t, J = 6.8, 2H); 2.71 (t, J = 7.7, 2H); 1.88 (p, J = 7.1, 2H); 1.06 (s, 9H); 0.28 (s, 6H).  13  C (acetone-d6): 153.5; 131.5; 130.3; 127.2;  121.2; 118.5; 50.9; 29.2; 27.6; 25.3; 18.0; -4.8. ESI: [M - N2 + H]+ 264.2. IR: 2096.  D.6.10 Preparation of 3-(2-(tert-butyldimethylsilyloxy)phenyl)propan-1-amine (254) NH2 OTBS  Palladium, 10 wt % on activated carbon (1.11 g, 1.05 mmol, 5.00 mol %) was added slowly to a solution of 253 (6.07 g, 20.9 mmol) in  EtOH (50.0 mL) under argon. Hydrogen was bubbled through the reaction mixture for 30 min with good stirring. The reaction was stirred at room temperature overnight. Upon the completion of the reaction, the mixture was filtered over Celite twice using EtOAc (100 mL). The crude product was concentrated and dried over high vacuum to give 4.82 g (18.2 mmol, 87.0 %) product as a light yellow oil without further purification. 1H (acetone-d6): 7.17 (dd, J = 7.5, 1.8, 1H); 7.07 (td, J = 7.7, 1.8, 1H); 6.91-6.81 (m, 2H); 3.22 (t, J = 6.8, 2H); 2.68 (t, J = 8.3, 2H); 1.94-1.77 (m, 4H); 1.05 (s, 9H); 0.26 (s, 6H). 13C (acetone-d6): 153.5; 132.9;  200  130.1; 126.6; 121.1; 118.5; 50.7; 31.4; 28.3; 25.4; 17.9; -4.9. HRMS: calc. for C15H28NOSi [M + H]+ 266.1940; found 266.1934. IR: 2930; 1253.  D.6.11 Preparation of compound 255 NHMs  Methanesulfonyl chloride (0.466 mL, 6.00 mmol) and triethylamine (1.04 mL, 7.50 mmol) was slowly added over a period of 30 min to a  OTBS  solution of 254 (1.33 g, 5.00 mmol) in DCM (6.00 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 20.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (15.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 1.65 g (4.80 mmol, 96.0 %) product as a light yellow oil. 1H (acetone-d6): 7.21 (dd, J = 7.4, 1.7, 1H); 7.10 (td, J = 7.7, 1.8, 1H); 6.93-6.84 (m, 2H); 3.14 (q, J = 7.1, 2H); 2.89 (s, 3H); 2.70 (t, J = 7.8, 2H); 1.88 (p, J = 7.5, 2H); 1.05 (s, 9H); 0.27 (s, 6H). 13C (acetone-d6): 153.5; 131.9; 130.2; 127.0; 121.2; 118.6; 42.8; 38.8; 30.5; 27.5; 25.4; 17.9; -4.8. HRMS: calc. for C16H29NO3SiS [M + Na]+ 366.1535; found 366.1525. IR: 3289; 2930; 1491.  D.6.12 Preparation of N-(3-(2-(tert-butyldimethylsilyloxy)phenyl)propyl)-2-nitro benzenesulfonamide (256) NHNs OTBS  2-Nitrobenzenesulfonyl  chloride  (1.11  g,  5.03  mmol)  and  triethylamine (0.826 mL, 5.94 mmol) was slowly added over a period  of 10 min to a solution of 254 (1.21 g, 4.57 mmol) in DCM (6.00 mL) at 0 °C and with good 201  stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 15.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 8.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 4) gave 1.95 g (4.34 mmol, 95.0 %) product as a light yellow oil. 1H (acetone-d6): 8.138.07 (m, 1H); 7.99-7.87 (m, 3H); 7.13-7.05 (m, 2H); 6.91-6.82 (m, 2H); 6.66 (t, J = 5, 1H); 3.16 (q, J = 7.2, 2H); 2.65 (t, J = 7.6, 2H); 1.85 (p, J = 7.3, 2H); 1.01 (s, 9H); 0.24 (s, 6H). 13  C (acetone-d6): 153.4; 148.3; 133.9; 133.5; 132.5; 131.7; 130.4; 130.2; 127.1; 124.8; 121.2;  118.5; 43.1; 30.1; 27.4; 25.3; 17.9; -4.9. HRMS: calc. for C21H30N2O5SiS [M + Na]+ 473.1542; found 473.1537. IR: 3421; 2930; 1541.  D.6.13 Preparation of N-(3-(2-hydroxyphenyl)propyl)-2-nitrobenzenesulfonamide (257) NHNs OH  1 M TBAF in THF solution (1.30 mL, 1.30 mmol) was added to a solution of 256 (533 mg, 1.18 mmol) in THF (5.00 mL) at 0 °C and  with good stirring. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 377 mg (1.12 mmol, 95.0 %) product as a colorless foam. 1H (acetone-d6): 8.26 (s, 1H); 8.14-8.07 (m, 1H); 7.96-7.83 (m, 3H); 7.07-6.97 (m, 2H); 6.86-6.79 (m, 1H); 6.74 (td, J = 7.4, 1.1, 1H); 6.66 (t, J = 6, 1H); 3.17 (q, J = 6.5, 2H); 2.66 (t, J = 7.5, 2H); 1.85 (p, J = 7.2, 2H).  13  C (acetone-d6): 154.9; 202  148.3; 133.9; 133.6; 130.4; 130.1; 127.5; 127.1; 124.8; 119.7; 114.9; 43.1; 29.8; 26.8. HRMS: calc. for C15H16N2O5S [M + Na]+ 359.0678; found 359.0666. IR: 3342; 1540.  D.6.14 Preparation of 1-(allyloxy)-4-bromobenzene (259) O  [known compound see reference: Moria, A.; Mizusakia, T.; Miyakawaa, Y.; Ohashia, E.; Hagaa, T.; Maegawaa, T.; Monguchia, Y.; Sajiki, H. Tetrahedron  Br  2006, 62, 11925.] 1H: 7.39 (d, J = 8.9, 2H); 6.82 (d, J = 8.9, 2H); 6.12-6.00 (m,  1H); 5.44 (dd, J = 17.3, 1.6, 1H); 5.33 (dd, J = 10.5, 1.6, 1H); 4.50 (d, J = 5.3, 2H).  13  C:  158.8; 134.0; 133.3; 118.8; 117.6; 114.0; 69.9. HREI: calc. for C9H9O81Br 213.98163; found 213.98155; calc. for C9H9O79Br 211.98368; found 211.98357. IR: 1488.  D.6.15 Preparation of 2-allyl-4-bromophenol (260) OH  [known compound, see reference: Kurosawa, W.; Kobayashi, H.; Kan, T.; Fukuyama, T. Tetrahedron 2004, 60, 9615.] 1-(Allyloxy)-4-bromobenzene  Br  (1.00 g, 4.74 mmol) was dissolved in diethyl aniline (4.50 mL). The reaction  mixture was heated to 220 °C overnight. Upon the completion of the reaction, the mixture was cooled to room temperature, diluted with EtOAc (20.0 mL). The organic layer was sequentially washed with 2.00 N HCl solution (3 x 10.0 mL), brine (15.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (DCM / hexanes = 1 / 1) gave 840 mg (3.98 mmol, 84.0 %) product as a colorless needle-like solid, m.p. 58.5-59 oC. 1H: 7.25-7.20 (m, 2H); 6.69 (d, J = 8.7, 1H); 6.04-5.92 (m, 1H); 5.22-5.13 (m, 2H); 5.05 (s, 1H); 3.37 (d, J = 6.2, 2H).  13  C:  154.1; 136.6; 134.0; 131.6; 129.0; 118.6; 118.2; 114.0; 35.7. HREI: calc. for C9H9O79Br 211.98368; found 211.98400. IR: 3463; 1493. 203  D.6.16 Preparation of (2-allyl-4-bromophenoxy)(tert-butyl)dimethylsilane (261) OTBS  t-Butyldimethylsilyl chloride (522 mg, 3.46 mmol) and imidazole (321 mg, 4.73 mmol) was added to a solution of 260 (664 mg, 3.15 mmol) in DMF  Br  (3.00 mL) at room temperature and with good stirring. Upon the completion  of the reaction, the mixture neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 8.0 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (100 % hexanes) gave 996 mg (3.06 mmol, 97.0 %) product as a colorless oil. 1H: 7.29 (d, J = 2.5, 1H); 7.22 (dd, J = 8.5, 2.5, 1H); 6.71 (d, J = 8.5, 1H); 6.05-5.89 (m, 1H); 5.15-5.05 (m, 2H); 3.37 (d, J = 6.6, 2H); 1.05 (s, 9H); 0.27 (s, 6H). 13C: 153.6; 137.1; 134.1; 133.9; 130.8; 121.1; 117.3; 114.4; 35.3; 26.8; 19.3; -3.1. HRMS: calc. for C15H23OSi79Br [M + H]+ 327.0780; found 327.0769. IR: 3418; 2930; 1484.  D.6.17 Preparation of 3-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)propan-1-ol (262) OTBS  OH  1 M BH3-THF complex in THF (10.0 mL, 10.0 mmol) was slowly added to a solution of 261 (1.63 g, 5.00 mmol) in THF (10.0 mL) at 0 °C and  Br  stirred for 2 h. Hydrogen peroxide, 30 % aq. solution (10.0 mL) and aq. sat.  NaHCO3 solution (10.0 mL) was added slowly to the reaction mixture at 0 °C and stirred overnight. Upon the completion of the reaction, the mixture was neutralized with aq. sat. NH4Cl (15.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (2 x 10.0 mL), brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the 204  residue (EtOAc / hexanes = 15 / 85) gave 1.43 g (4.15 mmol, 83.0 %) product as a light yellow oil. 1H: 7.24 (s, 1H); 7.17 (dd, J = 8.5, 2.5, 1H); 6.66 (d, J = 8.5, 1H); 3.63 (t, J = 6.4, 2H); 2.65 (t, J = 7.5, 2H); 1.89-1.77 (m, 2H); 1.01 (s, 9H); 0.23 (s, 6H). 13C: 152.7; 134.7; 132.9; 129.6; 120.2; 113.4; 62.1; 32.7; 26.4; 25.7; 18.3; -4.2. HREI: calc. for C15H25O2Si79Br 344.08072; found 344.08051; calc. for C15H25O2Si81Br 346.07867; found 346.07845. IR: 3300; 2932; 1485.  D.6.18 Preparation of 3-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)propyl methane sulfonate (263) Methanesulfonyl chloride (0.142 mL, 1.82 mmol) and triethylamine  OTBS OMs Br  (0.317 mL, 2.28 mmol) was slowly added over a period of 5 min to a solution of 262 (523 mg, 1.52 mmol) in DCM (3.00 mL) at -20 °C and  with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (1.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (5.00 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 4) gave 616 mg (1.46 mmol, 96.0 %) product as a light yellow oil. 1H: 7.24 (s, 1H); 7.19 (dd, J = 8.5, 2.6, 1H); 6.67 (d, J = 8.5, 1H); 4.22 (t, J = 6.5, 2H); 3.00 (s, 3H); 2.68 (t, J = 7.5, 2H); 2.08-1.97 (m, 2H); 1.00 (s, 9H); 0.23 (s, 6H).  13  C: 152.8; 133.3; 132.9; 130.1;  120.1; 113.2; 69.2; 37.4; 28.9; 26.7; 25.7; 18.2; -4.2. HRMS: calc. for C16H27O4SiS79Br [M + Na]+ 445.0480; found 344.0491. IR: 2930; 1485; 1176.  205  D.6.19 Preparation of (2-(3-azidopropyl)-4-bromophenoxy)(tert-butyl)dimethylsilane (264) Sodium azide (219 mg, 3.38 mmol) was slowly added to a solution of  OTBS N3 Br  263 (713 mg, 1.69 mmol) in DMF (10.0 mL) and H2O (5.00 mL) at room temperature and with good stirring. Then reaction mixture was  warmed to 60 °C and stirred over night. Upon the completion of the reaction, the mixture was cooled to room temperature, extracted with EtOAc (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (DCM / hexanes = 1 / 3) gave 592 mg (1.61 mmol, 95.0 %) product as a yellow oil. 1H: 7.24 (s, 1H); 7.19 (dd, J = 8.5, 2.4, 1H); 6.67 (d, J = 8.5, 1H); 3.29 (t, J = 6.8, 2H); 2.63 (t, J = 7.5, 2H); 1.93-1.80 (m, 2H); 1.02 (s, 9H); 0.24 (s, 6H). 13C: 152.8; 133.8; 132.8; 129.9; 120.1; 113.2; 50.9; 28.9; 27.6; 25.7; 18.2; -4.2. LRESI: [M - N2 + H]+ 344.1; 342.1. IR: 2930; 2096; 1486.  D.6.20 Preparation of N-(3-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)propyl) methanesulfonamide (265) 1 M PMe3 solution in THF (7.90 mL, 7.90 mmol) was slowly added  OTBS NHMs Br  to a solution of 264 (1.46 g, 3.95 mmol) in THF (20.0 mL) and H2O (10.0 mL) at room temperature and stirred for 6 h. Upon the  completion of the reaction, the mixture was evaporated to dryness under reduced pressure and diluted with EtOAc (20.0 mL). The organic layer was sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum to carry on next step without further purification. Methanesulfonyl chloride (0.368 mL, 4.74 mmol) and triethylamine (0.824 mL, 5.92 mmol) 206  was slowly added over a period of 10 min to a solution of crude product in DCM (10.0 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (4.00 mL) and extracted with EtOAc (3 x 15.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (15.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 1.43 g (3.40 mmol, 86.0 %) product as a light yellow oil. 1H: 7.24 (s, 1H); 7.18 (dd, J = 8.5, 2.6, 1H); 6.66 (d, J = 8.5, 1H); 4.63 (t, J = 5.8, 1H); 3.11 (q, J = 6.6, 2H); 2.93 (s, 3H); 2.63 (t, J = 7.2; 2H); 1.85 (p, J = 7.4, 2H); 1.00 (s, 9H); 0.23 (s, 6H). 13C: 152.7; 133.7; 132.8; 129.9; 120.2; 113.4; 42.6; 40.2; 30.0; 27.2; 25.7; 18.2; -4.2. HRMS: calc. for C16H28NO3SiS79Br [M + Na]+ 444.0640; found 444.0629. IR: 3290; 2931; 1495.  D.6.21 Preparation of N-(3-(5-bromo-2-hydroxyphenyl)propyl)methanesulfonamide (266) 1 M TBAF in THF solution (0.800 mL, 0.800 mmol) was added to a  OH NHMs Br  solution of 265 (306 mg, 0.730 mmol) in THF (5.00 mL) at 0 °C and with good stirring. Upon the completion of the reaction, the mixture  was cooled to 0 °C, neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 224 mg (0.690 mmol, 94.0 %) product as a light yellow oil. 1H (acetone-d6): 8.61 (s, 1H); 7.31 (s, 207  1H); 7.18 (dd, J = 8.5, 2.5, 1H); 6.81 (d, J = 8.5, 1H); 6.00 (br, 1H); 3.15 (q, J = 6.5, 2H); 2.92 (s, 3H); 2.71 (t, J = 7.6, 2H); 1.88 (p, J = 7.3, 2H). 13C (acetone-d6): 154.4; 132.6; 130.7; 129.6; 116.9; 110.9; 42.6; 38.9; 29.9; 26.8. HRMS: calc. for C10H14NO3S79Br [M + Na]+ 329.9775; found 329.9776. IR: 3296; 1311.  D.6.22 Preparation of 6-methylchroman-2-one (268) [known compound, see ref: Journal of Organic Chemistry, 74(4), 1759O  1762; 2009] Palladium, 10 wt % on activated carbon (3.21 g, 3.03 mmol,  O  5.00 mol %) was added slowly to a solution of compound 6-methyl coumarin (267) (9.70 g, 60.6 mmol) in EtOAc (60.0 mL) under Ar. The reaction flask was stirred under hydrogen atmosphere for 2 d. Upon the completion of the reaction, the mixture was filtered over Celite twice using EtOAc (50.0 mL). The crude product was concentrated and dried over high vacuum, filtered through a short silica pad using pure EtOAc to give 9.40 g (58.2 mmol, 96.0 %) product as a light yellow oil without the request for further purification. 1H: 7.05 (dd, J = 8.1, 1.8, 1H); 6.99 (s, 1H); 6.93 (d, J = 8.1, 1H); 3.00-2.91 (m, 2H); 2.80-2.72 (m, 2H); 2.32 (s, 3H).  13  C: 168.8; 149.9; 133.9; 128.7; 128.5; 122.3; 116.6; 29.3; 23.7; 20.7.  HRMS: calc. for C10H10O2 [M + Na]+ 185.0578; found 185.0574. IR: 3415; 1744.  D.6.23 Preparation of 3-(2-hydroxy-5-methylphenyl)propanamide (269) [known compound, see ref: Synthesis,  O NH2 OH  (11), 1607-1610; 2002]  Ammonia gas was bubbled through a solution of 268 (1.00 g, 6.17 mmol) in DCM (20.0 mL) for 20 min at room temperature. Then the  reaction mixture was stirred overnight at the same temperature. Upon the completion of the reaction, the mixture was evaporated to dryness. Chromatography of the residue (EtOAc / 208  hexanes = 3 / 1) gave 1.07 g (5.98 mmol, 97.0 %) product as a colorless foam. 1H: 6.92 (dd, J = 8.1, 2.1, 1H); 6.86 (d, J = 2.1, 1H); 6.80 (d, J = 8.1, 1H); 5.72 (br, 1H); 5.60 (br, 1H); 2.90-2.83 (m, 2H); 2.68-2.61 (m, 2H); 2.25 (s, 3H). 13C: 176.7; 152.4; 130.9; 129.6; 128.6; 127.4; 117.6; 36.5; 24.4; 20.5. HRMS: calc. for C10H13NO2 [M + Na]+ 202.0844; found 202.0849. IR: 3445; 3199; 1655.  D.6.24 Preparation of 3-(2-(tert-butyldimethylsilyloxy)-5-methylphenyl)propanamide (270) t-Butyldimethylsilyl chloride (582 mg, 3.88 mmol) and imidazole  O NH2 OTBS  (312 mg, 4.59 mmol) was added to a solution of 269 (631 mg, 3.53 mmol) in DMF (3.00 mL) at room temperature and with good  stirring. Upon the completion of the reaction, the mixture was neutralized with aq. sat. NH4Cl (10.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 8.00 mL), brine (3 x 8.00 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 962 mg (3.28 mmol, 93.0 %) product as a colorless oil. 1H: 6.95 (d, J = 2.1, 1H); 6.87 (dd, J = 8.2, 2.1, 1H); 6.68 (d, J = 8.1, 1H); 6.28 (br, 1H); 5.75 (br, 1H); 2.87 (t, J = 7.6, 2H); 2.49 (t, J = 7.6, 2H); 2.23 (s, 3H); 1.01 (s, 9H); 0.23 (s, 6H). 13C: 175.5; 151.1; 130.9; 130.8; 130.5; 127.7; 118.4; 36.1; 26.5; 25.8; 20.6; 18.2; -4.1. HRMS: calc. for C16H27NO2Si [M + Na]+ 316.1709; found 316.1706. IR: 3193; 2929; 1666.  209  D.6.25 Preparation of N-(3-(2-(tert-butyldimethylsilyloxy)-5-methylphenyl)propyl) methanesulfonamide (271) NHMs  Lithium aluminum hydride powder (272 mg, 7.16 mmol) was slowly added over a period of 5 min to a solution of 270 (1.05 g,  OTBS  3.58 mmol) in THF (20.0 mL) at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. The progress of the reaction was monitored by 1H NMR. Upon the completion of the reaction, the mixture was cooled to 0 °C. H2O (0.270 mL), 15 % NaOH (0.270 mL) solution, H2O (0.820 mL) and appropriate amount of drying reagent (MgSO4) was sequentially added in the interval of 20 min with vigorous stirring. The resulting suspension solution was warmed to room temperature and filtered through Celite using EtOAc (3 x 30.0 mL). The crude product was concentrated and dried over high vacuum to carry on next step without further purification. Methanesulfonyl chloride (0.334 mL, 4.30 mmol) and triethylamine (0.747 mL, 5.37 mmol) was slowly added over a period of 10 min to a solution of crude product in DCM (8.00 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (2.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 1.11 g (3.11 mmol, 87.0 % over 2 steps) product as a light yellow oil. 1H: 6.93 (d, J = 2.0, 1H); 6.88 (dd, J = 8.1, 2.0, 1H); 6.69 (d, J = 8.1, 1H); 4.58 (t, J = 6.1, 1H); 3.10 (q, J = 6.6, 2H); 2.90 (s, 3H); 2.64 (t, J = 7.3, 2H); 2.26 (s, 3H); 1.86 (p, J = 7.3, 2H); 1.01 (s, 9H); 0.23 (s, 6H).  13  C: 151.2; 130.94; 130.93; 130.4; 127.6; 118.4; 42.8; 40.0; 30.2; 27.4; 210  25.8; 20.6; 18.3; -4.1. HRMS: calc. for C17H31NO3SiS [M + Na]+ 380.1692; found 380.1679. IR: 3289; 2930; 1322.  D.6.26 Preparation of compound 272 NHMs OH  1 M TBAF in THF solution (0.950 mL, 0.950 mmol) was added to a solution of 271 (308 mg, 0.860 mmol) in THF (8.00 mL) at 0 °C  and with good stirring. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 15.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 192 mg (0.790 mmol, 92.0 %) product as a light yellow oil. 1H (acetone-d6): 8.01 (s, 1H); 6.95 (d, J = 2.0, 1H); 6.83 (dd, J = 8.1, 2.0, 1H); 6.72 (d, J = 8.0, 1H); 5.95 (br, 1H); 3.13 (q, J = 6.8, 2H); 2.90 (s, 3H); 2.67 (t, J = 7.3, 2H); 2.20 (s, 3H); 1.87 (p, J = 7.3, 2H).  13  C (acetone-d6): 152.7; 130.7; 128.2;  127.4; 127.3; 114.8; 42.7; 38.8; 30.2; 27.0; 19.6. HRMS: calc. for C11H17NO3S [M + Na]+ 266.0827; found 266.0828. IR: 3301; 2931; 1510.  D.7 General procedures for IMOA of ortho phenols (methods A and B, Table 15) Method A: substrate (1.00 eq.) in toluene and MeCN (v / v, 10 : 1) was added slowly in a solution of (diacetoxy)iodobenzene (1.10 eq.) and TFA (1.50 eq.) in toluene and MeCN (v / v, 10 : 1) via syringe pump at -78 °C with a final concentration of [C] = 10.0 mM / substrate. When the addition was complete, the reaction mixture was stirred at -78 °C for 30 min and then warmed to room temperature slowly. Upon the completion of the reaction, the 211  crude product was evaporated to dryness under reduced pressure. Chromatography of the residue gave the corresponding product.  Method B: (Diacetoxy)iodobenzene (1.10 eq.) was added slowly in a TFA ([C] = 0.300 M) solution of phenolic compound (1.00 eq.) at room temperature. Upon the completion of the reaction, the crude product was evaporated to dryness under reduced pressure. Chromatography of the residue afforded the corresponding spirocyclization product.  D.7.1 Characterization of compound 275, X = H 59 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 2 / 1), 1H: NMs  7.01 (ddd, J = 9.8, 5.8, 1.7, 1H); 6.55 (ddd, J = 9.6, 1.7, 0.8, 1H); 6.16 (ddd, J  O  = 9.6, 5.8, 1.0, 1H); 6.05 (dt, J = 9.8, 0.8, 1H); 3.78-3.57 (m, 2H); 2.96 (s, 3H);  2.27-1.97 (m, 4H).  13  C: 201.6; 146.1; 142.0; 124.9; 119.8; 73.2; 49.4; 39.7; 39.5; 22.8.  HRMS: calc. for C10H13NO3S [M + Na]+ 250.0514; found 250.0512. IR: 1655; 1318; 1147.  D.7.2 Characterization of compound 275, X = Br 30 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H: Br  NMs O  7.00 (dd, J = 10.1, 2.4, 1H); 6.74 (dd, J = 2.4, 0.4, 1H); 6.01 (dd, J = 10.1, 0.4, 1H); 3.76-3.55 (m, 2H); 2.96 (s, 3H); 2.27-2.02 (m, 4H). 13C: 199.1;  145.5; 144.0; 125.8; 112.9; 73.9; 49.1; 39.79; 39.76; 23.1. HRMS: calc. for C10H12NO3S79Br [M + Na]+ 327.9619; found 327.9611. IR: 1621.  212  D.7.3 Characterization of compound 275, X = Me 51 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H: NMs O  6.86 (dd, J = 9.8, 2.2, 1H); 6.23-6.20 (m, 1H); 6.02 (d, J = 9.8, 1H); 3.763.55 (m, 2H); 2.95 (s, 3H); 2.25-1.98 (m, 4H); 1.95 (d, J = 1.6, 3H).  13  C:  201.5; 146.3; 140.0; 127.6; 124.4; 72.4; 49.2; 40.0; 39.6; 22.9; 20.8. HRMS: calc. for C11H15NO3S [M + Na]+ 264.0670; found 264.0675. IR: 1677; 1321.  213  D.8 Proton and carbon-13 spectra for IMOA intermediates  OH HO  OH HO  Figure 47. NMR spectra of compound 197  214  OMs MsO  OMs MsO  Figure 48. NMR spectra of compound 198  215  N3 MsO  N3 MsO  Figure 49. NMR spectra of compound 199  216  NH2 MsO  NH2 MsO  Figure 50. NMR spectra of compound 200  217  NHMs MsO  NHMs MsO  Figure 51. NMR spectra of compound 201, R = Me  218  MsO  MsO  O O S N CF3 H  O O S N CF3 H  Figure 52. NMR spectra of compound 201, R = CF3  219  MsO  MsO  O O S N H  O O S N H  Figure 53. NMR spectra of compound 201, R = cyclopropyl  220  MsO  MsO  O O S N H  O O S N H  Figure 54. NMR spectra of compound 201, R = Bn  221  MsO  MsO  O O S N H  SO2Me  O O S N H  SO2Me  Figure 55. NMR spectra of compound 201, R = CH2SO2Me  222  NHTs MsO  NHTs MsO  Figure 56. NMR spectra of compound 201, R = PhMe  223  NHNs(2-) MsO  NHNs(2-) MsO  Figure 57. NMR spectra of compound 201, R = 2-NO2Ph  224  NHNs(3-) MsO  NHNs(3-) MsO  Figure 58. NMR spectra of compound 201, R = 3-NO2Ph  225  NHNs(4-) MsO  NHNs(4-) MsO  Figure 59. NMR spectra of compound 201, R = 4-NO2Ph  226  MsO  MsO  O O S N H  O O S N H  Br  Br  Figure 60. NMR spectra of compound 201, R = 4-BrPh  227  MsO  MsO  O O S N H  O O S N H  OMe  OMe  Figure 61. NMR spectra of compound 201, R = 4-OMePh  228  MsO  MsO  O O S N H  O O S N H  Figure 62. NMR spectra of compound 201, R = 2,4,6-triisopropylphenyl  229  O O S S N H  MsO  MsO  O O S S N H  Figure 63. NMR spectra of compound 201, R = 2-thienyl  230  MsO  MsO  NHMs NHTs  NHMs NHTs  Figure 64. NMR spectra of compound 223, R = Me  231  MsO  NHTs NHTs  MsO  NHTs NHTs  Figure 65. NMR spectra of compound 223, R = PhMe  232  NHMs HO  NHMs HO  Figure 66. NMR spectra of compound 202, R = Me  233  HO  HO  O O S N CF3 H  O O S N CF3 H  Figure 67. NMR spectra of compound 202, R = CF3  234  HO  HO  N H  O2 S  N H  O2 S  Figure 68. NMR spectra of compound 202, R = cyclopropyl  235  HO  HO  O O S N H  O O S N H  Figure 69. NMR spectra of compound 202, R = Bn  236  HO  HO  O O S N H  O O S N H  SO2Me  SO2Me  Figure 70. NMR spectra of compound 202, R = CH2SO2Me  237  NHTs HO  NHTs HO  Figure 71. NMR spectra of compound 232, R = 4-Me  238  NHNs(2-) HO  NHNs(2-) HO  Figure 72. NMR spectra of compound 232, R = 2-NO2  239  NHNs(3-) HO  NHNs(3-) HO  Figure 73. NMR spectra of compound 232, R = 3-NO2  240  NHNs(4-) HO  NHNs(4-) HO  Figure 74. NMR spectra of compound 232, R = 4-NO2  241  HO  HO  O O S N H  O O S N H  Br  Br  Figure 75. NMR spectra of compound 232, R = 4-Br  242  O O S N H  HO  HO  OMe  O O S N H  OMe  Figure 76. NMR spectra of compound 232, R = 4-OMe  243  HO  HO  O O S N H  O O S N H  Figure 77. NMR spectra of compound 232, R = 2,4,6-triisopropyl  244  HO  HO  NHMs NHTs  NHMs NHTs  Figure 78. NMR spectra of compound 224, R = Me  245  HO  HO  NHTs NHTs  NHTs NHTs  Figure 79. NMR spectra of compound 224, R = PhMe  246  O O S S N H  HO  HO  O O S S N H  Figure 80. NMR spectra of compound 234, Z = H, R = SO2-2-thienyl  247  TBSO  TBSO  O O S N H  O O S N H  O  O  Figure 81. NMR spectra of TBS analog of 121  248  HO  HO  O O S N H  O  O O S N H  O  Figure 82. NMR spectra of compound 232, R = 4-C(O)CH3  249  MsO  MsO  N H  N H  O S  O S  Figure 83. NMR spectra of compound 216  250  MsO  MsO  O S N H O  O S N H O  Figure 84. NMR spectra of compound 217  251  HO  HO  N H  N H  O S  O S  Figure 85. NMR spectra of sulfinamide analog of compound 218  252  HO  HO  O S N O H  O S N H O  Figure 86. NMR spectra of compound 218  253  I  NHMs  HO I  I  NHMs  HO I  Figure 87. NMR spectra of compound 220  254  OMe NHMs AcO  OMe NHMs AcO  Figure 88. NMR spectra of compound 226  255  OMe NHMs HO  OMe NHMs HO  Figure 89. NMR spectra of compound 227  256  H  O NHMs  HO  H  O NHMs  HO  Figure 90. NMR spectra of compound 229  257  HO  HO  O OMe P N H OMe  O OMe P N H OMe  Figure 91. NMR spectra of compound 240  258  O  N Ms  O  N Ms  Figure 92. NMR spectra of compound 231, R = Me  259  O  O  N O S O CF3  N O S O CF3  Figure 93. NMR spectra of compound 231, R = CF3  260  O  N O S O  O  N O S O  Figure 94. NMR spectra of compound 231, R = tBu  261  O  O  N O S O  N O S O  Figure 95. NMR spectra of compound 231, R = cyclopropyl  262  O  O  N SO2Bn  N SO2Bn  Figure 96. NMR spectra of compound 231, R = Bn  263  O  N O  O  N O  S Ms O  S Ms O  Figure 97. NMR spectra of compound 231, R = CH2SO2Me  264  O  O  N Ts  N Ts  Figure 98. NMR spectra of compound 233, R = 4-Me  265  O  O  N Ns(2-)  N Ns(2-)  Figure 99. NMR spectra of compound 233, R = 2-NO2  266  O  O  N Ns(3-)  N Ns(3-)  Figure 100. NMR spectra of compound 233, R = 3-NO2  267  O  O  N Ns(4-)  N Ns(4-)  Figure 101. NMR spectra of compound 233, R = 4-NO2  268  O  N O S O  Br  O  N O S O  Br  Figure 102. NMR spectra of compound 233, R = 4-Br  269  O  N O S O  CN  O  N O S O  CN  Figure 103. NMR spectra of compound 233, R = 4-CN  270  O  N O S O  O  O  N O S O  O  Figure 104. NMR spectra of compound 233, R = 4- C(O)CH3  271  O  N O S O  OMe  O  N O S O  OMe  Figure 105. NMR spectra of compound 233, R = 4-OMe  272  O  O  N O S O  N O S O  Figure 106. NMR spectra of compound 233, R = 2,4,6-triisopropyl  273  O  N O S O S  O  N O S O S  Figure 107. NMR spectra of compound 235, Z = H, R = SO2-2-thienyl  274  I O  N Ms  I  I O I  N Ms  Figure 108. NMR spectra of compound 235, Z = I, R = Ms  275  OH N Ms  O  OH O  N Ms  Figure 109. NMR spectra of compound 237, R = CH2OH  276  OMe O  N Ms  OMe O  N Ms  Figure 110. NMR spectra of compound 237, R = CH2OMe  277  O  O  N Ms  N Ms  O H  O H  Figure 111. NMR spectra of compound 237, R = CHO  278  NHTs O N Ms  NHTs O N Ms  Figure 112. NMR spectra of compound 238, R = Me  279  NHTs  O N Ts  NHTs  O N Ts  Figure 113. NMR spectra of compound 238, R = PhMe  280  O  N P O MeO OMe  O  N P O MeO OMe  Figure 114. NMR spectra of compound 241  281  OH OMe  OH OMe  Figure 115. NMR spectra of compound 246  282  OMs OMe  OMs OMe  Figure 116. NMR spectra of compound 247  283  Br OH  Br OH  Figure 117. NMR spectra of compound 248  284  N3 OMe  N3 OMe  Figure 118. NMR spectra of compound 249a  285  N3 OH  N3 OH  Figure 119. NMR spectra of compound 249b  286  NH2 OMe  NH2 OMe  Figure 120. NMR spectra of compound 250  287  NHMs OMe  NHMs OMe  Figure 121. NMR spectra of compound 251  288  NHMs OH  NHMs OH  Figure 122. NMR spectra of compound 252  289  N3 OTBS  N3 OTBS  Figure 123. NMR spectra of compound 253  290  NH2 OTBS  NH2 OTBS  Figure 124. NMR spectra of compound 254  291  NHMs OTBS  NHMs OTBS  Figure 125. NMR spectra of compound 255  292  NHNs OTBS  NHNs OTBS  Figure 126. NMR spectra of compound 256  293  NHNs OH  NHNs OH  Figure 127. NMR spectra of compound 257  294  O  Br  O  Br  Figure 128. NMR spectra of compound 259  295  OH  Br  OH  Br  Figure 129. NMR spectra of compound 260  296  OTBS  Br  OTBS  Br  Figure 130. NMR spectra of compound 261  297  OTBS  OH  Br  OTBS  OH  Br  Figure 131. NMR spectra of compound 262  298  OTBS OMs Br  OTBS OMs Br  Figure 132. NMR spectra of compound 263  299  OTBS N3 Br  OTBS N3 Br  Figure 133. NMR spectra of compound 264  300  OTBS NHMs Br  OTBS NHMs Br  Figure 134. NMR spectra of compound 265  301  OH NHMs Br  OH NHMs Br  Figure 135. NMR spectra of compound 266  302  O  O  O  O  Figure 136. NMR spectra of compound 268  303  O NH2 OH  O NH2 OH  Figure 137. NMR spectra of compound 269  304  O NH2 OTBS  O NH2 OTBS  Figure 138. NMR spectra of compound 270  305  NHMs OTBS  NHMs OTBS  Figure 139. NMR spectra of compound 271  306  NHMs OH  NHMs OH  Figure 140. NMR spectra of compound 272  307  NMs O  NMs O  Figure 141. NMR spectra of compound 275, X = H  308  Br  NMs O  Br  NMs O  Figure 142. NMR spectra of compound 275, X = Br  309  NMs O  NMs O  Figure 143. NMR spectra of compound 275, X = Me  310  E. HIMANDRINE EXPERIMENTAL SECTION E.1 Synthesis and characterization of various intermediates for tandem reactions E.1.1 Preparation of N-(3-(2-methoxyphenyl)propyl)ethenesulfonamide (292) O  OMe  N S H O  2-Chloro-1-ethane sulfonyl chloride (0.737 mL, 7.10 mmol) and triethylamine (1.96 mL, 14.1 mmol) was slowly added over a period of 5 min to a solution of 250 (1.08 g, 4.71 mmol) in THF  (20.0 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 20.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 684 mg (2.68 mmol, 57.0 %) product as a yellow oil. 1  H: 7.22-7.13 (m, 2H); 6.94 (d, J = 7.8, 1H); 6.87 (td, J = 7.4, 0.7, 1H); 6.65 (dd, J = 9.9,  6.7, 1H); 6.09 (d, J = 16.7, 1H); 6.10 (br, 1H); 5.94 (d, J = 9.9, 1H); 3.83 (s, 3H); 3.01 (q, J = 6.8, 2H); 2.68 (t, J = 7.4, 2H); 1.84 (p, J = 7.3, 2H). 13C (acetone-d6): 157.6; 137.3; 129.9; 129.7; 127.5; 124.9; 120.4; 110.5; 54.9; 42.7; 30.2; 27.3. HRMS: calc. for C12H17NO3S [M + Na]+ 278.0827; found 278.0829. IR: 3283; 1326; 1150.  E.1.2 Preparation of N-(3-(2-hydroxyphenyl)propyl)ethenesulfonamide (293) O  OH  N S H O  Method A: 1 M BBr3 in DCM solution (5.36 mL, 5.36 mmol) was slowly added over a period of 10 min to a solution of 292 (684 mg, 2.68 mmol) in DCM (10.0 mL) at 0 °C and with good stirring.  Then reaction mixture was warmed to room temperature and stirred for 5 h. Upon the 311  completion of the reaction, the mixture was cooled to 0 °C and transferred into 100 mL R.B. flask which filled with ice and aq. sat. NaHCO3 solution (20.0 mL). The reaction mixture was extracted with EtOAc (3 x 10.0 mL), washed with brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 407 mg (1.69 mmol, 63.0 %) product as a light yellow oil. Method B: HF (70 %) pyridine solution (2.00 mL) was added to a solution of 296 (1.40 g, 3.94 mmol) in THF (10.0 mL) at 0 °C and stirred overnight. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with solid NaHCO3 until no gas coming out. The reaction mixture was filtered over Celite using EtOAc. The filtrate was sequentially washed with aq. sat. NaHCO3 (3 x 15.0 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 817 mg (3.39 mmol, 86.0 %) product as a light yellow oil. 1H (acetone-d6): 8.24 (s, 1H); 7.12 (dd, J = 7.4, 1.6, 1H); 7.03 (td, J = 7.6, 1.5, 1H); 6.83 (dd, J = 7.9, 1.1, 1H); 6.77 (td, J = 7.4, 1.1, 1H); 6.66 (dd, J = 9.9, 6.6, 1H); 6.14 (br, 1H); 6.08 (d, J = 16.5, 1H); 5.94 (d, J = 9.9, 1H); 3.02 (q, J = 7.1, 2H); 2.69 (t, J = 7.8, 1H); 1.88 (p, J = 7.7, 2H).  13  C (acetone-d6): 155.0; 137.2; 130.1; 127.7;  127.0; 124.7; 119.5; 114.9; 42.6; 30.0; 27.0. HRMS: calc. for C11H15NO3S [M + Na]+ 264.0670; found 264.0663. IR: 3452; 2962; 1322; 1142.  E.1.3 Preparation of 2-(3-azidopropyl)phenyl acetate (294) N3 OAc  Cesium carbonate (2.70 g, 8.20 mmol) was added to a solution of 249b (1.32 g, 7.46 mmol) in acetic anhydride (3.00 mL) at room temperature  and with good stirring. Upon the completion of the reaction, the mixture was evaporated to dryness and then diluted with EtOAc (10.0 mL). The crude product was filtered over Celite 312  using EtOAc (15.0 mL). The filtrate was sequentially washed with aq. sat. NaHCO3 (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 5) gave 1.60 g (7.31 mmol, 98.0 %) product as a light yellow oil. 1H (acetone-d6): 7.33 (dd, J = 7.1, 2.1, 1H); 7.29-7.17 (m, 2H); 7.07 (dd, J = 6.1, 1.6, 1H); 3.38 (t, J = 6.7, 2H); 2.65 (t, J = 7.8, 2H); 2.32 (s, 3H); 1.92-1.80 (m, 2H). 13C (acetone-d6): 168.9; 149.3; 133.3; 130.2; 127.2; 125.9; 122.7; 50.6; 29.2; 26.9; 19.9. ESI: [M - N2 + H]+ 192.2. IR: 2936; 2298; 1763.  E.1.4 Preparation of 2-(3-aminopropyl)phenyl acetate (295) NH2 OAc  Palladium, 10 wt % on activated carbon (387 mg, 0.365 mmol, 5.00 mol%) was added to a solution of 294 (1.60 g, 7.31 mmol) in EtOH  (30.0 mL) under Ar. Hydrogen was bubbled through the reaction mixture for 20 min with good stirring. The reaction was stirred at room temperature overnight. Upon the completion of the reaction, the mixture was filtered over Celite twice using EtOAc (70.0 mL in total). The crude product was concentrated and dried over high vacuum to give 1.17 g (6.07 mmol, 83.0 %) product as a light yellow oil without further purification. 1H (acetone-d6): 8.36 (br, 1H); 7.11 (dd, J = 7.4, 1.6, 1H); 7.02 (td, J = 7.4, 1.6, 1H); 6.82 (dd, J = 8.1, 1.2, 1H); 6.75 (td, J = 7.4, 1.3, 1H); 3.20 (q, J = 6.5, 2H); 2.64 (t, J = 7.6, 2H); 1.86 (s, 3H); 1.78 (p, J = 7.2, 2H). 13C (acetone-d6): 169.3; 155.1; 130.0; 128.1; 126.8; 119.4; 115.0; 38.8; 29.9; 27.3; 22.1. HRMS: calc. for C11H15NO2 [M + Na]+ 216.1000; found 216.0999. IR: 3291; 1632.  313  E.1.5 Preparation of N-(3-(2-(tert-butyldimethylsilyloxy)phenyl)propyl) ethane sulfonamide (296) O  OTBS  N S H O  2-Chloro-1-ethane sulfonyl chloride (3.11 mL, 29.7 mmol) and triethylamine (5.51 mL, 39.6 mmol) was slowly added over a period of 10 min to a solution of 254 (5.25 g, 19.8 mmol) in THF  (30.0 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (15.0 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 15.0 mL), brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 5) gave 5.90 g (16.6 mmol, 84.0 %) product as a yellow oil. 1  H (acetone-d6): 7.19 (dd, J = 7.4, 1.7, 1H); 7.10 (td, J = 7.7, 1.7, 1H); 6.93-6.82 (m, 2H);  6.64 (dd, J = 9.9, 6.6, 1H); 6.17 (br, 1H); 6.09 (d, J = 16.5, 1H); 5.95 (d, J = 9.9, 1H); 3.03 (q, J = 7.5, 2H); 2.69 (t, J = 7.4, 2H); 1.86 (p, J = 7.4, 2H); 1.05 (s, 9H); 0.26 (s, 6H). 13C (acetone-d6): 153.4; 137.1; 131.9; 130.2; 127.0; 124.7; 121.1; 118.5; 42.6; 30.3; 27.5; 25.4; 17.9; -4.8. HRMS: calc. for C17H29NO3SiS [M + H]+ 356.1716; found 356.1728. IR: 2930; 1331; 1151.  E.1.6 Preparation of 2-(3-(vinylsulfonamido)propyl)phenyl acetate (297) O  OAc  N S H O  2-Chloro-1-ethane sulfonyl chloride (1.40 mL, 13.4 mmol) and triethylamine (2.49 mL, 17.9 mmol) was slowly added over a period of 10 min to a solution of 295 (1.73 g, 8.96 mmol) in THF  (20.0 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become 314  cloudy. Then reaction mixture was warmed to room temperature and stirred overnight. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (15.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (15.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / MeOH = 99 / 1) gave 2.00 g (7.08 mmol, 79.0 %) product as a yellow oil. 1  H (acetone-d6): 7.43-7.37 (m, 1H); 7.34-7.25 (m, 3H); 7.12 (br, 1H); 7.12 (dd, J = 10.1, 6.2,  1H); 6.42 (dd, J = 8.1, 0.6, 1H); 6.37 (d, J = 1.2, 1H); 3.26-3.16 (m, 2H); 2.74 (t, J = 7.8, 2H); 1.87 (s, 3H); 1.85-1.73 (m, 2H).  13  C (acetone-d6): 169.0; 148.0; 135.1; 133.2; 131.5;  130.8; 127.3; 127.2; 122.1; 38.6; 30.0; 27.3; 22.1. HRMS: calc. for C13H17NO4S [M + Na]+ 306.0776; found 306.0772. IR: 1651; 1371; 1151.  E.1.7 Preparation of bis(3-(2-(tert-butyldimethylsilyloxy)phenyl)propyl)amine (299) OTBS  OTBS N H  Compound 253 was filtered through a 2-inch silica pad using hexanes and EtOAc. Then this crude product was concentrated and hydrogenated using 10 wt % palladium  on carbon. For a similar procedure, see the preparation of compound 295. 75.0 % yield, a light yellow oil, eluting solvent (EtOAc / hexanes = 2 : 1), 1H (acetone-d6): 7.17 (dd, J = 7.3, 1.7, 2H); 7.07 (td, J = 7.6, 1.8, 2H); 6.91-6.82 (m, 4H); 2.72-2.58 (m, 8H); 1.75 (p, J = 7.4, 4H); 1.05 (s, 18H); 0.26 (s, 12H). 13C (acetone-d6): 153.5; 132.9; 130.2; 126.7; 121.1; 118.5; 49.5; 30.6; 28.2; 25.4; 17.9; -4.9. HRMS: calc. for C30H51NO2Si2 [M + H]+ 514.3537; found 514.3525. IR: 2930; 1490; 1252.  315  E.1.8 Preparation of N,N-bis(3-(2-(tert-butyldimethylsilyloxy)phenyl)propyl) ethenesulfonamide (303) OTBS  OTBS N O S O  For similar procedure, see the preparation of compound 196, 65.0 % yield, a light yellow oil, eluting solvent (EtOAc / hexanes = 3 : 1), 1H: 7.13-7.03 (m, 4H); 6.87  (t, J = 7.2, 2H); 6.77 (d, J = 7.9, 2H); 6.38 (dd, J = 9.9, 6.7, 1H); 6.14 (d, J = 16.5, 1H); 5.84 (d, J = 9.8, 1H); 3.15 (t, J = 7.6, 4H); 2.56 (t, J = 7.6, 4H); 1.85 (p, J = 7.6, 4H); 1.00 (s, 18H); 0.23 (s, 12H). 13C: 153.6; 135.4; 131.8; 130.1; 127.2; 126.2; 121.2; 118.6; 47.5; 29.1; 27.8; 25.9; 18.4; -3.9. HRMS: calc. for C32H53NO4Si2S [M + Na]+ 626.3132; found 626.3134. IR: 3444; 1345; 1149.  E.1.9 Preparation of 2-allyl-4-bromo-1-methoxybenzene (304) OMe  Dimethyl sulfate (0.416 mL, 4.38 mmol) and potassium carbonate (824 mg, 5.97 mmol) was added to a solution of 260 (840 mg, 3.98 mmol) in acetone  Br  (10.0 mL) at room temperature and with good stirring. Then reaction mixture  was heated to 60 °C and stirred overnight. Upon the completion of the reaction, the mixture was evaporated to dryness, filtered over Celite using EtOAc (30.0 mL). The filtrate was sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (15.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (Et2O / MeOH = 1 / 12) gave 878 mg (3.90 mmol, 98.0 %) product as a light yellow oil. 1H: 7.35-7.25 (m, 2H); 6.73 (d, J = 8.5, 1H); 6.06-5.92 (m, 1H); 5.15-5.11 (m, 1H); 5.105.05 (m, 1H); 3.82 (s, 3H); 3.38 (d, J = 6.6, 2H).  13  C: 156.4; 136.1; 132.4; 130.1; 129.9;  116.2; 112.7; 111.9; 55.6; 33.9. HREI: calc. for C10H11O79Br 225.99933; found 225.99866. IR: 2936; 1486. 316  E.1.10 Preparation of 3-(5-bromo-2-methoxyphenyl)propan-1-ol (305) OMe  1 M BH3-THF complex in THF (4.00 mL, 4.00 mmol) was slowly added  OH  to a solution of 304 (451 mg, 2.00 mmol) in THF (2.00 mL) at 0 °C and stirred for 2 h. Hydrogen peroxide, 30 % aq. solution (3.00 mL) and 3.00  Br  N NaOH solution (3.00 mL) was added slowly to the reaction mixture at 0 °C and stirred for 4 h. Upon the completion of the reaction, the mixture was neutralized with aq. sat. NH4Cl (15.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 439 mg (1.80 mmol, 90.0 %) product as a light yellow oil. 1H: 7.31-7.24 (m, 2H); 6.73 (d, J = 8.4, 1H); 3.82 (s, 3H); 3.61 (br, 2H); 2.68 (t, J = 7.6, 2H); 1.89-1.78 (m, 2H); 1.70 (br, 1H). 13C: 156.6; 132.7; 132.4; 129.7; 112.8; 111.9; 61.8; 55.6; 32.6; 25.8. HRMS: calc. for C10H13O279Br [M + Na]+ 266.9997; found 267.0004. IR: 3340; 1489.  E.1.11 Preparation of 3-(5-bromo-2-methoxyphenyl)propyl methanesulfonate (306) Methanesulfonyl chloride (0.325 mL, 4.18 mmol) and triethylamine  OMe OMs Br  (0.726 mL, 5.22 mmol) was slowly added over a period of 5 min to a solution of 305 (850 mg, 3.48 mmol) in DCM (6.00 mL) at 0 °C and  with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was 317  concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 1.05 g (3.27 mmol, 94.0 %) product as a light yellow oil. 1H: 7.28 (dd, J = 8.5, 2.5, 1H); 7.23 (s, 1H); 6.71 (d, J = 8.5, 1H); 4.21 (t, J = 6.3, 2H); 3.79 (s, 3H); 3.00 (s, 3H); 2.69 (t, J = 7.4, 2H); 2.07-1.97 (m, 2H). 13C: 156.6; 132.6; 131.1; 130.2; 112.5; 112.0; 69.5; 55.5; 37.4; 28.8; 26.2. HRMS: calc. for C11H15O4S79Br [M + Na]+ 344.9772; found 344.9760. IR: 2941.  E.1.12 Preparation of 2-(3-(5-bromo-2-methoxyphenyl)propyl)isoindoline-1,3-dione (307) Potassium phthalimide (175 mg, 0.950 mmol) was added to a solution  OMe NPht Br  of 306 (276 mg, 0.860 mmol) in DMF (5.00 mL) at room temperature and with good stirring. Then reaction mixture was heated to 90 °C and  stirred overnight. Upon the completion of the reaction, the mixture neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (3 x 5.00 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 279 mg (0.750 mmol, 87.0 %) product as a colorless solid, m.p. 120-121°C. 1H: 7.85-7.78 (m, 2H); 7.72-7.65 (m, 2H); 7.24-7.16 (m, 2H); 6.64 (d, J = 8.5, 1H); 3.74 (s, 3H); 3.72 (t, J = 7.3, 2H); 2.62 (t, J = 7.3, 2H); 1.96 (p, J = 7.3, 2H). 13C: 168.4; 156.5; 133.8; 132.4; 132.1; 131.8; 129.7; 123.1; 112.5; 111.8; 55.5; 37.9; 28.1; 27.5. HRMS: calc. for C18H16NO379Br [M + Na]+ 396.0211; found 396.0217. IR: 1708.  318  E.1.13 Preparation of 3-(5-bromo-2-methoxyphenyl)propan-1-amine (308) Hydrazine monohydrate (0.0800 mL, 1.57 mmol) was slowly added to  OMe NH2  a solution of 307 (196 mg, 0.525 mmol) in EtOH (4.00 mL) at room temperature and with good stirring. Then reaction mixture was heated  Br  to 50 °C and stirred overnight. Upon the completion of the reaction, the resulting precipitate was filtered out and re-dissolved in EtOAc (10.0 mL) and 1.00 N HCl solution (7.00 mL). The organic phase was separated from aqueous phase, and washed again with 1 N HCl solution (7.00 mL). Aqueous phases were collected and adjusted to pH = 10 using 3.00 M NaOH solution. The mixture was extracted with EtOAc (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum to afford 108 mg (0.450 mmol, 85.0 %) product as a light yellow oil without request for further purification. 1H: 7.29-7.17 (m, 2H); 6.68 (d, J = 8.3, 1H); 3.77 (s, 3H); 2.70 (t, J = 6.8, 2H); 2.59 (t, J = 7.5, 2H); 2.00 (br, 2H); 1.71 (p, J = 7.5, 2H).  13  C: 156.5; 132.7; 132.4; 129.6;  112.6; 111.8; 55.5; 41.6; 33.5; 27.1. HRMS: calc. for C10H14NO79Br [M + H]+ 244.0337; found 244.0332. IR: 2936; 1489.  E.1.14 Preparation of N-(3-(5-bromo-2-methoxyphenyl)propyl)ethenesulfonamide (309) OMe  Br  O S N H O  2-Chloro-1-ethane sulfonyl chloride (0.0560 mL, 0.540 mmol) and triethylamine (0.125 mL, 0.900 mmol) was slowly added over a period of 5 min to a solution of 308 (108 mg, 0.450 mmol) in  THF (2.00 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred overnight. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (1.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined 319  extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (5.00 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 97.0 mg (0.290 mmol, 65.0 %) product as a yellow oil. 1H: 7.29 (dd, J = 8.7, 2.5, 1H); 7.22 (d, J = 2.5, 1H); 6.72 (d, J = 8.7, 1H); 6.50 (dd, J = 9.9, 6.7, 1H); 6.25 (d, J = 16.6, 1H); 5.94 (d, J = 9.9, 1H); 4.48 (t, J = 5.7, 1H); 3.81 (s, 3H); 3.01 (q, J = 6.3, 2H); 2.65 (t, J = 7.3, 2H); 1.83 (p, J = 7.3, 2H). 13  C: 156.4; 136.0; 132.7; 131.4; 130.1; 126.6; 112.8; 112.1; 55.6; 42.2; 29.8; 26.6. HRMS:  calc. for C12H14NO3S79Br [M + H]+ 331.9956; found 331.9949. IR: 3285; 2938; 1489; 1150.  E.1.15 Preparation of N-(3-(5-bromo-2-hydroxyphenyl)propyl)ethenesulfonamide (310) OH  Br  O S N O H  Method A: 1 M BBr3 in DCM solution (0.580 mL, 0.580 mmol) was slowly added via syringe pump over a period of 5 min to a solution of 309 (97.0 mg, 0.290 mmol) in DCM (2.00 mL) at -  20 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C and transferred into 100 mL R.B. flask which filled with ice and aq. sat. NaHCO3 solution (10.0 mL). The reaction mixture was extracted with EtOAc (3 x 10.0 mL), washed with brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 55.0 mg (0.170 mmol, 60.0 %) product as a colorless oil. Method B: HF (70 %) pyridine solution (0.500 mL) was added to a solution of 311 (503 mg, 1.16 mmol) in THF (12.0 mL) at 0 °C and stirred overnight. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with solid NaHCO3 until no gas coming out. The reaction mixture was filtered over Celite using EtOAc. The filtrate was sequentially washed with aq. sat. NaHCO3 (3 x 15.0 mL), 320  brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 336 mg (1.06 mmol, 91.0 %) product as a light yellow oil. 1H: 7.23-7.12 (m, 2H); 6.69 (d, J = 8.6, 1H); 6.51 (dd, J = 9.6, 6.7, 1H); 6.23 (d, J = 16.5, 1H); 5.95 (d, J = 9.8, 1H); 5.17 (br, 1H); 2.99 (q, J = 6.2, 2H); 2.65 (t, J = 7.5, 2H); 1.83 (p, J = 6.6, 2H). 13C: 152.9; 135.5; 132.9; 130.2; 129.5; 127.2; 117.2; 112.7; 41.9; 29.8; 26.1. HRMS: calc. for C11H14NO3S79Br [M + Na]+ 341.9775; found 341.9774. IR: 3295; 2933; 1488.  E.1.16 Preparation of N-(3-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)propyl) ethenesulfonamide (311) OTBS  Br  O S N H O  1 M PMe3 solution in THF (3.30 mL, 3.30 mmol) was slowly added to a solution of 264 (601 mg, 1.63 mmol) in THF (10.0 mL) and H2O (5.00 mL) at room temperature and stirred for 4 h. Upon  the completion of the reaction, the mixture was evaporated to dryness under reduced pressure and diluted with EtOAc (20.0 mL). The organic layer was sequentially washed with aq. sat. NH4Cl (3 x 8.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum to carry on next step without further purification. 2-Chloro-1-ethane sulfonyl chloride (0.255 mL, 2.44 mmol) and triethylamine (0.680 mL, 4.89 mmol) was slowly added over a period of 5 min to a solution of crude product in DCM (5.00 mL) at -20 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred overnight. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 15.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (10.0 mL) and 321  dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 571 mg (1.32 mmol, 81.0 % over 2 steps) product as a light yellow oil. 1H: 7.20 (td, J = 8.6, 2.6, 2H); 6.66 (d, J = 8.6, 1H); 6.48 (dd, J = 9.8, 6.8, 1H); 6.23 (d, J = 16.5, 1H); 5.93 (d, J = 9.8, 1H); 4.45 (t, J = 5.8, 1H); 3.01 (q, J = 6.5, 2H); 2.61 (t, J = 7.5, 2H); 1.83 (p, J = 7.4, 2H); 1.00 (s, 9H); 0.23 (s, 6H). 13C: 152.7; 135.9; 133.7; 132.8; 130.0; 126.6; 120.2; 113.4; 42.3; 29.9; 27.2; 25.7; 18.3; -4.2. HRMS: calc. for C17H28NO3SiS79Br [M + Na]+ 456.0640; found 456.0645. IR: 3291; 2930; 1485.  E.1.17 Preparation of N-(3-(2-(tert-butyldimethylsilyloxy)-5-methylphenyl)propyl) ethenesulfonamide (312) O S  N H O OTBS  Lithium aluminum hydride powder (87.0 mg, 2.30 mmol) was slowly added over a period of 5 min to a solution of 270 (337 mg, 1.15 mmol) in THF (10.0 mL) at 0 °C and with good  stirring. Then reaction mixture was warmed to room temperature and stirred over night. The progress of the reaction was monitored by 1H NMR. Upon the completion of the reaction, the mixture was cooled to 0 °C. H2O (0.0870 mL), 15.0 % NaOH (0.0870 mL) solution, H2O (0.260 mL) and appropriate amount of drying reagent (MgSO4) was sequentially added in the interval of 20 min with vigorous stirring. The resulting suspension solution was warmed to room temperature and filtered through Celite using EtOAc (3 x 15.0 mL). The crude product was concentrated and dried over high vacuum to carry on next step without further purification. 2-Chloro-1-ethane sulfonyl chloride (0.172 mL, 1.64 mmol) and triethylamine (0.305 mL, 2.19 mmol) was slowly added over a period of 5 min to a solution of crude product in DCM (5.00 mL) at -20 °C and with good stirring. At the end of the addition, the 322  solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred overnight. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 15.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 7.00 mL), brine (8.00 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 352 mg (0.950 mmol, 87.0 % over 2 steps) product as a light yellow oil. 1H: 6.95-6.84 (m, 2H); 6.68 (d, J = 7.9, 1H); 6.45 (dd, J = 9.8, 6.7, 1H); 6.21 (d, J = 16.5, 1H); 5.90 (d, J = 9.8, 1H); 4.46 (t, J = 6.5, 1H); 3.00 (q, J = 6.5, 2H); 2.62 (t, J = 7.2, 2H); 2.25 (s, 3H); 1.84 (p, J = 7.2, 2H); 1.01 (s, 9H); 0.23 (s, 6H). 13C: 151.2; 136.0; 130.9; 130.8; 130.5; 127.7; 126.4; 118.5; 42.5; 30.2; 27.3; 25.9; 20.6; 18.3; -4.1. HRMS: calc. for C18H31NO3SiS [M + H]+ 370.1872; found 370.1867. IR: 2929; 1500.  E.1.18 Preparation of N-(3-(2-hydroxy-5-methylphenyl)propyl)ethenesulfonamide (313) O S  N H O OH  HF (70 %) pyridine solution (3.50 mL) was added to a solution of 312 (150 mg, 0.410 mmol) in THF (12.0 mL) at 0 °C and stirred overnight. Upon the completion of the reaction, the  mixture was cooled to 0 °C, neutralized with solid NaHCO3 until no gas coming out. The reaction mixture was filtered over Celite using EtOAc. The filtrate was sequentially washed with aq. sat. NaHCO3 (3 x 15.0 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 94.0 mg (0.370 mmol, 90.0 %) product as a light yellow oil. 1H: 6.936.84 (m, 2H); 6.67 (d, J = 7.8, 1H); 6.51 (dd, J = 9.9, 6.6, 1H); 6.23 (d, J = 16.4, 1H); 5.92 (d, J = 9.9, 1H); 5.45 (br, 1H); 5.03 (t, J = 6.5, 1H); 3.01 (q, J = 6.3, 2H); 2.67 (t, J = 7.1, 323  2H); 2.25 (s, 3H); 1.86 (p, J = 7.0, 2H). 13C: 151.2; 135.9; 131.1; 130.0; 127.9; 126.7; 126.6; 115.3; 41.9; 30.1; 26.1; 20.5. HRMS: calc. for C12H17NO3S [M + Na]+ 278.0827; found 278.0832. IR: 3298; 1510; 1146.  E.2 General procedures tandem reactions (conditions C and D, Table 17) Conditions C: substrate (1.00 eq.) in Toluene and MeCN (v / v, 10 : 1) was added slowly in a solution of (diacetoxy)iodobenzene (1.10 eq.) and TFA (1.50 eq.) in Toluene and MeCN (v / v, 10 : 1) via syringe pump over a period of 1 h at -78 °C with a final concentration of [C] = 10.0 mM / substrate. When the addition was complete, the reaction mixture was stirred at -78 °C for 15 min and then warmed to room temperature for 10 min and heated to reflux for 1.5 h. Upon the completion of the reaction, the crude product was evaporated to dryness under reduced pressure. Chromatography of the residue gave the corresponding product. Conditions D: (Diacetoxy)iodobenzene (1.10 eq.) was added slowly in a TFA ([C] = 0.300 M) solution of phenolic compound (1.00 eq.) at room temperature. Toluene (twice as much as TFA by volume) was added and heated to reflux for 1.5 h. Upon the completion of the reaction, the crude product was evaporated to dryness under reduced pressure. Chromatography of the residue would afford the corresponding spirocyclization product.  E.2.1 Characterization of compound 315, Y = H O  O S N  O  35.0 % yield, light yellow solid, m.p. 121-122 °C, eluting solvent (EtOAc / hexanes / toluene = 1 / 1 / 3), 1H (acetone-d6): 6.55-6.48 (m, 1H); 6.39-6.32 (m, 1H); 3.77-3.63 (m, 2H); 3.47-3.38 (m, 2H); 3.04-2.92 (m, 1H); 2.87 (dt, J  = 14, 2.5, 1H); 2.32-2.19 (m, 1H); 2.16-1.93 (m, 3H); 1.64-1.54 (m, 1H). 13C (acetone-d6): 324  202.4; 134.2; 130.0; 71.2; 56.8; 46.3; 44.8; 43.9; 30.8; 27.2; 27.0. HRMS: calc. for C11H13NO3S [M + Na]+ 262.0514; found 262.0515. IR: 1735; 1304; 1133.  E.2.2 Characterization of compound 315, Y = Br O  Br  O S N  30.0 % yield, colorless solid, eluting solvent (EtOAc / hexanes = 1 / 2), 1H: 6.64 (dd, J = 7.4, 2.4, 1H); 3.79 (dd, J = 4.3, 1.7, 1H); 3.78-3.69 (m, 1H); 3.64 (ddd, J = 10.8, 4.3, 2.0, 1H); 3.52-3.45 (m, 1H); 3.06-2.93 (m, 1H);  O  2.88 (ddd, J = 15.1, 2.9, 1.9, 1H); 2.39-2.23 (m, 1H); 2.20-1.92 (m, 3H);  1.88-1.78 (m, 1H).  13  C: 200.2; 132.2; 119.7; 71.5; 56.6; 53.3; 48.2; 45.1; 29.6; 27.0; 26.9.  HRMS: calc. for C11H12NO3S79Br [M + Na]+ 339.9619; found 339.9611. IR: 3459; 1739; 1305.  E.2.3 Characterization of compound 315, Y = Me O  Me  43.0 % yield, colorless solid, eluting solvent (EtOAc / hexanes = 1 / 2), 1H: O S N  6.09 (dt, J = 6.9, 1.6, 1H); 3.76-3.66 (m, 1H); 3.47-3.40 (m, 2H); 3.37-3.30 (m, 1H); 3.02-2.91 (m, 1H); 2.83 (dt, J = 14.5, 2.3, 1H); 2.31-2.18 (m, 1H);  O  1H).  13  2.17-2.05 (m, 1H); 2.05-1.92 (m, 2H); 1.94 (d, J = 1.6, 3H); 1.63-1.54 (m,  C: 202.4; 139.8; 125.8; 71.3; 56.6; 48.8; 45.7; 44.7; 29.6; 27.3; 27.1; 21.7. HRMS:  calc. for C12H15NO3S [M + Na]+ 276.0670; found 276.0664. IR: 1731.  325  E.3 Synthesis and characterization of various intermediates for routes A, B and C E.3.1 Preparation of compound 317 O  O S N OH  1 M Ethylmagnesium bromide solution in THF (3.85 mL, 3.85 mmol) was added slowly to a solution of trimethyl acetylene (0.750 mL, 5.42 mmol) in THF (1.00 mL) at 0 °C and stirred for 2 h at room temperature. Then a solution of 315, Y = H (185 mg, 0.770 mmol) was added slowly to such a  TMS  reaction mixture at 0 °C with good stirring. Then reaction mixture was warmed to room temperature and leave overnight. Upon the completion of the reaction, the crude product was filtered through a short silica pad using THF (25.0 mL) and concentrated under reduced pressure. Chromatography of the residue (EtOAc / hexanes = 1 / 4) gave 241 mg (0.720 mmol, 93.0 %) product as a colorless solid. 1H: 6.58 (tapp, J = 7.5, 1H); 6.13 (tapp, J = 7.2, 1H); 4.34 (s, 1H); 3.90-3.81 (m, 1H); 3.37-3.29 (m, 1H); 3.11 (ddd, J = 11.3, 3.9, 1.4, 1H); 3.04-2.97 (m, 1H); 2.96-2.88 (m, 1H); 2.64 (dt, J = 15.5, 2.6, 1H); 2.37-2.23 (m, 1H); 1.981.78 (m, 3H); 1.72-1.63 (m, 1H); 0.13 (s, 9H).  13  C: 139.8; 125.1; 106.4; 89.4; 77.2; 72.1;  56.3; 45.7; 43.3; 42.7; 35.2; 25.9; 22.4; -0.28. HRMS: calc. for C16H23NO3SiS [M + Na]+ 360.1066; found 360.1072. IR: 3269; 2383.  E.3.2 Preparation of compound 318 O  O  S N  OH  1 M TBAF in THF solution (0.690 mL, 0.690 mmol) was added to a solution of 317 (212 mg, 0.630 mmol) in THF (5.00 mL) at 0 °C and with good stirring. The reaction was warmed to room temperature and stirred for 3 h. Upon the completion of the reaction, the mixture was cooled to 0 °C,  neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 326  mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 159 mg (0.600 mmol, 95.0 %) product as a colorless solid. 1H: 6.62 (tapp, J = 7.4, 1H); 6.17 (tapp, J = 7.5, 1H); 3.93-3.81 (m, 1H); 3.41-3.31 (m, 1H); 3.13 (ddd, J = 11.1, 2.6, 1.3, 1H); 3.08-3.02 (m, 1H); 3.01-2.89 (m, 1H); 2.67 (dt, J = 15.2, 2.6, 1H); 2.39 (s, 1H); 2.35-2.24 (m, 1H); 2.00-1.81 (m, 3H); 1.771.48 (m, 2H).  13  C: 139.6; 125.4; 84.9; 76.7; 72.8; 71.9; 56.3; 45.8; 43.3; 42.6; 35.2; 25.9;  22.4. HRMS: calc. for C13H15NO3S [M + Na]+ 288.0670; found 288.0677. IR: 3258; 2951; 1295.  E.3.3 Preparation of compound 316 O  O  S N  OH  Lithium aluminum hydride powder (27.0 mg, 0.720 mmol) was slowly added over a period of 5 min to a solution of 318 (64.0 mg, 0.240 mmol) in THF (5.00mL) at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred for 3 h. The progress of the reaction was  monitored by 1H NMR. Upon the completion of the reaction, the mixture was cooled to 0 °C. H2O (0.0270 mL), 15 % NaOH (0.0270 mL) solution, H2O (0.0810 mL) and appropriate amount of drying reagent (MgSO4) was sequentially added in the interval of 20 min with vigorous stirring. The resulting suspension solution was warmed to room temperature and filtered through Celite using EtOAc (3 x 10.0 mL). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 4) gave 42.0 mg (0.158 mmol, 66.0 %) product as a colorless foam. 1H: 6.58 (tapp, J = 7.4, 1H); 6.12 (tapp, J = 7.1, 1H); 5.72 (dd, J = 16.9, 10.7, 1H); 5.51 (dd, J = 16.9, 2.5, 1H); 5.09 (dd, J = 10.5, 2.3, 1H); 3.87-3.77 (m, 1H); 3.39-3.32 (m, 1H); 3.20-3.10 (m, 1H); 2.91-2.82 (m, 1H); 2.812.72 (m, 1H); 2.69-2.62 (m, 1H); 1.91-1.76 (m, 3H); 1.69-1.50 (m, 2H). 13C: 140.0; 139.9; 327  124.8; 114.5; 77.2; 76.1; 57.1; 45.1; 43.9; 43.4; 34.1; 26.0; 23.6. HRMS: calc. for C13H17NO3SNa [M + Na]+ 290.0827; found 290.0826. IR: 3408; 2948; 1313.  E.3.4 Preparation of compound 316a O  H  O S N OH  3-Butenylmagnesium bromide solution in THF (0.500 M, 1.45 mL, 0.720 mmol) was added to a THF (1.50 mL) solution of compound 315, Y = H (155 mg, 0.650 mmol) at room temperature with good stirring. The progress of the  reaction was monitored by 1H NMR. Upon the completion of the reaction, the mixture cooled to 0 °C, neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 110 mg (0.460 mmol, 70.0 %) product as a colorless solid. 1H: 6.56 (tapp, J = 7.6, 1H); 6.08 (tapp, J = 7.4, 1H); 3.90-3.80 (m, 1H); 3.44-3.26 (m, 3H); 3.17-3.07 (m, 1H); 2.98-2.85 (m, 1H); 2.832.75 (m, 1H); 2.59 (dt, J = 15.1, 2.7, 1H); 1.95-1.82 (m, 3H); 1.77-1.57 (m, 2H). 13C: 138.9; 125.4; 73.2; 72.5; 56.9; 45.4; 42.2; 38.2; 36.6; 25.4; 21.7. HRMS: calc. for C11H15NO3SNa [M + Na]+ 264.0670; found 264.0676. IR: 3432; 2932; 1334.  328  E.3.5 Preparation of compound 319 O  O S N OH  Lindlar’s catalyst (5.00 mol %) and quinoline (10.0 mol%) were added to a benzene (2.00 mL) and MeOH (0.500 mL) solution of compound 317 (236 mg, 0.700 mmol) under argon at room temperature. Hydrogen gas was bubbled into the solution for 20 min. Upon the completion of the reaction, the  mixture was filtered through 2-inch Celite pad using EtOAc. The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 4) gave 160 mg (0.600 mmol, 85.0 %) product as a light yellow oil. 1H: 3.85-3.75 (m, 1H); 3.28 (dt, J = 11.5, 3.3, 1H); 2.96-2.84 (m, 1H); 2.65-2.60 (m, 1H); 2.59-2.50 (m, 2H); 2.41-2.18 (m, 2H); 2.16-2.02 (m, 2H); 2.01-1.72 (m, 5H); 1.54-1.39 (m, 1H). 13C: 83.6; 77.9; 74.4; 71.5; 54.8; 45.7; 38.2; 37.2; 32.3; 25.8; 23.6; 22.3; 16.3. HRMS: calc. for C13H17NO3S [M + Na]+ 290.0827; found 290.0821. IR: 3378; 2949; 1289.  E.3.6 Preparation of (E)-buta-1,3-diene-1-sulfonyl chloride (E-327) [known compound, see reference: Lee, Y. S.; Ryu, E. K.; Yun, K-Y.; Kim,  (E) SO2Cl  Y. H. Synlett 1996, 247.] 1H: 7.31 (dd, J = 14.7, 10.9, 1H); 6.79 (d, J =  14.7, 1H); 6.55-6.39 (m, 1H); 5.91 (d, J = 16.8, 1H); 5.84 (d, J = 10.5, 1H).  13  C: 144.6;  133.0; 132.1; 130.9. HREI: calc. for C4H5O235ClS 151.9699; found 151.9696. LREI: 152. IR: 3065; 2929; 1577.  329  E.3.7 Preparation of (Z)-buta-1,3-diene-1-sulfonyl chloride (Z-327) [known compound, see reference: Lee, Y. S.; Ryu, E. K.; Yun, K-Y.; Kim,  (Z) SO2Cl  Y. H. Synlett 1996, 247.] 1H: 7.50-7.34 (m, 1H); 6.78 (t, J = 11.0, 1H); 6.58  (d, J = 10.4, 1H); 5.86 (s, 1H); 5.82 (d, J = 6.9, 1H). 13C: 143.2; 132.2; 130.3; 129.3. HREI: calc. for C4H5O235ClS 151.9699; found 151.9696. LREI: 152.  E.3.8 Preparation of (E)-N-(3-(2-(tert-butyldimethylsilyloxy)phenyl)propyl)buta-1,3diene-1-sulfonamide (329) O S N H O OTBS  (E)-327 (123 mg, 0.815 mmol) and triethylamine (0.227 mL, 1.63 mmol) was slowly added over a period of 5 min to a solution of 254 (144 mg, 0.540 mmol) in DCM (2.00 mL) at  -20 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred overnight. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (1.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 5.00 mL), brine (5.00 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 123 mg (0.320 mmol, 60.0 %) product as a light yellow oil. 1H (acetone-d6): 7.18 (dd, J = 7.5, 1.7, 1H); 7.10 (td, J = 7.6, 1.9, 1H); 7.04-6.92 (m, 1H); 6.91-6.83 (m, 2H); 6.66-6.43 (m, 2H); 6.17 (br, 1H); 5.73 (d, J = 16.8, 1H); 5.55 (d, J = 9.9, 1H); 3.02 (q, J = 7.1, 2H); 2.68 (t, J = 7.3, 2H); 1.86 (p, J = 7.6, 2H); 1.05 (s, 9H); 0.27 (s, 6H).  13  C (acetone-d6): 153.4; 139.8; 133.2; 131.9; 130.25; 130.22; 127.0; 125.4;  121.1; 118.5; 42.6; 30.4; 27.5; 25.3; 18.0; -4.9. HRMS: calc. for C19H31NO3SiS [M + H]+ 382.1872; found 382.1878. IR: 3286; 2930; 1253. 330  E.3.9 Preparation of (E)-N-(3-(2-hydroxyphenyl)propyl)buta-1,3-diene-1-sulfonamide (331) O S N H O OH  HF (70 %) pyridine solution (0.500 mL) was added to a solution of 329 (50.0 mg, 0.130 mmol) in THF (4.00 mL) at 0 °C and stirred overnight. Upon the completion of the  reaction, the mixture was cooled to 0 °C, neutralized with solid NaHCO3 until no gas coming out. The reaction mixture was filtered over Celite using EtOAc. The filtrate was sequentially washed with aq. sat. NaHCO3 (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 32.0 mg (0.120 mmol, 93.0 %) product as a light yellow oil. 1H (acetone-d6): 8.25 (br, 1H); 7.11 (dd, J = 7.4, 1.6, 1H); 7.04-6.93 (m, 2H); 6.83 (dd, J = 7.9, 0.8, 1H); 6.76 (td, J = 7.4, 1.1, 1H); 6.64-6.46 (m, 2H); 6.13 (br, 1H); 5.72 (d, J = 16.6, 1H); 5.54 (d, J = 9.9, 1H); 3.03 (q, J = 6.5, 2H); 2.69 (t, J = 7.5, 2H); 1.87 (p, J = 7.3, 2H). 13C (acetone-d6): 154.9; 139.7; 133.2; 130.3; 130.1; 127.7; 127.0; 125.3; 119.5; 114.9; 42.5; 30.0; 27.0. HRMS: calc. for C13H17NO3S [M + Na]+ 290.0827; found 290.0819. IR: 3297; 1140.  E.3.10 Preparation of compound 339 O  O  S N  (Diacetoxy)iodobenzene (42.5 mg, 0.130 mmol) was added slowly in a TFA (0.400 mL, [C] = 0.300 M) solution of phenolic compound 331 (32.0 mg, 0.120 mmol) at room temperature. Toluene (0.800 mL) was added and heated  O  to reflux for 1.5 h. Upon the completion of the reaction, the crude product was evaporated to dryness under reduced pressure. Chromatography of the residue (EtOAc / hexanes = 1 / 2) 331  gave 12.0 mg (0.0440 mmol, 34.0 %) product as a colorless foam. 1H: 6.42-6.36 (m, 2H); 5.68-5.53 (m, 1H); 5.23 (d, J = 16.8, 1H); 5.16 (d, J = 10.2, 1H); 3.79-3.63 (m, 3H); 3.523.45 (m, 1H); 3.29-3.25 (m, 1H); 3.05-2.93 (m, 1H); 2.33-2.19 (m, 1H); 2.18-2.06 (m, 1H); 2.05-1.91 (m, 1H); 1.65-1.56 (m, 1H).  13  C: 201.7; 135.4; 132.0; 129.6; 118.1; 70.6; 62.3;  52.2; 44.8; 43.8; 42.0; 30.7; 27.2. HRMS: calc. for C13H15NO3S [M + Na]+ 288.0670; found 288.0675. IR: 3448; 1735; 1302.  E.3.11 Preparation of compound 338 O  O  S N  H  For a similar procedure, see the preparation of compound 339. 27.0 % yield, a colorless foam, eluting solvent (EtOAc / hexanes = 1 / 2), 1H: 6.57 (tapp, J = 7.5, 1H); 6.34 (tapp, J = 7.2, 1H); 6.29-6.14 (m, 1H); 5.25 (d, J = 4.0, 1H);  O  5.21 (sapp, 1H); 3.85-3.69 (m, 2H); 3.49 (dd, J = 10.1, 4.0, 1H); 3.37 (dt, J = 6.9, 1.5, 1H); 3.05-2.93 (m, 1H); 2.81 (t, J = 9.6, 1H); 2.33-2.20 (m, 1H); 2.18-1.94 (m, 2H); 1.68-1.58 (m, 1H).  13  C: 202.3; 134.5; 134.3; 129.3; 117.0; 70.7; 59.4; 53.0; 45.5; 45.2; 44.7; 31.2; 27.3.  HRMS: calc. for C13H16NO3S [M + H]+ 266.0851; found 266.0852. IR: 3450; 1755; 1328.  E.3.12 Preparation of methyl 3-(4-(tert-butyldimethylsilyloxy)phenyl)propanoate (341) t-Butyldimethylsilyl chloride (2.37 g, 15.7 mmol) and imidazole  O OMe TBSO  (1.34 g, 19.7 mmol) was added to a solution of methyl 3-(4hydroxyphenyl)propionate (340) (2.36 g, 13.1 mmol) in DMF  (13.0 mL) at room temperature and with good stirring. Upon the completion of the reaction, the mixture neutralized with aq. sat. NH4Cl (10.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over 332  high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 3.62 g (12.3 mmol, 94.0 %) product as a light yellow oil. 1H: 7.04 (d, J = 8.2, 2H); 6.75 (d, J = 8.3, 2H); 3.67 (s, 3H); 2.88 (tapp, J = 7.8, 2H); 2.59 (tapp, J = 7.9, 2H); 0.98 (s, 9H); 0.18 (s, 6H). 13C: 173.4; 153.9; 133.1; 129.1; 120.0; 51.5; 35.9; 30.2; 25.6; 18.2; -4.4. HRMS: calc. for C16H26O3Si [M + H]+ 295.1729; found 295.1734. IR: 2954; 1741; 1510.  E.3.13 Preparation of 3-(4-(tert-butyldimethylsilyloxy)phenyl)propan-1-ol (342) OH TBSO  Lithium aluminum hydride powder (283 mg, 7.40 mmol) was slowly added over a period of 30 min to a solution of 341 (1.80 g,  6.20 mmol) in THF (50.0 mL) at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. The progress of the reaction was monitored by 1H NMR. Upon the completion of the reaction, the mixture was cooled to 0 °C. H2O (0.280 mL), 15.0 % NaOH (0.280 mL) solution, H2O (0.840 mL) and appropriate amount of drying reagent (MgSO4) was sequentially added in the interval of 20 min with vigorous stirring. The resulting suspension solution was warmed to room temperature and filtered through Celite using EtOAc (3 x 30.0 mL). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 1.52 g (5.70 mmol, 92.0 %) product as a colorless oil. 1H: 7.05 (d, J = 8.2, 2H); 6.76 (d, J = 8.3, 2H); 3.67 (t, J = 6.3, 2H); 2.64 (tapp, J = 7.4, 2H); 1.92-1.82 (m, 2H); 0.99 (s, 9H); 0.19 (s, 6H).  13  C: 153.8; 134.4; 129.2; 119.9; 62.3; 34.4; 31.2; 25.7; 18.2; -4.4. HRMS: calc. for  C15H26O2Si [M + H]+ 267.1780; found 267.1787. IR: 3338; 2929; 1509.  333  E.3.14 Preparation of 3-(4-(tert-butyldimethylsilyloxy)phenyl)propyl methanesulfonate (343) OMs  Methanesulfonyl  chloride  (1.16  mL,  15.0  mmol)  and  triethylamine (2.60 mL, 18.8 mmol) was slowly added over a  TBSO  period of 30 min to a solution of 342 (3.32 g, 12.5 mmol) in DCM (50.0 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (10.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 15.0 mL), brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 4) gave 4.08 g (11.8 mmol, 95.0 %) product as a light yellow oil. 1H: 7.04 (d, J = 8.4, 2H); 6.77 (d, J = 8.4, 2H); 4.22 (t, J = 6.5, 2H); 2.99 (s, 3H); 2.68 (t, J = 7.6, 2H); 2.10-1.99 (m, 2H); 0.98 (s, 9H); 0.19 (s, 6H). 13C: 154.0; 132.8; 129.3; 120.1; 69.2; 37.2; 30.7; 30.6; 25.6; 18.1; -4.4. HRMS: calc. for C16H28O4SiS [M + Na]+ 367.1375; found 367.1369. IR: 2930; 1510; 1259.  E.3.15 Preparation of (4-(3-azidopropyl)phenoxy)(tert-butyl)dimethylsilane (344) Sodium azide (780 mg, 12.0 mmol) was slowly added to a N3 TBSO  solution of 343 (2.06 g, 6.00 mmol) in DMF (20.0 mL) and H2O  (10.0 mL) at room temperature and with good stirring. Then reaction mixture was warmed to 60 °C and stirred over night. Upon the completion of the reaction, the mixture was cooled to room temperature, extracted with EtOAc (3 x 20.0 mL), brine (20.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the 334  residue (100 % hexanes) gave 1.59 g (5.46 mmol, 91.0 %) product as a yellow oil. 1H: 7.04 (d, J = 8.2, 2H); 6.78 (d, J = 8.3, 2H); 3.28 (t, J = 7.0, 2H); 2.65 (t, J = 7.4, 2H); 1.89 (p, J = 7.4, 2H); 0.99 (s, 9H); 0.21 (s, 6H). 13C: 153.9; 133.4; 129.2; 120.0; 50.6; 31.9; 30.6; 25.6; 18.1; -4.4. LRMS: [M - N2 + H]+ 264.3. IR: 2930; 2096; 1510.  E.3.16 Preparation of (E)-N-(3-(4-(tert-butyldimethylsilyloxy)phenyl)propyl)buta-1,3diene-1-sulfonamide (345) O  TBSO  N H  S  O  Palladium, 10 wt % on activated carbon (194 mg, 0.180 mmol, 5.00 mol %) was added slowly to a solution of 344 (1.06 g, 3.66 mmol) in EtOH (10.0 mL)  under argon. Hydrogen was bubbled through the reaction mixture for 25 min with good stirring. The reaction was stirred at room temperature overnight. Upon the completion of the reaction, the mixture was filtered over Celite twice using EtOAc (50.0 mL in total). The crude product was concentrated and dried over high vacuum to carry on next step. (E)-1,3butadiene-1-sulfonyl chloride (718 mg, 4.76 mmol) and triethylamine (1.07 mL, 7.68 mmol) was slowly added over a period of 10 min to a solution of crude product in DCM (8.00 mL) at -20 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred overnight. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 15.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 8.00 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 739 mg (1.94 mmol, 53.0 % over 2 steps) product as a light yellow oil. 1H: 7.09-7.03 (m, 1H); 7.01 (d, J = 8.2, 2H); 6.75 (d, J = 8.2, 2H); 6.48335  6.32 (m, 1H); 6.26 (d, J = 14.9, 1H); 5.65 (d, J = 16.5, 1H); 5.56 (d, J = 9.9, 1H); 4.66 (t, J = 5.9, 1H); 3.01 (q, J = 6.4, 2H); 2.60 (t, J = 7.4, 2H); 1.84 (p, J = 7.5, 2H); 0.98 (s, 9H); 0.19 (s, 6H). 13C: 153.8; 141.4; 133.5; 132.5; 129.2; 128.4; 127.0; 120.0; 42.3; 31.9; 31.5; 25.6; 18.2; -4.4. HRMS: calc. for C19H31NO3SiS [M + H]+ 382.1872; found 382.1874. IR: 3287; 2929; 1510; 1258.  E.3.17 Preparation of (E)-N-(3-(4-hydroxyphenyl)propyl)buta-1,3-diene-1-sulfonamide (285) O  HO  N H  S  O  HF (70 %) pyridine solution (0.9 mL) was added to a solution of 345 (100 mg, 0.260 mmol) in THF (4.00 mL) at 0 °C and stirred overnight. Upon the completion of the  reaction, the mixture was cooled to 0 °C, neutralized with solid NaHCO3 until no gas coming out. The reaction mixture was filtered over Celite using EtOAc. The filtrate was sequentially washed with aq. sat. NaHCO3 (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 64.0 mg (0.240 mmol, 92.0 %) product as a light yellow oil. 1H (acetone-d6): 8.09 (br, 1H); 7.04 (d, J = 8.5, 2H); 7.00-6.93 (m, 1H); 6.75 (d, J = 8.5, 2H); 6.65-6.46 (m, 2H); 6.15 (br, 1H); 5.73 (d, J = 16.8, 1H); 5.54 (d, J = 9.9, 1H); 3.07-2.93 (m, 2H); 2.60 (t, J = 7.5, 2H); 1.83 (t, J = 7.5, 2H). 13C (acetone-d6): 155.5; 139.8; 133.2; 132.2; 130.2; 129.2; 125.4; 115.1; 42.2; 31.8; 31.6. HRMS: calc. for C13H17NO3S [M + H]+ 268.1007; found 268.1010. IR: 3287; 1514; 1140.  336  E.3.18 Preparation of compound 283 O2S N H  H  (Diacetoxy)iodobenzene (142 mg, 0.440 mmol) was added slowly in a TFA (1.40 mL, [C] = 0.300 M) solution of phenolic compound 285 (107 mg, 0.400 mmol) at room temperature. Toluene (2.50 mL) was added and heated to  O  reflux for 10 h. Upon the completion of the reaction, the crude product was  evaporaed to dryness under reduced pressure. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 41.0 mg (0.156 mmol, 39.0 %) product as a colorless solid. 1H: 6.53 (d, J = 10.4, 1H); 6.28-6.18 (m, 1H); 6.12 (d, J = 10.4, 1H); 5.89 (dt, J = 10.0, 2.8, 1H); 3.943.83 (m, 1H); 3.75-3.65 (m, 1H); 3.59-3.47 (m, 1H); 3.30 (dd, J = 12.4, 8.7, 1H); 3.06-2.94 (m, 1H); 2.92-2.84 (m, 1H); 2.34-1.94 (m, 4H); 1.92-1.80 (m, 1H). 13C: 195.8; 149.9; 132.3; 129.6; 118.3; 66.4; 57.1; 50.9; 45.1; 40.6; 39.4; 24.3; 23.3. HRMS: calc. for C13H15NO3S [M + Na]+ 288.0670; found 288.0672. IR: 3440; 1753; 1330.  337  E.4 Proton and carbon-13 spectra for himandrine skeletons  O  OMe  N S H O  O  OMe  N S H O  Figure 144. NMR spectra of compound 292  338  O N S H O  OH  O  OH  N S H O  Figure 145. NMR spectra of compound 293  339  N3 OAc  N3 OAc  Figure 146. NMR spectra of compound 294  340  NH2 OAc  NH2 OAc  Figure 147. NMR spectra of compound 295  341  O  OTBS  N S H O  O  OTBS  N S H O  Figure 148. NMR spectra of compound 296  342  O  OAc  N S H O  O  OAc  N S H O  Figure 149. NMR spectra of compound 297  343  OTBS  OTBS N H  OTBS  OTBS N H  Figure 150. NMR spectra of compound 299  344  OTBS  OTBS N O S O  OTBS  OTBS N O S O  Figure 151. NMR spectra of compound 303  345  OMe  Br  OMe  Br  Figure 152. NMR spectra of compound 304  346  OMe  OH  Br  OMe  OH  Br  Figure 153. NMR spectra of compound 305  347  OMe OMs Br  OMe OMs Br  Figure 154. NMR spectra of compound 306  348  OMe NPht Br  OMe NPht Br  Figure 155. NMR spectra of compound 307  349  OMe NH2 Br  OMe NH2 Br  Figure 156. NMR spectra of compound 308  350  OMe  O S N H O  Br  OMe  O S N H O  Br  Figure 157. NMR spectra of compound 309  351  OH  O S N H O  Br  OH  O S N H O  Br  Figure 158. NMR spectra of compound 310  352  OTBS  O S N O H  Br  OTBS  O S N O H  Br  Figure 159. NMR spectra of compound 311  353  OTBS  OTBS  O S N H O  O S N H O  Figure 160. NMR spectra of compound 312  354  OH  OH  O S N H O  O S N H O  Figure 161. NMR spectra of compound 313  355  O  O S N  O  O  O S N  O  Figure 162. NMR spectra of compound 315, Y = H  356  O  O S N  O  Figure 163. HMQC spectrum of compound 315, Y = H  O  O S N  O  Figure 164. HMBC spectrum of compound 315, Y = H  357  O  Br  O S N  O  O  Br  O S N  O  Figure 165. NMR spectra of compound 315, Y = Br  358  O  Br  O S N  O  Figure 166. HMQC spectrum of compound 315, Y = Br  O  Br  O S N  O  Figure 167. HMBC spectrum of compound 315, Y = Br  359  O  Me  O S N  O  O  Me  O S N  O  Figure 168. NMR spectra of compound 315, Y = Me  360  O  Me  O S N  O  Figure 169. HMQC spectrum of compound 315, Y = Me  O  Me  O S N  O  Figure 170. HMBC spectrum of compound 315, Y = Me  361  O  O S N OH  TMS  O  O S N OH  TMS  Figure 171. NMR spectra of compound 317  362  O  O S N OH  O  O S N OH  Figure 172. NMR spectra of compound 318  363  O  O S N OH  O  O S N OH  Figure 173. NMR spectra of compound 316  364  O  O S N OH  Figure 174. HMQC spectrum of compound 316  O  O S N OH  Figure 175. HMBC spectrum of compound 316  365  O  H  O  H  O S N OH  O S N OH  Figure 176. NMR spectra of compound 316a  366  O  O S N OH  O  O S N OH  Figure 177. NMR spectra of compound 319  367  (E) SO2Cl  (E) SO2Cl  Figure 178. NMR spectra of compound E-327  368  (Z) SO2Cl  (Z) SO2Cl  Figure 179. NMR spectra of compound Z-327  369  O S N H O OTBS  O S N H O OTBS  Figure 180. NMR spectra of compound 329  370  O S N H O OH  O S N H O OH  Figure 181. NMR spectra of compound 331  371  O H  O S N  O  O H  O S N  O  Figure 182. NMR spectra of compound 338  372  O H  O S N  O  Figure 183. HMQC spectrum of compound 338  O H  O S N  O  Figure 184. HMBC spectrum of compound 338  373  O  O S N  O  O  O S N  O  Figure 185. NMR spectra of compound 339  374  O  O S N  O  Figure 186. HMQC spectrum of compound 339  O  O S N  O  Figure 187. HMBC spectrum of compound 339  375  O OMe TBSO  O OMe TBSO  Figure 188. NMR spectra of compound 341  376  OH TBSO  OH TBSO  Figure 189. NMR spectra of compound 342  377  OMs TBSO  OMs TBSO  Figure 190. NMR spectra of compound 343  378  N3 TBSO  N3 TBSO  Figure 191. NMR spectra of compound 344  379  O  O  N H  TBSO  O  TBSO  S  S  O  N H  Figure 192. NMR spectra of compound 345  380  O  HO  S  N H  O  HO  O  S  O  N H  Figure 193. NMR spectra of compound 285  381  O2S N H  H  O  O2S N H  H  O  Figure 194. NMR spectra of compound 283  382  O2S N H  H  O  Figure 195. HMQC spectrum of compound 283  O2S N H  H  O  Figure 196. HMBC spectrum of compound 283  383  F. LEPADIFORMINE EXPERIMENTAL SECTION F.1 Synthesis and characterization of various homotyrosinol derivatives F.1.1 Preparation of (S)-methyl 2-(methylsulfonamido)-4-(methylthio)butanoate (358) O S  OMe NHMs  Methanesulfonyl chloride (5.80 mL, 75.0 mmol) and triethylamine (13.9 mL, 100 mmol) was slowly added over a period of 50 min. to a solution of L-Methionine methyl ester hydrochloride (357) (10.0 g,  50.3 mmol) in DCM (150 mL) at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (50.0 mL) and extracted with EtOAc (3 x 75.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 50.0 mL), brine (50.0 mL) and dried (Na2SO4) and evaporated to afford 12.1 g (50.3 mmol, 100 %) product as a colorless solid, m.p. 41-42 °C, without request for further purification. 1H: 5.40 (d, J = 9, 1H); 4.31-4.21 (m, 1H); 3.77 (s, 3H); 2.96 (s, 3H); 2.61 (br, 2H); 2.08 (s, 3H); 2.19-1.86 (m, 2H). 13C: 172.6; 54.7; 52.9; 41.2; 32.1; 29.7; 15.2. HRMS: calc. for C7H15NO4S2 [M + Na]+ 264.0340; found 264.0338. IR: 3278; 1740; 1317; 1109. [α]D23 = -19.2° (CHCl3, c = 0.85)  F.1.2 Preparation of (S)-N-(1-hydroxy-4-(methylthio)butan-2-yl)methanesulfonamide (359) S  Lithium aluminum hydride powder (941 mg, 24.8 mmol) was slowly OH NHMs  added over a period of 30 min to a solution of 358 (3.00 g, 12.4 mmol)  in THF (70.0 mL), at 0 °C and with good stirring. At the end of the addition, the solution had become cloudy. Then reaction mixture was warmed to room temperature and stirred over night. The progress of the reaction was monitored by 1H NMR. Upon the completion of the 384  reaction, the mixture was cooled to 0 °C. H2O (0.940 mL), 15.0 % NaOH (0.940 mL) solution, H2O (2.82 mL) and appropriate amount of drying reagent (Na2SO4) was sequentially added in the interval of 20 min with vigorous stirring. The resulting suspension solution was warmed to room temperature and filtered through Celite using EtOAc (3 x 100 mL). The crude product was evaporated to afford 2.40 g (11.3 mmol, 91.0 %) product as a light yellow color oil without request for further purification. 1H: 5.34 (br, 1H); 3.79-3.70 (m, 1H); 3.65-3.53 (m, 2H); 3.05 (s, 3H); 3.00 (br, 1H); 2.68-2.52 (m, 2H); 2.09 (s, 3H); 1.871.74 (m, 2H).  13  C: 64.9; 54.6; 41.5; 30.9; 30.3; 15.3. HRMS: calc. for C6H15NO3S2 [M +  Na]+ 236.0391; found 236.0393. IR: 3285; 1308; 1100. [α]D20 = -34.5° (CH2Cl2, c = 1.13)  F.1.3 Preparation of (S)-2-(methylsulfonamido)-4-(methylthio)butyl acetate (360) S  Acetic anhydride (0.440 mL, 4.70 mmol) and pyridine (0.470 mL, 5.80 OAc NHMs  mmol) was slowly added to a solution of 359 (836 mg, 3.92 mmol) in  DCM (8.00 mL), at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the solvent was evaporated and diluted with EtOAc (15.0 mL). The mixture was sequentially washed with aq. sat. NaHCO3 (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 2 / 1) gave 948 mg (3.72 mmol, 95.0 %) product as an light yellow oil. 1H: 5.23 (d, J = 9, 1H); 4.12-3.99 (m, 2H); 3.79-3.66 (m, 1H); 2.96 (s, 3H); 2.64-2.46 (m, 2H); 2.03 (s, 3H); 2.01 (s, 3H); 1.84-1.64 (m, 2H).  13  C: 170.8;  66.2; 51.8; 41.6; 31.4; 29.9; 20.7; 15.2. HRMS: calc. for C8H11NO4S2 [M + Na]+ 278.0497; found 278.0494. IR: 3281; 1739; 1316; 1150. [α]D20 = -33.6° (CH2Cl2, c = 1.63)  385  F.1.4 Preparation of (S)-N-(1-(tert-butyldiphenylsilyloxy)-4-(methylthio)butan-2yl)methane sulfonamide (361) S  TBDPSCl (11.8 g, 43.0 mmol) and imidazole (4.00 g, 59.0 OTBDPS NHMs  mmol) was slowly added to a solution of 359 (8.36 g, 39.2  mmol) in DMF (75.0 mL), at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (35.0 mL) and extracted with EtOAc (3 x 30.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 30.0 mL), brine (30.0 mL) and dried (Na2SO4) and evaporated to afford 17.7 g (39.2 mmol, 100 %) product as a light yellow oil without request for further purification. 1H: 7.677.61 (m, 4H); 7.49-7.37 (m, 6H); 4.64 (d, J = 8.6, 1H); 3.80-3.63 (m, 2H); 3.61 (br, 1H); 2.87 (s, 3H); 2.55 (br, 2H); 2.08 (s, 3H); 1.92-1.82 (m, 2H); 1.08 (s, 9H). 13C: 135.5; 132.67; 132.65; 130.1; 127.95; 127.92; 65.8; 54.3; 41.5; 31.5; 30.3; 26.9; 19.2; 15.2. HRMS: calc. for C22H33NO3SiS2 [M + Na]+ 474.1569; found 474.1573. IR: 3283; 2930; 1323; 1152. [α]D19 = -26.4° (CH2Cl2, c = 0.94)  F.1.5 Preparation of (S)-N-(1-(tert-butyldimethylsilyloxy)-4-(methylthio)butan-2yl)methane sulfonamide (362) S  TBSCl (182 mg, 1.20 mmol) and imidazole (112 mg, 1.60 mmol) was OTBS NHMs  slowly added to a solution of 359 (236 mg, 1.10 mmol) in DMF (2.00  mL), at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the mixture was cooled to 0 °C, neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (10.0 386  mL) and dried (Na2SO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 323 mg (0.990 mmol, 90.0 %) product as an light yellow oil. 1H: 4.65 (br, 1H); 3.78-3.54 (m, 2H); 3.61 (br, 1H); 3.00 (s, 3H); 2.62 (br, 2H); 2.10 (s, 3H); 1.87-1.76 (m, 2H); 0.89 (s, 9H); 0.079 (s, 3H); 0.072 (s, 3H). 13C: 65.3; 54.3; 41.6; 31.4; 30.3; 25.8; 18.3; 15.2; -5.45; -5.48. HRMS: calc. for C12H29NO3SiS2 [M + H]+ 328.1436; found 328.1445. IR: 3283; 2928; 1317; 1152. [α]D19 = -31.8° (CH2Cl2, c = 0.83)  General procedure for preparation of vinyl glycinol derivatives Sodium periodate (234 mg, 1.10 mmol) in H2O (3.00 mL) was slowly added to a solution of compound 360-362 (1.00 mmol) in MeOH (3.00 mL), at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred for 4 h. Upon the completion of the reaction, the mixture was diluted with EtOAc. The organic layer was separated and sequentially washed with aq. sat. NaHCO3 (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4) and concentrated. The crude product was then dissolved in 1,2dicholobenzene (2.00 mL), followed by addition of Na2CO3 powder (212 mg, 2.00 mmol). The reaction was heated to reflux and stirred overnight. Upon the completion of the reaction, the mixture was diluted with EtOAc (10.0 mL), washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4) and concentrated. Additional extraction was performed using hexanes (10.0 mL) and acetonitrile (10.0 mL) to remove excess 1,2-dichlorobenzene. Chromatography of the residue afforded product.  387  F.1.6 Preparation of (S)-2-(methylsulfonamido)but-3-enyl acetate (363) OAc NHMs  72.0 % over two steps, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 1), 1H: 5.87-5.73 (m, 1H); 5.41 (d, J = 17, 1H); 5.32 (d, J = 10, 1H);  4.89 (br, 1H); 4.25 (br, 1H); 4.21-4.09 (m, 2H); 2.98 (s, 3H); 2.09 (s, 3H). 13C: 170.8; 134.0; 118.6; 65.8; 55.2; 42.1; 20.8. HRMS: calc. for C7H13NO4S [M + Na]+ 230.0463; found 230.0457. IR: 3280; 1741; 1319; 1147. [α]D20 = -20.3° (CH2Cl2, c = 1.25)  F.1.7 Preparation of (S)-N-(1-(tert-butyldiphenylsilyloxy)but-3-en-2-yl)methane sulfonamide (364) OTBDPS NHMs  83.0 % over two steps, yellow solid, m.p. 71.5-72.5 °C, eluting solvent (EtOAc / hexanes = 1 / 3), 1H: 7.71-7.62 (m, 4H); 7.51-7.37  (m, 6H); 5.91-5.77 (m, 1H); 5.36 (d, J = 17, 1H); 5.27 (d, J = 10, 1H); 4.94 (br, 1H); 4.06 (br, 1H); 3.83-3.63 (m, 2H); 2.94 (s, 3H); 1.09 (s, 3H).  13  C: 135.58; 135.55; 135.46;  132.69;132.66; 130.03; 130.02;127.9;127.8; 118.1; 66.3; 57.8; 41.9; 26.9; 26.8; 19.3. HRMS: calc. for C21H29NO3SSi [M + Na]+ 426.1535; found 426.1525. IR: 3290; 2931; 1361. [α]D23 = -10.12° (CHCl3, c = 1.00)  F.1.8 Preparation of (S)-N-(1-(tert-butyldimethylsilyloxy)but-3-en-2-yl)methane sulfonamide (365) OTBS NHMs  85.0 % over two steps, light yellow oil, eluting solvent (EtOAc / hexanes = 1/3), 1H: 5.88-5.74 (m, 1H); 5.35 (d, J = 17, 1H); 5.25(d, J =  10.3, 1H); 4.82 (br, 1H); 3.99 (br, 1H); 3.78-3.54 (m, 2H); 2.96 (s, 3H); 0.88 (s, 9H); 0.067 (s, 3H); 0.059 (s, 3H). 13C: 135.5; 117.9; 65.7; 57.8; 41.9; 25.8; 18.2; -5.4; -5.5. HRMS: calc.  388  for C11H25NO3SSi [M + Na]+ 302.1222; found 302.1222. IR: 3284; 2857; 1325; 1154. [α]D19 = -14.7° (CH2Cl2, c = 1.08)  F.1.9 Preparation of (S)-N-(1-hydroxybut-3-en-2-yl)methanesulfonamide (355, P’ = H) OH NHMs  1 M TBAF solution in THF (1.2 mL, 1.2 mmol) was slowly added to a solution of 365 (484 mg, 1.2 mmol) in THF (3 mL), at 0 °C and with good  stirring. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the solvent was evaporated and diluted with EtOAc (15 mL). The mixture was sequentially washed with aq. sat. NH4Cl (3 x 10 mL), brine (10 mL) and dried (Na2SO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 181 mg (1.1 mmol, 93 %) product as an light yellow oil. 1H: 5.89-5.73 (m, 1H); 5.52-5.43 (m, 1H); 5.38 (d, J = 17, 1H); 5.30 (d, J = 10, 1H); 4.11-4.00 (m, 1H); 3.82-3.52 (m, 2H); 3.00 (s, 3H). 13C: 134.8; 118.3; 64.9; 58.1; 41.8. HRMS: calc. for C5H11NO3S [M + Na]+ 188.0357; found 188.0358. IR: 3280. [α]D20 = -21.81° (CH2Cl2, c = 0.94)  General procedure for Heck coupling in Table 20 Pd(OAc)2 (10.0 mol%), SPhos (20.0 mol%), and potassium carbonate (0.550 mmol) was added to a solution of 4-halophenol derivative (0.500 mmol) and vinyl glycinol derivative (0.500 mmol) in degassed DMF (1.50 mL), at room temperature and with good stirring. Then reaction mixture was heated to 110 °C under inert atmosphere. Upon the completion of the reaction, the mixture was cooled to room temperature, neutralized with aq. sat. NH4Cl (10.0 mL) and extracted with EtOAc (15.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4) and concentrated. Chromatography of the residue afforded product. 389  F.1.10 Preparation of (S,E)-4-(4-(tert-butyldiphenylsilyloxy)-3-(methylsulfonamido) but-1-enyl)phenyl acetate (367) 91.0 % yield, light yellow oil, eluting solvent ( EtOAc / AcO  OTBDPS NHMs  hexanes = 1 / 2.5), 1H: 7.68-7.60 (m, 4H); 7.49-7.31 (m,  8H); 7.06 (d, J = 8.6, 2H); 6.62 (d, J =15.7, 1H); 6.07 (dd, J = 15.7, 7.5, 1H); 4.93 (d, J = 6.7, 1H); 4.25-4.15 (m, 1H); 3.90-3.68 (m, 2H); 2.93 (s, 3H); 2.31 (s, 3H); 1.08 (s, 9H). 13C: 169.4; 150.4; 135.56; 135.54; 133.7; 132.5; 132.3; 130.07; 130.04; 127.95; 127.90; 127.50; 126.5; 121.8; 66.4; 57.4; 42.2; 26.8; 21.1; 19.2. HRMS: calc. for C29H35NO5SSi [M + Na]+ 560.1903; found 560.1894. IR: 3288; 2931; 1750; 1324; 1156. [α]D20 = -16.6° (CH2Cl2, c = 1.17). EA: calc. for C29H35NO5SSi: C, 64.77; H, 6.56; N, 2.60, found: C, 64.50; H, 6.52; N, 2.79.  F.1.11 Preparation of (S,E)-N-(1-(tert-butyldiphenylsilyloxy)-4-(4-hydroxyphenyl)but3-en-2-yl) methanesulfonamide (370, P = H, P’ = TBDPS) 10.0 % yield, light yellow oil, eluting solvent (EtOAc / HO  OTBDPS NHMs  hexanes = 1 / 2), 1H: 7.70-7.61 (m, 4H); 7.48-7.34 (m,  6H); 7.16 (d, J = 8.6, 2H); 6.78 (d, J = 8.6, 2H); 6.54 (d, J = 15.4, 1H); 5.98-5.85 (m, 2H); 5.01 (d, J = 6.5, 1H); 4.24-4.13 (m, 1H); 3.89-3.67 (m, 2H); 2.95 (s, 3H); 1.09 (s, 9H). 13C: 155.9; 135.58; 135.56; 132.9; 132.65; 132.63; 130.07; 130.03; 128.5; 127.97; 127.94; 127.91; 123.4; 115.6; 66.5; 57.8; 42.2; 26.9; 19.3. HRMS: calc. for C27H33NO4SSi [M + Na]+ 518.1797; found 518.1797. IR: 3295; 2931; 1362; 1152. [α]D21 = -3.76° (acetone, c = 1.75). EA: calc. for C27H33NO4SSi: C, 65.42; H, 6.71; N, 2.83, found: C, 65.23; H, 6.36; N, 2.69.  390  F.1.12 Preparation of (S,E)-N-(1-(tert-butyldimethylsilyloxy)-4-(4-hydroxyphenyl)but3-en-2-yl) methanesulfonamide (370, P = H, P’ = TBS) OTBS NHMs  HO  21.0 % yield, light yellow oil, eluting solvent (EtOAc / hexanes = 1 / 2), 1H (acetone-d6): 8.47 (br, 1H); 7.31 (d, J =  8.6, 2H); 6.82 (d, J = 8.6, 2H); 6.67 (d, J = 15.8, 1H); 6.13 (dd, J =15.8, 7.36, 1H); 6.12-6.07 (m, 1H); 4.22-4.16 (m, 1H); 3.80 (d, J = 5.7, 2H); 2.94 (s, 3H); 0.92 (s, 9H); 0.11 (s, 3H); 0.10 (s, 3H).  13  C (acetone-d6):157.3; 131.8; 128.3; 127.7; 124.4; 115.4; 66.3; 57.9; 41.0;  25.4; 18.0; -6.1. HRMS: calc. for C17H29NO4SSi [M + Na]+ 394.1484; found 394.1493. IR: 3380. [α]D20 = +20.70° (acetone, c = 1.15)  F.1.13 Preparation of compound 370, P = P’ = Ac 41.0 % yield, light yellow oil, eluting solvent (EtOAc / AcO  OAc NHMs  hexanes = 1 / 1), 1H: 7.37 (d, J = 8.6, 2H); 7.05 (d, J = 8.6,  2H); 6.68 (d, J = 15.6, 1H); 6.04 (dd, J = 15.6, 7.0, 1H); 5.23 (d, J = 8.2, 1H); 4.45-4.33 (m, 1H); 4.27-4.12 (m, 1H); 2.96 (s, 3H); 2.29 (s, 3H); 3.10 (s, 3H).  13  C: 170.8; 169.4; 150.6;  133.4; 132.7; 127.6; 125.1; 121.9; 65.9; 55.0; 42.1. HRMS: calc. for C15H19NO6S [M + Na]+ 364.0831; found 364.0826. IR: 3277; 1735. [α]D20 = +16.49° (CH2Cl2, c = 1.025)  F.1.14 Preparation of (S,E)-N-(1-hydroxy-4-(4-hydroxyphenyl)but-3-en-2-yl)methane sulfonamide (370, P = P’ = H) 36.0 % yield, light yellow solid, m.p. 142-143 °C, eluting HO  OH NHMs  solvent (EtOAc / hexanes = 3 / 1), 1H (acetone-d6): 8.46 (br,  1H); 7.30 (d, J = 8.6, 2H); 6.82 (d, J = 8.6, 2H); 6.65 (d, J = 16, 1H); 6.17-6.06 (m, 2H); 4.21-4.06 (m, 2H); 3.76-3.62 (m, 2H); 2.96 (s, 3H).  13  C (acetone-d6): 157.2; 131.7; 128.3; 391  127.7; 124.5; 115.4; 65.1; 58.3; 41.0. HRMS: calc. for C11H15NO4S [M + Na]+ 280.0619; found 280.0616. IR: 3426; 1644. [α]D23 = -63.6° (acetone, c = 0.79). EA: calc. for C11H15NO4S: C, 51.35; H, 5.88; N, 5.44, found: C, 51.75; H, 5.80; N, 5.49.  General procedure for silyl group deprotection Pyridine-HF complex (70 %, 2.00 mL) was slowly added to a solution of Heck coupling product (1.00 mmol) in THF (3.00 mL), at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred for 8 h. Upon the completion of the reaction, the mixture was neutralized with solid NaHCO3, diluted with EtOAc (15.0 mL). The organic layer was separated and sequentially washed with aq. sat. NaHCO3 (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4) and concentrated. Chromatography of the residue affords compound.  F.1.15 Preparation of (S,E)-4-(4-hydroxy-3-(methylsulfonamido)but-1-enyl)phenyl acetate (371) 95.0 % yield, light yellow solid, m.p. 125.5-126.5 °C, eluting AcO  OH NHMs  solvent (EtOAc / hexanes = 3 / 1), 1H: 7.39 (d, J = 8.6, 2H);  7.06 (d, J = 8.6, 2H); 6.68 (d, J = 16, 1H); 6.10 (dd, J = 16, 7.2, 1H); 4.27-4.17 (m, 1H); 3.88-3.62 (m, 2H); 2.99 (s, 3H); 2.30 (s, 3H). 13C: 169.4; 150.5; 133.5; 132.5; 127.6; 125.7; 121.9; 65.2; 57.7; 42.1; 21.1. HRMS: calc. for [M + Na]+ 322.0725; found 322.0722. IR: 3504; 3284; 1754. [α]D23 = -63.7° (CHCl3, c = 0.73). EA: calc. for C13H17NO5S: C, 52.16; H, 5.72; N, 4.68, found: C, 52.10; H, 5.74; N, 4.66.  392  General procedure for hydrogenation Commercial 10 wt % palladium on carbon (53.0 mg, 5.00 mol %) and potassium carbonate (138 mg, 1.00 mmol) was added to a solution of substrate (1.00 mmol) in MeOH (5.00 mL) under inert atmosphere, at room temperature and with good stirring. Hydrogen gas was bubbled into the solution for 20 min. Upon the completion of the reaction, the mixture was filtered through 2-inch silica pad using EtOAc. The product was concentrated and carried on next step without further purification.  F.1.16 Preparation of (S)-N-(1-(tert-butyldiphenylsilyloxy)-4-(4-hydroxyphenyl)butan2-yl) methanesulfonamide (373) 95.0 % yield, light yellow oil, eluting solvent (EtOAc / HO  OTBDPS NHMs  hexanes = 1 / 3), 1H: 7.67-7.59 (m, 4H); 7.49-7.36 (m,  6H); 7.00 (d, J = 8.6, 2H); 6.74 (d, J = 8.6, 2H); 4.56 (d, J = 8, 1H); 3.77-3.62 (m, 2H); 3.493.38 (m, 1H); 2.82 (s, 3H); 2.67-2.49 (m, 2H); 1.94-1.81 (m, 2H); 1.08 (s, 9H). 13C: 153.8; 135.5; 133.1; 132.7; 130.0; 129.4; 127.94; 127.91; 115.3; 65.7; 55.1; 41.7; 34.4; 31.0; 26.9; 19.2. HRMS: calc. for C27H35NO4SSi [M + Na]+ 520.1954; found 520.1967. IR: 3294; 2930; 1316; 1113. [α]D21 = -15.8° (acetone, c = 1.51)  F.1.17 Preparation of (S)-N-(1-hydroxy-4-(4-hydroxyphenyl)butan-2-yl)methane sulfonamide (353) 95.0 % yield, light yellow solid, m.p. 112.5-113.5 °C, eluting HO  OH NHMs  solvent (EtOAc / hexanes = 3 / 1), 1H (acetone-d6): 8.08 (br,  1H); 7.07 (d, J = 8.5, 2H); 6.75 (d, J = 8.5, 2H); 5.94 (d, J = 8.5, 1H); 3.99 (br, 1H); 3.63 (d, J = 5.5, 2H); 3.49-3.38 (m, 1H); 2.98 (s, 3H); 2.81-2.56 (m, 2H); 1.98-1.65 (m, 2H).  13  C  393  (acetone-d6): 155.4; 132.7; 129.2; 115.1; 64.7; 55.8; 40.8; 34.4; 30.9. HRMS: calc. for [M + Na]+ 282.0776; found 282.0778. IR: 3417; 1644. [α]D23 = -6.03° (acetone, c = 0.63). EA: calc. for C11H17NO4S: C, 50.95; H, 6.61; N, 5.40, found: C, 50.98; H, 6.59; N, 5.39.  F.1.18 Preparation of (S)-((S,E)-4-(4-acetoxyphenyl)-2-(methylsulfonamido)but-3-enyl) 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate, (S)-MTPA ester (372) Triethylamine (0.0330 mL, 0.240 mmol), DMAP  O OMe AcO  O NHMs  (29.0 mg, 0.24 mmol) and (R)-MTPACl (50.0 mg,  CF3  0.200 mmol) was slowly added to a solution of 371 (50.0 mg, 0.170 mmol) in DCM (1.00 mL), at 0 °C and with good stirring. Then reaction mixture was warmed to room temperature and stirred over night. Upon the completion of the reaction, the solvent was evaporated and diluted with EtOAc (15.0 mL). The mixture was sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (10.0 mL) and dried (Na2SO4) and concentrated. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 61.0 mg (0.120 mmol, 70.0 %) product as an light yellow oil. 1H: 7.53-7.46 (m, 2H); 7.45-7.30 (m, 5H); 7.06 (d, J = 8.5, 2H); 6.66 (d, J = 16, 1H); 4.81-4.73 (m, 1H); 4.53-4.41 (m, 3H); 3.53 (s, 3H); 2.89 (s, 3H); 2.31 (s, 3H).  13  C: 169.3; 166.4; 150.7; 133.3; 133.0; 131.7; 129.8;  128.6; 127.6; 127.2; 124.4; 121.9; 84.7; 67.7; 55.5; 54.7; 42.2; 21.1. F-NMR: -71.66. HRMS: calc. for C23H24NO7F3S [M + Na]+ 538.1123; found 538.1132. IR: 1751. [α]D20 = 6.09° (CH2Cl2, c = 0.92)  394  F.1.19 Large-scale Heck coupling reaction, followed by deprotection of OAc group for easy purification Pd(OAc)2 AcO  I  Phenyl Urea OTBDPS RO K2CO3 or NaHCO3 NHMs DMF  OTBDPS NHMs K2CO3 MeOH  R = Ac R=H  Pd(OAc)2 (139 mg, 0.620 mmol, 5.00 % mmol), phenyl urea (168 mg, 1.24 mmol, 10.0 mol %), and K2CO3 (or NaHCO3) (2.06 g, 14.9 mmol) was added to a solution of 4iodophenyl acetate (3.90 g, 14.9 mmol) and vinyl glycinol derivative 364 (5.00 g, 12.4 mmol) in degassed DMF (35.0 mL), at room temperature and with good stirring. Then reaction mixture was heated to 100~105 °C under inert atmosphere. Upon the completion of the reaction (ca. 2 hours), which was monitored by NMR, the mixture was cooled to room temperature, neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (20.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 15.0 mL), brine (3 x 15.0 mL) and dried (Na2SO4) and concentrated. Then K2CO3 (1.71 g, 12.4 mmol) was added to a solution of above reaction crude product in MeOH (30.0 mL) and stirred at room temperature for 3 hours. When the reaction was completed, the mixture was diluted with EtOAc (20.0 mL) and filtered through Celite. The combined organic layers were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (2 x 10.0 mL) and dried (Na2SO4) and concentrated. Chromatography of the residue afforded the Heck coupling 4.91 g product (9.92 mmol, 80.0 % yield over 2 steps).  395  F.2 Synthesis and characterization of various lepadiformine derivatives F.2.1 Preparation of compound 375 OTBDPS N  t-Butyldiphenylsilyl chloride (437 mg, 1.60 mmol) and imidazole (128 mg, 1.89 mmol) was added to a solution of 374 (373 mg,  Ms  O  1.45 mmol) in DMF (3.00 mL) at room temperature and with  good stirring. Upon the completion of the reaction, the mixture neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 20.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 654 mg (1.32 mmol, 91.0 %) product as a light yellow oil. 1H (acetone-d6): 7.80-7.71 (m, 4H); 7.53-7.41 (m, 6H); 7.29 (dd, J = 10.1, 3.0, 1H); 6.93 (dd, J = 10.1, 3.0, 1H); 6.19 (dd, J = 10.1, 2.0, 1H); 6.07 (dd, J = 10.1, 2.1, 1H); 4.22-4.14 (m, 1H); 4.02 (dd, J = 10.1, 3.5, 1H); 3.90 (dd, J = 10.1, 7.3, 1H); 2.96 (s, 3H); 2.54-2.45 (m, 1H); 2.33-2.26 (m, 1H); 1.98-1.90 (m, 1H); 1.11 (s, 9H).  13  C  (acetone-d6): 184.3; 152.8; 147.8; 135.5; 135.4; 133.1; 129.9; 129.8; 128.2; 127.8; 127.3; 65.8; 64.4; 62.4; 38.7; 37.4; 26.4; 26.2; 18.9. HRMS: calc. for C27H33NO4SiSNa [M + Na]+ 518.1797; found 518.1804. IR: 2931; 1668; 1332. [α]D23 = -14.20° (acetone, c = 0.954)  F.2.2 Preparation of compound 377 Commercial LHMDS in THF (1.0 M, 1.72 mL, 1.72 mmol) was OTBDPS N SO2 O  H  added to a solution of 374 (200 mg, 0.780 mmol) in THF (10.0 mL) via syringe pump at -100 oC and with good stirring. The  progress of the conversion was monitored by 1H NMR. Upon the completion of the reaction, the mixture was warmed to 0 oC, neutralized with aq. sat. NH4Cl (10.0 mL) and extracted 396  with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. t-Butyldiphenylsilyl chloride (206 mg, 0.760 mmol) and imidazole (60.0 mg, 0.890 mmol) was added to above crude product in DMF (2.00 mL) at room temperature and with good stirring. Upon the completion of the reaction, the mixture neutralized with aq. sat. NH4Cl (5.00 mL) and extracted with EtOAc (3 x 10.0 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 282 mg major isomer 357 and 20.0 mg minor isomer (302 mg in total, 0.610 mmol, 78.0 % overall yield over 2 steps) in a ca. 14 : 1 ratio as a light yellow oil. 1H: 7.73-7.65 (m, 4H); 7.48-7.36 (m, 6H); 6.61 (dd, J = 10.3, 1.8, 1H); 6.00 (dd, J = 10.3, 0.7, 1H); 4.30 (br, 1H); 3.67 (dd, J = 4.7, 1.4, 2H); 3.45 (dd, J = 13.2, 7.7, 1H); 3.25 (t, J = 12.4, 1H); 3.07-2.95 (m, 1H); 2.78-2.56 (m, 2H); 2.19-2.08 (m, 4H); 1.09 (s, 9H). 13C: 194.5; 150.6; 135.7; 135.6; 132.9; 132.8; 129.9; 129.8; 127.8; 71.1; 66.4; 61.1; 53.4; 40.7; 36.7; 34.9; 27.3; 26.8; 19.2. HRMS: calc. for C27H34NO4SiS [M + H]+ 496.1978; found 496.1975. IR: 2930; 1682; 1315; 1147. [α]D23 = 55.52° (acetone, c = 1.005)  F.2.3 Preparation of compound 381 Commercial LHMDS in THF (1.0 M, 2.85 mL, 2.85 mmol) was added N SO2 O  H  to a solution of 380 (431 mg, 1.90 mmol) in THF (15.0 mL) via syringe pump at -78 oC and with good stirring. The progress of the conversion  was monitored by 1H NMR. Upon the completion of the reaction, the mixture was warmed to 0 oC, neutralized with aq. sat. NH4Cl (3.00 mL) and extracted with EtOAc (3 x 10.0 mL). 397  The combined extracts were sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 388 mg (1.70 mmol, 90.0 %) product as a colorless solid. 1H: 6.61 (dd, J = 10.2, 1.8, 1H); 6.05 (d, J = 10.2, 1H); 3.95-3.83 (m, 1H); 3.40 (dd, J = 12.9, 6.8, 1H); 3.22 (tapp, J = 12.8, 1H); 3.18-3.07 (m, 1H); 3.03-2.90 (m, 1H); 2.76 (dd, J = 17.3, 5.7, 1H); 2.59 (dd, J = 17.4, 1.7, 1H); 2.30-2.13 (m, 1H); 2.12-1.85 (m, 3H).  13  C: 194.4; 150.2; 127.6; 70.7; 52.5; 46.8; 40.5; 36.6; 35.7; 25.5.  HRMS: calc. for C10H14NO3S [M + H]+ 228.0694; found 228.0691.  F.2.4 Preparation of compound 384 Palladium, 10 wt % on activated carbon (106 mg, 0.100 mmol, 10.0 N SO2 O  H  mol %) was added slowly to a solution of 381 (227 mg, 1.00 mmol) in EtOH (5.00 mL) under argon. Hydrogen was bubbled through the  reaction mixture for 20 min with good stirring. The reaction was stirred at room temperature overnight. Upon the completion of the reaction, the mixture was filtered over Celite twice using EtOAc (50.0 mL). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 1) gave 195 mg (0.850 mmol, 85.0 %) product as a colorless foam. 1H: 3.62-3.50 (m, 1H); 3.38-3.20 (m, 2H); 3.06 (dd, J = 13.2, 4.7, 1H); 2.92 (dd, J = 15.6, 9.4, 1H); 2.84-2.70 (m, 1H); 2.59-2.44 (m, 2H); 2.38-2.20 (m, 2H); 2.16-1.76 (m, 5H).  13  C: 209.2; 70.4; 51.9; 48.8; 42.2; 39.2; 38.8; 36.4; 32.9; 24.9.  HRMS: calc. for C10H15NO3SNa [M + Na]+ 252.0670; found 252.0667.  398  F.2.5 Preparation of compound 385 Thiophenol (206 mg, 1.87 mmol) and BF3·OEt2 (35.0 mg, 0.250 N SO2  PhS PhS  H  mmol) was added to a solution of 384 (195 mg, 0.850 mmol) in DCM (2.50 mL) at 0 oC. The reaction was warmed to room temperature and  stirred over night. The progress of the conversion was monitored by 1H NMR. Upon the completion of the reaction, the mixture was warmed to 0 oC, neutralized with aq. sat. K2CO3 (2.00 mL) and extracted with EtOAc (3 x 20.0 mL). The combined extracts were sequentially washed with aq. sat. K2CO3 (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 315 mg (0.730 mmol, 86.0 %) product as a light yellow oil. 1H: 7.76-7.66 (m, 4H); 7.48-7.28 (m, 6H); 3.76-3.62 (m, 2H); 3.22 (dd, J = 13.0, 7.1, 1H); 3.07-2.95 (m, 1H); 2.69-2.55 (m, 1H); 2.40 (dd, J = 14.9, 7.3, 1H); 2.17-1.99 (m, 2H); 1.98-1.59 (m, 7H).  13  C: 136.51; 136.48; 131.0; 130.7; 129.46;  129.43; 128.87; 128.84; 72.2; 63.0; 52.6; 45.9; 37.4; 37.3; 36.6; 32.4; 31.5; 25.0. HRMS: calc. for C22H25NO2S3Na [M + Na]+ 454.0945; found 454.0938.  F.2.6 Preparation of compound 386 Anhydrous NiCl2 (473 mg, 3.65 mmol) was added to a solution of 385 (315 N SO2 H  mg, 0.730 mmol) in MeOH / EtOH (7.00 mL, v / v, 1 : 3) at 0 oC with good stirring for 30 min. NaBH4 (138 mg, 3.65 mmol) was then added in this  solution in small portions at the same temperature. The progress of the conversion was monitored by 1H NMR. Upon the completion of the reaction, the mixture was filtered through Celite using EtOAc. The eluate was sequentially washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). The crude product was concentrated and 399  dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 2) gave 109 mg (0.510 mmol, 70.0 %) product as a colorless solid. 1H: 3.72-3.60 (m, 1H); 3.48 (t, J = 13.1, 1H); 3.24 (dd, J = 13.1, 7.0, 1H); 3.13-3.00 (m, 1H); 2.53-2.40 (m, 1H); 2.03-1.87 (m, 4H); 1.86-1.50 (m, 6H); 1.46-1.15 (m, 2H). 13C: 73.4; 52.8; 45.5; 40.6; 36.5; 35.4; 26.1; 24.9; 23.2; 20.0. HRMS: calc. for C10H18NO2S [M + H]+ 216.1058; found 216.1061.  F.2.7 Preparation of compound 387 OTBDPS N  87.0 %, a light yellow oil, eluting solvent (EtOAc / hexanes = 1 :  SO2 O  For a similar procedure, see the preparation of compound 384.  2), 1H: 7.73-7.76 (m, 4H); 7.47-7.36 (m, 6H); 4.10-4.00 (m, 1H);  H  3.79-3.63 (m, 2H); 3.31-3.19 (m, 1H); 3.12-2.97 (m, 2H); 2.82-2.68 (m, 1H); 2.57-2.45 (m, 2H); 2.39-2.05 (m, 5H); 2.03-1.93 (m, 1H); 1.89-1.76 (m, 1H); 1.08 (s, 6H).  13  C: 209.4;  135.6; 133.2; 133.1; 129.8; 129.7; 127.7; 70.7; 66.2; 63.6; 51.6; 42.2; 38.6; 38.1; 36.2; 32.8; 27.1; 26.8; 19.2. HRMS: calc. for C27H35NO4SiSNa [M + Na]+ 520.1954; found 520.1964. [α]D23 = -20.92° (acetone, c = 0.98)  F.2.8 Preparation of compound 388 OTBDPS N PhS PhS  SO2 H  For a similar procedure, see the preparation of compound 385. 84.0 %, a light yellow oil, eluting solvent (EtOAc / hexanes = 1 : 4), 1H: 7.76-7.61 (m, 8H); 7.47-7.32 (m, 12H); 4.15-4.05  (m, 1H); 3.84 (dd, J = 12.9, 8.2, 1H); 3.64 (dd, J = 10.4, 4.9, 1H); 3.51 (dd, J = 10.3, 6.5, 1H); 3.19 (dd, J = 13.0, 7.5, 1H); 2.63-2.50 (m, 1H); 2.41 (dd, J = 15.4, 6.7, 1H); 2.31-2.18 (m, 1H); 2.13-1.77 (m, 4H); 1.76-1.52 (m, 4H); 1.05 (s, 9H). 13C: 136.6; 136.3; 135.6; 133.3; 133.1; 131.1; 130.8; 129.7; 129.6; 129.4; 127.7; 127.6; 72.3; 66.2; 62.6; 60.9; 52.7; 38.1; 400  36.8; 36.2; 32.9; 31.8; 27.4; 26.8; 19.2. HRMS: calc. for C39H45NO3SiS3Na [M + Na]+ 722.2229; found 722.2237. [α]D23 = -37.6° (acetone, c = 1.0)  F.2.9 Preparation of compound 389 OTBDPS N SO2  For a similar procedure, see the preparation of compound 386. 71.0 %, a light yellow oil, eluting solvent (EtOAc / hexanes = 1 : 2), 1  H  H: 7.73-7.65 (m, 4H); 7.47-7.34 (m, 6H); 4.19-4.07 (m, 1H); 3.67  (dd, J = 10.1, 4.9, 1H); 3.54-3.41 (m, 2H); 3.25 (dd, J = 13.1, 7.4, 1H); 2.56-2.43 (m, 1H); 2.16-1.50 (m, 10H); 1.43-1.13 (m, 2H); 1.07 (s, 9H). 13C: 135.6; 133.4; 133.3; 129.7; 129.6; 127.6; 73.9; 66.3; 59.5; 53.1; 40.9; 35.5; 35.1; 27.9; 24.6; 23.4; 19.6; 19.2. HRMS: calc. for C27H37NO3SiSNa [M + Na]+ 506.2162; found 506.2160. IR: 1678; 1307; 1150. [α]D23 = 27.25° (acetone, c = 0.943)  F.2.10 Preparation of compound 390 Commercial t-BuLi in hexanes solution (1.4 M, 0.220 mL, 0.310 OTBDPS N SO2 H  C6H13 O  mmol) was added to a solution of 389 (125 mg, 0.260 mmol) in THF (4.00 mL) at -78 oC and with good stirring. After 20 min, 1,2epoxyhexane (33.0 mg, 0.260 mmol) was added slowly into above  solution. The mixture was stirred for 15 min at the same temperature. Then BF3·OEt2 (36.0 mg, 0.260 mmol) was added slowly into this reaction mixture and stirred for 2 h at -78oC. The progress of the conversion was monitored by 1H NMR. Upon the completion of the reaction, the mixture was warmed to -30 oC, neutralized with aq. sat. NH4Cl (5.00 mL) and warmed to room temperature. The crude product was diluted with EtOAc (20.0 mL) and washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). The 401  crude product was concentrated and dried over high vacuum. Commercial Dess-Martin periodinane (110 mg, 0.260 mmol) was added in a solution of above crude product in DCM (3.00 mL). The mixture was stirred for 2 h at room temperature. The progress of the conversion was monitored by 1H NMR. Upon the completion of the reaction, the crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 140 mg (0.230 mmol, 89.0 % over 2 steps) product as a light yellow oil. 1H: 7.72-7.63 (m, 4H); 7.46-7.33 (m, 6H); 4.18-4.01 (m, 2H); 3.67 (dd, J = 10.1, 4.9, 1H); 3.50 (dd, J = 10.1, 7.1, 1H); 3.13 (dd, J = 18.3, 5.4, 1H); 2.65-2.39 (m, 3H); 2.091.12 (m, 21H); 1.06 (s, 9H); 0.88 (tapp, J = 6.6, 3H). 13C: 206.3; 135.6; 133.3; 133.2; 129.7; 129.6; 127.6; 71.9; 66.2; 59.6; 56.9; 47.5; 43.0; 40.8; 35.9; 34.9; 31.5; 28.7; 27.8; 26.8; 23.9; 23.6; 23.5; 22.4; 19.5; 19.2; 14.0. HRMS: calc. for C35H51NO4SiSNa [M + Na]+ 632.3206; found 632.3214. IR: 2930; 1730; 1460; 1429; 1300. [α]D23 = -10.43° (acetone, c = 0.94)  F.2.11 Preparation of compound 391 OTBDPS NH  added to a solution of 390 (140 mg, 0.230 mmol) in DMF (1.00 mL) C6H13  H  1,8-Diazabicyclo[5.4.0]undec-7-ene (52.0 mg, 0.340 mmol) was  O  at room temperature and with good stirring for 15 min. Upon the  completion of the reaction, the mixture was neutralized with aq. sat. NH4Cl (5.00 mL) and diluted with EtOAc (10.0 mL). The crude product was washed with aq. sat. NH4Cl (3 x 10.0 mL), brine (3 x 10.0 mL) and dried (Na2SO4). Chromatography of the residue (EtOAc / hexanes = 1 / 3) gave 116 mg (0.210 mmol, 93.0 %) product as a light yellow oil. 1H: 7.717.63 (m, 4H); 7.48-7.34 (m, 6H); 6.92 (dd, J = 16.1, 9.4, 1H); 6.07 (d, J = 16.1, 1H); 3.713.64 (m, 1H); 3.56-3.49 (m, 1H); 3.25-3.15 (m, 1H); 2.55 (t, J = 14.9, 2H); 2.19-2.05 (m, 1H); 1.81-1.18 (m, 21H); 1.06 (s, 9H); 0.87 (tapp, J = 6.7, 3H).  13  C: 201.4; 150.3; 135.6; 402  133.5; 131.0; 129.6; 127.7; 127.6; 65.9; 63.0; 61.0; 50.3; 40.0; 39.4; 37.6; 31.6; 29.2; 29.0; 27.5; 26.8; 24.4; 22.9; 22.5; 19.2; 14.0. HRMS: calc. for C35H52NO2Si [M + H]+ 546.3767; found 546.3762. [α]D23 = -45.74° (acetone, c = 0.88)  403  F.3 Proton and carbon-13 spectra for homotyrosinol and lepadiformine intermediates  Figure 197. NMR spectra of compound 358  404  Figure 198. NMR spectra of compound 359  405  Figure 199. NMR spectra of compound 360  406  Figure 200. NMR spectra of compound 361  407  Figure 201. NMR spectra of compound 362  408  Figure 202. NMR spectra of compound 363  409  Figure 203. NMR spectra of compound 364  410  Figure 204. NMR spectra of compound 365  411  Figure 205. NMR spectra of compound 355, P’ = H  412  Figure 206. NMR spectra of compound 367  413  Figure 207. NMR spectra of compound 370, P = H, P’ = TBDPS  414  Figure 208. NMR spectra of compound 370, P = H, P’ = TBS  415  Figure 209. NMR spectra of compound 370, P = P’ = Ac  416  Figure 210. NMR spectra of compound 370, P = P’ = H  417  Figure 211. NMR spectra of compound 371  418  Figure 212. NMR spectra of compound 373  419  Figure 213. NMR spectra of compound 353  420  Figure 214. NMR spectra of compound 372  421  Figure 215. 19F-NMR spectra of compound 372  422  OTBDPS N  Ms  O  OTBDPS N  Ms  O  Figure 216. NMR spectra of compound 375  423  OTBDPS N SO2 O  H  OTBDPS N SO2 O  H  Figure 217. NMR spectra of compound 377  424  N SO2 O  H  N SO2 O  H  Figure 218. NMR spectra of compound 381  425  N SO2 O  H  N SO2 O  H  Figure 219. NMR spectra of compound 384  426  N PhS PhS  SO2 H  N PhS PhS  SO2 H  Figure 220. NMR spectra of compound 385  427  N SO2 H  N SO2 H  Figure 221. NMR spectra of compound 386  428  OTBDPS N SO2 O  H  OTBDPS N SO2 O  H  Figure 222. NMR spectra of compound 387  429  OTBDPS N SO2  PhS PhS  H  OTBDPS N PhS PhS  SO2 H  Figure 223. NMR spectra of compound 388  430  OTBDPS N SO2 H  OTBDPS N SO2 H  Figure 224. NMR spectra of compound 389  431  OTBDPS N SO2 H  C6H13 O  OTBDPS N SO2 H  C6H13 O  Figure 225. NMR spectra of compound 390  432  OTBDPS NH C6H13 H  O  OTBDPS NH C6H13 H  O  Figure 226. NMR spectra of compound 391  433  G. X-RAY CRYSTALLOGRAPHY DATA G.1 X-ray data of compound 184  O MeO HN  O  O  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  C11H13NO4 223.22 colorless, tablet 0.12 X 0.42 X 0.44 mm orthorhombic primitive a = 9.1076(11) Å b = 14.6326(15) Å c = 16.516(3) Å α = 90 o β = 90 o γ = 90o V = 2201.0(5) Å3 P bca (#61) 8 1.347 g/cm3 944.00 1.03 cm-1 978 exposures @ 10.0 seconds 36.00 mm 55.8o Total: 21687 0.060; 0.098 1.03 0.038; 0.086  434  G.2 X-ray data of compound 233 (R = 4-NO2)  O  N O S O  NO2 =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  C15H14N2O5S 334.34 yellow, tablet 0.13 X 0.28 X 0.50 mm monoclinic primitive a = 15.3980(5) Å b = 14.0863(4) Å c = 21.2842(6) Å α = 90 o β = 101.984(1) o γ = 90 o V = 4515.9(2) Å3  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax  P21/c (#14) 12 1.475 g/cm3 2088.00 2.43 cm-1 1304 exposures @ 5.0 seconds 36.00 mm 56.3o  No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator No. Observations (I>2.00σ(I)) Residuals (refined on F): R1; wR2  Total: 54451 0.070; 0.111 1.01 7930 0.043; 0.097  435  G.3 X-ray data of compound 233 (R = 3-NO2)  O S N O O2N O  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  C15H14N2O5S 334.34 colorless, plate 0.05 X 0.12 X 0.30 mm triclinic primitive a = 7.3616(7) Å b = 8.4583(9) Å c = 12.1965(11) Å α = 93.808(6) o β = 96.907(7) o γ = 96.229(6) o V = 747.04(13) Å3 P -1 (#2) 2 1.486 g/cm3 348.00 2.45 cm-1 1904 exposures @ 30.0 seconds 36.00 mm 56.0o Total: 12414 0.079; 0.105 1.11 0.046; 0.095  436  G.4 X-ray data of compound 237, R = CH2OH or compound 374  O  O  S O N  OH  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  C11H15NO4S 257.30 colorless, needle 0.12 X 0.20 X 0.25 mm orthorhombic primitive a = 5.6476(6) Å b = 9.7999(12) Å c = 21.490(3) Å α = 90 o β = 90 o γ = 90 o V = 1189.4(2) Å3  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator No. Observations (I>2.00σ(I)) Residuals (refined on F): R1; wR2  P 212121 (#19) 4 1.437 g/cm3 544.00 2.75 cm-1 804 exposures @ 15.0 seconds 36.00 mm 56.2o Total: 10763 0.047; 0.082 1.03 2471 0.035; 0.076  437  G.5 X-ray data of compound 238  O  O S O NH N O S O  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  C23H24N2O5S2 472.56 colourless, irregular 0.07 X 0.10 X 0.25 mm triclinic primitive a = 9.7156(4) Å b = 10.9531(5) Å c = 10.9900(5) Å α = 87.433(2) o β = 75.485(2) o γ = 76.942(2)o V = 1102.82(8) Å3 P -1 (#2) 2 1.423 g/cm3 496.00 2.80 cm-1 925 exposures @ 45.0 seconds 36.00 mm 47.7o Total: 9930 0.071; 0.119 1.30 0.056; 0.115  438  G.6 X-ray data of compound 315 (Y = H)  O  O  S N  O  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  C11H13NO3S 239.28 colorless, prism 0.34 x 0.48 x 0.60 mm monoclinic primitive a = 11.5644(17) Å b = 16.574(2) Å c = 12.1519(19) Å α = 90.0 o β = 116.832(6) o γ = 90.0 o V = 2078.4(5) Å3  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F): R1; wR2 Goodness of Fit Indicator Residuals (refined on F2, all data): R1; wR2  P 21/c (#14) 4 1.529 g/cm3 1008.00 3.02 cm-1 1304 exposures @ 5.0 seconds 36.00 mm 55.6o Total: 24398 0.034; 0.091 1.05 0.040; 0.094  439  G.7 X-ray data of compound 315 (Y = Br)  O Br  O S N  O  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  C11H12NO3SBr 318.19 colorless, plate 0.03 X 0.30 X 0.56 mm monoclinic primitive a = 7.6175(5) Å b = 17.6754(12) Å c = 9.3509(6) Å α = 90 o β = 110.762(3) o γ = 90 o V = 3178.6(2) Å3 P 21/n (#14) 4 1.795 g/cm3 640.00 36.64 cm-1 1156 exposures @ 10.0 seconds 36.00 mm 56.1o Total: 13359 0.038; 0.064 1.04 0.027; 0.061  440  G.8 X-ray data of compound 315 (Y = Me)  O Me  O S N  O  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  C12H15NO3S 253.31 colorless, prism 0.32 X 0.40 X 0.40 mm monoclinic primitive a = 8.3546(10) Å b = 12.3929(16) Å c = 11.2319(14) Å α = 90 o β = 97.713(6) o γ = 90 o V = 1152.4(2) Å3 P 21/n (#14) 4 1.460 g/cm3 536.00 2.76 cm-1 1336 exposures @ 10.0 seconds 36.00 mm 55.8o Total: 13252 0.036; 0.089 1.05 0.032; 0.086  441  G.9 X-ray data of compound 316a  O  O  S N  HO  H  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  C11H15NO3S 241.30 colourless, needle 0.05 X 0.10 X 0.60 mm monoclinic primitive a = 6.4672(4) Å b = 19.0972(13) Å c = 17.1840(11) Å α = 90 o β = 95.212(2) o γ = 90o V = 3022.9(2) Å3 P 21/c (#14) 8 1.517 g/cm3 1024.00 2.97 cm-1 1088 exposures @ 60.0 seconds 36.00 mm 52.4o Total: 24451 0.061; 0.090 1.01 0.036; 0.079  442  G.10 X-ray data of compound 317  O  O S N OH  TMS  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  C16H23NO3SSi 337.50 colorless, rod 0.20 X 0.25 X 0.60 mm monoclinic primitive a = 6.5038(6) Å b = 20.795(2) Å c = 19.367(2) Å α = 90 o β = 96.390(5) o γ = 90 o V = 2603.1(4) Å3 P 21/c (#14) 6 1.292 g/cm3 1080.00 2.67 cm-1 1163 exposures @ 10.0 seconds 36.00 mm 55.8o Total: 30494 0.055; 0.106 1.01 0.040; 0.097  443  G.11 X-ray data of compound 318  O  O S N OH  = Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  C13H15NO3S 265.32 colorless, prism 0.18 X 0.27 X 0.35 mm monoclinic C-centered a = 24.113(3) Å b = 6.6202(7) Å c = 15.111(2) Å α = 90 o β = 92.625(5) o γ = 90 o V = 2409.6(5) Å3 C 2/c (#15) 8 1.463 g/cm3 1120.00 2.68 cm-1 1042 exposures @ 5.0 seconds 36.00 mm 56.0o Total: 14704 0.040; 0.095 1.03 0.034; 0.091  444  G.12 X-ray data of compound 339  O  O S HN  O  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  C13H15NO3S 265.32 colorless, needle 0.05 X 0.12 X 0.30 mm monoclinic primitive a = 15.167(2) Å b = 7.7915(9) Å c = 20.381(3) Å α = 90 o β = 91.260(5) o γ = 90 o V = 2407.9(6) Å3  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  P 21/c (#14) 8 1.464 g/cm3 1120.00 2.68 cm-1 846 exposures @ 60.0 seconds 36.00 mm 46.5o Total: 20803 0.100; 0.232 1.16 0.079; 0.220  445  G.13 X-ray data of compound 283  O2S N H  H  O  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  C13H15NO3S 265.32 colorless, needle 0.04 X 0.08 X 0.25 mm orthorhombic primitive a = 5.8345(3) Å b = 14.1073(7) Å c = 14.6506(7) Å α = 90 o β = 90 o γ = 90 o V = 1205.9(1) Å3 P 212121 (#19) 4 1.461 g/cm3 560.00 2.68 cm-1 737 exposures @ 15.0 seconds 36.00 mm 53.1o Total: 9445 0.053; 0.102 1.06 0.043; 0.098  446  G.14 X-ray data of compound 381  N SO2 O  H  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  C10H13NO3S 227.27 colorless, plate 0.10 X 0.45 X 0.55 mm monoclinic primitive a = 12.2735(14) Å b = 5.7211(7) Å c = 15.0266(17) Å α = 90.0 o β = 100.205(5) o γ = 90.0 o V = 1038.4(2) Å3  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  P 21/c (#14) 14 1.454 g/cm 480.00 2.97 cm-1 949 exposures @ 10.0 seconds 36.00 mm 55.9o Total: 16536 0.045; 0.092 1.06 0.036; 0.087  447  G.15 X-ray data of compound 386  N O2 S H  =  Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters  Space Group Z value Dcalc F000 μ(MoKα) Data Images Detector Position 2θmax No. of Reflections Measured Residuals (refined on F2, all data): R1; wR2 Goodness of Fit Indicator Residuals (refined on F): R1; wR2  C10H17NO2S 215.31 colorless, irregular 0.33 X 0.40 X 0.42 mm monoclinic primitive a = 10.1762(2) Å b = 8.9255(2) Å c = 12.1863(3) Å α = 90 o β = 114.411(1) o γ = 90o V = 1007.90(4) Å3 P 21/c (#14) 4 1.419 g/cm3 464.00 2.95 cm-1 1127 exposures @ 5.0 seconds 36.00 mm 56.1o Total: 10483 0.036; 0.090 1.07 0.032; 0.088  448  

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