LIBRARY Michigan State University PLACE iN RHURN BOX to remove this checkout from your record. TO AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE DATE DUE (MAR) 2 702005 079??)962005 mm mm.“ SW" SYNTHETIC STUDIES TOWARDS THE PHOMACTINS By Baoyu Mi A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 2000 Sl'Wi ' I -;--'-v.~ .‘F, n. ‘ t .-' \I‘ I" -' .-.ls.lt.kll \\..;..\t.\ v * 'F 3.41.7.2 the Irmt h etch. Tran: \ pr» 1")! w.¢;_n:u- “ " ‘ O ‘- ‘ " ' ‘ E it“, u, . “\d L\‘ 1.11. n .. i 37“.; ‘ . ' . ‘ ) . A ~Muwu t \Qd‘i .hc ‘ 7"3".)S»” “i q “truth dd\‘i|di :' o x T‘ . ills seam ‘ :19 (1'1 [1' 3"‘I‘ -, \.,,.\\ d r.“ . .. t. \ war 4"’ ABSTRACT SYNTHETIC STUDIES TOWARDS THE PHOMACTINS By Baoyu Mi The goal of this project has been to establish a strategy to construct the bicyclo[9.3.1]pentadecane skeleton of phomactin based PAF antagonists. The first generation synthetic plan utilized a strain energy promoted ring growing sequence including the Trost three-carbon ring expansion. During the examination of this approach, Trost’s process was discovered to work on bicyclo[3.2.1] systems. However, when applied to the properly elaborated bicyclo[3.2. 1] starting material, this protocol was limited because the steric hindrance of the bicyclic system prevented installation of the required auxiliary groups needed for the ring expansion process. The second generation strategy was based on the disconnection of the C(7)-C(8) rt—bond of the bicyclo[9.3.l]pentadecane system. This approach was originally designed to employ a ring-closing metatheses (RCM) or McMurry olefination as the macrocyclization step. Experimentally, these cyclization methods furnishing only dimerization by-products rather than desired ring closed products. Thus adjustments to this approach were required. The employment of a modified Julia olefination as the chain homologation step allowed construction of the C(7)-C(8) rt-bond of the phomactin skeleton. Nozaki— Hiyama-Kishi (NHK) coupling then served as the macrocyclization step and led to the successful construction of phomactin’s bicyclic system at high efficiency. Via this Strategy, three model compounds representing two types of phomactin structures were prepared and will be tested for PAF antagonistic activities. To my family iii F13: of all. 1 \ lLszi c. it to! h=~ x 5:35. ldl\0 MI" ' icifl Slim-Am l \ihl‘. to 'l' n this! R - . . i',” Y r 'b . ‘ J l;r: .‘jl mic-tr h“ " t\-. I d ACKNOWLEDGMENTS First of all, I would like to express my sincere gratitude to Professor Robert E. Maleczka, Jr. for his guidance and encouragement throughout the course of my Ph.D. Studies. I also want to thank Professors Michael W. Rathke, Milton R. Smith. III, and John L. McCracken for serving in the guidance committee. I wish to thank Professors William H. Reusch, Gregory L. Baker, and Babak Borhan for their help. I also acknowledge Professor Harold Hart for a fellowship founded in his name. Dr. Donald Ward is acknowledged for conducting the single crystal X-ray diffraction analysis. I must also thank all my colleagues in Professor Maleczka’s group for their friendship and cooperation, notably Lamont Terrell, Feng Geng, Joseph Ward, Eric Ruggles, Jerome Lavis, and William Gallagher. Finally, I appreciate the love and support from my parents, my wife Wenjun, and my daughters Dongfang and Kelly. Without them, this thesis would have been impossible. HST OF TABLES . LIST OF FlGl'RliS LlSTOFSl'XlBtllS CiRPTER l VIRODl'Clll l\ la. lM‘ld..‘.\‘I-. at lb CUTL‘SI 3"} lc. Dc~:;";:";g HAPTER 3 EDI OF TRUST ' PRCTOC 0L 0.\ B It In. lrttrtgxitttx 3b. Exocrirm -c no irctlt CizjliER 3 LElTlAllOXS DI“ :rHPTERi t“ RING-C L051? «AJXlCXll'RRY l ~14 D3 1b Ir‘\ \1‘ 4C1 ‘I€\: HM. “" X: 'n :5. TBS E . 3" EMT: ~ . ii. I.‘. Jhiu TABLE OF CONTENTS LIST OF TABLES ............................................................................................................ vii LIST OF FIGURES .......................................................................................................... viii LIST OF SYMBOLS AND ABBREVIATIONS .............................................................. xv CHAPTER 1 INTRODUCTION la. Isolation and Biological Activities of the Phomactins ...................................... 1 1b. Current Synthetic Studies on the Phomactins ................................................... 3 1c. Designing the Model Compounds and Their Synthetic Plan ............................ 5 CHAPTER 2 STUDY OF TROST'S THREE-CARBON RING EXPANSION PROTOCOL ON BICYCLIC SYSTEMS 2a. Introduction ....................................................................................................... 8 2b. Experimental Results and Discussion ............................................................... 9 2c. Theoretical Calculations .................................................................................. 13 CHAPTER 3 LIMITATIONS OF THE RING EXPANSION STRATEGY .......................................... 16 CHAPTER 4 THE RING-CLOSING METATHESIS (RCM) AND MCMURRY ROUTES 4a. Designing the Second Generation Synthesis ................................................... 19 4b. Installation of the Two Side Chains ................................................................ 20 4c. Investigation of the RCM/McMurry Protocol ................................................. 23 CHAPTER 5 THE SUCCESSFUL JULIA OLEFINATION AND NOZAKI-HIYAMA-KISHI (NHK) COUPLING ROUTE 5a. Adjustment of the Second Generation Synthetic Plan .................................... 26 5b. TBS Ether Protected Starting Material ............................................................ 27 5c. Examination of One-Pot Julia Olefination as the Annulation Step ................. 28 5d. The Julia Olefination Homologation and NHK Coupling Sequence .............. 29 5e. Final Transformations to the Model Compounds ............................................ 32 5f. Conclusion ....................................................................................................... 34 EXPERIMENTAL PROCEDURES ................................................................................. 36 REFERENCES CITED ..................................................................................................... 70 . PEXDlX l l-T’l} iztglc Cn \ldl ‘ v .33?E.\'Dl.\' I lu$gk€nqn~ lPPENDlX 3 like“. llXMR 4nd APPENDIX 1 X-ray Single Crystal Structure Determination of Compound V-IS .................................. 73 APPENDIX 2 X-ray Single Crystal Structure Determination of Compound V-16 .................................. 77 APPENDIX 3 Relevant lHNMR and I3CNMR Spectra ............................................................................ 81 vi .. ,_ . f. .. ‘ Tli'lsi Blk‘lk‘glkdl .\ a _ _ l Till: .. TheolL‘lls .1l l {515: 0 ‘i.\‘ I. v iii-.1». pawn/tin“, £35, A: mt (“M 'r at. c PLQ..lCtL’r\ TQCI‘ CMIdl D . I a u.“ u T"- LIST OF TABLES Table 1. Biological Activities of the Phomactins ................................................................ 2 Table 2. Theoretical Calculation Results .......................................................................... 14 Table 3. Optimization of the NHK Coupling .................................................................... 30 Table 4. Crystal Data and Structure Refinement for Compound V-15 ............................. 74 Table 5. Atomic Coordinates (x 10‘), Equivalent Isotropic Displacement Parameters (A‘ x 10“), and Occupancies for Compound V-15 ........................... 76 Table 6. Crystal Data and Structure Refinement for Compound V-16 ............................. 78 Table 7. Atomic Coordinates (x 104), Equivalent Isotropic Displacement Parameters (A2 x 103), and Occupancies for Compound V-16 ........................... 80 vii Err: l.\:i‘d.'.1ll} U .o. F‘Z‘Jff :. Timid; \ l 5’ ‘ »"1r~ I g . r.:.'rs.~.Pa.it.;..tn s 353: 4. Tozah's S\ 3' \ c 55355 llrlmrth's ,. ">"l't3. ., o . Hg.» 6. Fl-\l G'Cli'C.’ b Fzggre .7. The Trust l :-\ ll le‘i‘fc" «N F f": r:.'. .:..g ‘6. In‘ 1 . . «- E. “1.1.6. “I . ‘ I It'- In‘he\ti v .- . :u Agra ‘Q ‘L‘ In‘\e\’1'\ 51“ K K Fm. ‘i'.;'\~ .Q . s~ .P-‘sfi 4 'J' Drul‘i. PM {‘3‘} w ‘E‘ l . ‘. k.“ '1 U41; LIST OF FIGURES Figure 1. Naturally Occuring Phomactins ........................................................................... 2 Figure 2. Yamada’s Total Synthesis of Phomactin D ......................................................... 3 Figure 3. Pattenden’s Synthesis of a Core Structure of Phomactin A ................................. 4 Figure 4. Totah’s Synthesis of a Core Structure of Phomactin A ....................................... 4 Figure 5. Halcomb’s Synthesis of the Skeleton of Phomactin D ........................................ 5 Figure 6. First Generation Synthetic Plan of the Model Compounds ('Pharmacophores)... 6 Figure 7. The Trost Three-Carbon Ring Expansion Process ............................................... 8 Figure 8. The Primary Route to Make Ring Expansion Precursors .................................... 9 Figure 9. The Alternative Route to Make Ring Expansion Precursors ............................. 10 Figure 10. Behavior of Bicyclic Systems Under Ring Expansion Conditions .................. l 1 Figure 11. Theoretical Consideration of the Ring Expansion Process .............................. 13 Figure 12. Preparation of Bicycle [-32 and Installation of the Side Chains ..................... 16 Figure 13. Limitations of the Trost Ring Expansion Strategy .......................................... 17 Figure 14. Designing the RCM/McMurry Protocol .......................................................... 20 Figure 15. Efforts to Install the gem-Disubstituted Olefin Side Chain ............................. 2l Figure 16. Installation of the Second Olefin Side Chain ................................................... 22 Figure 17. Investigation of the RCM Process ................................................................... 23 Figure 18. Investigation of the McMurry Reaction ........................................................... 24 Figure 19. Adjustment of the Second Generation Synthetic Plan ..................................... 26 Figure 20. Preparation of the TBS Ether Protected Starting Material ............................... 27 Figure 21. Evaluation of a One-Pot Julia Olefination as the Annulation Step .................. 29 Figure 22. Julia Olefination Elongation and Optimization of the NHK Coupling ........... 30 Figure 23. Preparation of Model Compound [-26 ............................................................. 32 Figure 24. Preparation of Model Compound [-25 ............................................................. 34 Figure 25. ORTEP Drawing of the Structure of Compound IV-15 .................................. 75 viii F223: 26 ORTEP r' ‘T f" I; l. .Ldib I u no ‘3'?) \ g...» -2. fv‘l r1 L _‘ r» ll \0 ll_\'.\lR C MIR ll .\‘.\lR1 . ‘. C.\.\1R :’:.H\.\ER «a ‘ Ind-D . -. s CMIR Fig.5}? H .\'.\ll\’ . CNXIR H .\'.\lR Cw; .. HXXlR 3C X.\‘.l . ll XXI;- ‘c .\'.\n H.\‘_\1i cm, “NW "C .\‘.\'. H Xx” C\'_\«i H \M: .C Mr H .\'.\1 Figure 26. Figure 27. Figure 28. Figure 29. Figure 30. Figure 31. Figure 32. Figure 33. Figure 34. Figure 35. Figure 36. Figure 37. Figure 38. Figure 39. Figure 40. Figure 41. Figure 42. Figure 43. Figure 44. Figure 45. Figure 46. Figure 47. Figure 48. Figure 49. Figure 50. Figure 51. Figure 52. ORTEP Drawing of the Structure of Compound IV-l6 .................................. 79 'H NMR (300 MHz, CDCl,) Spectrum of Compound “-53 ........................... 82 '3C NMR (75 MHz, CDCl,) Spectrum of Compound "-52 ............................. 83 1H NMR (300 MHz, CDC13) Spectrum of Compound Il-Sb ........................... 84 13C NMR (75 MHz, CDC13) Spectrum of Compound II-Sb ............................ 85 1H NMR (300 MHz, CDCl,) Spectrum of Compound II-Sc ............................ 86 13C NMR (75 MHz, CDCl,) Spectrum of Compound II-5c ............................. 87 lH NMR (300 MHz, CDCl,) Spectrum of Compound II-Sd ........................... 88 ‘3C NMR (75 MHz, CDCl,) Spectrum of Compound Il-Sd ............................ 89 1H NMR (300 MHz, CDCl,) Spectrum of Compound II-Se ............................ 90 13C NMR (75 MHz, CDC1_,) Spectrum of Compound II-Se ............................. 91 1H NMR (300 MHz, CDCl_,) Spectrum of Compound II-Sf ............................ 92 13C NMR (75 MHz, CDCl,) Spectrum of Compound II-Sf ............................. 93 1H NMR (300 MHz, CDCl,) Spectrum of Compound II-6a ........................... 94 UC NMR (75 MHz, CDC13) Spectrum of Compound "-63 ............................. 95 lH NMR (300 MHz, CDC13) Spectrum of Compound II-6b ........................... 96 13C NMR (75 MHz, CDCl,) Spectrum of Compound II-6b ............................ 97 lH NMR (300 MHz, CDCl,) Spectrum of Compound II-6c ............................ 98 ”C NMR (75 MHz, CDCl,) Spectrum of Compound II-6c ............................. 99 1H NMR (300 MHz, CDCl,) Spectrum of Compound II-6d ......................... 100 '3C NMR (75 MHz, CDC13) Spectrum of Compound II-6d .......................... 101 lH NMR (300 MHz, CDC13) Spectrum of Compound “-93 ......................... 102 13’C NMR (75 MHz, CDCl,) Spectrum of Compound II-9a ........................... 103 ‘H NMR (300 MHz, CDC13) Spectrum of Compound II-9b ......................... 104 13C NMR (75 MHz, CDCl,) Spectrum of Compound II-9b .......................... 105 lH NMR (300 MHz, CDCl,) Spectrum of Compound II-9c .......................... 106 13C NMR (75 MHz, CDC13) Spectrum of Compound II-9c ........................... 107 ix a ‘\ Fugrt )3. ." - 5").4 ,‘.d.5.‘ u . . ....... I- n~ r.-.:.‘9 ." 311 p "'S'TJ «l i..‘_§ ' _ s h . .I :49 b“‘\. . Lr...‘ 1" N 0 ' H.\'.\1R. H NMR "C NMR f. CXMRI H NMR (NMR. H NMR C NMR H.\.\1R- C NMR -. H NMR . CXXIR ~~ HXMR LCM}; .H.\'.\lR 3C XXL: HXMR ‘ - 'C .\'.\11 - HNME, - lC NW :. My} ' C.\'.\lj :. HXM} ‘ 1C .\'.\1 ‘ C.\‘.\« 'HNM Figure 53. Figure 54. Figure 55. Figure 56. Figure 57. Figure 58. Figure 59. Figure 60. Figure 61. Figure 62. Figure 63. Figure 64. Figure 65. Figure 66. Figure 67. Figure 68. Figure 69. Figure 70. Figure 71. Figure 72. Figure 73. Figure 74. Figure 75. Figure 76. Figure 77. Figure 78. Figure 79. 1H NMR (300 MHz, CDCl,) Spectrum of Compound lI-9d ......................... 108 13C NMR (75 MHz, CDCl_,) Spectrum of Compound Il-9d .......................... 109 lH NMR (300 MHz, CDCl,) Spectrum of Compound II-6e .......................... 1 10 13C NMR (75 MHz, CDC1_,) Spectrum of Compound II-6e ........................... 1 l 1 1H NMR (300 MHz, CDC1_,) Spectrum of Compound II-6f .......................... l 12 ”C NMR (75 MHz, CDC1,) Spectrum of Compound II-6f ........................... 1 13 lH NMR (300 MHz, CDCl,) Spectrum of Compound II-9e .......................... 1 14 ”C NMR (75 MHz, CDC13) Spectrum of Compound II-9e ........................... 1 15 1H NMR (300 MHz, CDCl,) Spectrum of Compound II-9f .......................... l 16 ”C NMR (75 MHz, CDC1,) Spectrum of Compound II-9f ........................... 1 17 lH NMR (300 MHz, CDCl,) Spectrum of Compound II-lOa ....................... 1 18 13C NMR (75 MHz, CDCl,) Spectrum of Compound II-10a ......................... 1 19 IH NMR (300 MHz, CDC13) Spectrum of Compound II-ll ......................... 120 BC NMR (75 MHz, CDCl,) Spectrum of Compound II-ll ........................... 121 1H NMR (300 MHz, CDCl3) Spectrum of Compound II-10b ....................... 122 13C NMR (75 MHz, CDCl_,) Spectrum of Compound II-lOb ........................ 123 1H NMR (300 MHZ, CDCI3) Spectrum Of Compound "-13 ......................... 124 13C NMR (75 MHz, CDCl,) Spectrum of Compound 11-13 ........................... 125 1H NMR (300 MHz, CDCl,) Spectrum of Compound II-10c ........................ 126 13C NMR (75 MHz, CDC13) Spectrum of Compound II-10c ......................... 127 1H NMR (300 MHz, CDC13) Spectrum of Compound 11-14 ......................... 128 13C NMR (75 MHz, CDCl,) Spectrum of Compound II-14 ........................... 129 1H NMR (300 MHz, CDC13) Spectrum of Compound lI-10d ....................... 130 [3C NMR (75 MHz, CDCl,) Spectrum of Compound II-10d ........................ 131 lH NMR (300 MHz, CDCl,) Spectrum of Compound “-15 ......................... 132 13C NMR (75 MHz, CDCl,) Spectrum of Compound “-15 ........................... 133 1H NMR (300 MHz, CDCl_,) Spectrum of Compound II-10e ........................ 134 3:21:30. "C suit Ewil. H .\'.\lRe ...1s '. b £97532 «CNXlR! Fgurtil. H NMR Egreii 1C NMR £52255. H NMR- “;86. CXMR 9;: 5.", H .\'.\ll Fists ii. 'C NMR f:;.:: N H \XlH @300. AC X.\ll $2.191. H \th PCT-:91. C XV, .;;1293. H X.\‘.' 17;}: '94. ”C X31 95. H NM v» luv “ ' ‘ .1“ . . ‘sLlCM ‘ ' 5 1'“, \\ '- h‘v‘ 3.. Figure 80. ”C NMR (75 MHz, CDCl,) Spectrum of Compound II-10e ......................... 135 Figure 81. IH NMR (300 MHz, CDCl,) Spectrum of Compound II-10f ........................ 136 Figure 82. ”C NMR (75 MHz, CDCl,) Spectrum of Compound II-10f ......................... 137 Figure 83. lH NMR (300 MHz, CDCl,) Spectrum of Compound 11-16 ......................... 138 Figure 84. ”C NMR (75 MHz, CDC1,) Spectrum of Compound 11-16 ........................... 139 Figure 85. 1H NMR (500 MHz, CDCl,) Spectrum of Compound III-l .......................... 140 Figure 86. ”C NMR (125 MHz, CDC13) Spectrum of Compound III-l ......................... 141 Figure 87. lH NMR (500 MHz, CDC13) Spectrum of Compound III-2 .......................... 142 Figure 88. ”C NMR (125 MHz, CDCl,) Spectrum of Compound III-2 ......................... 143 Figure 89. lH NMR (500 MHz, CDCI3) Spectrum of Compound [-32 ........................... 144 Figure 90. ”C NMR (125 MHz, CDCl,) Spectrum of Compound [-32 .......................... 145 Figure 91. 1H NMR (500 MHz, CDCl,) Spectrum of Compound III-3 .......................... 146 Figure 92. ”C NMR (125 MHz, CDC1_,) Spectrum of Compound III-3 ......................... 147 Figure 93. 'H NMR (500 MHz, CDCl,) Spectrum of Compound III-5 .......................... 148 Figure 94. l3C NMR (125 MHz, CDCl,) Spectrum of Compound III-5 ......................... 149 Figure 95. lH NMR (500 MHz, CDC13) Spectrum of Compound III-6 .......................... 150 Figure 96. ‘3C NMR (125 MHz, C6D6) Spectrum of Compound III-6 ............................ 151 Figure 97. lH NMR (500 MHz, CDC1_,) Spectrum of Compound III-8 .......................... 152 Figure 98. ”C NMR (125 MHz, CDC1_,) Spectrum of Compound III-8 ......................... 153 Figure 99. lH NMR (500 MHz, CDC13) Spectrum of Compound III-9 .......................... 154 Figure 100. ”C NMR (125 MHz, CDCl,) Spectrum of Compound III-9 ....................... 155 Figure 101. lH NMR (300 MHz, CDCl,) Spectrum of Compound IV-S ........................ 156 Figure 102. ”C NMR (75 MHz, CDC13) Spectrum of Compound IV-S ......................... 157 Figure 103. 'H NMR (300 MHz, CDCl,) Spectrum of Compound IV-l ........................ 158 Figure 104. I3C NMR (75 MHz, CDCl,) Spectrum of Compound IV-l ......................... 159 Figure 105. 1H NMR (300 MHz, CDC13) Spectrum of Compound IV-9 ........................ 160 Figure 106. ”C NMR (75 MHz, CDCl,) Spectrum of Compound IV-9 ......................... 161 xi figs: 10'. H .\'.\ll~. izgn 1:13 "C .\'.\13 141321119 H _\'.\l;». thgrt 110. ’C .\'.\l}-~ Figurelll. H.\'.\11x Fgurtllé. 'C NMR ng372 117. H NMR 13.16118. 1C \.\11l F:g.rc119. H NMR 2.1121111. 1C .\'.\li 111. H .\'.\11- - I. 1C .\'.\1. H .\‘.\11 1":§.:e1:4. ’c xxx: ‘ H .\‘.\1} ‘ - C NM t's. _ . . ~1 Fzrlr-1‘_ ”C“: .._S 2C \ E» - X ‘HXM . .C:){\ . - .\ f'». "$33150 ‘~~ C \‘ \ 1t. ‘ 't-i'c 12; Figure 107. Figure 108. Figure 109. Figure 110. Figure 111. Figure 112. Figure 113. Figure 114. Figure 115. Figure 116. Figure 117. Figure 118. Figure 119. Figure 120. Figure 121. Figure 122. Figure 123. Figure 124. Figure 125. Figure 126. Figure 127. Figure 128. Figure 129. Figure 130. Figure 131. Figure 132. Figure 133. lH NMR (300 MHz, CDC13) Spectrum of Compound IV-10 ...................... 162 ”C NMR (75 MHz, CDC13) Spectrum of Compound IV-10 ....................... 163 lH NMR (300 MHz, CDC13) Spectrum of Compound IV-8 ........................ 164 l3C NMR (75 MHz, CDCl,) Spectrum of Compound IV-8 ......................... 165 lH NMR (300 MHz, CDCl,) Spectrum of Compound IV-ll ...................... 166 ”C NMR (75 MHz, CDCl,) Spectrum of Compound IV-ll ....................... 167 IH NMR (300 MHz, CDCl,) Spectrum of Compound IV-l3 ...................... 168 ”C NMR (75 MHz, CDCl,) Spectrum of Compound lV-l3 ....................... 169 1H NMR (300 MHz, CDCl,) Spectrum of Compound IV-l4 ...................... 170 13C NMR (75 MHz, CDC13) Spectrum of Compound IV-l4 ....................... 171 1H NMR (300 MHz, CDC1_,) Spectrum of Compound IV-lS ...................... 172 ”C NMR (75 MHz, CDCl,) Spectrum of Compound IV-lS ....................... 173 1H NMR (300 MHz, CDCl,) Spectrum of Compound IV-l6 ...................... 174 ”C NMR (75 MHz, CDC13) Spectrum of Compound IV-l6 ....................... 175 IH NMR (300 MHz, CDCl,) Spectrum of Compound IV-l9 ...................... 176 ”C NMR (75 MHz, CDCl,) Spectrum of Compound IV-19 ....................... 177 1H NMR (300 MHz, CDCl,) Spectrum of Compound IV-20 ...................... 178 ”C NMR (75 MHz, CDC1_,) Spectrum of Compound IV-20 ....................... 179 1H NMR (300 MHz, CDC13) Spectrum of Compound IV-21 ...................... 180 ”C NMR (75 MHz, CDC13) Spectrum of Compound IV-21 ....................... 181 1H NMR (300 MHz, CDC13) Spectrum of Compound IV-3 ........................ 182 ”C NMR (75 MHz, CDCl,) Spectrum of Compound IV-3 ......................... 183 1H NMR (300 MHz, CDCl,) Spectrum of Compound V-l .......................... 184 ”C NMR (75 MHz, CDCl,) Spectrum of Compound V-l ........................... 185 1H NMR (300 MHz, CDCl,) Spectrum of Compound V-2 .......................... 186 ”C NMR (75 MHz, CDC1,) Spectrum of Compound v-2 ........................... 187 lH NMR (300 MHz, CDC13) Spectrum of Compound V-3 .......................... 188 xii ’ ‘ p"‘1'|1 1‘4 phi.» . v- 1" " 1“ her: 1.- ‘. H\.\1R . -. 'C NMR . ‘C .\'.\11-- .HNME- :. . 'C We . (NW '. . H .\'_\li H .\'.\1lx; C .\'\li~. . H.\'.\1R CNXlR "'..'H.\.\1R 1“] '1 \i I 'nu. j-Q s l" "71', ‘. r" ' 5d,; ’ u» '7. r.-. l'. 1‘] 1h .a'{1 “'- C.\'.\1R - H\\1R -' C.\.\1R . H.\'.\1R . 'C .\'.\11: “T: I: . H \\lR . 3C x1111 " 1 3- H_\1\1R ‘ EC M11» - (NMR H MIR - C X1111 ‘ HX’XIR , AC MIR ‘ - HNMR l\ Figure 134. Figure 135. Figure 136. Figure 137. Figure 138. Figure 139. Figure 140. Figure 141. Figure 142. Figure 143. Figure 144. Figure 145. Figure 146. Figure 147. Figure 148. Figure 149. Figure 150. Figure 151. Figure 152. Figure 153. Figure 154. Figure 155. Figure 156. Figure 157. Figure 158. Figure 159. Figure 160. ”C NMR (75 MHz, CDCl,) Spectrum of Compound V-3 ........................... 189 lH NMR (300 MHz, CDC13) Spectrum of Compound V-4 .......................... 190 ”C NMR (75 MHz, CDC1_,) Spectrum of Compound V-4 ........................... 191 1H NMR (300 MHz, CDC1_,) Spectrum of Compound V-6 .......................... 192 ”C NMR (75 MHz, CDCl,) Spectrum of Compound V-6 ........................... 193 1H NMR (300 MHz, CDCl,) Spectrum of Compound V-9 .......................... 194 ”C NMR (75 MHz, CDCl,) Spectrum of Compound V-9 ........................... 195 1H NMR (300 MHz, CDC13) Spectrum of Compound V-lO ........................ 196 ”C NMR (75 MHz, CDCl,) Spectrum of Compound V-10 ......................... 197 lH NMR (500 MHz, CDCl,) Spectrum of Compound V-14 ........................ 198 ”C NMR (75 MHz, CDC1_,) Spectrum of Compound V-14 ......................... 199 1H NMR (500 MHz, CDCl,) Spectrum of Compound V-15 ........................ 200 ”C NMR (125 MHz, CDC13) Spectrum of Compound V-15 ....................... 201 'H NMR (500 MHz, CDCl,) Spectrum of Compound V-16 ........................ 202 ”C NMR (125 MHz, CDCl,) Spectrum of Compound V-16 ....................... 203 'H NMR (500 MHz, CDC13) Spectrum of Compound V-17 ........................ 204 ”C NMR (125 MHz, CDCl,) Spectrum of Compound V-17 ....................... 205 'H NMR (500 MHz, CDC13) Spectrum of Compound V-18 ........................ 206 '3C NMR (125 MHz, CDCl,) Spectrum of Compound V-18 ....................... 207 lH NMR (500 MHz, CDC13) Spectrum of Compound V-19 ........................ 208 ”C NMR (125 MHz, CDC13) Spectrum of Compound V-l9 ....................... 209 lH NMR (500 MHz, CDC1_,) Spectrum of Compound [-27 ......................... 210 ”C NMR (125 MHz, CDCl,) Spectrum of Compound [-27 ........................ 21 1 1H NMR (500 MHz, CDC13) Spectrum of Compound V-20 ........................ 212 ”C NMR (125 MHz, CDCl,) Spectrum of Compound V-20 ....................... 213 1H NMR (500 MHz, CDCl,) Spectrum of Compound [-26 ......................... 214 ”C NMR (125 MHz, CDC1,) Spectrum of Compound [-26 ........................ 215 xiii 1:53: 161. 'C XV." FELT: 1115 H .\'.\ll.' 5;: on CNN} Figure 161. 1H NMR (500 MHz, CDC13) Spectrum of Compound V-22 ........................ 216 Figure 162. ”C NMR (125 MHz, CDCl,) Spectrum of Compound V-22 ....................... 217 Figure 163. 'H NMR (500 MHz, CDCl,) Spectrum of Compound V-23 ........................ 218 Figure 164. ”C NMR (75 MHz, CDC13) Spectrum of Compound V-23 ......................... 219 Figure 165. lH NMR (500 MHz, CDC13) Spectrum of Compound I-25 ......................... 220 Figure 166. ”C NMR (75 MHz, CDCl,) Spectrum of Compound [-25 .......................... 221 xiv Ac ac ac AIBN aq C I DBU DIAD DIBAL DMAP DME DMF DMSO EI eq FAB HMPA HRMS HS-BT KHMDS LHMDS mCPBA min LIST OF SYMBOLS AND ABBREVIATIONS acetyl acetylacetonate 2,2’-azobisisobutyronitrile aqueous chemical ionization cyclohexyl 1,8-diazabicyclo[5,4,0]undec-7-ene diisopropyl azodicarboxylate disiobutylaluminum hydride 4-(dimethylamino)pyridine dimethoxylethane N,N-dimethylformamide dimethyl sulfoxide electric ionization equivalent fast atom bombardment hour hexamethyl phosphoramide high resolution mass spectrometry mercaptobenzothiazole Homer-Wadsworth-Emmons reaction potassium bis(trimethylsily1)amide lithium bis(trimethylsily1)amide m-chloroperbenzoic acid minute XV 111111 7:01 111111 111 1361105 1155 NHK NOE 1.11 HEB 101 mL MMFF mmol MOM NaHMDS NBS NHK NOE PAF PMB Py RCM SE TBAF TBS Tf THF TMS TSA milliliter Merck molecular force field millimole methoxymethyl methanesulfonyl sodium bis(trimethylsily1)amide N-bromosuccinimide Nozaki-Hiyama-Kishi nuclear Overhauser effect platelet activating factor p-methoxybenzyl pyridine ring closing metathesis room temperature strain energy tetrabutylammonium fluoride t-butyldimethylsilyl trifluoromethanesulfonyl tetrahydrofuran trimethylsilyl p-toluenesulfonic acid xvi it Isolation and Ir; recent 1.3K; 01min: I s 1 h glib: «their: ." ~\ » ~p-1 . ‘1‘. I"? ‘W» ar- ”"k rl1~{l’.\O-ii "vn'a' 11 \1'1 l.'. . uu\.l.d.~.‘|.\ “LIKE £111 . ‘ Y. .-1- \ Pit s - ‘. :‘ I"‘"’~‘\‘ ‘ D J _‘_, \ ‘\b\d\h ln\f" a.\ 117.11sz . 'kihint 1" I .. ‘.\€.’e K 5’65. 1-, ..‘\ 33373:» . 5:15;; :1" y ‘1 n h ‘ .411 R. u "0 l s ‘ :‘ .1‘1 _3 1 \,\I a“"V- ‘. n 3:4"; k ’43.“. . "1V3 (it sky“: “ii-ILATW“ “ CHAPTER 1 INTRODUCTION la. Isolation and Biological Activities of Phomactins In recent years, natural product scientists have payed increasing attention to the diversity of naturally occurring molecules derived from the sea. With two thirds of the globe submerged under the sea, it is not surprising that many natural compounds which show promising therapeutic activities come from ocean.1 The phomactins, including the structurally novel macrocycle phomactin A (I-l), were recently isolated from the marine fungus Phoma sp.2 by chemists from both Japan and the US. based Schering Plough Research Institute (Figure 1). Phoma sp. was isolated from the shell of a crab. C hionoecetes opilio, collected off the coast of Fukui prefecture, Japan. These metabolites have demonstrated marked biological properties, particularly platelet activating factor (PAF) antagonistic activities.3 Platelet activating factor (1-0—a1kyl-2(R)-(acetylglyceryl)- 3-phosphorylcholine) causes platelet aggregation, hypotension, smooth muscle contraction, and vascular permeability. Recent studies have shown PAF to contribute to chemotaxis and degranulation of polymorphonuclear leukocytes, indicating possible involvement in carcinogenic as well as inflammatory, respiratory, and cardiovascular diseases. Interestingly, while phomactin A (H) inhibited PAF-induced platelet aggregation, no effect on adenosine diphosphate, arachidonic acid, and collagen—induced platelet aggregation was observed. Thus phomactin A (H) is a new type of PAF antagonist. Furthermore, phomactin D (1-6) has been shown to possess 3-500 times the activities of other phomactins inhibiting PAF-induced platelet aggregation and inhibiting the binding of PAF to its receptors as shown in Table 1. Pthr-uttant Figure 1. Naturally Occurring Phomactins phomactin A phomactin B [-1 [-2 CH0 0 CHO O phomactin C phomactin D phomactin F. phomactin F phomactin G [-5 [-6 1-7 [-8 [-9 Table 1. Biological Activities of Phomactins Phomactins Platelet aggregation PAF binding 1&1th 19.1li A 10.0 2.3 B 17.0 47.9 B] 9.8 20.0 B2 1.6 22.1 C 6.4 63.0 D 0.80 0.12 E 2.3 5.19 F 3.9 35.9 G 3.2 0.38 Because of their unique molecular architecture and interesting biological activities, the phomactins have attracted the attention of the synthetic community since the first report of their isolation. Synthetic studies of such molecules would assist in elucidating the mechanism of action and facilitate the optimization of the therapeutic :firttrttcs mhcrcz' .‘tt'n'flililltl the :2 its: annuals 1' lb. Current 8) nthl Sc'tcrdl :11 35:11an 1-6 1251111111131. 11» ' awn“ t, l .. awn”: Allin 1111‘ ‘ \ 11111-12 mac 1': 1*. v I natal-10 111111 pru: i5 1'12 101101133, XVLLSCl‘xtttgt-c‘j ~\ ~ \ I 111.141.1111 01 tut properties inherent to this class of compounds. Additionally the synthetic challenge of constructing the macrocyclic furochroman ring, unique to phomactin A, clearly makes these compounds intriguing synthetic targets. 1b. Current Synthetic Studies of Phomactins Several groups are engaged in synthetic ventures focused on the phomactins. Phomactin D (1-6), which has the strongest PAF antagonistic activity among these metabolites, was the first member to be synthesized.4 The Japanese group which accomplished this synthesis started from an optically active bicyclo[2.2.2]octane building block [-12 made from the diastereoselective sequential Michael reaction of 2-cyclohexen- 1-one [-10 with propenoate I-ll (Figure 2). Oxidative cleavage of the C(2)-C(19) bond in [-12 followed by several steps of functional group manipulations afforded pentasubstituted cyclohexane segment I-13. Finally the key annulation step involves the cyclization of sulfone [-15 obtained from the coupling of aldehyde [-13 with lithiated sidechain segment I-14, to produce the phomactin bicyclo[9.3. 1 ]pentadecane ring system. Figure 2. Yamada’s Total Synthesis of Phomactin D 4 _. phomactin D ”-6) In addition to above synthesis of phomactin D, Pattenden reported the synthesis of a tricyclic furanochroman core structure of phomactin A (1-19).5 His approach started from a cyclohexenone building block [-16 (Figure 3). A key intermediate [-17 was .. ' ,u , :fttdid 1mm nit tastorrttutturts. A 18.31: 31111} 1.1mm i-iu T0141] 111)}: 1.H\ira\ :hc \\ r .L ’1’" LL.11TTJ,!~ ‘_ ._.1.wt1; \r') "_ ”\1L ‘1. J‘h. { u...\ul'“"‘n ,, __| 3 . ~ r§ 1 \ QR I \1‘1; 1 . W15" .,\. \ 1‘; q .‘5; Ar- ‘ ‘ ‘1 in“ “is . 1 la. “x a. s.""'\ I \‘I\Al prepared from the installation of the sidechain followed by several functional group transformations. After stepwise formation of the dihydrofuranochroman ring system of [- 18, the fully functionalized core structure [-19 was obtained via the oxidative elimination of the selenyl group in [-18, followed by dihydroxylation of the resulting double bond. Figure 3. Pattenden’s Synthesis of a Core Structure of Phomactin A Totah from the University of Iowa recently also published a report on her efforts towards the synthesis of phomactin A” Her work has focused on the construction of the chroman core structure by the Diels-Alder reaction of an oxygenated diene [-20 with dihydropyrone [-21 (Figure 4). From the Diels-Alder adduct [-22, a core structure [-19’, an analog of [-19 was prepared via a sequence of functional group elaborations. Figure 4. Totah’s Synthesis of a Core Structure of Phomactin A OMe o McO E o / EIOQC ., + l I ‘" T850 0 TBSO o "’0 1-20 1.21 1-22 Halcomb from the University of Colorado has recently published his synthesis of a phomaction D skeleton [-24. The ring closure was effected by an intramolecular Suzuki coupling, which proceeded with very low efficiency as outlined in Figure 5.7 The yield of the macrocyclization step of this protocol could potentially be optimized to practical level in the future as Danishefsky reported a higher yield in the construction of a I ‘i v 1 " ‘ «.1117 11111-1110“ 3 O. .' .‘.t*'1§,',.11201'l 01 W 111 summon. 31:13.1: 0. ARM .1"; -. x 0 3‘5““ 01') wixf‘ut 1t Designing of the The not cl ! .4]...de IS‘Ul' 11.12" .C‘ 5 O I .Ji - Li ‘1 "g.\ L‘\'\:Lr.\ ’3'.” s 1151 nu..- .‘ 1 .j 4&1‘»."lti’1$,1flf‘ in 1v“ ' ‘ Ills "21".1. "A “the l V I ‘ ‘ wl%1.11.‘.1lnlc \Kkl «.1116. 112 1 db’ 1‘1""; \:A.l\n1 d T ‘i - -‘~ ML. THEC‘ji‘ulln ‘ v kt.“ 1R”) {1- lnlm . K Us)"; . "“Q 10 \lh‘i 3.51" 11:1 ‘-‘\l 3017*». \.m3vjpj\ ”ECT‘CI .11" . u.“ ( 1 ,- 1 - 1 1)! Eric I \‘fi‘L; . ‘~:;\:S ‘1‘, . ‘ -. )chsn :. ,"1 le \‘T‘ .u.'."“. «11.13,! H i similar multicyclic framework also using a Suzuki coupling but with a different combination of catalysts.“ Figure 5. Halcomb’s Synthesis of the Skeleton of Phomactin D CNH QTBS Me ’ i 1. 9-BBN Me [VIC 69‘ l _._____5 | j / 2. Pd M‘ I MC DAL (160/0) L [-23 In summary, all prior synthetic studies have focused on either phomactin A or phomactin D. Although the total synthesis of the latter had been achieved, no significant progress on constructing the macrocyclic phomactin A system has yet been reported. 1c. Designing of the Model Compounds and Their Retrosynthetic Plan The novel structure and important biological properties of the phomactins captured our interest since their first disclosure. All phomactins are characterized by a moderately oxygenated bicyclo[9.3.l]pentadecane framework. In phomactin A, this macroskeleton is intervened by a furanochroman core structure while in the remaining 8 phomactins, the skeletons are funtionalized as a,B-unsaturated or saturated keto epoxides. Therefore, we designed [-25 which contains the dihydro or tetrahydro chroman core segment, as a model of phomactin A. By incooperating the a,B-unsaturated keto epoxide functionality into the bicyclo[9.3.1]pentadecane system, another model compound [-26 was devised to simulate the remaining phomactins (Figure 6). The preparation of these model compounds would not only enable us to develop a general strategy for the. construction of the macrocyclic skeleton of phomactins, but also provide insights into the synthesis of each individual phomactin members. These model molecules would also provide structural diversity, thus their biological evaluations would help probe the venture-acts 1t§ : ‘ 1‘ .11\ ‘1 51 k u l‘ 9:1 .. J T- 1 xx Kr : 4k .; “55:6 structure-activity relationship of phomactin based PAF antagonists. Figure 6. First Generation Synthetic Plan of the Model Compounds (Pharrnacophores) OH acid :> 125 / _ ep0x1dat1on O b-el1m1ndtion I “In” 0 """H' OP ' : - - ~ — _ .- - ‘ 2 : : : n - ‘ , Q - - ' \ - N \l u- o N 9‘ O p O ring Cope OP expansmn :: :> / / [~29 [ 30 ° :3 2&5 0 OP ”VOP TMS S PhSOz [~31 [~32 [~33 As illustrated in Figure 6, L25 can be derived from [-27 via acid mediated transannular nucleophilic addition. The other model compound, I-26, can also be made from [-27 by way of a ,B-elimination. I-27 would be obtained from the epoxidation of [- 28. Thus I-28 was viewed as a key intermediate. Its preparation would enable us to establish a general strategy for the synthesis of the phomactin class of natural compounds. Our first generation retrosynthetic plan of I-28 (Figure 6) reveals several synthetic challenges presented by this molecule. Essential to the design of this synthesis were sequential strain energy promoted ring expansions. To avoid the kinetic barriers present in medium size ring construction, we proposed that the 12/14 membered rings of the bicyclo[9.3.l] ring system of I-28 would be formed via a ring growing sequence. Immediate access to the macrocycle was planned via a [3,3]-sigmatropic transposition of 1” olefin tttth d. t} the emplut mt" 'lr strdn mm. 13111573 ['32 '11 4\ L" ‘ 1 Right. 3 \r‘! . 11L L1U\.u 4 I ~13, 44 .1 ‘ | .. ..l".'111‘.\. hi1»; 1": 1‘ t;=:€\1‘.11..\ltlll u! T‘ Tiersfare. \tc 11cc. '“l”""",ll"\1"tt I ”1' . I' ' _\ 1....11. ,.;,\ 11,, ‘ . . I-29, a [5.3.1] bicycle. Crucial to this four-carbon expansion will be installation of the A” olefin with defined geometry9 in 1-30. The synthesis of 1-30 was intended to proceed by the employment of a Trost three-carbon ring expansion protocol.'“ Here, we expected the strain associated with the precursor [3.2.1] ketone I-31 to be exploited. Bicyclic ketone I-32 was envisaged to be readily available from a known compound I-33 reported by Rigby.” The crucial step in the above plan was Trost’s three—carbon ring expansion. This method had been proved effective to build monocyclic rings. However, its reliability in the expansion of bicyclic systems remained a question at the time we began our study. Therefore, we decided to initiate a detailed investigation of this method, namely its incompatibility with bicyclic rings, before a full synthetic effort towards phomactins was put forth. STl 21 Introduction Effie: it t L‘ 3:46:26 tor \\ r.'. b . C(‘TJC‘SWML‘ flfl“ - Hi, . l . 311‘!) A \ V _ M. tiltlfl Li: " v. - 0i . ‘ “730.7” L ‘ULKT‘QL "I 3 3,". y- I . : . A" t twat; .hl\ cr-c ". . lit m5. Cf'UN-I ._. . s ,V vn-v ‘ l . 9 -. .\. 5 ~ It‘s“... I”; \Ird rl 5“! | la \\ l id useful m {7 217K ”g A“ ' tall “g' ‘b EFL. i’ , . i Aelcase 1n 4‘ aim NJ CHAPTER 2 STUDY OF TROST'S THREE-CARBON RING EXPANSION PROTOCOL ON BICYCLIC SYSTEMS 2a. Introduction Efficient construction of medium to macrocyclic compounds has long been a challenge for synthetic chemists. In 1980, Trost reported a silane mediated three-carbon condensative ring expansion approach leading to such systems (Figure 7).” In terms of bond-energy changes, Trost noted that the conversion of “-2 to “-3 is a neutral event, therefore successful ring expansions of this type require release of strain energy. In order to estimate this energy change, the strain energy of II-2 was approximated as the sum of the strain energies of cyclopentane and an n membered cycloalkane, and then compared against the strain energy of the expanded product II-3. This method of calculation proved useful in predicting the successful ring enlargements of 5, 8. and 12 membered rings, as well as the failure of 6 and 7 membered rings to expand. Figure 7. The Trost Three-Carbon Ring Expansion Process 0 | /o TBAF TMS —’ ——-—> SOzPh SOZPh S()3Ph 11.1 "-2 "-3 We have planed to apply this methodology to bicyclic molecules, and ultimately in the synthesis of phomactins. However, we were soon to realize that estimating the strain release in bicyclic systems was difficult as not many experimental strain energy data are available for the products. Furthermore approximating the strain energy of intermediate cyclopentyl species by adding the energies of the cyclopentane and the l- :m biqcic xx. 10d Figure 10. rathod might IX" gun at ucrc ilit‘imjfliim in I? “F‘ ;‘n i " SLl|rul-"\| Jr) e\?’\I—. amends. lb. Experimental Our stutij» Lone [14d or pr Elfiii'dllt‘n \JI~ Kilt v i‘ 1‘81 \. . ‘fl-“CCA {he 4?“... Filer. s parent bicycle would afford equal numbers for [3.2.1] bicyclic molecules II-10c and II- 10d (Figure 10, Vida infra), a conclusion we viewed with skepticism. An alternative method might be to only consider the most strained ring component of the bicycle, but again we were unsure as to the accuracy of such a simplification. Given these uncertainties in the theoretical treatment of this ring expansion process, we decided to conduct an experimental investigation of the ring expansion process on bridged bicyclic compounds. 2b. Experimental Results and Discussion Our study began with the purchase of norcamphor Il-4a and bicyclo[3.2.l]octan- 2-one II-4d or preparation of various [3.2.1],l2 [4.2.1],‘3 and [222]” bicyclic ketones. Elaboration of these carbonyls into a,a-disubstituted ring expansion precursors II-9a-d 10 followed the approach outlined in Figure 8. Figure 8. The Primary Route to Make Ring Expansion Precursors O LDA PhSSPh O 78 C- rt Oxone NaH/Nal (98%) Il-7(l.0eq.i SO Ph [Ma [Ma TMS 0M5 TMS o o + TMS PhOgs SOzPh “-88 (39%) MAX. "-98 (53%) :fkf ,0 V :1: .0 :§0 MS O M O M P110: 5 PhD: 3 PhD: 5 [14¢ II- 9b [1- 9c II- 9d .' htldllt“ ‘ 31558111137“ U ~11 E‘ mp Iumhhcd A [kproirmzzun U?- ' mtsihilsilflillif mitt. mm} 14:2. ahseie this li‘nf. éijiaizon. F.1d". yrzxiucts Ha Chi: x 1.3136 group I 5.11:0 the 81.1.". It.” 75 r“ . l ‘ ~~-:2.i\1 mt. {stem tor n I ' . 5‘ [14. t \’.‘5. Ix-li h ‘Llhrx. . 1‘ .\ -.' -‘ . yak? A :1, . :. " ~~ 1‘ uZ-f . “ - ~, M II‘ ‘9‘ IH‘: —‘. Ketones such as norcamphor (II-4a) were subjected to enolate formation and subsequent trapping with diphenyl disulfide. Oxone® oxidation15 of the a-phenylthio group furnished tan-benzenesulfonyl bicyclic ketones in good to excellent yields. Deprotonation of the B-ketosulfones with sodium hydride was followed by allylation with trimethylsilylallyl mesylate II-7l6 in the presence of sodium iodide. In contrast to the smooth installation of this siiane side chain to monocyclic ketones, it proved difficult to achieve this installation onto bicyclic ketones without an intrusive amount of 0- allylation. Furthermore, efforts to convert the O-allylated material into the C-allylated products via Claisen rearrangement failed, presumably due to the steric hindrance of the sulfone group. However, the O-allylated by-products could be quantitatively hydrolyzed back to the starting benzenesulfonyl bicyclic ketones under aqueous acidic conditions. Though not idea], this approach provided us pure II-9a-d with a level of through put necessary for our study. Figure 9. The Alternative Route to Make Ring Expansion Precursors LDA NaH/Nal PhSSPh 55_ 65 “C [MA/1M5 78 C n "-7 SPh l DIBAL 2.1)css- Martin II-4e II-Se (90‘7 ) II-6e (259 7:) II- 8e (61%) (8792. 2 steps) 1 mCPBA O O O Ph802 Ph502 TMS TMS II-4f II-9f Il-9c (84‘)? ) Attempts to synthesize the [2.2.2] and [4.2.1] ring expansion precursors via the same approach failed in that their B—keto-sulfones afforded no significant amounts of C- allylated material. Fortunately, the C—allylated products could be accessed via a slightly lO moizticd toutc m it £22113 prcior mm lt’dtit‘l‘ audition 2M t minded tnc CL‘V' 93315 react: Oil \t‘ t. lit. and [ muzor under nta- . .',, . itii 111C C a a ‘I ll -.---‘ [Mb modified route as depicted in Figure 9. While O-allylation of the sulfide derived from II- 4e again predominated, the by-product enol ether II-8e could be rearranged via DIBAL mediated reductive [3,3]-sigmatropic shift'7 which when followed by Dess-Martin oxidation'8 gave C—allylated II-6e in high yield. Oxidation of sulfide lI-6e with mCPBA, provided the desired product II-9e in good yield. Compound II-9f was prepared in the same reaction sequence. With the desired fully functionalized [2.2.1] (II-9a), [3.2.1] (II-9b-d), [4.2.1] ([1- 9e), and [2.2.2] (II-9f) precursors in place, we were now prepared to investigate their behavior under ring expanding conditions (Figure 10). Figure 10. Behavior of Bicyclic Systems Under Ring Expansion Conditions OH 0 II-9a —a—> + Ph 802 b (8.3m Il-10a(67‘7¢ )—-—* II- II (29%) a Il-9b —> Phso2 H-10b(92%) 1142 11.13 (30%) u 9c 1119.: u 9e u-9r Phso2 Phso2 PhSO PhSO? n 10c(82‘7()lI-10d(92%) u 10e (96% u 10f(6 lb 1c ((38% 0 OH OH decomposrtion 11.14 (87%) “-15 (90%) "-16 (74%) (a) 0.25 eq. TBAF. THF. 55 "C; (m to eq. t-BuOK. THF. n; (c) 1.0 cq.1-Bu()K.I)ME.-A ll A5 tllUVi eagle: the c551; :11 did not re» :0.) ring exp-4.9.1. pit: menu in tit. Tat treatment taxation-dug ri' Figure 10 . trait" ll'st‘lt‘lilt‘lll (it the LL15 5cmzenc~ultmz§ rigours (it ll-ltil figment-tum pro 51mg}: elimzmtiur ltd ll-lllf Will if't‘it“ '1 (9 - u....p(x._)(\fj up ll): tuned \"'?J(' L““"ed GUI Ct") ~~ (1. U ()3)?! l '\i..‘L“E,‘\‘ \ '1‘“. c ‘kth 05‘ '11? other 5» ,‘tn' L|\-|‘le 1* ‘ll [4 u g dry inf] '1‘C EQ'FD -T’ \- ‘\ lik,l Y ‘— Y ’ ‘— ' Y PhOQS PhOgS PhOgS 11.17 “-18 ".19 l- 502% l - SOzPh l - SOzPh X OH X 0 X 0 z- ,_ ’ . . 2151? 4"]. ‘——’—’ AL \ Y Y _ Y __ 11.20 "-21 11.22 13 Alutlh‘hl‘ ll-l0a ”.ltlb 11.1(k‘ ll-lOd “-109 MM llt‘ stall-CC. enmitgttrin grads. .1. 1117.23th e'. i" ' .- 1 . ‘ r (we; «(in the C . ”‘fl 3 .' Nil-{Infill ill“. JR“ tilde”: 1T6” 4' - - ‘ J-~:1’Cull“.’l‘ ll"- ! I lit ”34' “ . a - ‘4 ~50 theme.” We started the computational study at the MMFF94 leve Table 2. Theoretical Calculation Results l9 |, SE (Kcal/mol) AHf (Kcal/mol) Alcohols “-20 "-21 ASE II-20 II-21 AAH, “-103 57.62 41.93 -15.69 3.44 - l 9.03 -22.47 II-10b 68.52 62.75 -5. 77 l 1.04 3.01 ~8.03 II-lOc 47.30 43.17 -4. l3 - l 6.69 -25.47 -8. 78 II-10d 38.45 48.74 10.29 -22.73 —22.94 -0.2] II-10e 47.59 51.14 3.55 -26.69 -27.50 -0.81 II-10f 45.96 53.23 7.27 -22.63 -20.47 2.16 by examining the elimination products II-20 and “-21 which were derived from alcohols II-lOa-f (Figure 10). Minimum energy conformers (within 3.0 kcal/mol of the global minimum) were located with the Osawa searching method.20 A semiempirical AMl level study was then performed on these MMFF94 derived conformers. The calculated strain energy (SE) and heats of formation (AH,) values are listed in Table 2. A satisfyingly consistent result was obtained from these theoretical calculations compared to the experimental results. There was also excellent agreement between the trends determined by molecular mechanics strain energies and those by semi-empirical heats of formation. From the calculated SE and AHf data (Table 2), ring expansion product dienones from bicyclic ring systems II- 9a-c are favored over the corresponding dienols. Experimentally, high yields of dienones “-11 and “-14 were obtained. The lower yield of II-13 may be explained by the high absolute SE or AHI of the unisolated intermediate trienone “-12. Finally, calculations on [LI], “-13, and II-14 also supported the observed movement of the exocyclic olefin into conjugation with the keto group. These calculations also explain the failed ring expansions. For example, the expansion products from II-10d and II-lOe are disfavored by MMFF94 calculations 14 thllt the All l ' (trial-non pit . sirmtmn prt reason other It... (221: he we .1 Sanitation 01 die: firming thew I l Wraiv‘u1 \ \n hb'JlsLhU I“ U. ... 54357.13 ”ll dIlLl lite t .entett. sastriitt energf. fast 4‘ Kctl‘mnie heretical revel?» IltltaSlbllli} (31‘ \l llfills. Fran: 1:33.215: "-14 tn. "'A-w- .. ........(cdi.(te I-3l will)“ V' ll» . .. .(.a.:;\ in ~. while the AM] results barely favor (by less than 1 Kcal/mol) expansions over the simple elimination product dienols. Experimentally exposure of II-10d to t-BuOK gave elimination product II-15, whereas prolonged heating of II-lOe with t-BuOK gave no reaction other than decomposition. For ring system II-10f, both the SE and AHr values make the case against ring expansion, which would be consistent with the exclusive formation of dienol II-16. Based on these results, it would appear that the feasibility of performing these three carbon ring expansions on bicyclic molecules can accurately be predicted by comparing MMFF94 estimated strain energies of eliminated intermediates such as II-21 and fused methylenecyclopentenes “-20. The theoretical study of this ring expansion process supported the assumption that it is a strain energy controlled process, which is successful when significant amount (at least 4 Kcal/mole) of strain energy is released. The combination of experimental and theoretical results have allowed us to develop an MMFF94 based method for predicting the feasibility of applying Trost's three-carbon condensative ring expansion to bicyclic systems. From this study, we are also encouraged that high yield of ring expansion product “-14 was obtained from precursor II-9c which exhibits the same skeleton as the intermediate I-31 to prepare 1-28 as planned in Figure 6. We will discuss the application of this strategy to the synthesis of phomactins in next Chapter. 15 “'8 \1 t'l'.‘ tiree-ea'hin nt. 5 ilSIt’lll (ll-6C4. I preemtton (it (i). .epxtec :n Fragra- Iliix pm“ (Figs: 12). Dim: ‘4 r "1"! Q 3 35.4516 \lL‘IL‘u: stratifiemixtr} ”I fill“ “Witt-ed . it; in [11.3 W '1‘ CHICJCO' I .19.“ J ...t\e.. Ml; d (:4 u, A 4 :t (Cu. (.33 I r Lg: F“ is?» , V CHAPTER 3 LIMITATIONS OF THE RING EXPANSION STRATEGY We were encouraged by the positive results from the method study. The Trost three-carbon ring expansion process had indeed succeeded on a saturated bicyclo[3.2.l] system (II-6c). As II-6c possesses the same skeleton as 1-31, a building block for the preparation of the phomactin skeletons, I planned to carry out the synthetic protocol as depicted in Figure 6 (vide supra). This process began with the preparation of bicyclic ketone 1-32 from 1-33H (Figure 12). Dithiane I-33 was reduced with NaBH4 to furnish exclusively alcohol III-1 as a single stereoisomer which was then protected as MOM ether III-2. The relative stereochemistry of alcohol III-1 was assigned according to literature model studies21 and further supported by NOE experiments (Figure 12). The hydrolysis of the benzodithiane group in III-2 proved difficult. It was resistant to several mild hydrolyzing reagents such as CH3I/CaCO3, PhI(COzCF3)2, or HgO/BF3-OEt,.n'” To our delight, it was ultimately cleaved with a strong oxidative agent NBS to afford bicyclic ketone I-32 in acceptable yield.23 Figure 12. Preparation of Bicycle I-32 and Installation of Side Chains H s s H NOE MOMCI 0 man, H i Pr Nu NBS ————> S (99%) S (99 K) (64(7) | OMOM OH ()MOM I-33 III-I III- 2 l-32 IN LDA o g g o T15 o PhSSPh LiH/LII ———+ —.——> + (9| %) II-7 TMS PhS I I )M IV PhS OMOM OMOM PhS ( 01 III-3 III-4 X> III-S (47%) Claisen (heating or Dibal-H) (47%, l6 With 1):. lltTlClanJillI 3'1, is installed \Y‘ xmrlanee \( :th tit-Jere: prior tn literefore. mired iijdttton (ll Ill- terg'eti Cali} '53: lie: Witching I I?) .iil"T“' In " Hull‘( | LA A Mr» .I l Minted IO [Cfr‘ H 1115 C' \ HS:- 1 (2 Hi“ nth/ll .-;‘hl|}-., With bicyclic ketone 1-32 in hand, we were ready to install the required functionality and the side chain for the ring expansion process. The phenylthio group was installed smoothly to provide phenylthiobicyclic ketone III-3 in high yield. In accordance with the experience from our methods study, the a-carbon of III-3 is less hindered prior to the oxidation of the a-phenylthio group into a benzenesulfonyl group. Therefore, introduction of the allylsilane side chain was executed at this stage. The alkylation of III-3 with mesylate II-7 in the presence of NaH/NaI as the base afforded desired C-alkylation product III-5 in poor yield along with undesired enol ether III-4. After switching to LiH/LiI as the base, the yield of III-5 increased moderately to 47%. Any attempt to transfer III-4 to III-5 via 3,3-sigmatropic rearrangement failed due to the steric hindrance inherent to the bicyclic system. However, undersired III-4 can be recycled to reproduce III-3 by stirring with aqueous H2804. Figure 13. Limitations of the Trost Ring Expansion Strategy 0 mCPBA TMS 0 .,,,OMOM TMS .,,, OM OM III-5 ——> or Oxone PhS\\O SOzPh III-6 (51%) III-7 (0%) TBAF KH/l 8- C- 6 , , or! BuOK ’IOMOM mCPBA "’OMOM Decomposmon<———- or Oxone PhS \0172%)PhS \0 III- 8 (79%) III- 9 With the allylsilane side chain installed, attention was shifted to oxidation of the Phenylthio group. Unfortunately, oxidation of sulfide III-5 with either mCPBA or Oxone® did not deliver any desired sulfone (III-7), but rather the partially oxidized Product sulfoxide III-6. This must be due to the sterically hindered environment of the 17 Mumsywn (a stint). (thoutint tri. it: pre~ence (it ranmtuisuhx. Tme\g seatitndrane‘ . . l1 - I. ' - -h v 1.3.4.. .ttlll (ll (T egammtttb' 115 madamanep bicyclic system. Upon treatment of III-6 with TBAF, only condensative product III-8 was obtained. Oxidation of III-8 with mCPBA or Oxone® furnished epoxide III-9 without any trace of desired sulfone. Compound III-8 was stirred with t-BuOK or KH in the presence of I8-crown-6, so as to trigger the ring expansion process. Unfortunately no reaction was observed except decomposition. The experimental results at this stage were discouraging. We had learned that the steric hindrance expOsed by the substituted bicyclo[3.2.l] system of I-32 hampered the installation of the required benzenesulfonyl group. This fact curbed the potential application of the three-carbon ring expansion strategy to the preparation of I-28. As such, alternative protocols had to be designed. l8 IaDesigning t1 lll \Cart‘l 28. 9e pereezte. entitle Us to ((1);: ROI-5‘ or Me) J '\ , .. aetetcpment (n R it: .‘(nximetxon 4‘ grill) is nitftft' its :90 CC tit“. 1143136161 in our c 1.3.: 01C}tllt‘ ran tied (in 1911(th ‘;n;(:.4rr.pltc.tzed, “IMF" ~~r~:‘.ll.‘ll LIFPZ'UQ Priress as the RC 11510535.)“ ‘1\ ( F’ Intrun (tilt-k CHAPTER 4 THE RING—CLOSING METATHESIS (RCM) AND MCMURRY ROUTES 4a. Designing the Second Generation Synthesis In search of alternative routes to the synthesis of the bicyclo[9.3.l] skeleton of I- 28, we perceived that retrosynthetic disconnection of the C(7)-C(8) double bond should enable us to implement a ring forming strategy based on either a ring-closing metatheses (RCM)24 or McMurry olefination.25 In recent years, RCM methods fostered by the development of RCM catalysts by Grubbs and Schrock, have been shown to be useful in the construction of cyclic structures for natural product synthesis."‘ Generally, the RCM approach is more reliable when constructing strain free ring systems, particularly when the two C-C double bonds participating in the RCM process are monosubstitutedf7 However in our case, one of the participating double bond is gem-disubstituted and the target bicyclic ring system is moderately strained. The decision to employ this strategy is based on following considerations. First, the RCM methodology is experimentally uncomplicated. The RCM route is also strategically flexible compared to the ring expansion approach. It would be easy to switch from the RCM method to a McMurry process as the RCM substrate IV-2 can be converted to a McMurry starting material IV-3 via ozonolysis (Figure 14). Intramolecular McMurry olefinations are frequently enlisted to construct highly strained ring systems although the application of this protocol can be experimentally difficult and often results in low yields.28 This second generation synthetic plan was designed to utilizes the same starting material ketone [~32 (Figure 14). As outlined in Figure 14, the cleavage of the bicyclic system of 1-32 at C(2)—C(3) will be followed by the installation of the two side chains bearing the two terminal C-C (or C-O) double bonds required for the RCM (or McMurry) process. Finally an RCM (or McMurry) l9 1b. lnstallation ( Thix sct‘t’t m: of the Rt 1111\le did It: II ' I a °.‘ 11in 001.13% I fit _(I :13. (ting the $51.3? _ . .atguluie ' CCU?" a; 4.3.”! I ‘ Nkeiiuc EQQI ‘75:“;ho ‘b ' I . «Lam-ii amid puplr - ‘l;(\..-3FI' - . "I ‘ 1.5 . l“ J \(tk‘t reaction would lead to the construction of the bicyclo[9.3. I] skeleton of 1-28. Figure 14. Designing the RCM/McMurry Protocol 0 1 MeO 2 -._;-* O -_-.-_-;+ 3 1 ocnzocn, OHC ' OCH30CH: 1-32 lV-l O 3 11~ 2 l RCM or McMurry :: -------------- 4» 5 3: 0P ‘\\)\/\: 5 3 7 [v.4 9 I-28 4b. Installation of the Two Side Chains This second generation synthetic route started with the installation of the two side chains of the RCM/McMurry substrate (Figure 15). Ketone I-32 was enolized with KHMDS and then alkylated with MeOTf to afford enol ether IV-S. Good yield of pure IV-S was obtained after purification on basic alumina (activity III) or silica gel buffered by mixing the effluent with 1-2% triethylamine so as to minimize unwanted acid- mediated decomposition of sensitive enol ether IV-5. Ozonolysis of IV-S afforded aldehyde ester IV-l in good yield. Upon indium mediated coupling of IV-l with 29 methallylbromide, alcohol IV-6 was generated in high yield as an unseparable 1:1 mixture of stereoisomers. The hindered nature of this secondary homoallylic alcohol excluded the possibility of removing it by reducing its mesylate or tosylate derivertives with LiAlH.1 or LiBHEt3. A radical route of deoxygenation was examined as shown in Figure 15.30 The alcohol was converted to (thiocarbonyl)imidazolide IV-7 followed by reduction with neat Bu38nH. However this process did not provide any desired reduction product IV-8. Only 20 tritium b) -,“' (Med. 013‘. \12‘: {total me. (.3: 4, INN ’. 3““). ~ “A“ “AC U?“ L‘- I It A( 'b, V “41191. -1 “Axis?” r_ unknown by-products in which the double bond was lost (as indicated by lHNMR) were observed. Obviously the attempted reductive removal of the homoallylic hydroxyl group via radical mechanism was complicated by the nearby C-C rr—bond. Figure 15. Efforts to Install the gem-Disubstituted Olefin Side Chain MeO O MeOOC 4““ OH 1-32 ——a—» —b> “460% —C> MOMO]? (30%) OMOM (809;) OHC I (839;) OMOM [v.1 was \ -‘\\ MeOOC M OMO IV-7 IV-8 (a). KHMDS/MeOTf; (b). OelMeZS. MeOH-CHgClZ; (c). In, Methallyl bromide. EtOH-HZO (4 : l); (d). Thiocarbonyldiimidazole (2.0 eq.).CH2C13. reflux. 24 h. (e). Bu;SnH. neat. 110 "C. 1.5 h; (f) Ph;P=CHCOCH3. toluene. 165 ”C. 48 h; tg). H3. Pd-C; (h). Ph_~,P=CH:. -3() "CH. overnight. In search for new routes to install the side chain, it was discovered that the stepwise utilization of Wittig reactions as described in Figure 15 smoothly met this challenge. Aldehyde IV-l was coupled with triphenylphosphoranylideneacetone ylide31 at high temperature to furnish only the (E)-isomer of enone IV-9 in high yield. Hydrogenation of enone IV-9 followed by a second Wittig reaction provided desired gem-disubstituted olefin IV-8 in excellent overall yield. With the gem-disubstituted olefin side chain successfully installed, we turned to introduction of the second side chain (Figure 16). The original plan was to install the 21 emit \ltlt‘ (Eh (it). tll.)l pl)" Facial ph‘np‘: met) 01 lldv'. pra‘ducts 111111. . pteefttlhlt .15; second side chain via HWE (Homer-Wadsworth-Emmons) coupling of hex-5—en-2-one with ethyl phosphonate IV-ll which itself would be made from the reaction of methyl diethyl phosphonate and ester IV-8. Unfortunately, the attempted coupling under a variety of basic conditions such as KOH, KHMDS, or DBU only gave elimination by- products without any observation of the desired normal coupling product (IV-2), presumably due to the low reactivity of hex-5-en-2-one. Figure 16. Installation of the Second Olefin Side Chain T T O mBuLi M CH3P(O)tOEt)3 —-———> X: IV-8 NaH or DBU IV-ll (96%) IV-2 0 ML NaH, THF x H 0 ~35 On. 3 h IV-IZ (X = H/CH3) MeMgBr-Cul ————'> IV-l3 (87%. X = H) IV-I4 (86%, X = H) IV-15(84%. X = Me) IV-l6 (68%. X = Me) An alternative route involving the HWE coupling of IV-ll with 4-pentenal (IV- 12, X = H) was studied. Here, excellent yields of desired coupling product trienone IV- 13 were obtained. The B-methyl group was installed via 1,4-addition of MeMgBr-Cul to IV-l3 delivering ketone IV-14 in very good yield. At this stage, we needed to address the fact that the two C-C double bonds of the RCM process partners are differently substituted and therefore may lead to different reaction rates towards the RCM catalyst. Thus, we also prepared another RCM precursor IV-16 in the same manner as described in 22 Figure 16. 1' substitution p; Illlullll) bl.llltl\ It'- 1t.1nie5tigati(t Fllldll}. ‘ I Plitll‘fstlls l\ .1: \“L\; at»; L1”NTWI'». Attic?“ LI Figure 16. In IV-l6, both double bonds are disubstituted although with different substitution patterns. We hope the closely matched substitution patterns of the two double bonds would lead to closer reactivity toward the RCM catalyst. 4c. Investigation of the RCM/McMurry Protocol Finally, we were prepared to investigate the RCM reaction on all four possible precursors IV-l3, IV-lS, IV-l4, and IV-16 (Figure 17). Figure 17. Investigation of the RCM Process IV-l3 or IV-IS IV-l4 or IV-l6 IV-l7 t- 0.30 cq) [v.17 post-q} CHZCIQ. 0.001 M CH3C13(0.0()1 M) rt or reflux. 28 h rt or reflux. 24 -36 h IV-20 (48%) P C ' '1 H3 Ph ClzRUZ/ I I N Plcyll ROI”'uo:/< Ro' IV-l7 IV-18 Because of the higher functional group compatibility and lower sensitivity to environment as well as its commercial availability, Grubbs’ catalyst (IV-17) is usually more popular among synthetic organic chemists than Schrock’s catalyst (IV-18). We first tested lV-17. To our disappointment, in all cases only dimerization products IV-19 23 mi 11420 1) er “llll SChltX‘lt' ~ tubtzrttex or d. We .111." state limiting. 12.4.1 complex:- :oefd not at em. tIJLJthAlIlS‘ l‘Ix‘ he attempted t(~ Slim or re; '1'4nu 9914‘..le led‘s‘r" v ‘ III \ L ‘I I 434:7.) \[r 4 .4‘ ¥ -. . (~11an I" 10:11;.\1;irr\ [Site 18. and IV-20 were observed without any trace of desired RCM products. The same reaction with Schrock’s catalyst (IV-18)32 in toluene also proved discouraging. Only isomerized substrates or dimers were observed without any sign of RCM products. We attributed the failure of the RCM process on all four substrates to the inherent steric hindrance posed by potential bicyclic transition states. It might also be due to the weak complexing effect of the catalysts with the CC double bonds of the substrates that could not overcome the strain barrier (~7.5 Kcal/mol estimated by molecular force field calculations) brought on by potential bicyclo[9.3.l] products. Based on this hypothesis, we attempted to convert the substrates to a species that could strongly complex with a catalyst or reagent. In McMurry reactions, the strong complexing effects between titanium reagents and dicarbonyl substrates are often utilized to effect construction of highly strained or hindered cyclic systems. The conversion of the RCM precursor IV-16 to a McMurry reaction substrate and the subsequent McMurry reaction were discussed in Figure 18. Figure 18. Investigation of the McMurry Reaction OTBS IV-22 d —-> Decomposition or e MOMO 0 IV-3 (68% from IV-21) (a) NaBH4. MeOH. (b) TBSCl/Py. DMAP( cat). DMF. 85 "C. 4.0 h. (c) o,/Me:s (d) TiCl3/Zn-Cu. pyridine-DME. reflux. 30 h. (e) TiClJZn. pyridine-THF. reflux. 20 h. 24 RCLllA' (men '01 ll Without thin." 0207101105. l Figure 11 t. r. min: the 5 congunetion u pTL‘lXUl in l‘iil. Reduction of IV-l6 with sodium borohydride resulted in a mixture of two alcohol isomers of IV-21 in high yield. The major isomer was protected as TBS ether IV-22. Without chromatograph purification, diene IV-22 was converted to dicarbonyl IV-3 via ozonolysis. Unfortunately, under two common sets of McMurry coupling conditions”‘25 (Figure 18), no desired coupling product was observed. Even worse, almost nothing including the starting material was recovered from these reactions. This negative result in conjunction with the literature experience that the yield of building medium to large strained cyclic systems via McMurry reactions is often low34 forced us to adjust this protocol by building the C(7)-C(8) Tr—bond of I-28 via other means. 25 51 Adjustmi FIG 1]] 11C.\1'.\1e\1.. .0..‘ ‘ I‘Y“. | :‘li‘i-‘B‘Y’: \-\I IllL ‘ ”9:“ ’3‘.) in {‘Lu‘u “Ik I‘M i \ ‘ 3‘ '.‘ @303“ in Fly 1 1 . "afl- ‘. ' "nu‘o vlr “1‘ ‘ s ‘- I '1 CHAPTER 5 THE SUCCESSFUL JULIA OLEFINATION AND NOZAKI-HIYAMA-KISHI COUPLING ROUTE 5a. Adjustment of the Second Generation Synthetic Plan From the results discussed in Chapters 3 and 4, both the ring expansion and RCM/McMurry protocols were limited due to the high steric hindrance and strained nature of the bicyclic systems. Alternative ring construction methods were still needed to build the phomactin bicyclic skeleton. We planned to make some adjustments to the second generation synthetic plan while still using the same starting material (Figure 19). Figure 19. Adjustment of the Second Generation Synthetic Plan 1 H O 2 Julia Olefination - - - § 0 .............. § 3 (Sp X l or NHK coupling I-32 I-28 We decided that the modified one-pot Julia olefination35 should be investigated for building the C(7)-C(8) rt-bond in I-28 as either a homologation or annulation step. Another disconnection at the C(2)—C(3) o-bond should allow the construction of this bond via vinyl anionic nucleophilic addition or Nozaki-Hiyama-Kishi (NHK) coupling. The NHK coupling has been frequently deployed in natural product synthesis in both intermolecular and intramolecular varieties.36 When applied in the latter manner, it has been proven a valuable annulation approach for building ring systems of various sizes."7 The high stability of the emerging O-Cr(III) bond constitutes a formidable driving force for the formation of rather strained medium-sized ring systems which are difficult to construct otherwise. In this chapter, deployment of the NHK coupling as the annulation step leading to the successful construction of the phomactin bicyclic system is discussed. 26 5h. TBS Ethe Along llO.\1 ether it its decided ' )Uiit‘fsl‘it‘ to iiitilldlt‘ NHK l m) 1. 1'4\l g 'Ihll‘ll\\1\ “fir .1 I35 , 5b. TBS Ether Protected Starting Material Along the route to build the RCM/McMurry precursors, the B-elimination of the MOM ether was often a problematic side reaction. So, in this new synthetic sequence, it was decided to protect the secondary alcohol III-1 as a TBS ether which is much less vulnerable to B-elimination. Perhaps more important, TBS ether groups generally facilitate NHK coupling reactions in terms of yields and stereochemical outcomes.m Figure 20. Preparation of the TBS Ether Protected Starting Material 0 s N 1 TBSOTt/ P NE 1. KHMDS/MeOTf Mto »' S ' r L A- CHO on 2. NBS OTBS 2. O3/Me38 TBSO 111-1 v.1(61%) v2 (65% ) MeOOC ‘ H ““7 MeOOC Ph1P=CHCOCH3 m—. 2 NaBH, m PhCHg T850 3 2 HS BT TBSO S—BT 165 c.2411 DMD PM, V-3 (85%) V-4 (879? from V-3) (WED) This sequence commenced with the protection of alcohol III-1 as a TBS ether using TBSOTf/iPrgNEt (Figure 20). The crude TBS ether was submitted to dithiane hydrolysis with NBS to provide good overall yield of bicyclic ketone V-l. Ketone V-l was converted to its methyl enol ether with KHMDS/MeOTf. According to the experiences of Chapter 4, this enol ether intermediate should be highly sensitive to silica gel purification. Therefore we decided to submit it directly to ozonolysis without column purification. In this way, aldehyde ester V-2 was obtained in reasonable overall yield. Wittig olefination of V-2 with triphenyl phosphoranylideneacetone provided exclusively 27 tie ltstlllllli '1. 111th I-merea; ‘ Held Milt-"1H .7 5t Examinatit At the 31 (l. v. ,',-P L‘\Illd‘l!)n \.\1 . l P211111 redatt u \uaeopnzne a; TIUUIC 0i i“ \‘ “(Li made lit)?! pictectitm sit; the: ‘he crude -l-.4v ._ ill-~11 ellC hen/1. Flt" '. Wkllgn 01 L‘:) ‘li‘nl‘; [ditlx ‘ A ‘ pll;h4‘dce trans enone V-3 in excellent yield. Hydrogenation of V-3 and subsequent reduction of the resulting ketone was followed by a Mitsonobu substitution of the intermediate alcohol with 2—mercaptobenzothiazole (2113131)35 to furnish sulfide v-4 in a satisfactory overall yield without purification of the two intermediates. 5c. Examination of One-Pot Julia Olefination as the Annulation Step At the beginning, I hoped to deploy the modified Julia olefination as the cyclization step (Figure 21). However the experimental results proved disappointing. Partial reduction of ester V-4 with DIBAL provided aldehyde V-7 in good yield. Nucleophilic addition of the lithiated vinyl iodide V-6 to V-7 resulted in the isolation of a mixture of two alcohol isomers V-8 in good yield and in a ratio of 1:1. Vinyl iodide V-6 was made from a known compound (Z)-5-iodo-4-methyl-4-pentenal (V-5)“x via a dithiane protection step as shown in Figure 21. Alcohol V-8 was protected as a PMB ether and then the crude intermediate was submitted to dithiane hydrolysis conditions. It was found that the benzothiazole moiety was affected and no desired hydrolysis product was produced. Because the benzothiazole moiety in V-8 could not survive the dithiane hydrolysis, I decidied to try the coupling of vinyl iodide V-6 with the substrate at a later stage with the sulfone vs the sulfide. The sulfone is strongly electron withdrawing and therefore may inhibit hydrolysis of the neighboring benzothiazole moiety (Figure 21). Sulfide V-4 was oxidized to sulfone V-9 with mCPBA in very good yield. Partial reduction of V-9 with DIBAL produced aldehyde V-l0 also in good yield. Unfortunately, the coupling of aldehyde V-10 with lithiated vinyl iodide V-6 failed to produce any practical yield of desired coupling product. We may blame this failure on interference by the acidic a-proton of the sulfone group or the unstability of the benzothiazole moiety under the extremely strong basic reaction conditions. 28 FISUI \4- Figure 21. Evaluation of One-Pot Julia Olefination as the Annulation Step HStCHg) s//_\ o ——* 1 \ 9 BF 0E1 ‘ V-6 (919? ) OHCD/Y a . V-4 —C> Decomposed TBSOD/Y — HT 5 TBSO BT—S V-7t86‘7c) V-8(83‘7r. l ‘. l) .‘\\\ MCOOCD/YL 0mm —b> Decomposed T850 T880 BT__SO BT—so v-9 (85%) V-lO (86%) (a) DIBAL; (b) I-BuLi. -78 UC. V-6; (c) NaHMDS/PMBCl; (d) CaCOa/Mel; (c) mCPBA. rt, 16 h. 5d. The Julia Olefination Homologation and NHK Coupling Sequence Given the failure to install the aldehyde segment for an intramolecular Julia coupling, I decided to utilize this olefination step as a means of homologation, forming the bicyclo[9.3.l] ring sytem later via an intramolecular NHK coupling process (Figure 22). This protocol proved very successful. Aldehyde V-10 was protected as dimethyl acetal V-12 with dimethoxypropane catalyzed by TSA. The crude acetal V-12 was submitted to Julia coupling without column purification. The one-pot coupling began with the stirring of V-12 with NaHMDS (1.3 eq.) for about 45 minutes at -78 °C before the addition of vinyl iodide aldehyde V-5. The crude olefination product V-l3 was stirred with a mixture of AcOH/THF/H20 (3:111) to reproduce aldehyde V-l4 which existed as an unseparable mixture of two olefin isomers. The ratio and stereochemistry of the two isomers were assigned according to 1H NMR and NOE experiments. It was discovered that in DMF, the reaction strongly favors the undesired (Z)-olefination (E /Z = 1:2), while in DME the reaction is slightly selective toward (E)-olefination (E /Z = 1.3: l ). 29 11) other sohents st KHMDS ()r Lill.\lli Figure II. 1111). 47S)... In other solvents such as THF, diethyl ether, or toluene or when other bases such as KHMDS or LiHMDS were utilized, the overall reaction yield dropped to below 40%. Figure 22. Julia Olefination Elongation and Optimization of the NHK Coupling x x TBSO tar—so2 TBSO 1 E v.10 [x = 0] [7 V-13 [X = (OMCM v.121x = (OMe)3] C —» v=14 [x = 0) (F12 = 1.3;). 6692 from mm P Me _ H 8 7 V]: / . TBSO O/‘E/ \ Ln v.15 V-l6 (a)TSA. dimethoxypropane; (b) NaHMDS. V-S; (c) Ac(.)H/THF/HZO(3:1:1); td)CrC13/Nitacac13. DMSOfTHF Table 3. Optimization of the NHK Coupling _ Solvents Reaction Conversion Total Yield (%) Entry V 14 (ll/(E) (V/V) Time (h) Rate (%) (v-15 IV-l6) 1 2:1 DMF-THF (4:3) 2 100 24 (3:1) , THF-DMF-t-BuPy . , 2 2.1 (12:6:1) 4 28 27 (3.1) 3 2:1 DMF—DMSO (3:1) 2.5 100 35 (3.5:1) 4 1:1.3 DMSO-THF (3:1) 23 74 55 (1:1) 5 1:1.3 DMSO-THF (3:1) 26 75 60 (1:12) 6 1:1.3 DMSO-THF (3:1) 45 100 29 (1:1) 30 \Vitl‘) the mnulall reg-£11011 Ol- ‘ NHK c0111 D)”: is illL ((5115 ut‘tt‘ cometshm increase th thlcont: art imprm Kristian c seg‘aexterii in 109 cor treated \t? .".l '21- E has 3:1. obtained. reaction u Tl" .WR and C" 1» 1 Ole“ l With the vinyl iodide aldehyde V-14 in hand, we were now ready to investigate the annulation step via the NHK coupling method (Figure 22). The intramolecular NHK reaction of V-l4 proved very rewarding. We observed the yield and reaction speed of the NHK coupling to be sensitive to the reaction media as illustrated in Table 3. Deploying DMF as the solvent usually led to fast reaction but low yield. In DMSO, higher reaction yields were obtained although the reaction usually took about 24 hr to reach a reasonable conversion rate. THF was mixed into the reaction media in most cases in order to increase the solubility of the substrate V-14 in DMF or DMSO. In all cases, 8.0 eq. of CrClzcontaining 0.5-l% of NiCl2 or Ni(acac)2 was applied and the reaction was dealt with an improved work-up procedure39 by treating the reaction mixture with an aqueous solution of sodium d,l-serinate which was found to be exceptionally effective for sequestering chromium ion. Using a lower ratio (4 eq) of chromium dichloride resulted in low conversion rates. Contrary to literature reports, no obvious beneficial effects were noticed when additive 4-tert-butylpyridine was added to the reaction.39 When V-14 was a 2:1 (Z)/(E) mixture of isomers (Entry 1, 2, and 3), the product distribution of V-15 / V-16 was 3:1. When starting from a 1:13 mixture (Entry 4, 5, and 6), a mixture of 1:1 was obtained. From the last entry, it was observed that prolonged reaction times drove the reaction to full completion but at the cost of decreased yields. The structures of V-15 and V-16 were assigned according to their 500 MHz |H NMR and NOE spectra. The strong NOE (about 5%) between the C(8)-methyl group and C(7) olefinic hydrogen atom in V-15 proves the cis stererochemistry of this n-bond. While the absence of such NOE effects enables us to assign the trans stereochemistry of the same bond in V-l6. The relatively large coupling constants (>8 Hz) between C(2)-H and C(3)-H or C(1)-H in both V-lS and V-16 indicate these protons are in axial positions and therefore allowed us to assign the conformations and relative stereochemistry of V-15 and V-16 as shown in Figure 22. This assignment was later secured by single crystal X- ray analysis of both V-15 and V-16 (see ORTEP drawings in Appendix 1 and 2). 31 The hi :1- We proposed t ether forced th chromium) 111.) Le formation C Se. final Tran The ttm in order to pro 810011 epm temperature. C13 ‘r-Oll gruu steretxhemixti elil‘enments a The high stereoselectivity of this NHK coupling process is also very impressive. We proposed that in the course of the coupling reaction (Figure 22), the bulky B-TBS ether forced the carbonyl group point to the opposite direction which allow the vinyl chromium(III) approach the carbonyl group with minimum steric hindrance, thus led to the formation of only one isomer with preferred 1,3-anti stereochemistry. Se. Final Transformations to the Model Compounds The two bicyclic alcohols were now to be converted to the final model compounds in order to provide samples for biological studies (Figure 23). The VO(acac)2 mediated I- BuOOH epoxidation40 of V-lS/V-l6 led to V-17/V-18 in excellent yield at ambient temperature. The quick and easy epoxidation of the allylic n-bonds indicates that the C(2)-OH groups in V-lS/V-16 are well positioned to direct the epoxidation with required stereochemistry. The stereochemistry of V-17/V-18 was further supported by NOE experiments as indicated in Figure 23. Figure 23. Preparation of Model Compound I-26 Me Noe K/ V-I7(86%) V-l9(87%) b V46 —* TBSO H Me NOE \/ V-18 (100%) I-27 (95%) I-26 (74% ) (a). VO(acac)3/t-BuOOH. 35 ()C, 40 min; (b).VO(acac)3/r-BuOOH. rt, 10 min; (c). Swern. -78 HC. 60 mm; (d). TBAF. 0C. 8 min. 32 The oxidation 0 hoped. Almost 110 Wt tetodinane itere Used nature 01 the bie_tltc .~ conditions it prolottget FigureIS). Non. ue need male model compour Chapter :4 TBS ether 1 group. intact. no e1): or DXIAP was \llTTCx contert the resulting fielintinition. To ( THF at rt. a small .4. -.... ' annotated (some: t i- ‘00 C the Helimi‘. trrv ' - - ae or antrcrpateti accomplished m 011 Elit’t‘iencv. After the \u 34’? ' eilfn’ L“ 116 or the T83 Ether The oxidation of the allylic hydroxyl groups in V-17/V-18 was not as facile as hoped. Almost no reaction was observed when SO3-Py/DMSO complex or Dess-Martin periodinane were used in refluxing methylene chloride, probably due to the hindered nature of the bicylic system. Gratifyingly, this oxidation was achieved under Swern conditions at prolonged reaction times (about 60 min) to produce V-19/I-27 in high yield (Figure 23). Now, we need to remove the TBS ether group in 1-27 via B-elimination in order to make model compound I-26. However, as we had mentioned at the beginning of this Chapter a TBS ether group is less vulnerable to B—elimination compared to a MOM ether group. In fact, no elimination was observed when the mixtures of V-19/l-27 and pyridine or DMAP was stirred for a few days at rt. So I decided to deprotect the TBS ether and convert the resulting alcohol to its mesylate derivative which should be more inclined to flelimination. To our surprise, when TBS ether V-19/I-27 was stirred with TBAF in THF at rt, a small amount (about 25%) of B-elimination product V-20/I-26 and its deconjugated isomers were instantly observed. After I lowered the reaction temperature to 0 °C, the fl-elimination product V-20/I-26 was isolated in good yield. In all cases, no trace of anticipated hydrolyzed products were noticed. The desired B-elimination was accomplished in one step, delivering the final products V-20/I-26 with unexpectedly high efficiency. After the successful preparation of model compound I-26 and its isomer V-20, the attention was turned to another model compound I-ZS (Figure 24). Because deprotection of the TBS ether group in I-27 with TBAF led to B—elimination and no reaction was observed when AcOH buffered TBAF was used, the deprotection was performed on V-18 to deliver diol V-21. Without chromatographic purification, crude diol V-21 was subjected to Swern oxidation to afford hydroxyl ketoepoxide V-22 in good overall yield without any observable trace of diketone V-23. The second Swern oxidation then converted purified V-22 to V-23 in excellent yield. 33 Figure 24. Preparation of Model Compound I-25 THC Me (a) (b) ”W / V-I8 —" 1 Ho 0 0 Me Me V-21 V-22 (77% from V-18) V-23 (94%) £c) ortd) b) 1 0;:0 O :i: "lll‘ Z O ’5 I!” r \I I-25 (80%) (a). TBAF. 55 HC. 6 h; (b). Swern. -78 UC. 80 mm; (c). TSA. 65 ”C. 3.5 h; (d). silica gel/EtiN. 55 "C. Under mild acidic conditions, high yield of model compound I-25 was formed via acid mediated transannular nucleophilic addition of the hydroxyl group to C(4) quaternary center and concomitant epoxide ring opening. The stereochemical assignments of I-25 was primarily based on the reaction mechanism as well as its 500 MHz 1H NMR and NOE studies. We also attempted to make a,,8-unsaturated I-25 from V-23. However when diketone V-23 was exposed to a variety of mild acidic or basic conditions,‘I no reaction was noticed except decomposition. We attribute this failure to the low nucleophilicity of the diketone moiety in V-23 as well as that the two reaction centers are not in close proximity in space. Sf. Conclusion In summary, a general route to the carbon skeletons of the phomactin compounds has been established. Through the preparation of three model compounds (I-25, I-26 and isomer V-20), we have accessed the two structural types of the phomactins. The key 34 steps intnlte the tin; elongation through it annulation. The final 11% O)t’1’dll)lt’lcl trot 130114;» made in 11 1.11116 starting nidlt‘flc hie)clo[9.3. ll t‘rameu NHK coupling as the We ”also \\ am of (WC reagents an. metal. chromium. \\ solt‘ent. T116 three mt, results of these (6515 ph .omiietins as uell : steps involve the ring cleavage of a bicyclo[3.2.l] system via ozonolysis, side chain elongation through modified Julia olefination, and the most crucial NHK coupling annulation. The final model compound l-25 was made in 19 total linear steps/l3-pot in 2.1% overall yield from the known compound I-33. The other model compound I-26 (or V-20) was made in 18 total linear steps/l3-pot in 3.2% (or 2.5%) overall yield from the same starting material. Compared to published methods to construct the phomactins bicyclo[9.3.l] framework, highest efficiency was acquired through the employment of an NHK coupling as the annulation step. We also want to point out that in our synthesis of these model compounds, the use of toxic reagents and solvents was limited. In only one step, a moderately toxic heavy metal, chromium, was used as a reagent and in only one step benzene was used as a solvent. The three model compounds will be submitted for biological tests. Based on the results of these tests, future efforts will be focused on the total synthesis of the individual phomactins as well as designed pharmacophores. 35 All art or me under a nitrogen or (itinethooethnne (l) henzophenonelet .1 l . (ere distilled ur‘..l( inethtlsult‘oxide ( ca‘cium sulfate. A? Sources or otheru tst L‘t here dried o.\ er T Nuelear ma Gemini 300 lnox a .\'.\1R are reported EXPERIMENTAL PROCEDURES All air or moisture sensitive reactions were carried out in oven-dried glassware under a nitrogen or argon atmosphere, unless otherwise noted. Anhydrous THF, 1,2- dimethoxyethane (DME), and diethyl ether were freshly distilled under N2 from sodium benzophenoneketyl. Pyridine, triethylamine, and diisopropylethylamine (Hunnig’s base) were distilled under N2 from calcium hydride. N,N’-Dimthylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile were distilled under N2 from anhydrous calcium sulfate. All other solvents and reagents were used as received from chemical sources or otherwise noted. All organic solutions containing reaction products after work up were dried over MgSO4 or Na,SO,. Nuclear magnetic resonance ('H NMR and 13C NMR) spectra were recorded on Gemini 300, Inova 300 or VXR 500 spectrometers. Chemical shifts for 1H NMR and I“C NMR are reported in parts per million (ppm) relative to CDCl3 (5 = 7.24 ppm for |H NMR or 5 = 77.0 ppm for I3C NMR ). All Infrared (IR) spectra were recorded on a Nicolet IR/42 spectrometer. High resolution mass spectra (HRMS) data were obtained: (a) at the Michigan State University Mass Spectrometry Facility which is supported, in part, by a grant (DRR-OO480) from the Biotechnology Research Technology Program, National Center for Research Resources, National Institues of Health; (b) at the Mass Spectrometry Laboratory in the Department of Chemistry & Biochemistry at the University of South Carolina. Combustion analysis was performed by Robertson Microlit Laboratories, Inc., Madison, N.J.O7940. Melting points (m.p.) were determined uncorrected using a Thomas Hoover apparatus. 36 The general PH" PlIt‘ll}lilllt dizsoprop} lamine mL 1.6 .\l 111 he (run it the stimc l (135 sloul) llllt‘t mixture was thet rnl. HMPA and . further for 1.0 1 separation. the . srircn gel (hexar or "-521 in the 150mm". 1R the.) 1.19 (m. 5 H). L 40.6. 36.2. 2' ‘ The general procedures for the preparation of sulfides II-Sa-f Phenylthiobicyclo[2.2.1]heptanone II-Sa (Conditions A). To a solution of diisopropylamine (6.06 g, 7.8 mL, 60 mmol) in 80 mL THF was injected n-BuLi (37.5 mL, 1.6 M in hexane, 60 mmol) under argon at -78 “C. The mixture was stirred for 15 min at the same temperature. A solution of 3.3 g (30 mmol) norcamphor in 20 mL THF was slowly injected into the mixture at -78 0C and stirred for 30 min. The reaction mixture was then siphoned into a solution of diphenyl disulfide (10.0 g, 46 mmol) in 20 mL HMPA and 30 mL THF at -50 °C. The mixture was allowed to warm to rt and stirred further for 1.0 h. It was then quenched with aq NH4CI, extracted with ether. After separation, the organic layer was washed with aq NaHCO3, brine, dried, separated on silica gel (hexane/ether [8:1], Rf: 0.25 and 0.28), to afford a 3:1 mixture of two isomers of II-Sa in the total amount of 6.38 g (98%), as a light yellowish oil. For the major isomer: IR (neat) 2969, 1750, 1584, 1480, 1073 cm"; 1H NMR (300 MHz, CDCl,) 6 7.46- 7.19 (m, 5 H), 3.70 (d, J = 3.9 Hz, 1 H), 2.72 (s, broad, l H), 2.71 (d, J = 1.5, 1 H), 2.10- 1.49 (m, 6 H); l3C NMR (75 MHz, CDCl,) 8 213.4, 134.9, 130.9, 128.9, 126.9, 59.7, 49.8, 40.6, 36.2, 25.2, 21.8; HRMS (El) m/z 218.0773 [(M+); calcd for CUHNOS 218.0765]; Anal. Calcd for C,,H,,OS: C, 71.52; H, 6.46. Found: C, 71.55; H, 6.52. Phenylthiobicyclo[3.2.1]octenone II-Sb. Applying Conditions A to ketone II-4b (1.0 g, 8.2 mmol) afforded 1.58 g (83%) of II-Sb as light yellowish crystals, mp. 67-68 "C. IR (CHC13) 2948, 1750, 1479, 1439, 1113 cm"; 1H NMR (300 MHz, CDCl,) 6 7.46- 7.16 (m, 5 H), 5.80-5.66 (m, 2 H), 3.96 (d, J = 6.9 Hz 1 H), 2.98-2.30 (m, 4 H), 1.96 (t, J = 2.5 Hz, 2 H); 13C NMR (75 MHz, CDC],) 8 206.5, 135.9, 130.3, 129.4, 129.0, 126.7, 125.2, 59.2, 45.7, 35.1, 30.4, 28.2; HRMS (EI) m/z 230.0773 [(M+); calcd for CHHHOS 230.0766]. Phenylthiobicyclo[3.2.I]octanone Il-5c. Applying Conditions A to ketone II-4c (1.24 g, 10.0 mmol) afforded 2.13 g (91%) of II-Sc as a light yellowish oil. IR (neat) 3058, 1742, 1584, 1480, 1071 cm“; lH NMR (300 MHz, CDCl,) 5 7.50-7.17 (m, 5 H), 37 3.14411. 1 : 0.0 H). l ‘1 NMR (75 )1111. ('1 313.36.]. 19.1; llR)1\ 3-Phen} lthioluc 114d (0.85 g (1.115 m'.‘ (neit13059.1715. l4“ Ht.3.92(q.]: 11.1. 51 47511112. CDCl.) .4 21h 37.5;HR1151El1 nt/I I? Phentlthtohtete 4451112322 mmol) a Elli-11.1739. 1481. 111 39541.1:71111. l l 011147311111. CDC} 19.63.148.234; LR.\1 (11,03: .73.l3;H thllHllllOblC) (1.49g. 12.0 mmol) . 31156. 3948. 1725 l " .‘1.Tl1[,]:2.5.ll2 l .135. 134.4. 131.8. 1 53119151131"): calcc A general procedu rt Benzenesulfoi !~ Me “-53 (2 .r )1. .2g.l 4: mmol) in 15.0 ml 3.84 (d, J = 6.6 Hz, 1 H), 2.70 (s, broad, 1 H), 2.50 (s, broad, 1 H), 2.06-1.57 (m, 8 H); l3C NMR (75 MHz, CDC13) 5 217.3, 135.6, 130.8, 128.9, 126.8, 59.8, 45.4, 37.0, 35.3, 31.3, 26.7, 19.1; HRMS (EI) m/z 232.0918 [(M+); calcd for CMHMOS 232.0923]. 3-Phenylthiobicyclo[3.2.1]octan-2-one II-Sd. Applying Conditions A to ketone II-4d (0.85 g, 6.85 mmol) afforded 1.44 g (91%) of II-Sd as a light yellowish oil. IR (neat) 3059, 1715, 1478, 1198, 1146 cm"; lH NMR (300 MHz, CDC1_,) 5 7.40—7.18 (m, 5 H), 3.92 (q, J = 12.1, 8.0 Hz, 1 H), 2.91 (t, J: 5.2 Hz, 1 H), 2.43-1.50 (m, 9 H); l3C NMR (75 MHz, CDC13) 5 208.4, 134.0, 132.1, 128.8, 127.1, 52.2, 51.2, 41.5, 38.9, 35.0, 27.9. 27.5; HRMS (EI) m/z 232.0923 [(M+); calcd for CNHMOS 232.0922]. Phenylthiobicyclo[4.2.1]nonanone II-Se. Applying Conditions A to ketone Il-4e (445 mg, 3.22 mmol) afforded 716 mg (90%) of II-5e as a light yellowish oil. IR (neat) 3058, 1739, 1481, 1111, 1086 cm"; 1H NMR (300 MHz, CDC13) 5 7.50—7.15 (m, 5 H), 3.95 (d, J: 7.1 Hz, 1 H), 2.79 (m, 1 H), 2.55 (t, J: 8.2 Hz, 1 H), 2.20-1.20 (m, 10 H); 13C NMR (75 MHz, CDC13) 5 219.8, 135.6, 130.5, 128.9, 126.6, 60.6, 43.6, 38.4, 31.2, 30.7, 29.6, 24.8, 23.4; LRMS m/e 246.1 (M+), 218.1, 149.0, 136.1, 109.2, 67.]; Anal. Calcd for CISHWOS: C, 73.13; H, 7.36. Found: C, 73.28; H, 7.38. Phenylthiobicyclo[2.2.2]octanone II-Sf. Applying Conditions A to ketone II-4f (1.49 g, 12.0 mmol) afforded 2.41 g (86%) of II-Sf as a light yellowish oil. IR (neat) 3056, 2948, 1725, 1480, 1265 cm"; lH NMR (300 MHz, CDCl,) 5 7.50-7.20 (m, 5 H), 3.71 (t, J = 2.5 Hz, 1 H), 2.36 (m, 1 H), 2.22-1.47 (m, 9 H); l3C NMR (75 MHz, CDC13) 5 213.5, 134.4, 131.8, 128.9, 127.2, 57.5, 42.5, 33.0, 25.3, 23.5, 22.7, 19.9; HRMS (131) m/z 232.0915 [(M+); calcd for CNHMOS 232.0922]. A general procedure for the preparation of sulfone II-6a-d Benzenesulfonylbicyclo[2.2.1]heptanone “-63 (Conditions B). To a solution of sulfide lI-Sa (2.2 g, 10 mmol) in 150 mL CHZCI2 was added a solution of mCPBA (3.6 g, 21 mmol) in 150 mL CHIC]2 dropwise at -78 ”C over a period of 10 min. The cold 38 solution m 111101161 10% N150. T11 concentrated and st‘; 3.15g1869101u C menstalli/atiun fro 1somer1m.p. 153-12' 1308. 1148. 710 cn‘ 111.1111.-.231dd. 110112.1111. 1.94 .\’.\1R175.\1112.Cl 2431111313 1E11 (1.11.4013; C. 62.3.5 Benzenequ 11-5b1023 g. 1.0 1 118 C). 1R1CH( q 917 ’7 ‘ ' 1.5-1111. 5 1 broad. 1 111.171 18.6112. 1 H1 1 123.6. 134.0. 11‘. .6-.065911.\1‘)' t solution was allowed to warm to rt and stir for 30 min before being quenched with aq 10% Na2S03. The organic layer was washed with aq NH4C1, NaHCOS, brine, concentrated and separated on silica gel (cyclohexane/EtOAc [4:1], Rr = 0.13) to provide 2.15 g (86%) of a crystalline mixture of two isomers (in a ratio of 3:1) of “-63. After recrystallization from the same mixed solvent, a pure analytical sample of the major isomer (mp. 153-156 °C) was collected as a colorless crystal. IR (CHC13) 1752, 1447, 1308, 1148, 720 cm"; 1H NMR (300 MHz, CDCl,) 8 7.92-7.53 (m, 5 H), 3.36 (d, J = 3.1 Hz, 1 H), 3.23 (dd, J: 2.2, 1.1, 1 H), 2.70 (d, broad, J = 3.1 Hz, 1 H), 2.52 (d, broad, J = 11.0 Hz, 1 H), 1.94-1.81 (m, 2 H), 1.58 (dm, J: 11.0 Hz, 1 H), 1.52-1.40 (m, 2 H); ”C NMR (75 MHz, CDCl,) 8 204.9, 139.2, 133.9, 129.0, 128.7, 73.3, 49.2, 38.5, 35.3, 27.7, 24.3; HRMS (EI) m/z 250.0657 [(M+); calcd for C,_,H,4O,S 250.0663]; Anal. Calcd for C,_,H,,O3S: C, 62.38; H, 5.64. Found: C, 62.41; H, 5.54. Benzenesulfonylbicyclo[3.2.1]octenone II-6b. Applying Conditions B to ketone II-Sb (0.23 g, 1.0 mmol) afforded 182 mg (70%) of II-6b as colorless crystals (mp. 116- 118 0C). IR (CHC13) 1750, 1447, 1310, 1146, 716 cm"; 1H NMR (300 MHz, CDCl,) 8 7.90-7.52 (m, 5 H), 5.70 (m, 2 H), 3.69 (s, broad, 1 H), 3.33 (s, broad, 1 H), 2.98 (s, broad, 1 H), 2.71 (dd, J = 19.2, 4.6 Hz, 1 H), 2.31 (q, J = 11.8, 4.6 Hz, 1 H), 2.05 (d, J = 18.6 Hz, 1 H), 1.71 (dd, J = 11.8, 1.9 Hz, 1 H); 13C NMR (75 MHz, CDC],) 8 199.9, 138.6, 134.0, 129.0, 128.9, 128.5, 126.5, 74.2, 47.1, 34.9, 33.3, 30.0; HRMS (EI) m/z 262.0659 [(M+); calcd for CMHMOSS 262.0664]. Benzenesulfonylbicyclo[3.2.l]octanone II-6c. Applying Conditions B to ketone II-Sc (1.05 g, 4.5 mmol) afforded 1.15 g (96%) of II-6c as colorless crystals (mp. 118- 120 0C). IR (CHC13) 1750, 1653, 1308, 1142, 1071 cm"; lH NMR (300 MHz, CDCl,) 8 7.91-7.52 (m, 5 H), 3.48 (d, J = 1.7 Hz, 1 H), 3.31 (s, broad, 1 H), 2.55 (s, broad, l H), 2.50 (m, 1 H), 1.90-1.60 (m, 7 H); l3C NMR (75 MHz, CDC13) 8 209.6, 138.7, 134.0. 129.1, 128.9, 73.5, 46.8, 35.2, 35.1, 31.4, 31.0, 18.9; HRMS (EI) m/z 264.0823 [(M+); calcd for C H 038 264.0821]. 14 16 39 3-Bcnzcnesu1 letonc ll-Sd 1430 m ~‘m.p. 153-155 C1. 1 CDC1,1 8 8.04-7.49 1 2.581m.1111.2..‘3 138.7. 133.7. 129.6 261.0821 [1.\l’1;cult .4 general procedur 3-Benzencm suspension 0151 mg 149.5 added a solutio mixture was stirred DMF was added 1m before being quchl we “:13th “ 11h 3-Benzenesu1fonylbicyclo[3.2.1]octan-2-one II-6d. Applying Conditions B to ketone II-Sd (430 mg, 1.85 mmol) afforded 398 mg (82%) of II-6d as colorless crystals (mp. 153-155 0C). IR (CHC13) 3065, 1718, 1447, 1148, 1086 cm"; lH NMR (300 MHz, CDCl,) 8 8.04-7.49 (m, 5 H), 4.00 (q, J = 12.1, 8.0 Hz, 1 H), 2.74 (t, J = 5.3 Hz, 1 H), 2.58 (m, l H), 2.33 (m, 1 H), 2.15-1.60 (m, 7 H); 13C NMR (75 MHz, CDC1_,) 8 202.7, 138.7, 133.7, 129.6, 128.7, 66.8, 51.5, 37.5, 33.8, 33.4, 27.7, 27.0; HRMS (E1) m/z 264.0821 [(M+): calcd for CNHMO_,S 264.0820]. A general procedure for the preparation of disubstituted bicyclic ketones II-9a-d 3-Benzenesulfonyl-3-allylbicyclo[2.2.1]heptanone II-9a (Conditions C). To a suspension of 51 mg NaH (95%, 2.0 mmol) and 300 mg NaI (2.0 mmol) in 2.0 mL DMF was added a solution of sulfone II-6a (0.5 g, 2.0 mmol) in 2.0 mL DMF at 0 “C. The mixture was stirred at 55 °C for 50 min. Mesylate “-7 (0.45 g, 2.0 mmol) in 2.0 mL DMF was added into the mixture at 50 ”C. Then the mixture was stirred at 55 "C for 4 h before being quenched with H20 and extracted with 3,0 (3 x). The combined extracts were washed with brine and dried, concentrated, separated on silica gel (hexane/ether [4:1], Rf = 0.60) to afford 0.34 g (53 %) ketone II-9a as a colorless oil. IR (neat) 1748, 1447, 1152, 1138, 1082 cm"; lH NMR (500 MHz, CDCl,) 8 7.98-7.50 (m, 5 H), 4.72 (s, broad, 1 H), 4.60 (s, broad, l H), 3.02 (d, J = 2.0 Hz, 1 H), 2.75-1.14 (m, 9 H), 1.20 (s, 2 H), -0.25 (s, 9 H); l3C NMR (75 MHz, CDCl,) 8 209.7, 141.1, 138.4, 133.6, 130.3, 128.6, 113.9, 78.6, 49.8, 43.6, 42.7, 34.6, 27.7, 25.5, 24.2, -1.9; HRMS (CI) m/z 377.1625 [(M‘r + H); calcd for CmHng3SSi 377.1607]. Benzenesulfonylallylbicyclo[3.2.1]octenone II-9b. Applying Conditions C to [1- 6b (425 mg, 1.6 mmol) afforded 320 mg (61%) of II-9b as colorless crystals (mp. 96-98 °C). IR (neat) 1740, 1447, 1310, 1140, 857 cm"; IH NMR (500 MHz, CDC13) 8 7.94-7.45 (m, 5 H), 5.93 (d, broad, J = 9.0 Hz, 1 H), 5.71 (t, broad, J = 7.5 Hz, 1 H), 4.79 (s, broad, 1 H), 4.60 (s, broad, 1 H), 3.22-1.67 (m, 8 H), 1.22 (ABq, JAB = 19.1 Hz, AVAB = 105.5 40 Hz.2H1.-0.261.\. ‘1 130.9. 128.3. 122.7. 388153011311; 1111. Benzenesulr 6(1844 mg. 3.21.) r 30.71.1742. 13118. 0021111114560 = 13.5 Hz. AV : 141.11.391.13} 17.4. -1.9‘. HRMS 3-Bcnrcnc ltr ll-(Kl 1280 mg ‘neat13073. 1705 3.751sbroad. 1 1 3V4; 1' 89.1 HZ. HRMS 1E1) nz/: 1 A general pm“. Phemlthi 20 mg, 1.06 1, ml ether ll-8e 1 To a 50111 Q m_1€€[ed 0 § enfor ”hand 51.715 . 5 ‘..I iv] Hz, 2 H), -0.26 (s, 9 H); l3C NMR (75 MHz, CDCl,) 8 205.2, 141.1, 138.2, 133.6, 131.9, 130.9, 128.3, 122.7, 114.1, 80.0, 47.5, 45.3, 39.8, 31.5, 30.4, 27.5, -1.9; HRMS (E1) m/z 388.1530 [(M+); calcd for Clesz3SSi 388.1529]. Benzenesulfonylal1ylbicyclo[3.2.1]octanone Il-9c. Applying Conditions C to 11- 6c (844 mg, 3.20 mmol) afforded 235 mg (25%) of II-9c as a colorless oil. IR (neat) 3071, 1742, 1308, 1142 cm"; 'H NMR (300 MHz, CDC13) 5 8.15-7.50 (m, 5 H), 4.73 (s, broad, 1 H), 4.56 (s, broad, 1 H), 2.97 (s, broad, 1 H), 2.68-1.45 (m, 11 H), 1.22 (ABq, JAB = 13.5 Hz, AVA,B = 95.5 Hz, 2 H), -0.26 (s, 9 H); ”C NMR (75 MHz, CDC13) 8 214.7, 141.1, 139.1, 133.5, 130.4, 128.6, 113.6, 81.3, 46.9, 45.0, 42.2, 33.7, 32.1, 29.3, 27.3. 17.4, -1.9; HRMS (El) m/z 390.1688 [(M”); calcd for C,,H OJSSi 390.1685]. 3-Benzenesu1fonylallylbicyclo[3.2.1]octan-2-one II-9d. Applying Conditions C to II-6d (280 mg, 1.06 mmol) afforded 236 mg (57%) of II-9d as a colorless oil. IR (neat) 3073, 1705, 1449, 1144 cm"; 1H NMR (300 MHz, CDC],) 8 7.76-7.45 (m, 5 H), 4.75 (s, broad, 1 H), 4.63 (s, broad, l H), 2.75-1.53 (m, 12 H), 1.22 (ABq, JAB = 81.6 Hz, AVAB = 89.1 Hz, 2 H), -0.20 (s, 9 H); ”C NMR (75 MHz, CDC1_,) 8 208.6, 140.8, 136.0, 133.7, 121.2, 128.1, 115.7, 74.2, 51.4, 46.3, 33.3, 32.2, 31.5, 29.1, 27.9, 27.6, -l.6; HRMS (E1) m/z 390.1663 [(M+); calcd for Cle O,SSi 390.1686]. A general procedure for disubstituted ketone II-6e-f Phenylthioal1y1bicyclo[4.2.1]nonanone II-6e. Applying Conditions C to Il-Se (260 mg, 1.06 mmol) afforded 96 mg (25%) of II-6e as a colorless oil. The by-product enol ether “-81! (241 mg, 61%) was also isolated in this process. To a solution of 60 mg (0.16 mmol) enol ether lI-8e in 10 mL methylene chloride was injected 0.5 mL DIBAL (1.0 M in hexane) at 0 °C. The resulting mixture was stirred at rt for 15 h and then diluted with 20 mL ether, washed with 0.5 M HCl, NaHC03, dried, and concentrated to afford 61 mg (100%) crude intermediate alcohol as a single isomer. This material was used without further purification. 41 To a solution .17 mLt nets added 1 mixture “Lb stirred :11 sat..\'uHCO, 11:11 for dned and concentrate churned. Spectra of 11- 11112.CDC1.1 8 7.611- 51111175 81111.. CD 13.5.1211. 32.3. 311.1 noncossr 372.1 Phen11th111411 111g.3.0 mmolt 111.1111 ether "-81 15.92 mg. To a solutior 1111 injected 1.0 mL atretlux for 7‘ h be 11121. aq. NuHCO, t #811,101 two alcol The abote 111108.101] under th- To a solution of the above alcohol (208 mg, 0.556 mmol) in methylene chloride (17 mL) was added Bess-Martin periodinane (329 mg, 0.776 mmol) and the resulting mixture was stirred at rt for 3.5 h before being quenched by stirring with 10% aq Na,S,O_,- sat. NaHCO3 (1:1) for 30 min. The mixture was extracted with ether, washed with brine, dried and concentrated. After silica gel purification, 193 mg (93%) ketone II-6e was obtained. Spectra of II-6e. IR (neat) 3069, 1740, 1476, 1246, 1098 cm"; 1H NMR (300 MHz, CDCl,) 8 7.60-7.20 (m, 5 H), 4.62 (m, 2 H), 2.78-1.15 (m, 16 H), -0.28 (s, 9 H); ”C NMR (75 MHz, CDC13) 8 222.5, 143.0, 133.6, 133.2, 128.8, 127.1, 112.2, 67.1, 44.9, 43.5, 42.0, 32.3, 30.8, 29.7, 27.4, 24.7, 24.1, -1.9; HRMS (E1) m/z 372.1937 [(Mi); calcd for CanOSSi 372.1943]. Phenylthioallylbicyclo[2.2.2]octanone II-6f. Applying Conditions C to II-Sf (696 mg, 3.0 mmol) afforded 186 mg (17%) of II-6f as a colorless oil. The by-product enol ether II-8f (592 mg, 61%) was also isolated as a colorless oil. To a solution of 125 mg (0.35 mol) enol ether II-8f in 10 mL methylene chloride was injected 1.0 mL DIBAL (1.0 M in hexane) at 0 0C. The resulting mixture was stirred at reflux for 72 h before it was cooled and diluted with 100 mL ether, washed with 0.5 M HCl, aq. NaHCO3, dried, and concentrated to give 1 16 mg (92%) of crude oil as a mixture (~ 8:1) of two alcohol isomers. This material was used without further purification. The above alcohol mixture (350 mg, 0.89) was subjected to Dess-Martin oxidation under the same condition as for the preparation of II-6e to furnish 319 mg (85% from II-8f) of ketone II-6f. Spectra of lI-6f. IR (neat) 3061, 1717, 1439, 1248, 1026 cm"; lH NMR (300 MHz, CDCl,) 8 7.60-7.22 (m, 5 H), 5.05 (s, broad, l H), 4.76 (s, broad, 1 H), 2.50-1.42 (m, 12 H), 1.58 (ABq, JAB = 12.5 Hz, AVAB = 52.5 Hz, 2 H), -0.10 (s, 9 H); ”C NMR (75 MHz, CDC13) 8 212.5, 142.8, 136.5, 131.5, 128.9, 128.4, 111.7, 60.4, 42.7, 38.3, 34.6, 28.9, 25.0, 23.4, 23.1, 22.2, -1.6; HRMS (E1) m/z 358.1794 [(M+); calcd for C,,H,,,OSSi 42 35117811 .1 general 11'0“"dun Benzenexult'o letone 11-6e 1 1115 1111 1.150 mg 184‘? 11m" 14481144. 1082e11 1 111.-1.80 1s. broad 175 31112. CDClt & 45.0. 31.1. 31.0. 2'. 2151,1471. 135.0 065.6911. 8.02. Benzenesult 121211011 sulfide ”-6 refluxed for 36 h. Separated on 511m "‘91- IR trieatt 31; "451m. 5 H1. 5. 1 358.1786]. A general procedure for the oxidation of II-6e-f to II 9e-f Benzenesulfonylallylbicyclo[4.2.1]nonanone II-9e. Applying Conditions B to ketone II-6e (105 mg, 0.28 mmol) afforded 46 g (39%) of II-9e as a colorless oil as well as 50 mg (84% based on 46% conversion rate) of recovered Il-6e. IR (neat) 3071, 1740, 1448, 1144, 1082 cm"; 1H NMR (300 MHz, CDC13) 8 8.20-7.50 (m, 5 H), 4.75 (s, broad, l H), 4.60 (s, broad, 1 H), 3.01 (m, 1 H), 2.75-1.10 (m, 15 H), -0.21 (s, 9 H); I3C NMR (75 MHz, CDCl,) 8 216.7, 141.4, 139.3, 133.6, 130.7, 128.5, 113.5, 82.1, 46.4, 45.2, 45.0, 31.1, 31.0, 27.5, 27.3, 24.9, 24.2, -1.9; MS m/e 404.3 (M+), 389.3, 349.2, 263.3, 215.1, 147.1, 135.0, 91.1, 73.1; Anal. Calcd for C,,H_,,O_,SSi: C, 65.30; H, 7.97. Found: C, 65.69; H, 8.02. Benzenesulfonylallylbicyclo[2.2.2]octanone II-9f. A solution of 120 mg (0.33 mmol) sulfide II-6f and 0.12 g ( 0.70 mmol) mCPBA in 10 mL methylene chloride was refluxed for 36 h. The solution was then washed with aq. NaZSO3, NaHC03, brine and separated on silica gel (petroleum/ether [7:1], Rf = 0.41) to furnish 94 mg (69%) sulfone II-9f. IR (neat) 3080, 1727, 1447, 1248, 1117 cm"; 1H NMR (300 MHz, CDC1_,) 8 8.00- 7.45 (m, 5 H), 5.13 (d, J = 1.1 Hz, 1 H), 4.70 (s, broad, 1 H), 2.99-1.28 (m, 14 H), -0.20 (s, 9 H); ”C NMR (75 MHz, CDC13) 8 210.9, 140.1, 138.6, 133.7, 130.5, 128.4, 111.8, 78.3, 42.7, 41.5, 31.1, 29.9, 23.8, 23.2, 23.1, 22.5, -1.7; HRMS (EI) m/z 390.1682 [(M+); calcd for C2,H_,OO_,SSi 390.1686]. General procedures for the ring expansion process Alcohol II-10a and dienone II-ll (Conditions D). A solution of II-9a (1.83 g, 4.87 mmol) and TBAF (446 mg, 1.70 mmol) was dissolved in 150 mL THF and heated in oil bath at 60 °C for 3.0 h. The reaction mixture was cooled to rt and quenched with aq NH4C1, and extracted with CHzCl2 (2 x). The combined extracts were washed with brine, 43 dried. and 56119131” 1675;101'u1e1111t11 ”-11 The major isomer w. 395.. R. : 0.67 in h process. For “-1021: ll CDC1.187.99-7.5111 1m.12111: ‘C NMR 800. 49.5. 45.9. 45. 18011.08 305.12 11.11.57. For 11-11: 1 (00.18 5.71-5.55 190113111: 1C N.‘ 35.9. 30.3. 28.4. 27. The conversion of A solution 1 171171150ij 11:15 and extracted with 36' 1 - I oil. dried, and separated on silica gel (hexane/ether [1:1], Rf = 0.33, 0.25) to give 1.011 g (67%) of alcohol II-10a as a mixture of two stereoisomers (~ 4:1) both as corless crystals. The major isomer was fully characterized, mp. 136-137 °C. Dienone "-11 (230 mg. 29%, Rf = 0.67 in hexane/ether [l:1]) was also collected as a colorless oil from this process. For II-lOa: IR (CHC1_,) 3519, 1447, 1287, 1141, 1078 cm"; IH NMR (500 MHz, CDCl,) 8 7.99-7.50 (m, 5 H), 4.84 (m, 1 H), 4.76 (m, 1 H), 3.40 (s, broad, 1 H), 3.32-1.08 (m, 12 H); ”C NMR (75 MHz, CDC1_,) 8 146.2, 138.4, 133.4, 129.8, 128.7, 106.9, 90.6, 80.0, 49.5, 45.9, 45.3, 40.0, 39.1, 23.6, 23.0; HRMS (EI) m/z 305.1188 [(M+ + H); calcd for C,,H,,O,S 305.1212]. Anal. Calcd for C17H,,,O_,S: C, 67.08; H, 6.62. Found: C, 67.41; H, 6.57. For Il-ll: IR (neat) 1653, 1449, 1277, 1145, 756 cm"; lH NMR (300 MHz, CDC13) 8 5.71-5.55 (m, 3 H), 2.86 (m, 1 H), 2.66 (d, J = 3.7 Hz, 1 H), 2.00-1.60 (m, 6 H), 1.90 (s, 3H); ”C NMR (75 MHz, CDCl,) 8 209.1, 141.8, 137.8, 126.8, 126.1, 48.1, 42.8, 35.9, 30.3, 28.4, 27.9; HRMS (EI) m/z 162.1043 [(M+); calcd for CHHHO 162.1045]. The conversion of alcohol II-10a to dienone II-ll (Conditions E). A solution of II-lOa (1.312 g, 4.32 mmol) and t-BuOK (0.411g, 3.67 mmol) in THF (150 mL) was stirred at 55 °C for 2.0 h. The reaction was quenched with aq NH,C1 and extracted with ether. The extract was washed with brine, dried, separated on silica gel (hexane/ether [1:1], RI: 0.67) to provide dienone II-ll (580 mg, 83%) as a colorless oil. Alcohol Il-10b. Applying Conditions D to ketone II-9b (482 mg, 1.24 mmol) afforded 357 mg (92%) of II-lOb as colorless crystals (m.p. 157-8 "C). IR (CHC1,) 3522, 3042, 1670, 1445, 1078 cm"; ‘H NMR (300 MHz, CDC13) 5 8.10-7.42 (m, 5 H), 5.90 (m, 2 H), 4.33 (s, broad, 1 H), 4.09 (s, broad, 1 H), 4.03 (s, broad, 1 H), 3.27-1.80 (m, 10 H); ”C NMR (75 MHz, CDCl,) 8 145.8, 138.5, 133.4, 130.6, 129.8, 128.4, 127.9, 106.4, 93.2, 44 817. 48.3. 47.1. 41 01105 310,113.51 Transunnulnt 811011121 mg. 0.18 to rt and being que 111101 gel 1light petr isolated £15 a light y 11.1675} conxerxion 86.79111] : 8.8 l 111195153111. 1 128.3. 125.3. 123' 105.8 89.5. 80.4 111 0.11.081 1 Metinlbr mg.0.126 mmolr 137 .1179. 818 13.0. 7.7 H2. 1 l 81.7, 48.3, 47.1, 46.9, 45.6, 32.4, 31.4; HRMS (E1) m/z 316.1137 [(M+); calcd for C,,,H,,,O_,S 316.1133]. Transannulation dienone [1-13. A solution of II-lOb (60 mg, 0.190 mmol) and r- BuOK (21 mg, 0.188 mmol) in 15 mL DME was stirred at reflux for 48 h. After cooling to rt and being quenched with aq NH,C1, extracted with ether, dried, and separated on silica gel (light petroleum ether/Eth [3:1], R, = 0.45), 6 mg (20 %) dienone “-13 was isolated as a light yellowish oil as well as 19 mg recovered starting material (30% based on 67% conversion). IR (neat) 3032, 2926, 1663, 1310 cm": 1H NMR (300 MHz, CDC1_,) 8 6.79 (d, J = 8.8 Hz, 1 H), 5.88 (m, 1 H), 5.65 (m, 2 H), 5.56 (s, 1 H), 2.70-2.00 (m, 4 H), 1.95 (s, 3 H), 1.80-1.40 (m, 2 H); ”C NMR (75 MHz, CDCl,) 8 198.8, 160.7, 137.0, 128.3, 125.3, 123.7, 42.1, 38.7, 36.7, 34.2, 33.9, 24.7; HRMS (E1) m/z. 174.1039 [(M+); calcd for C,,H,,O 174.1045]. Alcohol II-10c. Applying Conditions D to ketone II-9c (195 mg, 0.5 mmol) afforded 130 mg (82%) of II-lOc as colorless crystals (mp. 190-192 °C). IR (CHCl,) 3517, 1653, 1559, 1420, 1086 cm"; 'H NMR (300 MHz, CDCl,) 8 8.10-7.47 (m, 5 H), 4.57 (s, broad, 1 H), 4.33 (s, broad, 1 H), 3.68 (s, broad, 1 H), 3.08 (d, J = 17.0 Hz, 1 H), 2.79-1.38 (m, 13 H); ”C NMR (75 MHz, CDC1_,) 8 145.9, 139.1, 133.4, 129.5, 128.7, 105.8, 89.5, 80.4, 52.1, 47.7, 47.4, 47.0, 35.6, 29.9, 28.2, 17.9; HRMS (E1) m/z 177.1278 [(M+ - CéHsOZS); calcd for C,,H,,O 177.1280]. Methylbicyclo[5.3.1]undecdienone II-14. Applying Conditions E to II-10c (41 mg, 0.126 mmol) afforded 20 mg (87%) of “-14 as a colorless oil. IR (neat) 1694, 1456, 1375, 1179, 818 cm"; lH NMR (300 MHz, CDCl,) 8 5.56 (s, broad, 1 H), 5.52 (dd, J = 13.0, 2.7 Hz, 1 H), 5.22 (ddd, J = 13.0, 3.3, 1.2 Hz, 1 H), 3.06 (dm, J = 14.3 Hz, 1 H), 2.66 (s, broad, l H), 2.49 (dm, J = 9.1 Hz, 1 H), 2.20 (s, broad, 1 H), 1.91-1.82 (m, 2 H), 1.81 (s, 3H), 1.71-1.20 (m, 4 H); ”C NMR (75 MHz, CDCl,) 8212.9, 138.0, 134.6, 128.1, 123.9, 44.9, 36.7, 33.0, 29.1, 25.8, 23.8, 19.7; HRMS (El) 711/: 176.1199 [(M+); 45 calcd for C :11 ‘0 1 Alcohol 11 afforded 144 mg 3546. 3070. 144' 4.821d.]:1.41 111.111.12.701; 135m. 10 H1; 35.2. 73. .518 LII cdcd for C111 Dicnol 1 111990571 of 11 1035,1448. 11' 1111.1 111.-1.701 130.9. 102.9. 1 1131‘1zca1cd fo calcd for C,,H,,O 176.1201]. Alcohol II-10d. Applying Conditions D to ketone II-9d (190 mg, 0.49 mmol) afforded 144 mg (92%) of II-10d as colorless crystals (m.p. 156.5-157.5 °C). IR (CHC1_,) 3546, 3070, 1447, 1142, 1084 cm"; 1H NMR (300 MHz, CDCl,) 8 7.95-7.50 (m, 5 H), 4.82 (d, J = 1.4 Hz, 1 H), 4.72 (d, J = 1.4 Hz, 1 H), 3.88 (s, broad, 1 H), 3.35 (d, J = 13.4 Hz, 1 H), 2.70 (ABq, J = 16.5, AVAB = 6.0 Hz, 2 H), 2.42 (dt, J = 16.0, 2.2 Hz, 1 H), 2.24- 1.35 (m, 10 H); ”C NMR (75 MHz, CDCl,) 8 144.5, 138.5, 133.4, 130.4, 128.7, 108.0, 85.2, 73.5, 51.8, 49.4, 47.2, 39.9, 33.5, 32.9, 28.5, 23.8; HRMS (El) m/z 318.1300 [(M+); calcd for C,8H,,O,S 318.1290]. Dienol II-lS. Applying Conditions E to II-lOd (54 mg, 0.176 mmol) afforded 24 mg (90%) of II-15 as light yellowish crystals (mp. 73-75 ”C). IR (CHC13) 3279 (broad), 1635, 1448, 1175, 849 cm"; IH NMR (300 MHz, CDCl,) 8 5.89 (d, J = 1.9 Hz, 1 H), 4.80 (m, 1 H), 4.70 (m, l H), 2.75-1.11 (m, 13 H); ”C NMR (75 MHz, CDCl,) 8 152.3, 150.6, 130.9, 102.9, 84.6, 45.4, 43.3, 35.4, 34.5, 33.8, 27.8, 25.5; HRMS (EI) m/z 176.1197 [(M+); calcd for C,,H,,O 176.1201]. Alcohol II-10e. Applying Conditions D to ketone II-9e (33 mg, 0.08 mmol) afforded 26 mg (96%) of II-10e as colorless crystals (mp. 188-190 ”C). IR (CHC1,) 3507, 1445, 1298, 1148, 1080 cm"; 'H NMR (300 MHz, CDCl_,) 8 8.10-7.50 (m, 5 H), 4.68 (s, broad, 1 H), 4.55 (s, broad, 1 H), 3.52 (s, broad, 1 H), 3.25 (d, J = 17.0 Hz, 1 H), 2.75-1.20 (m, 15 H); ”C NMR (75 MHz, CDCl,) 8 144.9, 139.0, 133.5, 129.9, 128.8, 106.6, 88.8, 81.2, 53.0, 50.7, 49.7, 48.1, 31.9, 31.7, 29.7, 25.6, 24.9; HRMS (El) 217/: 332.1445 [(M+); calcd for C,9H,,O,S 332.1446]. Alcohol II-10f. Applying Conditions D to ketone lI-9f (160 mg, 0.41 mmol) afforded 89 mg (68%) of lI-lOf as colorless crystals (mp. 143-144 "C). IR (CHC1,) 46 3546. 3061. 1443. 4.801s.br0;1d. 1 11 2.7515. broad. 2 11 1m.8111; 3C .\'.\11 75.4. 49.2. 43.8. 3: iorC,H_:OS 318 Dienol ll-1 mg148‘} or 74‘? 34201634. 1456 1111. 4.88 1111. l l 2.01-1.321m. to 34.2. 30.1. 29.7. 17112011. lellalions of u 7.7-( [.14 ”MUD“ of I. benzodithjgie m, 3546, 3061, 1443, 1286, 1156 cm"; lH NMR (300 MHz, CDC1_,) 8 8.00-7.50 (m, 5 H), 4.80 (s, broad, 1 H), 4.68 (s, broad, 1 H), 4.00 (s, broad, 1 H), 3.39 (d, J: 16.2 Hz, 1 H), 2.75 (s, broad, 2 H), 2.59 (m, 1 H), 2.26 (d, J = 16.2 Hz, 1 H), 2.10 (m, l H), 1.85-1.20 (m, 8 H); ”C NMR (75 MHz, CDCl,) 8 146.6, 138.1, 133.5, 129.8, 128.8, 106.1, 81.8, 75.4, 49.2, 43.8, 38.2, 33.2, 23.4, 22.7, 21.5, 20.0; HRMS (El) m/z 318.1275 [(M+):ca1cd for C,,,H,,O,S 318.1289]. Dienol “-16. Applying Conditions E to II-10f (60 mg. 0.189 mmol) afforded 16 mg (48% or 74% based on 65% conversion) of “-16 as a light yellowish oil. IR (neat) 3420, 1634, 1456, 1161, 1047 cm"; 1H NMR (300 MHz, CDCl,) 8 5.89 (s, 1 H), 4.93 (m, 1 H), 4.88 (m, 1 H), 2.62 [ABq (t, s), J: 15.5, 2.5, AVAB = 130.0 Hz, 2 H], 2.61 (m, 1 H), 2.01-1.32 (m, 10 H); ”c NMR (75 MHz, CDC],) 5 161.3, 151.2, 125.8, 104.6, 83.1, 43.4, 34.2, 30.1, 29.7, 23.8, 22.8, 21.1; HRMS (El) m/z 176.1197 [(M+): calcd for C,,H,,O3 176.1201]. Limitations of the Ring Expansion Protocol 7,7-(l,2-Benzenediyldithio)-5-methylbicyclo[3.2.1]octan-2-ol III-l. The reduction of I-33 with NaBH4 at O 0C in MeOH produced 0.57 g (99%) crude benzodithiole methylbicyclo[3.2.1]octanol III-l as a light yellowish solid. This material was used without further purification. An analytical sample was prepared by recrystallization from cyclohexane, m.p. 97-100 °C. IR (CHC13) 3403 (broad), 3058, 1459, 1256, 1015 cm"; lH NMR (500 MHz, CDC],) 8 7.21-7.00 (m, 4 H), 3.72 (ddd, J = 13.1, 6.0, 2.8 Hz, 1 H), 2.74 (m, l H), 2.34 (s, 2 H), 2.04 (dtt, J = 13.9, 5.3, 1.6 Hz, 1 H), 1.96 (ddd, J =12.4, 5.3, 2.9 Hz, 1 H), 1.65 (m, 1 H), 1.46-1.38 (m, 2 H), 1.28 (d, J =12.1 Hz, 1 H), 1.05 (s, 3 H), (OH not visible); ”c NMR (75 MHz, CDCl,) 5 139.4, 137.5 126.0, 125.8, 122.6, 122.2, 74.4, 74.3, 55.6. 50.2, 43.8, 39.6, 38.0, 29.8, 26.4; HRMS (E1) m/z 278.0800 [(M+); calcd for C H OS2 15 IX 278.0799]; Anal. Calcd for C,_,H,,,OS,: C, 64.70; H, 6.52. Found: C, 64.69: H, 6.78. 47 .\10.\l ether much in 80 mL C min. methox) metli 511111110161 211 11111 110 13 .11. dried. thexanee’ethcr [10: ineatt 3056. 1456. H1. 4.68 1.48,. 11,, 111335133111. 112. 1 111. 200-12 31112.CDC1._18 1 50.8. 44.6. 40.8. f ‘01 -3--.10611:Ana1. ( Bicyc10[3, 0 7 e. 0.- mmolt in (; min-011 1113 mL 8 p"311131111110 a mi, 41111 stirred f0, 4 3 Sn -— - . 4r 1 atiori on 8111 181011131, 0,] 1R MOM ether Ill-2. To a cold (0 “C) solution of crude alcohol III-1 (5.56 g, 20 mmol) in 80 mL CHZCl2 was added diisopropylethylamine (27 mL, 154 mmol). After 10 min, methoxymethyl chloride (6.44 g, 6.1 mL, 80 mmol) in 50 mL CHIC]2 was added slowly over 20 min. The mixture was stirred at room temperature for 24 h, washed with 11,0 (3 x), dried, concentrated and the residue was chromatographed on silica gel (hexane/ether [10:1], R{ = 0.35) to afford 6.40 g (98% from 1-33) as a colorless oil. IR (neat) 3056, 1456, 1375, 1105, 949 cm"; 1H NMR (500 MHz, CDC],) 6 7.25-6.98 (m, 4 H), 4.68 (ABq, JAB = 7.1, Hz, AVAB = 52.0 Hz, 2 H), 3.73 (ddd, J = 11.7, 5.9, 2.9 Hz, 1 H), 3.35 (s, 3 H), 2.95 (s, broad, 1 H), 2.60 (d, J = 14.5 Hz, 1 H), 2.36 (dd, J = 14.5, 2.1 Hz, 1 H), 2.00-1.90 (m, 2 H), 1.80 (m, 1H), 1.37 (m, 3 H), 1.03 (s, 3 H); 13C NMR (75 MHz, CDCl,) 5 139.8, 136,7, 125.4, 125.1, 122.4, 122.3, 94.6, 77.5, 74.5, 58.7, 55.6, 50.8, 44.6, 40.8, 38.2, 27.1, 26.6; HRMS (EI) m/z 322.1056 [(M+); calcd for C,,H,,O,S2 322.1061]; Anal. Calcd for C,,H,,O.S,: C, 63.31; H, 6.88. Found: C, 62.92: H, 7.15. Bicyclo[3.2.1]octanone 1-32. A cold (-5 ”C) solution of benzodithiole III-2 (0.065 g, 0.2 mmol) in 0.5 mL CH3CN was added dropwise to a solution of 0.25 g NBS (1.40 mmol) in 3 mL 80% aq CHJCN at 0—3 “C. The mixture was stirred for 5 min and then poured into a mixture of 3 mL cyclohexane, 3 mL CH2C12, and 5 mL saturated Na,SO,, and stirred for 3 min. The organic layer was washed with water, brine and dried. Separation on silica gel (hexane/ether [2:1], Rf = 0.15) afforded 0.027 g (67%) of a light yellowish oil. IR (neat) 2946, 1745, 1147, 1047, 951 cm"; lH NMR (500 MHz, CDC1_,) 8 4.70 (ABq, JAB: 7.1 Hz, AVAB = 31.6 Hz, 2 H), 3.74 (ddd, J = 11.4, 5.8, 3.4 Hz, 1 H), 3.37 (s, 3 H), 2.63 (s, broad, 1 H), 2.02 (ABq, J = 18.4 Hz, AVAB = 65.6 Hz, 2 H), 2.01 (m, 1 H), 1.77 (dq, J = 12.1, 6.0, 2.9 Hz, 1 H), 1.60-1.40 (m, 4 H), 1.15 (s, 3 H); I3C NMR (75 MHz, CDC13) 5 218.1, 94.7, 76.5, 55.4, 52.7, 50.3, 41.8, 37.3, 36.7, 27.6, 26.5; HRMS (E1) m/z 198.1247 [(M’); calcd for CHHmO3 198.1256]. 48 a-Phcmlth g. 10.0 mmolt .1111 C1. lRtCHCl.11 7.191‘m. 5 H1. 471 Hz 1 H1.3.4(l1x. 11315.3 H1; 'C 65.8. 55.7. 51.0.- cnzos 306.12 a-Phenylthiobicyclo[3.2.1]octanone III-3. Applying Conditions A to I-32 (1.98 g, 10.0 mmol) afforded 2.617 g (91%) of “-15 as light yellowish crystals (m.p. 92-93.5 °C). IR (CHC13) 1744, 1458, 1208, 1103, 916 cm"; 1H NMR (500 MHz, CDCl,) 6 7.60- 7.19 (m, 5 H), 4.70 (ABq, JAB = 7.1 Hz, AVAB = 26.3 Hz, 2 H), 3.75 (ddd, J = 14.2, 6.5, 3.3 Hz, 1 H), 3.40 (s, 3 H), 3.25 (s, 1 H), 2.79 (It, J = 5.0, 1.3 Hz, 1 Hz), 2.01-1.40 (m, 6 H), 1.12 (s, 3 H); 13C NMR (75 MHz, CDCl,) 8 214.8, 135.9, 131.8, 129.0, 127.1. 95.0, 77.2. 65.8, 55.7, 51.0, 42.2, 40.7, 32.9, 28.2, 25.4; HRMS (EI) m/z 306.1290 [(M+); calcd for C,,H,,O_,S 306.1290]. 01,01-Disubstitutedbicyclo[3.2.1]octanone III-5. Applying Conditions C to III-3 (4.59 g, 0.176 mmol) afforded 2.16 g (47%) of III-5 as light yellowish crystals (mp. 54- 55 °C. IR (CHC13) 1738, 1473, 1148, 1028, 852 cm"; lH NMR (500 MHz, CDCl,) 6 7.80-7.25 (m, 5 H), 4.74 (ABq, JAB = 7.0, AVAB = 29.1 Hz, 2 H), 4.68 (s, broad, 1 H), 4.54 (s, broad, 1 H), 3.79 (ddd, J = 10.2, 7.1, 3.3 Hz, 1 H), 3.41 (s, 3 H), 2.71 (ddd, J = 6.4, 3.3, 0.95 Hz, 1 H), 2.32 (m, 1 H), 2.30 (ABq, JAB = 13.7, AVAB = 80.4 Hz, 2 H), 2.13-2.00 (m, 3 H), 1.55 (s, broad, l H), 1.42-1.21 (m, 3 H), 1.20 (s, 3 H), -0.25 (s, 9 H); 13C NMR (125 MHz, CDCl,) 5 219.3, 144.6, 138.5, 130.3, 128.8, 128.2, 114.0, 94.6, 77.1, 64.7, 55.3, 51.6, 45.9, 45.1, 38.4, 37.2, 28.3, 26.5, 20.0, -l.8; HRMS (EI) m/z 432.2148 [(M+); calcd for C,,H,6O,SSi 432.2154]. a-Keto Sulfoxide III-6. A solution of 0.09 g (0.44 mmol) mCPBA in 2 mL CI-IZCI2 was added into a solution of 0.23 g (0.5 mmol) III-5 in 5 mL CHzCl2 over a period of 10 minutes at -78 0C. The resulting mixture was stirred and allowed to warm to rt. over 1.0 hr before being quenched with 10% aq sodium sulfite. The organic layer was washed with aq NHdCl, NaHCO3, brine, dried, concentrated and separated on silica gel (hexane/ether [2:1], Rf = 0.15) to give 0.08 g recovered III-5 and 0.08 g (51%) of III-6 as a colorless oil. IR (neat) 1732, 1464, 1148, 1076, 853 cm"; 1H NMR (500 MHz, CDCl,) 49 5 7.72-7.49 (m, 5 H), 4.82 (s, broad, 1 H), 4.77 (ABq, 1,, = 7.1, AVA, = 27.5 Hz, 2 H), 4.00 (ddd, J: 11.4, 6.2, 3.3, Hz, 1 H), 3.42 (s, 3 H), 2.98 (d, J: 13.5 Hz, 1 H), 2.72 (m, 1 H), 2.32-1.99 (m, 4 H), 1.76 (td, J = 14.4, 5.9 Hz, 1 H), 1.49 (s, 3 H), 1.46-0.80 (m, 4 H), -0.32 (s, 9 H); ”C NMR (75 MHz, CDC1_,) 5 215.9, 143.1, 139.6, 131.4, 128.0, 127.8. 115.1. 94.7, 78.2, 75.6, 55.4, 522,464, 39.4, 37.2, 37.1, 28.5, 26.8, 21.6, -20; HRMS (EI) m/z 322.1963 [(M+ - c.1463); calcd for C,,H,,o,81 322.1964]. Alcohol III-8. Applying Conditions D to III-6 (750 mg, 1.67 mmol) afforded 500 mg (79%) of III-8 as colorless crystals (mp. 91-93 °C). IR (CHC13) 3468, 3063, 1472, 1151, 1030 cm"; lH NMR (500 MHz, CDCl,) 6 8.02 (m, 2 H), 7.39 (m, 3 H), 4.76 (ABqd, JAB = 6.8, 0.66, AVAB = 7.2 Hz, 2 H), 4.08 (s, broad, 1 H), 4.02 (ddd, J = 10.6, 7.3, 2.7 Hz, 1 H), 3.92 (s, broad, 1 H), 3.41 (s, 3 H), 2.86-2.76 (m, 3 H), 2.40-2.22 (m, 5 H), 2.01 (s, broad, 1 H), 1.79 (ddd, J = 12.8, 5.5, 3.1 Hz, 1 H), 1.64 (m, 1 H), 1.27 (dd, J = 12.8, 1.4 Hz, 1 H), 1.08 (s, 3 H); 13C NMR (75 MHz, CDCl,) 6 146.9, 141.0, 130.2, 128.4, 127.6, 105.1, 94.9, 91.4, 80.9, 79.0, 55.7, 52.5, 48.8, 47.5, 41.4, 37.0, 35.3, 27.3, 23.2; HRMS (EI) m/z 376.1701 [(M+); calcd for C,,H,,O,S 376.1708]. Epoxide III-9. The Oxone® (1.1 eq) oxidation of III-8 (75 mg, 2.0 mmol) at pH 4-5 produced 57 mg (72%) epoxide III-9 as colorless crystal (mp. 148-150 °C). IR (CHC1,) 3461, 3059, 1468, 1300, 1026 cm"; ‘H NMR (500 MHz, CDC1_,) 5 8.18-7.40 (m, 5 H), 5.22 (s, 1 H), 4.72 (ABq, JAB = 6.9, AVAB = 4.0 Hz, 2 H), 4.03 (m, 1 H), 3.40 (s, 3 H), 2.79 (m, 2 H), 2.30-1.61 (m, 11 H), 1.18 (s, 3 H); 13C NMR (75 MHz, CDCI3) 6 142.3, 130.6, 128.3, 128.1, 94.9, 89.9, 81.1, 78.8, 62.3, 55.8, 55.7, 50.4, 48.8, 47.8, 41.2, 35.3, 34.9, 27.3, 23.2; HRMS (EI) m/z 392.1653 [(M+); calcd for C,,H,,O_.S 392.1657]. 50 MRCMNNUH Metlnl enol 3.2 ml. HMPA in t The resulting solun 35 C. Methil [ml and the mixture 11.1 mLXH,Cl.e\tr;1et gel thexane/etherfl lRtne8111628. l~‘ 16 = 6.8. A\' : 6.0.2.6111. 1 H1. 100.194.6736. [1.\1‘1;caled for C Aldeh} dc 1.111160}; 3nd 3: 78 5C for l5 min 1~l0 mini, and \\ 15512110” mIXIure . 31111 separated on f l,’ 1 Men 1116 [\.1 dx The RCM/McMurry Routes Methyl enol ether IV-S. To a cold solution of ketone 1-32 (1.28 g, 6.5 mmol) and 3.2 mL HMPA in 60 mL DME was added 14 mL KHMDS (0.5 M in toluene) dropwise. The resulting solution was then allowed to warm above 0 "C for 5 min and recooled to - 25 0C. Methyl triflate (0.9 mL, 1.31 g, 8.0 mmol) was added in portions over a few min and the mixture was allowed to warm up slowly to rt. The reaction was quenched with 80 mL NH4C1, extracted with ether (2 x), washed with aq NaHCO_,, dried, separated on silica gel (hexane/ether/Et3N [6:1:0.06], Rf = 0.35) to afford 1.1 g (80%) of a light yellowish oil. IR (neat) 1628, 1453, 1273, 1048, 916 cm]; lH NMR (300 MHz, CDC],) 6 4.66 (ABq, JAB = 6.8, AVAB = 12.0 Hz, 2 H), 4.30 (s, l H), 3.58 (s, 3 H), 3.33 (s, 3 H), 2.60 (dd, J = 6.0, 2.6 Hz, 1 H), 1.90-1.11 (m, 7 H), 1.01 (s, 3 H); l3C NMR (75 MHz, CDCl,) 6 160.8, 100.2, 94.6, 73.6, 56.5, 55.1, 48.0, 46.3. 41.6, 33.6, 27.1. 25.7; HRMS (E1) m/z 212.1417 [(M+); calcd for CnHmO3 212.1412]. Aldehyde ester IV-l. To a solution of enol ether IV-S (510 mg, 2.41 mmol) in 15 mL MeOH and 35 mL CHzCl2 (containing 0.3 g sodium bicarbonate) was bubbled 03 at — 78 °C for 15 min. The resulting light blue solution was flushed with N2 until colorless (~10 min) and was then quenched with Me,S (600 mg, 9.67 mmol) at -78 0C. The reaction mixture was allowed to warm slowly to rt overnight before being concentrated and separated on silica gel (petroleum ether/E00 [1:1], Rf: 0.25) to afford 469 mg (84%) aldehyde IV-l as a colorless oil. IR (neat) 1742, 1727, 1439, 1294, 1039 cm"; 'H NMR (300 MHz, CDC13) 6 9.42 (s, 1 H), 4.58 (m, 2 H), 4.10 (s, l H), 3.62 (s, 3 H), 3.24 (s, 3 H), 2.60 (m, 1 H), 2.10-1.15 (m, 6 H), 1.05 (s, 3 H); ”C NMR (75 MHz, CDCl,) 6 205.0, 173.2, 95.2, 71.8, 55.5, 51.7, 45.0, 42.0, 26.7, 24.6, 24.1, 16.6; HRMS (E1) 712/: 244.1310 [(M+); calcd for C 12H2005 244.131 1]. Methallylic alcohol IV-6. To a solution of 45 mg (0.20 mmol) aldehyde IV-l in 4 51 dtimid. C110; {‘1‘}, ( 5111\d : F». mL of an ethanol and water mixture (4:1), was added methallyl bromide (80 mg, 0.60 mmol) and indium powder (28 mg, 0.24 mmol). The mixture was stirred for 24 h at rt before being quenched with aq NH4C1, extracted with ether (4 x), dried, and separated on silica gel (hexane/ether [1:1], R, = 0.31) to give 46 mg (83%) IV-6 as an inseparable mixture of two isomers as a colorless oil. IR (neat) 3528, 1742, 1291, 1194, 1040 cm"; IH NMR (300 MHz, CDC1_,) 6 4.88 (s, 1 H), 4.78 (s, l H), 4.56 (d, ABq, J = 6.9, AVAB = 19.0 Hz, 2 H). 4.19 (s, 1 H), 3.64 (d, J = 1.7 Hz, 3 H), 3.31 (dt, J = 11.3, 2.8 Hz, 1 H), 3.28 (s, 3 H), 2.59 (m, 1 H), 2.23 (t, J = 14.6 Hz, 1 H), 2.05-1.77 (m, 4 H), 1.75 (s, 3 H), 1.65-1.40 (m, 4 H), 0.90 (s, 3 H); l3C NMR (75 MHz, CDC1_,) 6 174.0, 143.3, 113.8, 113.7, 95.1, 95.0, 76.5, 72.2, 55.4, 51.5, 42.9, 39.5, 36.6, 36.5, 29.6, 29.4, 27.3, 26.8. 25.4, 25.3, 22.0, 16.8, 16.1; HRMS (CI) m/z 301.2014 [(M+ + H); calcd for C,,H,,,O_, 301.2015]. (Alkoxythiocarbonyl)imidazolide IV-7. A solution of N,N-thiocarbonyl diimidazole (302 mg, 1.70 mmol) and alcohol lV-6 (254 mg, 0.85 mmol) in 10 mL CHzCl2 was stirred at reflux for 24 h. After concentration, the mixture was separated on silica gel (hexane/ether [1:1], R, = 0.15) to give 226 mg (62%) (alkoxythiocarbonyl)— imidazolide IV-7 as an oily 1:1 mixture of two isomers and 31 mg recovered alcohol (71% based on recovery). IR (neat) 3040, 2946, 1742, 1466, 1040 cm]; 'H NMR (300 MHz, CDC13) 6 8.24 (d, J = 5.8 Hz, 1 H), 7.56 (dt, J = 4.9, 1.3 Hz, 1 H), 6.95 (s, 1 H), 4.67- 4.46 (m, 4 H), 4.19 (s, 1 H), 3.64 (s, 1 H), 3.61 (s, 2 H), 3.24 (s, 1 H), 3.19 (s, 2 H), 2.60-1.82 (m, 6 H), 1.77 (s, 3 H), 1.75-1.40 (m, 4 H), 1.00 (s, 3 H); ”C NMR (75 MHz, CDC13) 6 184.6, 184.5, 173.3, 140.5, 140.5, 136.8, 136.6, 130.4, 117.8, 115.0, 95.1, 95.0. 89.2, 88.6, 71.7, 55.4, 55.3, 51.5, 42.6, 42.4, 38.1, 37.7, 37.6, 29.3, 28.6, 27.3, 26.7, 25.1, 25.0, 22.4, 18.3, 17.2; HRMS (EI) m/z 410.1875 [(M+), calcd for C,,,H_,,,OSN,S 410.1875]. a,,B-Unsaturated ketone IV-9. A solution of aldehyde IV-l (0.27 g, 1.11 mmol) 52 and lIlPllfll)lpl10\]‘i in a sealed tube 1 hexane/ether l l :l l 1111b 45. mg 195‘} 3930. 1742. 1676. 11.16.04 id. J = 6.1 11.13.0618. 3 H1. in 6 H1. 1.0518. 73.0. 55.5. 51 6 4 H1; calcd for C .11 Ketone I\ 111.\1e0H. After 10,7 5 951.9321 11. cm"; 'H NMR 1; and triphenylphosphoranylideneacetone (1.57 g, 5.55 mmol) in 30 mL toluene was heated in a sealed tube for 36 h at 165 0C. After concentration and silica gel separation (hexane/ether [1: l], R, = 0.25) 250 mg (79%) of lV-9 was isolated as a colorless oil along with 45 mg (95% based on recovered material) of recovered aldehyde IV-l. IR (neat) 2930, 1742, 1676, 1437,1038 cm"; 1H NMR (300 MHz, CDCl,) 6 6.75 (d, J = 6.4 Hz, 1 H), 6.04 (d, J = 6.4 Hz, 1 H), 4.59 (ABq, J = 7.1, AVAB = 18.0 Hz, 2 H), 4.23 (s, broad, 1 H), 3.66 (s, 3 H), 3.28 (s, 3 H), 2.60 (dt, J = 12.9, 3.3 Hz, 1 H), 2.14 (s, 3 H), 1.95-1.20 (m, 6 H), 1.05 (s, 3 H); ”C NMR (75 MHz, CDC],) 6 199.2, 173.4, 157.7, 126.6, 95.2, 72.0, 55.5, 51.6, 42.7, 35.6, 31.6, 29.3, 27.0, 25.4, 20.9; HRMS (CI) 771/: 285.1703 [(M+ + H): calcd for C,,H,SO_, 285.1702]. Ketone IV-10. Enone IV-9 was stirred with 10% Pd-C under H2 for 48 h at 45 0C in MeOH. After silica gel (hexane/EtOAc [3:2], R, = 0.40) purification, ketone IV-lO (0.79 g, 92%) was collected as a colorless oil. IR (neat) 1742, 1719, 1439, 1360, 1040 cm"; 'H NMR (300 MHz, CDCl,) 6 4.59 (ABq, J = 6.9, AVAB = 20.0 Hz, 2 H), 4.19 (s, broad, 1 H), 3.63 (s, 3 H), 3.28 (s, 3 H), 2.54 (dt, J = 13.2, 3.0 Hz, 1 H), 2.40 (m, 2 H), 2.10 (s, 3 H), 1.82-1.35 (m, 8 H), 0.81 (s, 3 H); ”C NMR (75 MHz, CDCl,) 6 209.3, 173.9, 95.1, 72.4, 55.4, 51.5, 43.1, 38.8, 38.0, 32.5, 31.8, 30.4, 29.9, 25.6, 21.2; HRMS (CI) m/z 304.2129 [(M+ + NH); calcd for C,_.H NO. 304.2124]. gem-Disubstituted olefin IV-8. A solution of methyl triphenyl phosphonium bromide (511mg, 1.432 mmol) in 20 mL THF was added NaHMDS (1.54 mL, 1.54 mmol, 1.0 M in THF) at 0 0C. The resulting solution was stirred at the same temperature for 30 min before being cooled to -30 “C at which time a solution of 390 mg (1.36 mmol) ketone IV-10 in 15 mL THF was added. The mixture was slowly warmed to rt and stirred overnight before being quenched with aq NH4C1, extracted with ether, washed with aq NaHCO3 and brine, dried, concentrated and separated on silica gel (hexane/E60 53 [9:1], R,= 0.18) to furnish olefin IV-8 (0.269 g, 70%) and recovered ketone IV-10 (66 mg, 84% based on recovery) both as colorless oils. IR (neat) 3073, 1746, 1647, 1437, 1040 cm"; lH NMR (300 MHz, CDCl,) 6 4.64 (d, broad, J = 1.1 Hz, 2 H), 4.59 (ABq, J = 6.9, AVAB = 20.0 Hz, 2 H), 4.20 (s, broad, 1 H), 3.65 (s, 3 H), 3.29 (s, 3 H), 2.58 (ddd, J = 13.2, 3.0, 0.8 Hz, 1 H), 2.01-1.80 (m, 3 H), 1.71 (s, 3 H), 1.18-1.10 (m, 7 H), 0.83 (s, 3 H); ”C NMR (75 MHz, CDCl,) 6 174.2, 146.8, 109.2, 95.1, 72.6, 55.4, 51.5, 44.0, 43.2. 33.0, 32.2, 31.4, 30.6, 25.7, 22.7, 21.1; MS m/e 252.2 (M1 MeOH), 207.1, 153.1, 121.1, 93.1; Anal. Calcd for C,,H,,O,: C, 67.57; H, 9.92. Found: C, 67.32; H, 10.28. Ethyl phosphonate IV-ll. A solution of diethyl methylphosphonate (324 mg, 2.13 mmol) in 6 mL THF was treated with n-BuLi (1.3 mL, 2.08 mmol, 1.6 M in hexane) at ~78 °C. The resulting solution was stirred at ~78 ”C for 20 min before a solution of 288 mg (1.01 mmol) of ester IV-8 in 5 mL THF was added dropwise. The mixture was stirred at ~78 "C for 20 min and warmed to 0 "C and stirred for 30 min before being quenched with aq NH4C1, extracted with ether, dried, concentrated and separated on silica gel (hexane/EtOAc [1:1], R, = 0.15) to furnish ethyl phosphonate IV-ll (0.347 g, 85%) as a colorless oil along with recovered starting material IV-8 (35 mg, 96% based on recovery). IR (neat) 3075, 1713, 1649, 1445, 1034 cm”; IH NMR (300 MHz, CDCl,) 6 4.61 (d, broad, 2 H), 4.55 (ABq, J = 6.9, AVAB = 48.0 Hz, 2 H), 4.22 (s, broad, 1 H), 4.08 (m, 4 H), 3.40 (m, 1 H), 3.21 (s, 3 H), 2.90 (m, 2 H), 1.90 (m, 3 H), 1.64 (s, 3 H), 1.60- 1.10 (m, 13 H), 0.82 (s, 3 H); ”C NMR (75 MHz, CDCl,) 6 202.7 ((1), 146.7, 109.2, 94.6, 72.2, 62.5, 62.4 (d), 55.7, 50.5, 43.9, 40.4, 38.7, 32.3 (d), 31.3 (d), 25.6, 22.6, 21.1, 16.2; HRMS (CI) m/z 405.2413 [(M+ + H); calcd for C2,,H3806P 405.2406]. The general procedure for the preparation of trienone IV-13 and IV-15 Trienone IV-l3 (Conditions F). To a suspension of NaH (13 mg, 60% dispersion in 011, 0.330 mmol) in 1.0 mL THF was injected phosphonate IV-ll (130 mg, 0.322 54 mmol) in 3 mL THF at ~35 "C. The mixture was slowly warmed to rt over a period of 1.5 h and then recooled to ~35 0C. A solution of pent-4-ena1 (61 mg, 0.75 mmol) in 1.5 mL THF was injected and the resulting mixture was stirred at ~35 "C to rt over a period of 3.5 h. The reaction was quenched with aq NH4C1 and extracted with ether, washed, dried and purified on silica gel (hexane/Ego [10:1]) to afford 94 mg (87%) trienone IV~13 as a colorless oil. IR (neat) 3077, 1698, 1630, 1449, 1038 cm”; lH NMR (300 MHz, CDCl,) 6 6.84 (m, 1 H), 6.30 (d, J = 5.2 Hz, 1 H), 5.78 (m, 1 H), 5.00 (m, 2 H), 4.63 (s, broad, 2 H), 4.51 (ABq, J = 6.9, AVAB = 42.0 Hz, 2 H), 4.21 (s, broad, 1 H), 3.21 (s, 3 H), 2.70 (d, J = 12.9 Hz, 1 H), 2.35—1.70 (m, 8 H), 1.65 (s, 3 H), 1.60-1.10 (m, 6 H), 0.84 (s, 3 H); ”C NMR (75 MHz, CDCl,) 6 200.2, 146.8, 145.7, 137.1, 128.1, 115.5, 109.2, 94.6, 72.0, 55.5, 48.8, 44.1, 32.3, 32.2, 32.1, 31.7, 31.4, 30.8, 25.9, 22.7, 21.3; HRMS (CI) m/z 335.2581 [(M+ + H); calcd for C,,H3SO3 335.2586]. Trienone IV-15. Applying Conditions F to the reaction of IV-ll (650 mg, 1.61 mmol) with (E)~hex-4-enal (300 mg, 3.06 mmol) afforded 470 mg (84%) of IV-15 as a colorless oil. IR (neat) 3075, 1698, 1628, 1456, 1040 cm"; lH NMR (300 MHz, CDC1_,) 6 6.82 (dt, J = 14.2, 6.9 Hz, 1 H), 6.32 (d, J = 14.2 Hz, 1 H), 5.60 (m, 2 H), 4.63 (s, broad, 2 H), 4.51 (ABq, J = 7.1, AVAB = 42.0 Hz, 2 H), 4.21 (s, broad, 1 H), 3.20 (s, 3 H), 2.70 (dt, J = 12.7, 3.1 Hz, 1 H), 2.25-1.77 (m, 6 H), 1.70 (s, 3 H), 1.62 (d, J = 4.7 Hz, 3 H), 1.58-1.10 (m, 8 H), 0.87 (s, 3 H); ”C NMR (75 MHz, CDC13) 6 200.2, 146.8, 146.1, 139.6, 127.9, 126.0, 109.2, 94.6, 72.0, 55.4, 48.7, 44.1, 32.4, 32.3, 32.1, 31.4, 31.1, 30.8, 25.9, 22.6, 21.3, 17.8; HRMS (E1) m/z 348.2665 [(M+); calcd for szHMO3 348.2664]. The general procedure for the preparation of dienone IV-14 and IV-16 Dienone IV~14 (Conditions G). To a flask charged with CuI (47 mg, 0.247 mmol) and ether (2 mL) was injected a solution of MeMgBr (0.16 mL, 3.0 M in ether, 0.48 mmol) at ~78 °C. The mixture was slowly warmed to 0 °C becoming a yellow slurry. After stirring for 15 min at the same temperature, a solution of ketone IV~13 (82 mg, 55 0.245 mmol, in 5 mL ether) was injected and stirred at O 0C for 1.5 h. The resulting reaction mixture was then quenched with aq NH4C1 and extracted with ether. The ether solution was washed with aq NaHCO3 and brine, dried, concentrated and separated on silica gel (hexane/ether [5:1], Rf = 0.49) to deliver 74 mg (86%) dienone IV-l4 as a colorless oil. IR (neat) 3077, 1711, 1456, 1096, 1040 cm"; 1H NMR (300 MHz, CDCl,) 6 5.79 (m, 1 H), 4.99 (m, 2 H), 4.63 (s, broad, 2 H), 4.57 (ABq, J = 6.9, AVAB = 34.0 Hz, 2 H), 4.20 (s, broad, 1 H), 3.27 (s, 3 H), 2.70-1.80 (m, 7 H), 1.70 (s, 3 H), 1.60-1.10 (m, 11 H), 0.85 (d, J = 8.5 Hz, 3 H), 0.84 (s, 3 H); ”C NMR (75 MHz, CDCl,) 6 211.1, 146.8, 138.7, 114.4, 109.2, 95.1, 72.9, 55.7, 50.2, 47.7, 44.1, 36.1, 32.6, 32.1, 31.4, 31.3, 30.8, 28.4, 25.9, 22.7, 21.3, 19.8; HRMS (EI) m/z 350.2822 [(M+); calcd for C,,H,,O_, 350.2821]. Ketone IV-l6. Applying Conditions G to IV~15 (88 mg, 0.253 mmol) afforded 63 mg (68%) of IV-16 as a colorless Oil. IR (neat) 3075, 1711, 1456, 1375, 1040 cm"; 1H NMR (300 MHz, CDC13) 6 5.38 (m, 2 H), 4.62 (s, broad, 2 H), 4.56 (ABq, J = 6.9, AVAB = 32.0 Hz, 2 H), 4.20 (s, broad, 1 H), 3.25 (s, 3 H), 2.50—1.80 (m, 7 H), 1.70 (s, 3 H), 1.69 (d, J = 3.9 Hz, 3 H), 1.60-1.10 (m, 11 H), 0.84 (s, 3 H), 0.82 (d, J = 6.3 Hz, 3 H); ”C NMR (75 MHz, CDCl,) 6 211.1, 146.7, 131.1, 124.8, 109.2, 95.0, 72.8, 55.7, 50.1, 47.7, 44.1, 36.8, 32.6, 32.1, 31.4, 30.7, 30.0, 28.3, 25.9, 22.7, 21.2, 19.8, 17.9; HRMS (EI) m/z 364.2984 [(M+); calcd for C,_,H,,,O_, 364.2977]. RCM dimmer IV~19 (Conditions H). A solution of trienone IV~13 (33.4 mg. 0.100 mmol) and Grubbs’ catalyst IV-17 (10 mg, 0.012 mmol) in 100 mL CH2C12 (0.001 M) was stirred at rt for 28 h. The reaction solution was concentrated and purified on silica gel (hexane/ Et,O [2:1], R, = 0.18) to furnish dimerization by-product lV-19 (12.2 mg, 38%) as a yellowish oil. IR (neat) 3077, 1698, 1630, 1447, 1038 cm"; 'H NMR (300 MHz, CDCl,) 6 6.81 (dt, J = 15.6, 6.6 Hz, 2 H), 6.32 (d, J = 15.6 Hz, 2 H), 5.40 (m, 2 H), 4.63 (s, broad, 4 H), 4.53 (ABq, J = 7.1, AVAB = 43.0 Hz, 4 H), 4.21 (s, broad, 2 H), 3.20 56 (s, 6 H), 2.70 (d, J = 12.9 Hz, 2 H), 2.35-1.20 (m, 28 H), 1.70 (s, 6 H), 0.88 (s, 6 H); ”C NMR (75 MHz, CDCl,) 6 200.2, 146.8, 145.6, 129.8, 129.2, 128.0, 109.2, 94.6, 72.0. 55.5, 48.8, 44.1, 32.3, 32.1, 31.4, 31.1, 30.8, 25.9. 22.7, 21.3; HRMS (CI) m/z 658.5043 [(M+ + NH,,); calcd for C,,,H,,,,NO,S 658.5047]. RCM dimmer trienone IV-20. Applying Conditions H to the RCM reaction of IV~16 (55 mg, 0.151 mmol) afforded 24 mg (48%) of IV-20 as a colorless oil. IR (neat) 1711, 1653, 1456, 1340, 1038 cm"; 1H NMR (300 MHz, CDC1_,) 6 5.36 (m, 2 H), 4.64 (s, broad, 4 H), 4.55 (ABq, J = 6.9, AVAB = 34.0 Hz, 4 H), 4.21 (s, broad, 2 H), 3.26 (s, 6 H), 2.70-1.80 (m, 12 H), 1.70 (s, 6 H), 1.60-1.10 (m, 24 H), 0.86 (d, J = 8.5 Hz, 6 H), 0.85 (s, 6 H); ”C NMR (75 MHz, CDC1_,) 6 211.1, 146.8, 130.1, 109.2, 95.1, 72.9, 55.7, 50.1, 47.7, 44.1, 36.9, 32.6, 32.2, 31.4, 30.8, 30.1, 28.4, 26.0, 22.7, 21.3, 19.8; HRMS (CI) m/z 690.5648 [(M+ + NH4); calcd for C,,H.,,O6 690.5673]. Alcohol IV-21. The reduction of ketone IV-16 (210 mg, 0.576 mmol) with NaBH4 in MeOH at 0 ”C produced 208 mg (99%) of alcohol IV~22 as two isomers (5:1) both as colorless oils. The major isomer was characterized (R, = 0.55 in pentane/EtzO [121]). IR (neat) 3530, 3073, 1649, 1453, 1036 cm"; lH NMR (300 MHz, CDCl,) 6 5.40 (m, 2 H), 4.64 (s, broad, 2 H), 4.68 (ABq, J = 6.9, AVAB = 42.0 Hz, 2 H), 3.96 (s, broad, 2 H), 3.41 (s, 3 H), 3.27 (s, 1 H), 2.01 (m, 5 H), 1.70 (s, 3 H), 1.63 (d, J = 3.9 Hz, 3 H), 1.60-1.10 (m, 13 H), 0.89 (d, J = 6.3 Hz, 3 H), 0.88 (s, 3 H); I3C NMR (75 MHz, CDC1,) 6 147.0, 131.7, 124.5, 109.2, 100.3, 94.2, 72.7, 56.0, 44.3, 41.9, 41.2, 37.7, 32.3, 31.5, 31.2, 30.5, 30.0, 28.7, 25.0, 22.7, 21.6, 19.0, 17.9; HRMS (EI) m/z 366.3131 [(M+); calcd for C,_,H,,O3 366.3134]. Dicarbonyl IV-3. To a solution of alcohol IV-21 (165 mg, 0.437 mmol) in 20 mL DMF was added TBSCl (660 mg, 4.37 mmol), pyridine (414 mg, 0.43 mL, 5.24 mmol) and catalytic amount of DMAP. The mixture was stirred at 85 “C for 5 h and quenched 57 with water. The organic layer was extracted with hexane-ether (1:1) and the extract was washed with brine, dried, and concentrated under high vacuum to furnish 230 mg (100%) crude TBS ether (IV-22) as a yellowish oil. The above crude oil (175 mg, 0.36 mmol) in MeOH-CH2C12 (2: 1) was subjected to ozonolysis and after silica gel purification (hexane/ether [2:1], R, = 0.19), 131 mg (68% from IV~21) dicarbonyl IV~3 was obtained as a colorless oil. IR (neat) 1723, 1462, 1360, 1256, 1040 cm"; 'H NMR (300 MHz, CDCl,) 6 9.73 (t, J = 1.9 Hz, 1 H), 4.59 (ABq, J = 6.6, AVAB = 14.0 Hz, 2 H), 3.82 (s, broad, 1 H), 3.60 (t, J = 7.4, Hz, 1 H), 3.34 (s, 3 H), 2.40 (m, 4 H), 2.10 (s, 3 H), 1.80-1.05 (m, 14 H), 0.83 (m, 15 H), 0.00 (s, 3 H), 001 (s, 3H); ”C NMR (75 MHz, CDC13) 6 209.6, 202.7, 95.3, 72.3, 72.2, 55.8, 42.7, 41.7, 40.6, 39.4, 38.2, 35.2, 32.4, 31.2, 30.4, 29.8, 28.5, 26.3, 26.0, 21.4, 19.4, 18.1, ~4.0, -4.l; HRMS (CI) m/z 471.3514 [(M+ + H); calcd for C,,H,,O_,Si 471.3506]. The Modified Julia Olefination and N HK Coupling Route TBS ether protected bicyclo[3.2.l]octanone V-l. To a solution of alcohol III-1 (6.05 g, 21.8 mmol) and Hunnig’s base (4.55 mL, 3.37 g, 26.1 mmol) in CHzClz (180 mL) was added TBSOTf (5.50 mL, 6.33 g, 24.0 mmol) dropwise at 0 ”C. After the addition, the mixture was stirred 0 ”C for 30 min. The reaction mixture was quenched with aq NH4C1, extracted with ether, washed with aq NaHC03 and brine, dried, and concentrated under high vacuum to produce 8.40 g (99%) crude TBS ether as yellowish oil. A solution of above crude product (1.01 g, 2.58 mmol) in a mixture of CH3CN (7 mL) and acetone (3 mL) was added drop wise to a solution of NBS (2.8 g, 15.9 mmol) in aq acetonitrile (80%, 65 mL) at -5 ”C. The stirring was continued for another 2-3 min before the reaction was quenched with aq 10% Na28203 (35 mL) and extracted with mixed solvent CHzClz-hexane (60 mL, 1:1). The organic layer was washed with brine, separated on silica gel (hexane/ether [10:1], Rf = 0.70) to furnish 0.43 g (61% from III-1) 58 »——v, ketone V-l as a colorless oil. IR (neat) 1748, 1458, 1252, 1101, 839 cm”; 1H NMR (300 MHz, CDCl,) 6 3.79 (m, 1 H), 2.38 (m, 1 H), 2.08-1.40 (m, 8 H), 1.10 (s, 3 H), 0.82 (s, 9 H), 0.01 (s, 3 H), 0.00 (s, 3 H); ”C NMR (75 MHz, CDCl,) 6 216.9, 72.5, 56.0, 49.9, 41.8, 36.9, 36.7, 30.6, 26.6, 25.7, 18.0, -4.7. -4.8; HRMS (CI) m/z 269.1939 [(M+ + H); calcd for C,,H,,O,Si 269.1937]. Aldehyde Ester V-Z. To a solution of ketone V-l (1.55 g, 5.78 mmol) and HMPA (3 mL) in DME (30 mL) was added KHMDS (0.5 M in toluene, 14 mL, 7.0 mmol) dropwise at ~40 ”C. The resulting solution was allowed to warm slowly to rt over a period of 30 min and cool again to ~25 ”C before MeOTf (0.85 mL, 1.23 g, 7.5 mmol) was added dropwise. After the addition, the mixture was slowly warmed to rt and stirred at rt for 45 min before being quenched with aq NaHCO3, extracted with ether, washed with brine, dried, and concentrated to furnish the intemediate enol ether as a light yellowish oil. The above crude oil was instantly submitted to ozonolysis, and after purification on silica gel (hexane/ether [5:1], Rf: 0.38), 1.10 g (65% from V-l) aldehyde ester V~2 was isolated as a colorless oil. IR (neat) 1736 (broad), 1466, 1258, 1072, 833 cm'”; IH NMR (300 MHz, CDCl,) 6 9.40 (s, 1 H), 4.40 (s, broad, 1 H), 3.64 (s, 3 H), 2.58-1.40 (m, 7 H), 1.08 (s, 3 H), 0.81 (s, 9 H), 0.01 (s, 3 H), 0.00 (s, 3 H); 13C NMR (75 MHz, CDC13) 6 205.2, 173.4, 67.0, 51.6, 45.1, 43.3, 28.3, 26.1, 25.6, 23.6, -4.5, -5.5; HRMS (CI) m/z 315.2004 [(M+ + H), calcd for C,,,H_,,O,Si 315.1992]. a,B-Unsaturated ketone V-3. A solution of 0.96 g (3.06 mmol) of V-2 and 2.96 g (9.17 mmol) of phosphoranylideneacetone ylide in toluene (20 mL) was heated in a sealed tube for 20 h at 170 ”C. After silica gel separation (hexane/ether [5:1], R, = 0.29), 920 mg (85%) of (1.0-unsaturated ketone V-3 was obtained as a colorless oil. IR (neat) 1744, 1676, 1437, 1255, 1068 cm”; lH NMR (300 MHz, CDCl_,) 6 6.75 (d, J = 6.3 Hz, 1 59 1111 .\'11. C1111 1111 H), 6.02 (d, J = 6.3 Hz, 1 H), 4.39 (s, broad, 1 H), 3.61 (s, 3 H), 2.50 (m, l H), 2.23 (s, 3 H), 2.00-1.20 (m, 6 H), 1.00 (s, 3 H), 0.80 (s, 9 H), 0.00 (s, 3 H), -004 (s, 3 H); ”C NMR (75 MHz, CDC1_,) 6 199.4, 173.6, 158.2, 126.5, 67.1, 51.5, 44.0, 35.8, 31.1, 29.0, 28.9, 27.1, 25.6, 20.9, 17.9, ~4.5, ~5.5; HRMS (CI) m/z 355.2299 [(M+ + H), calcd for C,9H_,_,O,Si 355.2305]. Benzothiazoyl sulfide ester V-4. Enone V-3 (1.95 g, 5.51 mmol) was stirred with Pd-C (10%) in MeOH under H2 at 45 ”C for 24 h to afford 1.96 g (100%) crude light yellowish oil. The above crude oil (0.54 g, 1.52 mmol) was dissolved in MeOH (40 mL), stirred with NaBH.. (30 mg, 0.79 mmol) at 0 ”C for 30 min. After being quenched with aq NH4C1, extracted with EtzO, dried, and concentrated under high vacuum, 0.54 g ( 100%) crude alcohol was collected as a light yellowish oil. To a solution of the above crude alcohol (0.94 g, 2.63 mmol) and 2- mercaptobenzothiazole (0.657 g, 3.93 mmol) was added Ph3P (1.10 g, 4.20 mmol) in THF (50 mL) and DIAD (0.794 g, 3.93 mmol) dropwise at rt. The resulting mixture was stirred at rt for 12 h and at 40 ”C for 12 h. The mixture was concentrated and purified on silica gel (hexane/ether [10:1], Rf: 0.45) to furnish 1.17 g (87% from V-3) benzothiazole sulfide ester V-4 as a sticky yellowish oil as a single isomer. IR (neat) 3050, 1744, 1458, 1429, 1252 cm"; lH NMR (300 MHz, CDCl,) 6 7.85 (d, J = 7.7 Hz, 1 H), 7.75 (d, J = 7.7 Hz, 1 H), 7.40-7.22 (m, 2 H), 4.36 (s, broad, 1 H), 3.90 (m, 1 H), 3.62 (s, 3 H), 2.47 (d, J = 12.9 Hz, 1 H), 1.80-1.00 (m, 13 H), 0.81 (s, 3 H), 0.80 (s, 9 H), 0.00 (s, 3 H), 003 (s, 3 H); 13C NMR (75 MHz, CDC13) 6 174.2, 166.7, 153.3, 135.2, 125.9, 124.1, 121.5, 120.8, 67.7, 51.3, 45.2, 45.1, 44.4, 43.1, 42.9, 32.3, 30.3, 30.2, 30.0, 29.4, 25.6, 21.9, -4.5, 54: HRMS (CI) m/z 508.2383 [(M+ + H), calcd for C,,I-I,,NO,S,S1 508.2375]. Dithiane V-6. To a solution of (E)-5-iodo-4~methyl-4-pentenal V-S (1.68 g, 7.50 60 46 0‘. the Oil. mmol) in CH2C12 (60 mL) was added 1.3-propanedithiol (1.22 g, 1.12 mL, 10.4 mmol) and 0.6 mL BF3-OEt2 at -78 ”C. The mixture was stirred at -78 ”C to ~20 ”C for 40 min before being quenched with 10 mL Et3N, diluted with water, extracted with ether, washed with brine, dried, concentrated and finally purified on silica gel (hexane/ether [20:1], Rf = 0.23) to afford 1.71 g (91%) dithiane V-6 as a colorless oil. IR (neat) 3054, 1618, 1421, 1273 cm"; ‘H NMR (300 MHz, c130,) 6 5.95 (s, 1 H), 3.95 (1, J = 6.8 Hz, 1 H), 2.80 (m, 4 H), 2.40 (t, J = 7.7 Hz, 2 H), 1.80 (m, 7 H); ”C NMR (75 MHz, CDC13) 6 146.3, 76.0. 46.3, 36.0, 33.2, 30.2, 25.9, 23.8; HRMS (EI) m/z 314.9726 [(M+ + H); calcd for C,H,,IS 314.9738]. Benzothiazoyl sulfide aldehyde V-7 (Conditions I). To a solution of ester V-4 (208 mg, 0.410 mmol) in 15 mL CH,Cl,-Et,0 (4:1) was injected DIBAL (0.60 mL, 1.0 M in hexane, 0.60 mmol) dropwise at ~80 ”C. After the injection, the reaction was further stirred for 15 min before being quenched with MeOH (2 mL) and slowly warmed to 0 ”C. To this cold solution was added dilute HCl. The mixture was extracted with Et,O. washed with NaHCO3 and brine, dried, concentrated, and purified on silica gel (hexane/ether [10:1], R, = 0.42) to furnish 168 mg (86%) of aldehyde V-7 as a colorless oil. IR (neat) 3063, 1728, 1458, 1427.993 cm”; lH NMR (300 MHz, CDCl,) 6 9.61 (s, 1 H), 7.83 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.40-7.22 (m, 2 H), 4.40 (s, broad, 1 H), 3.92 (m, 1 H), 2.30 (d, J: 12.9 Hz, 1 H), 1.80-1.10 (m, 13 H), 0.81 (s, 3 H), 0.80 (s, 9 H), 0.01 (s, 3 H), -0.01 (s, 3 H); ”C NMR (75 MHz, CDC1_,) 6 204.9, 166.5, 153.3. 135.2, 125.9, 124.1, 121.5, 120.8, 66.3, 50.9, 45.0, 42.7, 32.0, 30.8, 30.4, 30.3, 30.2, 29.1, 25.6, 21.5, 17.9, -4.3, —5.2; HRMS (CI) m/z 478.2270 [(M + H+); calcd for C,,H,,,NO,S,S1 478.2270]. Allylic alcohol V-8. To a solution of t-BuLi (1.14 mL, 1.7 M in pentane, 1.94 mmol) in 10 mL Eth was injected a solution of vinyl iodide dithiane V-6 (276 mg, 0.88 61 mmol) in ether (10 mL) dropwise at -78 ”C. The mixture was further stirred at the same temperature for 15-20 min before a solution of aldehyde V-7 (420 mg, 0.88 mmol) in ether (10 mL) was added dropwise. The resulting mixture was slowly warmed to 0 ”C over a period of 40 min before being quenched with aq NH4C1. The organic layer was washed with aq NaHCO3 and brine, dried, and purified on silica gel (hexane/ether [221]) to furnish 486 mg (83%) of V-8 as two allylic alcohol isomers (1.1:1) both as colorless oils. For the major isomer: IR (neat) 3451, 3063, 1603, 1460, 993 cm"; 1H NMR (300 MHz, CDCl,) 6 7.83 (d, J = 7.7 Hz, 1 H), 7.72 (d, J = 7.7 Hz, 1 H), 7.40 - 7.22 (m, 2 H), 5.26 (d, J = 8.0 Hz, 1 H), 4.42 (s, broad, 1 H), 4.02 (s, broad, 1 H), 3.92 (m, 2 H), 2.78 (m, 5 H), 2.20-1.10 (m, 23 H), 0.88 (s, 9 H), 0.81 (s, 3 H), 0.04 (s, 6 H); l3C NMR (75 MHz, CDC13) 6 166.7, 153.3, 136.9, 135.2, 127.2, 125.9, 124.0, 121.5, 120.8, 72.0, 71.7, 46.7, 45.2, 43.4, 43.2, 42.9, 36.1, 33.4, 32.3, 30.8, 30.6, 30.3, 30.2, 29.6, 25.9, 25.8, 21.9, 21.5, 17.9, -3.9, -5.2; HRMS (FAB) m/z 666.2936 [(M+ + H); calcd for C,,H_,,NO,S,Si 666.2963]. Benzothiazoyl sulfone ester V-9. To a stirred solution of sulfide V-4 (0.937 g. 1.85 mmol) in CH2C12 (55 mL) was added NaHCO3 (710 mg, 8.45 mmol) and mCPBA (680 mg, 3.93 mmol) at -45 ”C. This mixture was slowly warmed to rt over a period of about 2 h and stirred at rt for 14 h before being quenched with aq Na2S203. The organic layer was washed with brine, dried, concentrated, and purified on silica gel (hexane/ether [1:1], Rf: 0.40) to produce 0.85 g (85%) sulfone ester V-9 as a colorless oil. IR (neat) 3050, 1740, 1472. 1325, 833 cm"; ‘H NMR (300 MHz, CDC1_,) 5 8.20 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.58 (m, 2 H), 4.33 (s, broad, 1 H), 3.60 (s, 3 H), 3.50 (m, 1 H), 2.50-1.00 (m, 13 H), 0.80 (s, 3 H), 0.78 (s, 9 H), -001 (s, 3 H), -004 (s, 3 H); 13c NMR (75 MHz, CDC13) 6 174.0, 165.1, 152.8, 136.8, 127.8, 127.5, 125.4, 122.2, 67.5, 60.5, 60.4, 51.3, 44.3, 42.6, 42.4, 32.4, 32.3, 30.1, 29.3, 25.6, 22.5, 17.8, -4.5, -5.5; HRMS (FAB) m/z 540.2287 [(M+ + H); calcd for C,,H,,NO,S,Si 540.2274]. 62 Benzothiazoyl sulfone aldehyde V-10. Applying Conditions I to V-9 (435 mg, 0.81 mmol) afforded 343 mg (86%) of V-lO as a colorless oil (Rf = 0.52 in hexane/ether [1:1]). IR (neat) 3063, 1727, 1472, 1254, 1146 cm"; 'H NMR (300 MHz, CDC1_,) 6 9.59 (d, J = 3.6 Hz, 1 H), 8.20 (d, J = 7.4 Hz, 1 H), 7.99 (d, J = 7.4 Hz, 1 H), 7.59 (m, 2 H), 4.40 (s, broad, 1 H), 3.50 (m, 1 H), 2.30-2.10 (m, 2 H), 1.60-1.10 (m, 12 H), 0.81 (s, 3 H), 0.80 (s, 9 H), 0.01 (s, 3 H), -0.02 (s, 3 H); 13C NMR (75 MHz, CDC13) 6 204.6, 165.0, 152.8, 136.8, 127.9, 127.5, 125.4, 122.2, 66.1, 60.4, 60.3, 50.8, 46.1, 42.4, 32.2, 30.9. 30.5, 29.1, 25.6, 22.6, 17.9, -4.4, -5.3; HRMS (CI) m/z 510.2173 [(M+ + H); calcd for C,_,H,,,NO,S,Si 510.2168]. Vinyl iodide aldehyde V-14. A solution of aldehyde V-10 (230 mg, 0.452 mmol) and a trace amount of TSA (ca. 5 mg) in 2.2-dimethoxypropane was stirred at 65 ”C for 5 h. The solution was cooled, diluted with ether, washed with aq NaHCOg, dried, and filtered through a wad of silica gel. After concentration under high vacuum, 250 mg (100%) crude acetal V-12 was isolated. To a solution of crude V-12 (720 mg, 1.30 mmol) in DME (25 mL) was injected NaHMDS (1.70 mL, 1.0 M in THF) at -78 ”C and the resulting mixture was stirred at the same temperature for 45 min before a solution of (E)-5-iodo-4-methyl-4-pentenal V-5 (430 mg, 1.92 mmol) in DME (2 mL) was added dropwise. After the addition, the solution was stirred at ~78 ”C for 1.0 h, slowly warmed to rt and stirred at rt for 20 min before being quenched with aq NH4C1, extracted with ether, washed with brine, dried, and concentrated to produced a sticky oil containing vinyl iodide V-13. This crude oil from above was stirred in AcOH-THF—HgO (12 mL + 4 mL + 4 mL) at 45 ”C for 8 h. The resulting creamy liquid was diluted with ether, washed with water (7x), sodium bicarbonate and brine. After silica gel purification (hexane/ether [20:1], Rf = 0.27), 484 mg (E/Z = 1.321, 66% from V-lO) vinyl iodide aldehyde V-l4 was obtained as a colorless oil. IR (neat) 1728, 1472, 1253, 1069, 837 cm"; lH NMR (500 63 .1 ge' MHz, CDC13)6 9.61 (s, 1 H), 5.81 (s, 1 H), 5.00 (m, 1 H), 4.41 (s, broad, 1 H), 2.30-1.90 (m, 7 H), 1.81 (s, 3H), 1.63 (s, 3 H), 1.60-1.10 (m, 8 H), 0.84 (s, 3 H), 0.80 (s, 9 H), 0.01 (s, 3 H), -0.03 (s, 3 H); 13C NMR (125 MHz, CDC13) 6 205.1, 147.8, 136.9, 123.1, 122.5. 74.8, 66.5, 51.1, 44.4, 39.8, 33.3, 32.1, 30.9, 29.3, 26.3, 25.6, 23.9, 23.4, 21.5, 17.9, -4.3, ~5.2; HRMS (CI) m/z 519.2141 [(M++ H); calcd for C,,H,,IO,Si 519.2155]. A general N HK coupling procedure in DMSO/T HF To a flask charged with CrClz (470 mg, 3.82 mmol) and Ni(acac)2 (2 mg, 0.008 mmol) was injected DMSO (10 mL) and THF (3 mL) at rt. The resulting slurry was stirred at rt for 10 min before a solution of aldehyde V-14 (200 mg, 0.386 mmol, E/Z 1.3:1) in DMSO-THF (25 mL + 7 mL) was injected. The mixture was further stirred for 26 h at rt. The mixture was cooled in an ice-water bath and quenched with 5% potassium serinate, extracted with ether, washed with brine, dried, and separated on silica gel (hexane/ether [10:1]) to furnish 31 mg (20%) of bicyclic allylic alcohol (E, Z) isomer V- 15 (Rf = 0.22, mp. 100-101 0C) and 38 mg (25%) of the desired (E, E) isomer V-16 (Rf = 0.20, m.p. 127-9 ”C) both as colorless crystals in addition to 50 mg (60% total yield based on recovery) recovered vinyl iodide aldehyde V-14. For V~15: IR (CHC13) 3461, 1462, 1260, 1069 cm”; lH NMR (500 MHz, CDC1_,) 6 5.39 (d, J = 9.0 Hz, 1 H), 5.12 (q, J = 8.8, 5.2 Hz, 1 H), 4.80 (t, J = 8.8 Hz, 1 H), 4.38 (s, broad, l H), 3.90 (dt, J = 11.2, 4.0 Hz, 1 H), 2.50-2.30 (m, 3 H), 2.05-1.85 (m, 4 H), 1.71 (s, 3 H), 1.60 (s, 3 H), 1.60-1.10 (m, 8 H), 0.91 (s, 9 H), 0.78 (s, 3 H), 0.12 (s, 6 H); 13C NMR (125 MHz, CDC13) 6 143.0, 136.6, 125.0, 123.0, 66.8, 45.9, 41.2, 36.8, 36.0. 34.3, 31.7, 30.0, 29.4, 27.4, 26.5, 25.7 (4 C), 22.8, 21.1, 18.0, -4.5, -5.3; HRMS (CI) m/z 391.3033 [(M+ - H); calcd for C24H43OZSi 391.3032]. For V-16: IR (CHC13) 3378, 1458, 1252, 1057, 1020 cm"; IH NMR (500 MHZ. CDCl,) 6 5.05 (dt, J = 11.9, 1.5 Hz, 1 H), 4.97 (d, J = 10.2, 1 H), 4.37 (q, J = 9.9, 8.6 Hz, 1V. \\ 5 .11 ‘.la ‘7‘. l H), 4.10 (d, J = 2.4, l H), 2.50 -1.90 (m, 6 H), 1.61 (S, 3 H), 1.55 (S, 3 H), 1.50-1.14 (m, 9 H), 0.90 (S, 9 H), 0.88 (S, 3 H), 0.07 (S, 3 H), 0.04 (s, 3 H), (OH not visible); 13C NMR (125 MHZ, CDCl3) 5 138.1, 137.2, 129.3, 127.7, 69.4, 65.3, 43.4, 40.7, 40.3, 36.4, 34.6. 33.9, 33.0, 29.6, 25.9, 25.7, 20.7, 18.1, 15.9, 15.3, -4.6, ~5.0', HRMS (CI) m/z 393.3183 [(M” + H): calcd for C34H4503Si 393.3189]. Epoxide V-18 (Conditions J). To a flask charged with a benzene (16 mL) solution of (E, E) dienol V-16 (90 mg, 0.230 mmol) and a trace amount of vanadyl acetylacetonate (0.7 mg, 0.0026 mmol) was added t-BuOOH (33 mg, 90%, 0.33 mmol) at rt and the resulting mixture was stirred at rt for 10 min. The reaction was quenched by adding a few drops of dimethyl sulfide. The reaction mixture was concentrated and purified on silica gel (hexane/ether [2:1], Rf = 0.29) to furnish epoxide V-18 (94 mg, 100%) as colorless crystals (mp. 166-168 ”C). IR (CHC13) 3488, 1460, 1252, 1061, 1038 cm“; IH NMR (500 MHz, CDCl,) 6 5.10 (d, J = 11.5 Hz, 1 H), 4.07 (d, J = 2.0 Hz, 1 H), 3.39 (t, J = 9.3, l H), 2.60 (d, J = 9.3 Hz, 1 H), 2.40-2.00 (m, 6 H), 1.63 (s, 3 H), 1.60-1.21 (m, 10 H), 1.20 (s, 3 H), 0.95 (s, 3 H), 0.88 (s, 9 H), 0.02 (s, 3 H), 0.00 (s, 3 H); 13C NMR (125 MHz, CDC13) 6 137.9, 127.2, 70.1, 69.7, 64.9, 63.3, 42.4, 40.2, 38.9, 36.2, 34.5, 33.3. 31.5, 29.4, 25.8, 24.7, 20.8, 18.0, 17.5, 15.7, -4.6, -5.1; HRMS (CI) m/z 409.3127 [(M+ + H); calcd for C24H45038i 409.3138]. Epoxide V-17. Made in the same way by stirring of V-15 (70 mg, 0.178 mmol) with t-BuOOH at 35 ”C for 40 min to produce 63 mg (86%) of V-17 from silica gel purification (hexane/ether [2:1], Rf = 0.22) as a colorless crystal (mp. 140-142 ”C). IR (CHC13) 3472, 1482, 1379, 1252, 1028 cm"; lH NMR (500 MHz, CDCl,) 6 5.00 (d, J = 1 1.5 Hz, 1 H), 4.15 (s, broad, 1 H), 3.43 (t, J = 9.4, 1 H), 2.66 (d, J = 9.4 Hz, 1 H), 2.55- 2.40 (m, 2 H), 2.15-1.93 (m, 3 H), 1.70 (s, 3 H), 1.65—1.10 (m, 11 H), 1.25 (s, 3 H), 0.94 (s, 3 H), 0.91 (s, 9 H), 0.02 (s, 3 H), 0.01 (s, 3 H); 13C NMR (125 MHz, CDC13) 6 136.5, 65 124.4, 69.8, 66.2, 64.6, 62.7, 42.5, 40.8, 39.5, 34.1, 33.2, 30.2, 29.5, 26.1, 25.8 (4 C), 23.6, 21.1, 21.0, 18.0, ~4.6, -5.1; HRMS (CI) m/z 409.3139 [(M+ + H), calcd for C34H45O3Si 409.3138. a-Keto epoxide V-19 (Conditions K). To a solution of oxalyl chloride (37 mg, 0.282 mmol) in methylene chloride (5 mL) was added DMSO (42 mg, 0.56 mmol) at ~78 ”C. The resulting mixture was stirred at the same temperature for 10 min before a solution of alcohol V-17 (96 mg, 0.235 mmol) in methylene chloride (10 mL) was added dropwise. The mixture was stirred for 55 min at -78 ”C. The reaction was quenched by the addition of IPI‘zNEI (0.3 mL, 1.77 mmol) and allowed to warm slowly to rt. The mixture was washed with brine, dried, concentrated and purified on silica gel (hexane/ether [3:2], Rf = 0.50) to furnish 83 mg (87%) keto epoxide V-19 as colorless crystals (mp. 136-138 ”C). IR (CHC13) 1727, 1458, 1252, 1065, 1034 cm"; lH NMR (500 MHz, CDCl,) 6 5.08 (d, J = 11.5 Hz, 1 H), 4.41 (s, broad, l H), 3.45 (s, 1 H), 2.70 (q, J = 12.2 Hz, 1 H), 2.54 (dd, J = 14.6, 10.0 Hz, 1 H), 2.40 (d, J = 13.2 Hz, 1 H), 2.26 (d, J = 13.2 Hz, 1 H), 2.18 (dt, J = 13.2, 3.3 Hz, 1 H), 2.00 (d, J = 13.0 Hz, 1 H), 1.75 (s, 3 H), 1.55 (m, 9 H), 1.18 (s, 3 H), 1.06 (s, 3 H), 0.81 (s, 9 H), 0.06 (s, 6 H); l3C NMR (125 MHz, CDC13) 6 203.9, 136.9, 124.2, 64.4, 63.8, 63.0, 494,403, 38.8, 34.2, 33.3. 30.7, 29.5, 26.3, 25.9 (4 C), 23.3, 21.5, 19.3, 18.0, -4.7, -4.8; HRMS (CI) m/z 407.2982 [(M” + H); calcd for C24H43O3Si 407.2981]. a-Keto epoxide I-27. Applying Conditions K to V-18 (37 mg, 0.091 mmol) afforded 35 mg (95%) of I-27 as colorless crystals (mp. 106-107 ”C). IR (CHC13) 1723, 1252, 1061, 1039, 833 cm"; lH NMR (500 MHz, CDCl,) 6 5.18 (d, J = 11.5 Hz, 1 H), 4.38 (s, broad, 1 H), 3.38 (s, 1 H), 2.55 (d, J = 8.7 Hz, 1 H), 2.40 (t, J = 13.9 Hz, 1 H), 2.35 (t, J: 11.5 Hz, 1 H), 2.28 (dq, J = 13.9, 3.3, 1.7 Hz, 1 H), 2.21 (dt, J: 13.9, 3.3 Hz, 1 H), 2.10 (m 1 H), 1.70 (s, 3 H), 1.60-1.20 (m, 9 H), 1.08 (s, 3 H), 1.03 (s, 3 H), 0.81 (s, 9 H), 0.02 (s, 6 H); 13C (125 MHz, CDC13) 6 203.9, 138.0, 127.4, 67.8. 64.0, 63.4, 49.2, 66 11.1. 1110‘ 1111111 1111: 311 111111: 111] 39.8, 39.1, 36.2, 34.6, 33.3, 32.3, 29.2, 25.9, 24.7, 21.1, 18.0, 15.6, 15.4, -4.7, -4.8; HRMS (CI) m/z 407.2970 [(M+ + H); calcd for C34H43O3Si 407.2981]. Dienones V-20 (Conditions L). A solution of a-keto epoxide V-19 (15 mg, 0.037 mmol) in THF (6 mL) was stirred with TBAF (0.1 mL, 1.0 M in THF) at 0 0C for 8 min. The reaction mixture was quenched with aq NH4C1, extracted with ether, washed with NazCO3, dried, concentrated and purified on silica gel (hexane/ether [2:1], Rf = 0.41) to furnish 7.5 mg (74%) of dienone V-20 as colorless crystals (mp. 114-116 °C). IR (CHCl3) 1696, 1622, 1458, 1379, 1200 cm"; 1H NMR (500 MHz, CDCl_,) 5 6.63 (dd, J = 6.2, 3.3 Hz, 1 H), 4.98 (d, J = 11.9 Hz, 1 H), 3.82 (s, 1 H), 2.63 (m, 2 H), 2.48 (dd, J = 13.0, 6.9 Hz, 1 H), 2.20-2.00 (m, 4 H), 1.73 (m, 1 H), 1.60 (s, 3 H), 1.55-1.30 (m, 6 H), 1.06 (s, 3 H), 0.98 (s, 3 H); 13C NMR (125 MHz, CDC13) 5 196.4, 137.3, 136.6, 136.3, 123.0, 63.6, 63.2, 38.5, 35.6, 33.6, 33.3, 31.8, 26.5, 26.2, 25.5, 23.2, 22.9, 18.9; HRMS (BI) m/z 274.1932 [(M+); calcd for C18H2602 274.1933]. Model compound I-26. Applying Conditions L to 1-27 (30 mg, 0.074 mmol) afforded 15 mg (74%) of I-26 as colorless crystals (mp. 103-105 °C), Rf = 0.50 (hexane/ether [1:1]). IR (CHC13) 1692, 1622, 1462, 1192, 1140 cm]; 1H NMR (500 MHz, CDCl,) 8 6.89 (d, J = 1.5 Hz, 1 H), 5.20 (d, J = 10.8 Hz, 1 H), 3.75 (s, l H), 2.80 (d, J: 17.0 Hz, 1 H), 2.40-2.05 (m, 6 H), 1.96 (d, J: 17.0 Hz, 1 H), 1.62 (m, 1 H), 1.59 (s, 3 H), 1.40-1.20 (m, 5 H), 1.13 (s, 3 H), 1.05 (s, 3 H); 13C NMR (125 MHz, CDCl3) 5 195.2, 138.0, 136.3, 136.1, 124.7, 64.7, 63.4, 38.4, 35.3, 35.0, 33.3, 32.4, 30.3, 28.2, 24.8, 23.1, 16.0, 14.6; HRMS (EI) m/z 274.1932 [(M+); calcd for C13H2602 274.1933]. Hydroxyl ketoepoxide V-22. A solution of TBS ether V-18 (75 mg, 0.183 mmol) in THF (9 mL) was stirred with TBAF (0.25 mL, 1.0 M in THF) at 55 °C for 6.0 h. The reaction mixture was cooled and quenched with aq NH4C1, extracted with ether, washed 67 with NazCO3, dried, concentrated under high vacuum to furnish 55 mg crude V-21 as colorless solid. To a solution of oxalyl chloride (50 mg, 0.375 mmol) in methylene chloride (8 mL) was added DMSO (65 mg, 0.86 mmol) at -78 ”C and the resulting mixture was stirred at the same temperature for 10 min before a solution of crude alcohol V-Zl (55 mg, 0.188 mmol) in methylene chloride (6 mL) was added dropwise and stirred for 90 min at -78 ”C. The reaction was quenched by the addition of iPrgNEt (0.4 mL, 2.3 mmol) and allowed to warm slowly to rt. The mixture was washed with brine, dried, concentrated and purified on silica gel (hexane/EtOAc [4:1], Rf = 0.50) to furnish 41 mg (77%) of hydroketo epoxide V-22 as colorless crystals (mp. 194-196 °C). IR (CHCl3) 3528, 1711, 1381, 1140, 1090 cm"; 1H NMR (500 MHz, CDC13) 8 5.20 (d, J: 11.0 Hz, 1 H), 4.28 (s, broad, 1 H), 3.45 (s, 1 H), 2.69 (d, J: 13.4 Hz, 1 H), 2.65 (t, J: 2.2 Hz, 1 H), 2.53 (dt, J = 13.4, 3.3, Hz, 1 H), 2.42 (m, 2 H), 2.22 (dt, J: 14.2, 3.7 Hz, 1 H), 2.10 (m 2 H), 1.73 (ddd, J = 14.2, 6.5, 3.3 Hz, 1 H), 1.70 (s, 3 H), 1.60-1.30 (m, 7 H), 1.10 (s, 3 H), 1.03 (s, 3 H); l3C NMR (75 MHz, CDCl3) 8 208.6, 138.4, 127.1, 67.1, 64.0, 63.5, 48.6, 39.4, 38.7, 36.0, 34.9, 32.8, 32.5, 27.3, 24.6, 20.2, 15.6, 14.9; HRMS (EI) m/z 292.2039 [(M+); calcd for C18H3803 292.2038]. Diketone V-23. Applying Conditions K to V-22 (28 mg, 0.097 mmol) afforded 26 mg (94%) of V-23 as colorless crystals (mp. 114-116 °C), Rf = 0.70 (hexane/EtOAc [4:l]). IR (CHCl3) 3045, 1724, 1622, 1587, 1460, 1209 cm]; lH NMR (500 MHz, CDC],) 8 5.20 (d, J = 9.9 Hz, 1 H), 3.59 (s, 1 H), 2.86 (d, J = 14.8 Hz, 1 H), 2.45-2.28 (m, 8 H), 2.22 (dt, J: 13.1, 3.4 Hz, 1 H), 2.13 (d, J = 10.6 Hz, 1 H), 2.00 (d, J = 4.8 Hz, 1 H), 1.65 (m, 1 H), 1.59 (s, 3 H), 1.50 (m, 2 H), 1.28 (s, 3 H), 1.05 (s, 3 H); 13C NMR (75 MHz, CDC13)8 194.5, 179.0, 138.1, 125.0, 105.9, 64.2, 62.3, 38.4, 35.3, 35.2, 32.9. 31.4, 30.2, 28.1, 27.2, 25.0, 16.2, 14.9; HRMS (EI) m/z 290.1873 [(M+); calcd for C13H3603 290.1882]. 68 Model compound l-25. A solution of alcohol V-22 (7.5 mg, 0.026 mmol) and a catalytic amount of TSA in toluene (10 mL) was stirred at 65 0C for 3.5 h. The solution was cooled and purified on silica gel (hexane/ether [3:1], Rf = 0.66) to furnish 6.0 mg (80%) of tetrahydropyranone I-25 as colorless crystals (m.p. 115—1 17 0C). IR (CHCI3) 3482, 1705, 1456, 1074, 911, 733 cm"; 'H NMR (500 MHz, CDCl,) 8 5.57 (d, J = 11.7 Hz, 1 H), 4.41 (d, J = 4.4 Hz, 1 H), 3.82 (m, 1 H), 3.41 (d, J = 4.4 Hz, 1 H), 2.50 (m, 3 H), 2.37 (m, 3 H), 2.15 (dm, J = 15.9 Hz, 1 H), 2.00-1.70 (m, 4 H), 1.60 (s, 3 H), 1.56- 1.20 (m, 3 H), 1.01 (s, 3 H), 0.98 (dd, J: 13.5, 6.0 Hz, 1 H), 0.83 (s, 3 H); 13C NMR (75 MHz, CDC13) 8 213.5, 130.2, 129.0, 83.3, 71.5, 68.9, 49.4, 38.7, 37.7, 36.3, 32.5, 31.4, 29.7, 28.3, 25.8, 24.4, 19.1, 15.4; HRMS (E1) m/z 292.2026 [(M+); calcd for C18H3803 292.2038]. 69 10. 11. 12. l3. 14. REFERENCES CITED Science 1994, 266, 1324-1325. (a) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano, H.; Hata,T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463-5464. (b) Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.; Haruyama, H.; Yoda, K.; Hata, T. J. Org. Chem. 1994, 59, 564-569. (c) Chu, M.; Patel, M. G.; Gullo, V. P.; Truumees, 1.; Puar, M. S. J. Org. Chem. 1992, 57, 5817-5818. 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Tetrahedron Lett. 1988, 29, 3171-3174. 72 APPENDIX 1 X-RAY SINGLE CRYSTAL STRUCTURE DETERMINTAION OF COMPOUND V-15 Data Collection Colorless crystals were obtained from the recrystallization in petroleum ether (b.p. 60-90 0C). A crystal (approximate dimensions 0.8 x 1.3 x 1.9 mm) was placed onto the tip of a fine glass capillary and mounted on a Bruker SMART 1 K system for a data collection at 173(2) K. A preliminary set of cell constants was calculated from reflections harvested from three sets of 20 frames. These initial sets of frames were oriented such that orthogonal wedges of reciprocal space were surveyed. This produced an initial orientation matrix determined from 95 reflections. Final cell constants were calculated from the xyz centroids of 8192 strong reflections from the actual data collection after integration (SAINT 5.00 1998). The data collection was carried out using MoKa radiation (graphite monochromator) with a frame time of 19 seconds and a detector distance of 5.05 cm. A full sphere of reciprocal space was surveyed to a resolution of 0.75 A. Four runs of frames were collected with 0.300 scans in a) at 4 different ¢ settings and a detector position of —28° in 20. An additional partial run of frames was collected in order to model possible decay, however, no decay was observed. Data were corrected for absorption (SADABS, Sheldrick 1999). Structure Solution and Refinement The structure was solved and refined using SHELXS-97. The space group 141/a was determinted based on systematic absence and intensity statistics. A direct-methods solution was calculated which provided all non-hydrogen atoms the E-map. All non- hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen 73 atoms were placed in ideal positions and refined independently with isotropic displacement parameters. The final full matrix least squares refinement converged to R1 = 0.0486 and wR2 = 0.1431 (F, all 6247 data, F>4cs). Data collection and structure solution were conducted at the Crystallography Service Laboratory. Chemistry Department, Michigan State University. All calculations were performed using SGI O2 R10000 workstations using the SHELXTL V5.0 suite of program. Table 4. Crystal Data and Structure Refinement for Compound V-15 Identification code [A45] Empirical formula C24H440281 Formula weight 392.68 Temperature 173(1) K Wavelength 0.71073 A Crystal system tetragonal Space group I4(1)/a(# 88) Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F (000) Crystal size Theta range for data collection Index ranges Reflections collected / unique Completeness to theta = 28.27 Refinement method Data/ restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole a = 29.316 (4) A b = 29.316 (4) A c = 12.019 (2) A alpha = 90 degree beta = 90 degree gamma = 90 degree 10329 (3) A3 16 1.010 Mg/m3 0.105 mm‘1 3488 1.9 x 1.3 x 0.8 mm 1.39 to 28.27 degree -37Sh£37,-38Sk538,-15.<_1515 58259 / 6247 [R (int) = 0.0405] 97.6% Full-matrix least-squares on F2 6247 / 0 / 421 1.042 R1 = 0.0486, wR2 = 0.1310 R1 = 0.0645, wR2 = 0.1431 0.00003 (12) 0.724 and —0.258 e.A‘3 74 Figure 25. ORTEP Drawing of the Structure of Compound V-lS . 0 671'" 01191 Q «11110112 2113) 1Q, '- 79 !J 14>“ ' 0111 v7.1, . .,,,, 0N {/1201 03 01231 ‘4 .‘ ' 511211 0 . . ’ C‘? 0125189 @341) 01221 {(1, 01171 . €11, , ' O . . W‘ 012 ¥0271 \\)01261 f; b O . Table 5. Atomic Coordinates (x 104), Equivalent Isotropic Displacement Parameters (A2 x 103), and Occupancies for Compound V-15 x y z U(eq) Occ C(l) 9511(1) 6306(1) -2482(1) 30(1) 1 C(2) 9280(1) 6766(1) -2178(1) 30(1) 1 C(3) 9177(1) 7028(1) -3234(1) 37(1) 1 C(4) 8770(1) 7041(1) -3754(1) 40(1) 1 C(5) 8741(1) 7183(1) -4976(2) 51(1) 1 C (6) 8794 (1) 6772 (1) -5774 (2) 64 (1) 1 C (7) 8453(1) 6402(1) -5591(2) 60(1) 1 C (8) 8509(1) 5946(1) -5478 (2) 57 (1) l C (9) 8949 (1) 5673 (1) -5624 (2) 52 (1) 1 C(10) 9117(1) 5377(1) -4614(2) 44(1) 1 C(11) 9458(1) 5609(1) -3800(1) 36(1) 1 C(12) 9540(1) 5302(1) -2772 (2) 40 (1) 1 C(13) 9804(1) 5543(1) -1832(2) 39(1) 1 C(14) 9574(1) 5992(1) -1476(1) 31(1) 1 C(15) 9239(1) 6057(1) -3389(1) 32(1) 1 0(16) 9590(1) 6999(1) -1440(1) 40(1) 1 C (17) 8328 (1) 6875 (1) -3224 (2) 47 (l) 1 C (18) 8089(1) 5664(1) -5270 (3) 73(1) 1 C(19) 9910(1) 5706(1) -4412(2) 51(1) 1 C(20) 9131(1) 5895(1) -1009(1) 33(1) 1 Si (21) 8997(1) 5899(1) 331(1) 33(1) 1 C(22) 9131(1) 6464(1) 976(2) 53(1) 1 C(23) 9322(1) 5441(1) 1081(2) 50(1) 1 C(24) 8361(1) 5787(1) 341(2) 43(1) 1 C (25) 8254 (1) 5338 (1) -260 (2) 65 (l) 1 C(26) 8112(1) 6184(1) -241(3) 70(1) 1 C(27) 8190(1) 5756(1) 1555(2) 64(1) 1 U (eq) is defined as one third of the trace of the orthogonalized Uij tensor. 76 APPENDIX 2 X-RAY SINGLE CRYSTAL STRUCTURE DETERMINTAION OF COMPOUND V-16 Data Collection Colorless crystals were obtained from the recrystallization in petroleum ether (b.p. 60-90 °C)-methylene chloride mixed solvent. A crystal (approximate dimensions 0.2 x 0.3 x 0.5 mm) was placed onto the tip of a fine glass capillary and mounted on a Bruker SMART 1 K system for a data collection at 173(2) K. A preliminary set of cell constants was calculated from reflections harvested from three sets of 20 frames. These initial sets of frames were oriented such that orthogonal wedges of reciprocal space were surveyed. This produced an initial orientation matrix determined from 144 reflections. Final cell constants were calculated from the xyz centroids of 6710 strong reflections from the actual data collection after integration (SAINT 5.00 1998). The data collection was carried out using MoKa radiation (graphite monochromator) with a frame time of 26 seconds and a detector distance of 5.05 cm. A full sphere of reciprocal space was surveyed to a resolution of 0.75 A. Four runs of frames were collected with 0.300 scans in a) at 4 different (15 settings and a detector position of —280 in 20. An additional partial run of frames was collected in order to model possible decay, however, no decay was observed. Data were corrected for absorption (SADABS, Sheldrick 1999). Structure Solution and Refinement The structure was solved and refined using SHELXS-97. The space group 141/a was determinted based on systematic absence and intensity statistics. A direct-methods solution was calculated which provided all non-hydrogen atoms the E-map. All non- hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen 77 atoms were placed in ideal positions and refined independently with isotropic displacement parameters. The final full matrix least squares refinement converged to R. = 0.0403 and wR2 = 0.1026 (F, all 6293 data, F>4cy). Data collection and structure solution were conducted at the Crystallography Service Laboratory, Chemistry Department, Michigan State University. All calculations were performed using SGI 02 R10000 workstations using the SHELXTL V5.0 suite of program. Table 6. Crystal Data and Structure Refinement for Compound V-16 Identification code [A44] Empirical formula C2402 H44Cl()_()7OQ_Sl Formula weight 395.20 Temperature 173(2) K Wavelength 0.71073 A Crystal system tetragonal Space group I4(1)/a (# 88) Unit cell dimensions Volume 2 Density (calculated) Absorption coefficient F (000) Crystal size Theta range for data collection Index ranges Reflections collected / unique Completeness to theta = 28.28 Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole a = 24.146 (4) A b = 29.146 (4) A c = 12.129 (2) A alpha = 90 degree beta = 90 degree gamma = 90 degree 10303 (3) A3 16 1.019 Mg/m3 0.112 mm" 3507 02x03x05mm 1.40 to 28.28 degree -38£hS38,-38Sk£37,-16Sl£ 15 60391 / 6293 [R (int) = 0.0549] 98.3% Full-matrix least-squares on F2 6293 / 0 / 427 1.007 R1 = 0.0403, wR2 = 0.0908 R1 = 0.0711, wR2 = 0.1026 0.00018 (6) 0.282 and —0.202 e.A’3 78 Figure 26. ORTEP Drawing of the Structure of Compound V-l6 O ' v (1) C(23) ‘3’ . fl! 5112 1 O- ’ ' U .///\.(\;'\l‘ C(22) 01241 <1) , “’ ~‘o . “ ’2’ 01271 O €51) o 1'48 01171\\c1261 ' ' c ' ° 79 Table 7. Atomic Coordinates (x 104), Equivalent Isotropic Displacement Parameters (A2 x 103), and Occupancies for Compound V-16 x y z U(eq) Occ C(l) 9541(1) 6259(1) -2294(1) 24(1) 1 C(2) 9303(1) 6724(1) -2090(1) 25(1) 1 C(3) 9216(1) 6963(1) -3175(1) 29(1) 1 C(4) 8816(1) 6984(1) -3715(1) 31(1) 1 C(5) 8792(1) 7140(1) -4911(1) 43(1) 1 C (6) 8598(1) 6768(1) -5699 (1) 46(1) 1 C(7) 8876(1) 6328(1) -5693(1) 39(1) 1 C(8) 8739(1) 5905(1) -5427(1) 37(1) 1 C (9) 9075(1) 5505(1) -5424 (1) 36 (1) 1 C(10) 9176(1) 5273(1) -4298(1) 31(1) 1 C(11) 9503(1) 5526(1) -3497(1) 27(1) 1 C(12) 9557(1) 5242(1) —2434(1) 30(1) 1 C(13) 9811(1) 5504(1) -1514(1) 31(1) 1 C(14) 9584(1) 5967(1) -1244(1) 25(1) 1 C(15) 9289(1) 5990(1) -3189(1) 27(1) 1 0(16) 9601(1) 6980(1) -1372(1) 33(1) 1 C(17) 8366(1) 6832(1) -3227(1) 37(1) 1 C(18) 8252(1) 5781(1) -5130(2) 51(1) 1 C (19) 9975 (1) 5592(1) —4042 (2) 43 (1) 1 0(20) 9131(1) 5887(1) -814(1) 27(1) 1 Si (21) 8989(1) 5912(1) 504(1) 26(1) 1 C(22) 9123(1) 6491(1) 1082(2) 42(1) 1 C(23) 9310(1) 5468(1) 1304(1) 40(1) 1 C(24) 8353(1) 5793(1) 509(1) 35(1) 1 C(25) 8255(1) 5330(1) -51(2) 52(1) 1 C(26) 8101(1) 6174(1) ~126(2) 51(1) 1 C(27) 8173(1) 5780(1) 1703(2) 51(1) 1 Cl (28) 9605 (3) 7360(3) -7175 (7) 67 (3) 0.066(2) C (29) 10000 7500 -6250 62 (15) 0.066 (2) U (eq) is defined as one third of the trace of the orthogonalized Uij tensor. 80 APPENDIX 3 RELEVANT 1H NMR AND 13C NMR SPECTRA 81 0.0 m0 0._ r.._ 0N mN 0.». rim 04» m? of. rim 0.0 mb 0.5 m6 0w ma 0.0 we? . 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